2013管理指南动脉高血压

ESH AND ESC GUIDELINES
2013 ESHESC Guidelines for the management
of arterial hypertension
The Task Force for the management of arterial hypertension of the
European Society of Hypertension (ESH) and of the European Society
of Cardiology (ESC)
AuthorsTask Force Members Giuseppe Mancia (Chairperson) (Italy)* Robert Fagard
(Chairperson) (Belgium)* Krzysztof Narkiewicz (Section coordinator) (Poland)
Josep Redon (Section coordinator) (Spain) Alberto Zanchetti (Section coordinator)
(Italy) Michael Bo¨hm (Germany) Thierry Christiaens (Belgium) Renata Cifkova
(Czech Republic) Guy De Backer (Belgium) Anna Dominiczak (UK)
Maurizio Galderisi (Italy) Diederick E Grobbee (Netherlands) Tiny Jaarsma
(Sweden) Paulus Kirchhof (GermanyUK) Sverre E Kjeldsen (Norway)
Ste´phane Laurent (France) Athanasios J Manolis (Greece) Peter M Nilsson
(Sweden) Luis Miguel Ruilope (Spain) Roland E Schmieder (Germany)
Per Anton Sirnes (Norway) Peter Sleight (UK) Margus Viigimaa (Estonia)
Bernard Waeber (Switzerland) Faiez Zannad (France)
ESH Scientiﬁc Council Josep Redon (President) (Spain) Anna Dominiczak (UK) Krzysztof Narkiewicz (Poland)
Peter M Nilsson (Sweden) Michel Burnier (Switzerland) Margus Viigimaa (Estonia) Ettore Ambrosioni (Italy)
Mark Cauﬁeld (UK) Antonio Coca (Spain) Michael Hecht Olsen (Denmark) Roland E Schmieder (Germany)
Costas Tsiouﬁs (Greece) Philippe van de Borne (Belgium)
ESC Committee for Practice Guidelines (CPG) Jose Luis Zamorano (Chairperson) (Spain) Stephan Achenbach
(Germany) Helmut Baumgartner (Germany) Jeroen J Bax (Netherlands) He´ctor Bueno (Spain) Veronica Dean
(France) Christi Deaton (UK) Cetin Erol (Turkey) Robert Fagard (Belgium) Roberto Ferrari (Italy) David Hasdai
(Israel) Arno W Hoes (Netherlands) Paulus Kirchhof (GermanyUK) Juhani Knuuti (Finland) Philippe Kolh
(Belgium) Patrizio Lancellotti (Belgium) Ales Linhart (Czech Republic) Petros Nihoyannopoulos (UK)
Massimo F Piepoli (Italy) Piotr Ponikowski (Poland) Per Anton Sirnes (Norway) Juan Luis Tamargo (Spain)
Michal Tendera (Poland) Adam Torbicki (Poland) William Wijns (Belgium) Stephan Windecker (Switzerland)
* Corresponding authors The two chairmen equally contributed to the document Chairperson ESH Professor Giuseppe Mancia Centro di Fisiologia Clinica e Ipertensione Via F Sforza
35 20121 Milano Italy Tel +39 039 233 3357 Fax +39 039 322 274 Email giuseppemancia@unimibit Chairperson ESC Professor Robert Fagard Hypertension & Cardiovascular
Rehab Unit KU Leuven University Herestraat 49 3000 Leuven Belgium Tel +32 16 348 707 Fax +32 16 343 766 Email robertfagard@uzleuvenbe
These guidelines also appear in the Journal of Hypertension doi 10109701hjh000043174032696cc and in Blood Pressure doi 103109080370512013812549
With special thanks to Mrs Clara Sincich and Mrs Donatella Mihalich for their contribution
Other ESC entities having participated in the development of this document
ESC Associations Heart Failure Association (HFA) European Association of Cardiovascular Imaging (EACVI) European Association for Cardiovascular Prevention & Rehabilitation
(EACPR) European Heart Rhythm Association (EHRA)
ESC Working Groups Hypertension and the Heart Cardiovascular Pharmacology and Drug Therapy
ESC Councils Cardiovascular Primary Care Cardiovascular Nursing and Allied Professions Cardiology Practice
The content of these European Society of Cardiology (ESC) and European Society of Hypertension (ESH) Guidelines has been published for personal and educational use only No com
mercial use is authorized No part of the ESC Guidelines may be translated or reproduced in any form without written permission from the ESC Permission can be obtained upon sub
mission of a written request to Oxford University Press the publisher of the European Heart Journal and the party authorized to handle such permissions on behalf of the ESC
Disclaimer The ESHESC Guidelines represent the views of the ESH and ESC and were arrived at after careful consideration of the available evidence at the time they were written
Health professionals are encouraged to take them fully into account when exercising their clinical judgement The guidelines do not however override the individual responsibility of
health professionals to make appropriate decisions in the circumstances of the individual patients in consultation with that patient and where appropriate and necessary the patient’s
guardian or carer It is also the health professional’s responsibility to verify the rules and regulations applicable to drugs and devices at the time of prescription
& The European Society of Hypertension (ESH) and European Society of Cardiology (ESC) 2013 All rights reserved For permissions please email journalspermissions@oupcom
European Heart Journal (2013) 34 2159–2219
doi101093eurheartjeht151
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 2019Document Reviewers Denis L Clement (ESH Review Coordinator) (Belgium) Antonio Coca (ESH Review
Coordinator) (Spain) Thierry C Gillebert (ESC Review Coordinator) (Belgium) Michal Tendera (ESC Review
Coordinator) (Poland) Enrico Agabiti Rosei (Italy) Ettore Ambrosioni (Italy) Stefan D Anker (Germany)
Johann Bauersachs (Germany) Jana Brguljan Hitij (Slovenia) Mark Caulﬁeld (UK) Marc De Buyzere (Belgium)
Sabina De Geest (Switzerland) Genevie`ve Anne Derumeaux (France) Serap Erdine (Turkey) Csaba Farsang
(Hungary) Christian FunckBrentano (France) Vjekoslav Gerc (Bosnia & Herzegovina) Giuseppe Germano (Italy)
Stephan Gielen (Germany) Herman Haller (Germany) Arno W Hoes (Netherlands) Jens Jordan (Germany)
Thomas Kahan (Sweden) Michel Komajda (France) Dragan Lovic (Serbia) Heiko Mahrholdt (Germany)
Michael Hecht Olsen (Denmark) Jan Ostergren (Sweden) Gianfranco Parati (Italy) Joep Perk (Sweden) Jorge Polonia
(Portugal) Bogdan A Popescu (Romania) Zˇ eljko Reiner (Croatia) Lars Ryde´n (Sweden) Yuriy Sirenko (Ukraine)
Alice Stanton (Ireland) Harry StruijkerBoudier (Netherlands) Costas Tsiouﬁs (Greece) Philippe van de Borne
(Belgium) Charalambos Vlachopoulos (Greece) Massimo Volpe (Italy) David A Wood (UK)
The afﬁliations of the Task Force Members are listed in the Appendix The disclosure forms of the authors and reviewers are
available on the respective society websites httpwwweshonlineorg and wwwescardioorgguidelines
Online publishaheadofprint 14 June 2013

Keywords Hypertension † Guidelines † Antihypertensive treatment † Blood pressure † Blood pressure
measurement † Cardiovascular risk † Cardiovascular complications † Device therapy † Followup
† Lifestyle † Organ damage
Table of Contents
Abbreviations and acronyms 2162
1 Introduction 2163
11 Principles 2163
12 New aspects 2163
2 Epidemiological aspects 2164
21 Relationship of blood pressure to cardiovascular and renal
damage 2164
22 Deﬁnition and classiﬁcation of hypertension 2165
23 Prevalence of hypertension 2165
24 Hypertension and total cardiovascular risk 2165
241 Assessment of total cardiovascular risk 2165
242 Limitations 2166
243 Summary of recommendations on total cardiovascular
risk assessment 2167
3 Diagnostic evaluation 2167
31 Bood pressure measurement 2168
311 Ofﬁce or clinic blood pressure 2168
312 Outofofﬁce blood pressure 2168
313 Whitecoat (or isolated ofﬁce) hypertension
and masked (or isolated ambulatory) hypertension 2170
314 Clinical indications for outofofﬁce blood pressure 2170
315 Blood pressure during exercise and laboratory stress 2171
316 Central blood pressure 2172
32 Medical history 2172
33 Physical examination 2173
34 Summary of recommendations on blood pressure
measurement history and physical examination 2173
35 Laboratory investigations 2173
36 Genetics 2173
37 Searching for asymptomatic organ damage 2174
371 Heart 2174
372 Blood vessels 2176
373 Kidney 2176
374 Fundoscopy 2177
375 Brain 2177
376 Clinical value and limitations 2177
377 Summary of recommendations on the search for
asymptomatic organ damage cardiovascular disease and
chronic kidney disease 2178
38 Searching for secondary forms of hypertension 2178
4 Treatment approach 2178
41 Evidence favouring therapeutic reduction of high blood
pressure 2178
42 When to initiate antihypertensive drug treatment 2178
421 Recommendations of previous Guidelines 2178
422 Grade 2 and 3 hypertension and highrisk grade 1
hypertension 2179
423 Lowtomoderate risk grade 1 hypertension 2179
424 Isolated systolic hypertension in youth 2181
425 Grade 1 hypertension in the elderly 2181
426 High normal blood pressure 2181
427 Summary of recommendations on initiation
of antihypertensive drug treatment 2181
43 Blood pressure treatment targets 2182
431 Recommendations of previous Guidelines 2182
432 Lowtomoderate risk hypertensive patients 2182
433 Hypertension in the elderly 2182
434 Highrisk patients 2182
ESH and ESC Guidelines2160
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 2019435 The lower the better’ vs the Jshaped curve
hypothesis 2183
436 Evidence on target blood pressure from organ damage
studies 2184
437 Clinic vs home and ambulatory blood pressure
targets 2184
438 Summary of recommendations on blood pressure
targets in hypertensive patients 2184
5 Treatment strategies 2185
51 Lifestyle changes 2185
511 Salt restriction 2185
512 Moderation of alcohol consumption 2185
513 Other dietary changes 2185
514 Weight reduction 2185
515 Regular physical exercise 2186
516 Smoking cessation 2186
517 Summary of recommendations on adoption of lifestyle
changes 2186
52 Pharmacological therapy 2187
521 Choice of antihypertensive drugs 2187
522 Monotherapy and combination therapy 2189
523 Summary of recommendations on treatment
strategies and choice of drugs 2193
6 Treatment strategies in special conditions 2194
61 Whitecoat hypertension 2194
62 Masked hypertension 2194
621 Summary of recommendations on treatment
strategies in whitecoat and masked hypertension 2194
63 Elderly 2194
631 Summary of recommendations on antihypertensive
treatment strategies in the elderly 2195
64 Young adults 2195
65 Women 2195
651 Oral contraceptives 2195
652 Hormone replacement therapy 2196
653 Pregnancy 2196
654 Longterm cardiovascular consequences in gestational
hypertension 2196
655 Summary of recommendations on treatment
strategies in hypertensive women 2197
66 Diabetes mellitus 2197
661 Summary of recommendations on treatment
strategies in patients with diabetes 2198
67 Metabolic syndrome 2198
671 Summary of recommendations on treatment
strategies in hypertensive patients with metabolic syndrome 2198
68 Obstructive sleep apnoea 2199
69 Diabetic and nondiabetic nephropathy 2199
691 Summary of recommendations on therapeutic
strategies in hypertensive patients with nephropathy 2200
692 Chronic kidney disease stage 5D 2200
610 Cerebrovascular disease 2200
6101 Acute stroke 2200
6102 Previous stroke or transient ischaemic attack 2200
6103 Cognitive dysfunction and white matter lesions 2200
6104 Summary of recommendations on therapeutic
strategies in hypertensive patients with cerebrovascular
disease 2201
611 Heart disease 2201
6111 Coronary heart disease 2201
6112 Heart failure 2201
6113 Atrial ﬁbrillation 2201
6114 Left ventricular hypertrophy 2202
6115 Summary of recommendations on therapeutic
strategies in hypertensive patients with heart disease 2202
612 Atherosclerosis arteriosclerosis and peripheral artery
disease 2203
6121 Carotid atherosclerosis 2203
6122 Increased arterial stiffness 2203
6123 Peripheral artery disease 2203
6124 Summary of recommendations on therapeutic
strategies in hypertensive patients with atherosclerosis
arteriosclerosis and peripheral artery disease 2203
613 Sexual dysfunction 2203
614 Resistant hypertension 2204
6141 Carotid baroreceptor stimulation 2204
6142 Renal denervation 2205
6143 Other invasive approaches 2205
6144 Followup in resistant hypertension 2205
6145 Summary of recommendations on therapeutic
strategies in patients with resistant hypertension 2205
615 Malignant hypertension 2206
616 Hypertensive emergencies and urgencies 2206
617 Perioperative management of hypertension 2206
618 Renovascular hypertension 2206
619 Primary aldosteronism 2206
7 Treatment of associated risk factors 2207
71 Lipidlowering agents 2207
72 Antiplatelet therapy 2207
73 Treatment of hyperglycaemia 2207
74 Summary of recommendations on treatment of risk factors
associated with hypertension 2208
8 Followup 2208
81 Followup of hypertensive patients 2208
82 Followup of subjects with high normal blood pressure and
whitecoat hypertension 2208
83 Elevated blood pressure at control visits 2208
84 Continued search for asymptomatic organ damage 2209
85 Can antihypertensive medications be reduced or stopped 2209
9 Improvement of blood pressure control in hypertension 2209
10 Hypertension disease management 2210
101 Team approach in disease management 2211
102 Mode of care delivery 2211
103 The role of information and communication technologies 2211
11 Gaps in evidence and need for future trials 2212
APPENDIX Task Force members afﬁliations 2212
References 2213
ESH and ESC Guidelines 2161
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 2019Abbreviations and acronyms
ABCD Appropriate Blood pressure Control in Diabetes
ABI ankle–brachial index
ABPM ambulatory blood pressure monitoring
ACCESS Acute Candesartan Cilexetil Therapy in Stroke Sur
vival
ACCOMPLISH Avoiding Cardiovascular Events in Combination
Therapy in Patients Living with Systolic Hyperten
sion
ACCORD Action to Control Cardiovascular Risk in Diabetes
ACE angiotensinconverting enzyme
ACTIVE I Atrial Fibrillation Clopidogrel Trial with Irbesartan
for Prevention of Vascular Events
ADVANCE Action in Diabetes and Vascular Disease Preterax
and DiamicronMR Controlled Evaluation
AHEAD Action for HEAlth in Diabetes
ALLHAT Antihypertensive and LipidLowering Treatment to
Prevent Heart ATtack
ALTITUDE ALiskiren Trial In Type 2 Diabetes Using
Cardiorenal Endpoints
ANTIPAF ANgioTensin II Antagonist In Paroxysmal Atrial Fib
rillation
APOLLO A Randomized Controlled Trial of Aliskiren in the
Prevention of Major Cardiovascular Events in
Elderly People
ARB angiotensin receptor blocker
ARIC Atherosclerosis Risk In Communities
ARR aldosterone renin ratio
ASCOT AngloScandinavian Cardiac Outcomes Trial
ASCOTLLA AngloScandinavian Cardiac Outcomes Trial—
Lipid Lowering Arm
ASTRAL Angioplasty and STenting for Renal Artery Lesions
AV atrioventricular
BB betablocker
BMI body mass index
BP blood pressure
BSA body surface area
CA calcium antagonist
CABG coronary artery bypass graft
CAPPP CAPtopril Prevention Project
CAPRAF CAndesartan in the Prevention of Relapsing Atrial
Fibrillation
CHD coronary heart disease
CHHIPS Controlling Hypertension and Hypertension Im
mediately PostStroke
CKD chronic kidney disease
CKDEPI Chronic Kidney Disease—EPIdemiology collabor
ation
CONVINCE Controlled ONset Verapamil INvestigation of CV
Endpoints
CT computed tomography
CV cardiovascular
CVD cardiovascular disease
D diuretic
DASH Dietary Approaches to Stop Hypertension
DBP diastolic blood pressure
DCCT Diabetes Control and Complications Study
DIRECT DIabetic REtinopathy Candesartan Trials
DM diabetes mellitus
DPP4 dipeptidyl peptidase 4
EAS European Atherosclerosis Society
EASD European Association for the Study of Diabetes
ECG electrocardiogram
EF ejection fraction
eGFR estimated glomerular ﬁltration rate
ELSA European Lacidipine Study on Atherosclerosis
ESC European Society of Cardiology
ESH European Society of Hypertension
ESRD endstage renal disease
EXPLOR Amlodipine–Valsartan Combination Decreases
Central Systolic Blood Pressure more Effectively
than the Amlodipine–Atenolol Combination
FDA US Food and Drug Administration
FEVER Felodipine EVent Reduction study
GISSIAF Gruppo Italiano per lo Studio della Sopravvivenza
nell’Infarto MiocardicoAtrial Fibrillation
HbA1c glycated haemoglobin
HBPM home blood pressure monitoring
HOPE Heart Outcomes Prevention Evaluation
HOT Hypertension Optimal Treatment
HRT hormone replacement therapy
HT hypertension
HYVET HYpertension in the Very Elderly Trial
IMT intimamedia thickness
IPRESERVE Irbesartan in Heart Failure with Preserved Systolic
Function
INTERHEART Effect of Potentially Modiﬁable Risk Factors asso
ciated with Myocardial Infarction in 52 Countries
INVEST INternational VErapamil SRT Trandolapril
ISH Isolated systolic hypertension
JNC Joint National Committee
JUPITER Justiﬁcationfor theUse of Statins inPrimaryPreven
tion an Intervention Trial Evaluating Rosuvastatin
LAVi left atrial volume index
LIFE Losartan Intervention For Endpoint Reduction in
Hypertensives
LV left ventricleleft ventricular
LVH left ventricular hypertrophy
LVM left ventricular mass
MDRD Modiﬁcation of Diet in Renal Disease
MRFIT Multiple Risk Factor Intervention Trial
MRI magnetic resonance imaging
NORDIL The Nordic Diltiazem Intervention study
OC oral contraceptive
OD organ damage
ONTARGET ONgoing Telmisartan Alone and in Combination
with Ramipril Global Endpoint Trial
PAD peripheral artery disease
PATHS Prevention And Treatment of Hypertension Study
PCI percutaneous coronary intervention
ESH and ESC Guidelines2162
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 2019PPAR peroxisome proliferatoractivated receptor
PREVEND Prevention of REnal and Vascular ENdstage Disease
PROFESS Prevention Regimen for Effectively Avoiding Sec
ondary Strokes
PROGRESS Perindopril Protection Against Recurrent Stroke
Study
PWV pulse wave velocity
QALY Quality adjusted life years
RAA reninangiotensinaldosterone
RAS reninangiotensin system
RCT randomized controlled trials
RF risk factor
ROADMAP Randomized Olmesartan And Diabetes MicroAl
buminuria Prevention
SBP systolic blood pressure
SCAST AngiotensinReceptor Blocker Candesartan for
Treatment of Acute STroke
SCOPE Study on COgnition and Prognosis in the Elderly
SCORE Systematic COronary Risk Evaluation
SHEP Systolic Hypertension in the Elderly Program
STOP Swedish Trials in Old Patients with Hypertension
STOP2 The second Swedish Trial in Old Patients with
Hypertension
SYSTCHINA SYSTolic Hypertension in the Elderly Chinese trial
SYSTEUR SYSTolic Hypertension in Europe
TIA transient ischaemic attack
TOHP Trials Of Hypertension Prevention
TRANSCEND Telmisartan Randomised AssessmeNt Study in
ACE iNtolerant subjects with cardiovascular
Disease
UKPDS United Kingdom Prospective Diabetes Study
VADT Veterans’ Affairs Diabetes Trial
VALUE Valsartan Antihypertensive Longterm Use
Evaluation
WHO World Health Organization
1 Introduction
11 Principles
The 2013 guidelines on hypertension of the European Society of
Hypertension (ESH) and the European Society of Cardiology (ESC)
follow the guidelines jointly issued by the two societies in 2003 and
200712 Publication of a new document 6 years after the previous
one was felt to be timely because over this period important
studies have been conducted and many new results have been pub
lished on both the diagnosis and treatment of individuals with an ele
vated blood pressure (BP) making reﬁnements modiﬁcations and
expansion of the previous recommendations necessary
The 2013 ESHESC guidelines continue to adhere to some funda
mental principles that inspired the 2003 and 2007 guidelines namely
(i) to base recommendations on properly conducted studies identi
ﬁed from an extensive review of the literature (ii) to consider as
the highest priority data from randomized controlled trials (RCTs)
and their metaanalyses but not to disregard—particularly when
dealing with diagnostic aspects—the results of observational
and other studies of appropriate scientiﬁc calibre and (iii) to grade
the level of scientiﬁc evidence and the strength of recommendations
on major diagnostic and treatment issuesas in Europeanguidelines on
other diseases according to ESC recommendations (Tables 1 and 2)
While it was not done in the 2003 and 2007 guidelines providing the
recommendation class and the level of evidence is now regarded as
important for providing interested readers with a standard approach
by which to compare the state of knowledge across different ﬁelds of
medicine It was also thought that this could more effectively alert
physicians on recommendations that are based on the opinions of
the experts rather than on evidence This is not uncommon in medi
cine because for a great part of daily medical practice no good
science is available and recommendations must therefore stem
from common sense and personal clinical experience both of
which can be fallible When appropriately recognized this can
avoid guidelines being perceived as prescriptive and favour the per
formance of studies where opinion prevails and evidence is lacking
A fourth principle in line with its educational purpose is to provide
a large number of tables and a set of concise recommendations
that could be easily and rapidly consulted by physicians in their
routine practice
The European members of the Task Force in charge of the 2013
guidelines on hypertension have been appointed by the ESH and
ESC based on their recognized expertise and absence of major con
ﬂicts of interest [their declaration of interest forms can be found on
the ESC website (wwwescardioorgguidelines) and ESH website
(wwweshonlineorg)] Each member was assigned a speciﬁc
writing task which was reviewed by three coordinators and then
by two chairmen one appointed by ESH and another by ESC The
text was ﬁnalized over approximately 18 months during which the
Task Force members met collectively several times and corre
sponded intensively with one another between meetings Before
publication the document was also assessed twice by 42 European
reviewers half selected by ESH and half by ESC It can thus be conﬁ
dently stated that the recommendations issued by the 2013 ESHESC
guidelines on hypertension largely reﬂect the state of the art on
hypertension as viewed by scientists and physicians in Europe
Expenses for meetings and the remaining work have been shared
by ESH and ESC
12 New aspects
Because of new evidence on several diagnostic and therapeutic
aspects of hypertension the present guidelines differ in many
respects from the previous ones2 Some of the most important differ
ences are listed below
(1) Epidemiological data on hypertension and BPcontrolinEurope
(2) Strengthening of the prognostic value of home blood pressure
monitoring (HBPM) and of its role for diagnosis and manage
ment of hypertensionnextto ambulatory blood pressuremon
itoring (ABPM)
(3) Update of the prognostic signiﬁcance of nighttime BP white
coat hypertension and masked hypertension
(4) Reemphasis on integration of BP cardiovascular (CV) risk
factors asymptomatic organ damage (OD) and clinical compli
cations for total CV risk assessment
ESH and ESC Guidelines 2163
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 2019(5) Update of the prognostic signiﬁcance of asymptomatic OD
including heart blood vessels kidney eye and brain
(6) Reconsideration of the risk of overweight and target body mass
index (BMI) in hypertension
(7) Hypertension in young people
(8) Initiation of antihypertensive treatment More evidencebased
criteria and no drug treatment of high normal BP
(9) Target BP for treatment More evidencebased criteria and
uniﬁed target systolic blood pressure (SBP) (140 mmHg) in
both higher and lower CV risk patients
(10) Liberal approachto initial monotherapy without anyallranking
purpose
(11) Revised schema for priorital twodrug combinations
(12) New therapeutic algorithms for achieving target BP
(13) Extended section on therapeutic strategies in special conditions
(14) Revised recommendations on treatment of hypertension in the
elderly
(15) Drug treatment of octogenarians
(16) Special attention to resistant hypertension and new treatment
approaches
(17) Increased attention to ODguided therapy
(18) New approaches to chronic management of hypertensive
disease
2 Epidemiological aspects
21 Relationship of blood pressure to
cardiovascular and renal damage
The relationship between BP values and CV and renal morbid and
fatal events has been addressed in a large number of observational
studies3 The results reported in detail in the 2003 and 2007 ESH
ESC guidelines12 can be summarized as follows
(1) Ofﬁce BP bears an independent continuous relationship with the
incidence of several CV events [stroke myocardial infarction
sudden death heart failure and peripheral artery disease
(PAD)] as well as of endstage renal disease (ESRD)3–5 This is
true at all ages and in all ethnic groups67
(2) The relationship with BP extends from high BP levels to rela
tively low values of 110–115 mmHg for SBP and 70–
75 mmHg for diastolic BP (DBP) SBP appears to be a better
predictor of events than DBP after the age of 50 years89 and
inelderlyindividualspulsepressure(thedifferencebetween
SBP and DBP values) has been reported to have a possible
additional prognostic role10 This is indicated also by the par
ticularly high CV risk exhibited by patients with an elevated
SBP and a normal or low DBP [isolated systolic hypertension
(ISH)]11
(3) A continuous relationship with events is also exhibited by
outofofﬁce BP values such as those obtained by ABPM and
HBPM (see Section 312)
Table 1 Classes of recommendations
Classes of
recommendations
Suggested wording to
use
Class I Evidence andor general agreement
that a given treatment or procedure
Is recommendedis
indicated
Class II
divergence of opinion about the
treatment or procedure
Class IIa Weight of evidenceopinion is in Should be considered
Class IIb
established by evidenceopinion
May be considered
Class III Evidence or general agreement that
the given treatment or procedure
is not usefuleffective and in some
cases may be harmful
Is not recommended
Table 2 Levels of Evidence
Level of
evidence A
Data derived from multiple randomized
clinical trials or metaanalyses
Level of
evidence B
Data derived from a single randomized
clinical trial or large nonrandomized
studies
Level of
evidence C
Consensus of opinion of the experts
andor small studies retrospective
studies registries
ESH and ESC Guidelines2164
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 2019(4)TherelationshipbetweenBPandCVmorbidityandmortalityis
modiﬁed by the concomitance of other CV risk factors
MetabolicriskfactorsaremorecommonwhenBPishighthan
when it is low1213
22 Deﬁnition and classiﬁcation
of hypertension
The continuous relationship between BP and CV and renal events
makes the distinction between normotension and hypertension dif
ﬁcult when based on cutoff BP values This is even more so
because in the general population SBP and DBP values have a uni
modal distribution14 In practice however cutoff BP values are uni
versally used both to simplify the diagnostic approachand to facilitate
the decision about treatment The recommended classiﬁcation is un
changed from the 2003 and 2007 ESHESC guidelines (Table 3)
Hypertension is deﬁned as values ≥140 mmHg SBP andor
≥90 mmHg DBP based on the evidence from RCTs that in patients
with these BP values treatmentinduced BP reductions are beneﬁcial
(see Sections 41 and 42) The same classiﬁcation is used in young
middleaged and elderly subjects whereas different criteria based
on percentiles are adopted in children and teenagers for whom
data from interventional trials are not available Details on BP classi
ﬁcation in boys and girls according to their age and height can be
found in the ESH’s report on the diagnosis evaluation and treatment
of high BP in children and adolescents15
23 Prevalence of hypertension
Limited comparable data are available on the prevalence of hyperten
sion and the temporal trends of BP values in different European coun
tries16 Overall the prevalence of hypertension appears to be around
30–45 of the general population with a steep increase with ageing
There also appear to be noticeable differences in the average BP
levels across countries with no systematic trends towards BP
changes in the past decade17–37
Owing to the difﬁculty of obtaining comparable results among
countries and over time the use of a surrogate of hypertension
status has been suggested38 Stroke mortality is a good candidate
because hypertension is by far the most important cause of this
event A close relationship between prevalence of hypertension
and mortality for stroke has been reported39 The incidence
and trends of stroke mortality in Europe have been analysed by
use of World Health Organization (WHO) statistics Western Euro
pean countries exhibit a downward trend in contrast to eastern
European countries which show a clearcut increase in death rates
from stroke40
24 Hypertension and total cardiovascular
risk
For a long time hypertension guidelines focused on BP values as the
only or main variables determining the need for—and the type of—
treatment In 1994 the ESC ESH and European Atherosclerosis
Society (EAS) developed joint recommendations on prevention of
coronary heart disease (CHD) in clinical practice41 and emphasized
that prevention of CHD should be related to quantiﬁcation of total
(or global) CV risk This approach is now generally accepted and
had already been integrated into the 2003 and 2007 ESHESC guide
lines for the management of arterial hypertension12 The concept is
based on the fact that only a small fraction of the hypertensive popu
lation has an elevation of BP alone with the majority exhibiting add
itional CV risk factors Furthermore when concomitantly present BP
and other CV risk factorsmaypotentiate each other leading to atotal
CV risk that is greater than the sum of its individual components
Finally in highrisk individuals antihypertensive treatment strategies
(initiation and intensity of treatment use of drug combinations etc
see Sections 4 5 6 and 7) as well as other treatments may be differ
ent from those to be implemented in lowerrisk individuals There is
evidence that in highrisk individuals BP control is more difﬁcult and
more frequently requires the combination of antihypertensive drugs
with other therapies such as aggressive lipidlowering treatments
The therapeutic approach should consider total CV risk in addition
to BP levels in order to maximize costeffectiveness of the manage
ment of hypertension
241 Assessment of total cardiovascular risk
Estimation of total CV risk is easy in particular subgroups of patients
such as those with antecedents of established cardiovascular disease
(CVD) diabetes CHD or with severely elevated single risk factors In
all of these conditions the total CV risk is high or very high calling for
intensive CV riskreducing measures However a large number of
patients with hypertension do not belong to any of the above cat
egories and the identiﬁcation of those at low moderate high or
very high risk requires the use of models to estimate total CV risk
so as to be able to adjust the therapeutic approach accordingly
Several computerized methods have been developed for estimat
ing total CV risk41–48 Their values and limitations have been
reviewed recently49 The Systematic COronary Risk Evaluation
(SCORE) model has been developed based on large European
cohort studies The model estimates the risk of dying from CV (not
just coronary) disease over 10 years based on age gender smoking
habits total cholesterol and SBP43 The SCORE model allows calibra
tion of the charts for individual countries which has been done for
numerous European countries At the international level two sets
of charts are provided one for highrisk and one for lowrisk coun
tries The electronic interactive version of SCORE known as Heart
Score (available through wwwheartscoreorg) is adapted to also
Table 3 Deﬁnitions and classiﬁcation of ofﬁce blood
pressure levels (mmHg)a
Category Systolic Diastolic
Optimal <120 and <80
Normal 120–129 andor 80–84
High normal 130–139 andor 85–89
Grade 1 hypertension 140–159 andor 90–99
Grade 2 hypertension 160–179 andor 100–109
Grade 3 hypertension ≥180 andor ≥110
Isolated systolic hypertension ≥140 and <90
aThe blood pressure (BP) category is deﬁned by the highest level of BP whether
systolic or diastolic Isolated systolic hypertension should be graded 1 2 or 3
according to systolic BP values in the ranges indicated
ESH and ESC Guidelines 2165
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 2019allow adjustment for the impact of highdensity lipoprotein choles
terol on total CV risk
The charts and their electronic versions can assist in risk assess
ment and management but must be interpreted in the light of the phy
sician’s knowledge and experience especially with regard to local
conditions Furthermoretheimplicationthat total CVriskestimation
is associated with improved clinical outcomes when compared with
other strategies has not been adequately tested
Risk may be higher than indicated in the charts in
† Sedentary subjects and those with central obesity the increased
relative risk associated with overweight is greater in younger sub
jects than in older subjects
† Socially deprived individuals and those from ethnic minorities
† Subjects with elevated fasting glucose andor an abnormal glucose
tolerance test who do not meet the diagnostic criteria for dia
betes
† Individuals with increased triglycerides ﬁbrinogen apolipoprotein
B lipoprotein(a) levels and highsensitivity Creactive protein
† Individuals with a family history of premature CVD (before the age
of 55 years in men and 65 years in women)
In SCORE total CV risk is expressed asthe absolute riskof dying from
CVD within 10 years Because of its heavy dependence on age in
youngpatients absolute total CV risk can be lowevenin the presence
of high BP with additional risk factors If insufﬁciently treated
however this condition may lead to a partly irreversible highrisk
condition years later In younger subjects treatment decisions
should better be guided by quantiﬁcation of relative risk or by esti
mating heart and vascular age A relativerisk chart is available in
the Joint European Societies’ Guidelines on CVD Prevention in
Clinical Practice50 which is helpful when advising young persons
Further emphasis has been given to identiﬁcation of asymptomatic
OD since hypertensionrelated asymptomatic alterations in several
organs indicate progression in the CVD continuum which markedly
increases the risk beyond that caused by the simple presence of risk
factors A separate section (Section 37) is devoted to searching for
asymptomatic OD51–53 where evidence for the additional risk of
each subclinical alteration is discussed
For more than a decade international guidelines for the manage
ment of hypertension (the 1999 and 2003 WHO International
Society of Hypertension Guidelines and the 2003 and 2007 ESH
ESC Guidelines)125455 have stratiﬁed CV risk in different categor
ies based on BP category CV risk factors asymptomatic OD and
presence of diabetes symptomatic CVD or chronic kidney disease
(CKD) as also done by the 2012 ESC prevention guidelines50
The classiﬁcation in low moderate high and very high risk is
retained in the current guidelines and refers to the 10year risk
of CV mortality as deﬁned by the 2012 ESC prevention guidelines
(Figure 1)50 The factors on which the stratiﬁcation is based are
summarized in Table 4
242 Limitations
All currently available models for CV risk assessment have limitations
that must be appreciated The signiﬁcance of OD in determining
calculation of overall risk is dependent on how carefully the
damage is assessed based on available facilities Conceptual limita
tions should also be mentioned One should never forget that the ra
tionale of estimating total CV risk is to govern the best use of limited
resources to prevent CVD that is to grade preventive measures in
relation to the increased risk Yet stratiﬁcation of absolute risk is
often used by private or public healthcare providers to establish a
barrier below which treatment is discouraged It should be kept in
BP blood pressure CKD chronic kidney disease CV cardiovascular CVD cardiovascular disease DBP diastolic blood pressure HT hypertension
OD organ damage RF risk factor SBP systolic blood pressure
Other risk factors
asymptomatic organ damage
or disease
Blood Pressure (mmHg)
High normal
SBP 130–139
or DBP 85–89
Grade 1 HT
SBP 140–159
or DBP 90–99
Grade 2 HT
SBP 160–179
or DBP 100–109
Grade 3 HT
SBP ≥180
or DBP ≥110
No other RF Low risk Moderate risk High risk
1–2 RF Low risk Moderate risk Moderate to
high risk High risk
≥3 RF Low to
Moderate risk
Moderate to
high risk High Risk High risk
OD CKD stage 3 or diabetes Moderate to
high risk High risk High risk High to
very high risk
Symptomatic CVD CKD stage ≥4 or
diabetes with ODRFs Very high risk Very high risk Very high risk Very high risk
Figure 1 Stratiﬁcation of total CV risk in categories of low moderate high and very high risk according to SBP and DBP and prevalence of RFs
asymptomatic OD diabetes CKD stageor symptomatic CVD Subjects with a high normal ofﬁce but a raisedoutofofﬁce BP (maskedhypertension)
have a CV risk in the hypertension range Subjects with a high ofﬁce BP but normal outofofﬁce BP (whitecoat hypertension) particularly if there is
no diabetes OD CVD or CKD have lower risk than sustained hypertension for the same ofﬁce BP
ESH and ESC Guidelines2166
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 2019mind that any threshold used to deﬁne high total CV risk is arbitrary
as well as the use of a cutoff value leading to intensive interventions
above this threshold and no action at all below Finally there is a
strong effect of age on total CV risk models It is so strong that
younger adults (particularly women) are unlikely to reach highrisk
levels even when they have more than one major risk factor and a
clear increase in relative risk By contrast many elderly men (eg
70 years) reach a high total risk level whilst being at very little
increased risk relative to their peers The consequences are that
most resources are concentrated in older subjects whose potential
lifespan is relatively short despite intervention and little attention is
given to young subjects at high relative risk despite the fact that in
the absence of intervention their longterm exposure to an
increased risk may lead to a high and partly irreversible risk situation
in middle age with potential shortening of their otherwise longer life
expectancy
243 Summary of recommendations on total
cardiovascular risk assessment
3 Diagnostic evaluation
The initial evaluation of a patientwith hypertension should(i)conﬁrm
the diagnosis of hypertension (ii) detect causes of secondary hyper
tension and (iii) assess CV risk OD and concomitant clinical condi
tions This calls for BP measurement medical history including family
history physical examination laboratory investigations and further
diagnostic tests Some of the investigations are needed in all patients
others only in speciﬁc patient groups
Table 4 Factors—other than ofﬁce BP—inﬂuencing
prognosis used for stratiﬁcation of total CV risk inFigure 1
Risk factors
Male sex
Age (men ≥55 years women ≥65 years)
Smoking
Dyslipidaemia
Total cholesterol >49 mmolL (190 mgdL) andor
Lowdensity lipoprotein cholesterol >30 mmolL (115 mgdL)
andor
Highdensity lipoprotein cholesterol men <10 mmolL
(40 mgdL) women <12 mmolL (46 mgdL) andor
Triglycerides >17 mmolL (150 mgdL)
Fasting plasma glucose 56–69 mmolL (102–125 mgdL)
Abnormal glucose tolerance test
Obesity [BMI ≥30 kgm2 (height2)]
Abdominal obesity (waist circumference men ≥102 cm
women ≥88 cm) (in Caucasians)
Family history of premature CVD (men aged <55 years
women aged <65 years)
Asymptomatic organ damage
Pulse pressure (in the elderly) ≥60 mmHg
Electrocardiographic LVH (Sokolow–Lyon index >35 mV
RaVL >11 mV Cornell voltage duration product >244 mV*ms) or
Echocardiographic LVH [LVM index men >115 gm2
women >95 gm2 (BSA)]a
Carotid wall thickening (IMT >09 mm) or plaque
Carotid–femoral PWV >10 ms
Anklebrachial index <09
Microalbuminuria (30–300 mg24 h) or albumin–creatinine ratio
(30–300 mgg 34–34 mgmmol) (preferentially on morning spot
urine)
Diabetes mellitus
Fasting plasma glucose ≥70 mmolL (126 mgdL) on two repeated
measurements andor
HbA1c >7 (53 mmolmol) andor
Postload plasma glucose >110 mmolL (198 mgdL)
Established CV or renal disease
Cerebrovascular disease ischaemic stroke cerebral haemorrhage
transient ischaemic attack
CHD myocardial infarction angina myocardial revascularization
with PCI or CABG
Heart failure including heart failure with preserved EF
Symptomatic lower extremities peripheral artery disease
CKD with eGFR <30 mLmin173m2 (BSA) proteinuria
(>300 mg24 h)
Advanced retinopathy haemorrhages or exudates papilloedema
CKD with eGFR 30–60 mLmin173 m2 (BSA)
BMI ¼ body mass index BP ¼ blood pressure BSA ¼ body surface area CABG ¼
coronary artery bypass graft CHD ¼ coronary heart disease CKD ¼ chronic
kidney disease CV ¼ cardiovascular CVD ¼ cardiovascular disease EF ¼ ejection
fraction eGFR ¼ estimated glomerular ﬁltration rate HbA1c ¼ glycated
haemoglobin IMT ¼ intimamedia thickness LVH ¼ left ventricular hypertrophy
LVM ¼ left ventricular mass PCI ¼ percutaneous coronary intervention PWV ¼
pulse wave velocity
aRisk maximal for concentric LVH increased LVM index with a wall thicknessradius
ratio of 042
Total cardiovascular risk assessment
Recommendations Class a Level b RefC
In asymptomatic subjects
with hypertension but free
of CVD CKD and diabetes
using the SCORE model is
recommended as a minimal
requirement
I B 43
As there is evidence that
OD predicts CV death
independently of SCORE
a search for OD should be
considered particularly in
individuals at moderate risk
IIa B 51 53
It is recommended that
decisions on treatment
strategies depend on the initial
level of total CV risk I B 41 42 50
CKD ¼ chronic kidney disease CV ¼ cardiovascular CVD ¼ cardiovascular
disease OD ¼ organ damage SCORE ¼ Systematic COronary Risk Evaluation
aClass of recommendation
bLevel of evidence
cReference(s) supporting recommendation(s)
ESH and ESC Guidelines 2167
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 201931 Bood pressure measurement
311 Ofﬁce or clinic blood pressure
At present BP can no longer be estimated using a mercury sphygmo
manometer in many—although not all—European countries Aus
cultatory or oscillometric semiautomatic sphygmomanometers are
used instead These devices should be validated according to standar
dized protocols and their accuracy should be checked periodically
through calibration in a technical laboratory56 Measurement of BP
at the upper arm is preferred and cuff and bladder dimensions
should be adapted to the arm circumference In the event of a signiﬁ
cant (10 mmHg) and consistent SBP difference between arms
which has been shown to carry an increased CV risk57 the arm
with the higher BP values should be used A betweenarms difference
is meaningful if demonstrated by simultaneous arm measurement if
one gets a difference between arms with sequential measurement
it could be due to BP variability In elderly subjects diabetic patients
and in other conditions in which orthostatic hypotension may be fre
quent or suspected it is recommended that BP be measured 1 min
and 3 min after assumption of the standing position Orthostatic
hypotension—deﬁned as a reduction in SBP of ≥20 mmHg or in
DBP of ≥10 mmHg within 3 min of standing—has been shown to
carry a worse prognosis for mortality and CV events5859 If feasible
automated recording of multiple BP readings in the ofﬁce with the
patient seated in an isolated room though providing less information
overall might be considered as a means to improve reproducibility
and make ofﬁce BP values closer to those provided by daytime
ABPM or HBPM6061 BP measurements should always be associated
with measurement of heart rate because resting heart rate values in
dependently predict CV morbid or fatal events in several conditions
including hypertension6263 Instructions for correct ofﬁce BP mea
surements are summarized in Table 5
312 Outofofﬁce blood pressure
The major advantage of outofofﬁce BP monitoring isthatit provides
a large number of BP measurements away from the medical environ
ment which represents a more reliable assessment of actual BP than
ofﬁce BP Outofofﬁce BP is commonly assessed by ABPM or HBPM
usually by selfmeasurement A few general principles and remarks
hold for the two types of monitoring in addition to recommenda
tions for ofﬁce BP measurement64–67
† Theprocedureshouldbe adequatelyexplained to thepatient with
verbal and written instructions in addition selfmeasurement of
BP requires appropriate training under medical supervision
† Interpretation of the results should take into account that the re
producibilityof outofofﬁce BP measurements is reasonably good
for 24h day and night BP averages but less for shorter periods
within the 24 hs and for more complex and derived indices68
† ABPM and HBPM provide somewhat different information on the
subject’s BP status and risk and the two methods should thus be
regarded as complementary rather than competitive or alterna
tive The correspondence between measurements with ABPM
and HBPM is fair to moderate
† Ofﬁce BP is usually higher than ambulatory and home BP and the
difference increases as ofﬁce BP increases Cutoff values for the
deﬁnition of hypertension for home and ambulatory BP according
to the ESH Working Group on BP Monitoring are reported in
Table 664–67
† Devices should have been evaluated and validated according to
international standardized protocols and should be properly
maintained and regularly calibrated at least every 6 months The
validation status can be obtained on dedicated websites
Table 5 Ofﬁce blood pressure measurement
• To allow the patients to sit for 3–5 minutes before beginning
BP measurements
• To take at least two BP measurements in the sitting position
spaced 1–2 min apart and additional measurements if the
rst two are quite different Consider the average BP if deemed
appropriate
• To take repeated measurements of BP to improve accuracy in
p
• To use a standard bladder (12–13 cm wide and 35 cm long)
but have a larger and a smaller bladder available for large (arm
circumference >32 cm) and thin arms respectively
• To have the cuff at the heart level whatever the position of the
patient
• When adopting the auscultatory method use phase I and V
(disappearance) Korotkoff sounds to identify systolic and diastolic
BP respectively
• T
differences In this instance take the arm with the higher value as
the reference
• T
the standing position in elderly subjects diabetic patients and in
other conditions in which orthostatic hypotension may be
frequent or suspected
• To measure in case of conventional BP measurement heart rate
by pulse palpation (at least 30 s) after the second measurement in
the sitting position
BP ¼ blood pressure
Table 6 Deﬁnitions of hypertension by ofﬁce and
outofofﬁce blood pressure levels
Category Systolic BP
(mmHg)
Diastolic BP
(mmHg)
Daytime (or awake) ≥135 andor ≥85
Nighttime (or asleep) ≥120 andor ≥70
24h ≥130 andor ≥80
Home BP ≥135 andor ≥85
140 andor 90Office BP
Ambulatory BP
≥≥
BP ¼ blood pressure
ESH and ESC Guidelines2168
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 20193121 Ambulatory blood pressure monitoring
31211 Methodological aspects A number of methodological
aspects have been addressed by the ESH Working Group on Blood
Pressure Monitoring6465 ABPM is performed with the patient
wearinga portableBPmeasuring deviceusuallyon thenondominant
arm for a 24–25 h period so that it gives information on BP during
daily activities and at night during sleep At the time of ﬁtting of the
portable device the difference between the initial values and those
from BP measurement by the operator should not be greater than
5 mmHg In the event of a larger difference the ABPM cuff should
be removed and ﬁtted again The patient is instructed to engage in
normal activities but to refrain from strenuous exercise and at the
time of cuff inﬂation to stop moving and talking and keep the arm
still with the cuff at heart level The patient is asked to provide infor
mation in a diary on symptoms and events that may inﬂuence BP in
addition to the times of drug ingestion meals and going to and
rising from bed In clinical practice measurements are often made
at 15 min intervals during the day and every 30 min overnight exces
sive intervals between BP readings should be avoided because they
reduce the accuracy of 24h BP estimates69 It may be recommended
that measurements be madeatthe samefrequency duringthedayand
night—for example every 20 min throughout The measurements
are downloaded to a computer and a range of analyses can be
performed At least 70 of BPs during daytime and nighttime
periods should be satisfactory or else the monitoring should be
repeated The detection of artifactual readings and the handling
of outlying values have been subject to debate but if there are suf
ﬁcient measurements editing is not considered necessary and only
grossly incorrect readings should be deleted It is noteworthy that
readings may not be accurate when the cardiac rhythm is marked
ly irregular70
31212 Daytime nighttime and 24hour blood pressure In addition to
the visual plot average daytime nighttime and 24h BP are the most
commonly used variables in clinical practice Average daytime and
nighttime BP can be calculated from the diary on the basis of the
times of getting up and going to bed An alternative method is to
use short ﬁxed time periods in which the rising and retiring
periods—which differ from patient to patient—are eliminated It
has for example been shown that average BPs from 10 am to 8 pm
and from midnight to 6 am correspond well with the actual waking
and sleeping BPs71 butother shortﬁxed timeperiods havebeenpro
posed such as from 9 am to 9 pm and from 1 am to 6 am In the event
of different measurement intervals during the day and the night and
to account for missing values it is recommended thataverage 24h BP
be weighted for the intervals between successive readings or to cal
culate the mean of the 24 hourly averages to avoid overestimation of
average 24h BP72
The nighttoday BP ratio represents the ratio between average
nighttime and daytime BP BP normally decreases during the
night—deﬁned as dipping’ Although the degree of nighttime
dipping has a normal distribution in a population setting it is generally
agreed that the ﬁnding of a nocturnal BP fall of 10 of daytime
values (night–day BP ratio 09) will be accepted as an arbitrary
cutoff to deﬁne subjects as dippers’ Recently more dipping
categories have been proposed absence of dipping ie nocturnal
BP increase (ratio 10) mild dipping (09 ratio ≤10) dipping
(08 ratio ≤09) and extreme dipping (ratio ≤08) One should
bear in mind that the reproducibility of the dipping pattern is
limited7374 Possible reasons for absence of dipping are sleep
disturbance obstructive sleep apnoea obesity high salt intake in salt
sensitive subjects orthostatic hypotension autonomic dysfunction
chronic kidney disease (CKD) diabetic neuropathy and old age
31213 Additional analyses A number of additional indices may be
derived from ABPM recordings75–81 They include BP variability75
morning BP surge767781 blood pressure load78 and the ambulatory
arterial stiffness index7980 However their added predictive value is
not yet clear and they should thus be regarded as experimental
with no routine clinical use Several of these indices are discussed
in detail in ESH position papers and guidelines6465 including informa
tion on facilities recommended for ABPM software in clinical prac
tice which include the need for a standardized clinical report an
interpretative report atrend report to comparerecordings obtained
over time and a research report offering a series of additional para
meters such as those listed above
31214 Prognostic signiﬁcance of ambulatory blood pressure Several
studies have shown that hypertensive patients’ left ventricular hyper
trophy (LVH) increased carotid intimamedia thickness (IMT) and
other markers of OD correlate with ambulatory BP more closely
than with ofﬁce BP8283 Furthermore 24h average BP has been con
sistently shown to have a stronger relationship with morbid or fatal
events than ofﬁce BP84–87 There are studies in which accurately
measured ofﬁce BP had a predictive value similar to ambulatory
BP87 Evidence from metaanalyses of published observational
studies and pooled individual data88–90 however has shown that
ambulatory BP in general is a more sensitive risk predictor of clinical
CV outcomes such as coronary morbid or fatal events and stroke
than ofﬁce BP The superiority of ambulatory BP has been shown
in the general population in young and old in men and women in
untreated and treated hypertensive patients in patients at high risk
and in patients with CV or renal disease89–93 Studies that accounted
for daytime and nighttime BP in the same statistical model found
that nighttime BP is a stronger predictor than daytime BP9094
The night–day ratio is a signiﬁcant predictor of clinical CV outcomes
but adds little prognostic information over and above 24h BP9495
With regard to the dipping pattern the most consistent ﬁnding is
that the incidence of CV events is higher in patients with a lesser
or no drop in nocturnal BP than in those with greater
drop8991929596 although the limited reproducibility of this phe
nomenon limits the reliability of the results for small between
group differences89919295 Extreme dippers may have an increased
risk for stroke97 However data on the increased CV risk in extreme
dippers are inconsistent and thus the clinical signiﬁcance of this phe
nomenon is uncertain8995
3122 Home blood pressure monitoring
31221 Methodological aspects The ESH Working Group on Blood
Pressure Monitoring has proposed a number of recommendations
for HBPM6667 The technique usually involves selfmeasurement of
BP but in some patients the support of a trained health provider
or family member may be needed Devices worn on the wrist are cur
rentlynotrecommended buttheir usemight bejustiﬁedinobese sub
jects with extremely large arm circumference For diagnostic
evaluation BP shouldbe measured dailyon atleast 3–4 days and pref
erably on 7 consecutive days in the mornings as well as in the eve
nings BP is measured in a quiet room with the patient in the
seated position back and arm supported after 5 min of rest and
with two measurements per occasion taken 1–2 min apart the
results are reported in a standardized logbook immediately after
ESH and ESC Guidelines 2169
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 2019each measurement However BP values reported by the patient may
not always be reliable which can be overcome by storage in a
memoryequipped device Home BP is the average of these readings
with exclusion of the ﬁrst monitoring day Use of telemonitoring and
smartphone applications for HBPM may be of further advantage9899
Interpretation of the results should always be under the close guid
ance of the physician
When compared with ofﬁce BP HBPM yields multiple measure
ments over several days or even longer periods taken in the indivi
dual’s usual environment Compared with ambulatory BP it
provides measurements over extended periods and daytoday BP
variability is cheaper100 more widely available and more easily re
peatable However unlike ABPM it does not provide BP data
during routine daytoday activities and during sleep or the quantiﬁ
cation of shortterm BP variability101
31222 Prognostic signiﬁcance of home BP Home BP is more closely
related to hypertensioninduced OD than ofﬁce BP particularly
LVH8283 and recent metaanalyses of the few prospective studies
in the general population in primary care and in hypertensive
patients indicate that the prediction of CV morbidity and mortality
is signiﬁcantly better with home BP than with ofﬁce BP102103
Studies in which both ABPM and HBPM were performed show
that home BP is at least as well correlated with OD as is the
ambulatory BP8283 and that the prognostic signiﬁcance of home
BP is similar to that of ambulatory BP after adjustment for age and
gender104105
313 Whitecoat (or isolated ofﬁce) hypertension
and masked (or isolated ambulatory) hypertension
Ofﬁce BP is usually higher than BP measured out of the ofﬁce which
has been ascribed to the alerting response anxiety andor a condi
tional response to the unusual situation106 and in which regression
to the mean may play a role Although several factors involved in
ofﬁce or outofofﬁce BP modulation may be involved107 the differ
ence between the two is usually referred to—although somewhat
improperly—as the whitecoat effect’107108 whereas whitecoat’
or isolated ofﬁce’ or isolated clinic hypertension’ refers to the con
dition in which BP is elevated in the ofﬁce at repeated visits and
normal out of the ofﬁce either on ABPM or HBPM Conversely BP
may be normal in the ofﬁce and abnormally high out of the medical
environment which is termed masked’ or isolated ambulatory
hypertension’ The terms true’ or consistent normotension’ and
sustained hypertension’ are used when both types of BP measure
ment are respectively normal or abnormal Whereas the cutoff
value for ofﬁce BP is the conventional 14090 mmHg most studies
in whitecoat or masked hypertension have used a cutoff value of
13585 mmHg for outofofﬁce daytime or home BP and 130
80 mmHg for 24h BP Notably there is only moderate agreement
between the deﬁnition of whitecoat or masked hypertension diag
nosed by ABPM or HBPM101 It is recommended that the terms
whitecoat hypertension’ and masked hypertension’ be reserved
to deﬁne untreated individuals
3131 Whitecoat hypertension
Based on four population studies the overall prevalence of white
coat hypertension averaged 13 (range 9–16) and it amounted
to about 32 (range 25–46) among hypertensive subjects in
these surveys109 Factors related to increased prevalence of white
coat hypertension are age female sex and nonsmoking Prevalence
is lower in the case of target OD or when ofﬁce BP is based on
repeated measurements or when measured by a nurse or another
healthcare provider110111 The prevalence is also related to the
level of ofﬁce BP for example the percentage of whitecoat hyper
tension amounts to about 55 in grade 1 hypertension and to only
about 10 in grade 3 hypertension110 OD is less prevalent in white
coat hypertension than in sustained hypertension and prospective
studies have consistently shown this to be the case also for CV
events105109112113 Whether subjects with whitecoat hypertension
can be equalled to true normotensive individuals is an issue still under
debate because in some studies the longterm CV risk of this condi
tion was found to be intermediate between sustained hypertension
and true normotension105 whereas in metaanalyses it was not sig
niﬁcantly different from true normotension when adjusted for
age gender and other covariates109112113 The possibility exists
that because whitecoat hypertensive patients are frequently
treated the reduction of clinic BP leads to a reduced incidence
of CV events112 Other factors to consider are that compared
with true normotensive subjects in whitecoat hypertensive
patients (i) outofofﬁce BP is higher105109 (ii) asymptomatic OD
such as LVH may be more frequent114 and (iii) this is the case also
for metabolic risk factors and longterm risk of newonset diabetes
and progression to sustained hypertension115116 It is recommended
that the diagnosis of whitecoat hypertension be conﬁrmed within
3–6 months and these patients be investigated and followedup
closely including repeated outofofﬁce BP measurements (see
Section 61)
3132 Masked hypertension
The prevalence of masked hypertension averages about 13
(range 10–17) in populationbased studies109 Several factors
may raise outofofﬁce BP relative to ofﬁce BP such as younger
age male gender smoking alcohol consumption physical activity
exerciseinduced hypertension anxiety job stress obesity diabetes
CKD and family history of hypertension and the prevalence is higher
when ofﬁce BP is in the high normal range 117 Masked hypertension is
frequently associated with other risk factors asymptomatic OD and
increased risk of diabetes and sustained hypertension114–119
Metaanalyses of prospective studies indicate that the incidence of
CV events is about two times higher than in true normotension
and is similar to the incidence in sustained hypertension109112117
The fact that masked hypertension is largely undetected and
untreated may have contributed to this ﬁnding In diabetic patients
masked hypertension is associated with an increased risk of nephro
pathy especially when the BP elevation occurs mainly during the
night120121
314 Clinical indications for outofofﬁce blood pressure
It is now generally accepted that outofofﬁce BP is an important
adjunct to conventional ofﬁce BP measurement but the latter cur
rently remains the gold standard’ for screening diagnosis and man
agement of hypertension The timehonoured value of ofﬁce BP
however has to be balanced against its important limitations which
have led to the increasingly frequent suggestion that outofofﬁce
BP measurements play an important role in hypertension manage
ment Although there are important differences between ABPM
ESH and ESC Guidelines2170
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 2019and HBPM the choice between the two methods will depend on
indication availability ease cost of use and if appropriate patient
preference For initial assessment of the patient HBPM may be
more suitable in primary care and ABPM in specialist care
However it is advisable to conﬁrm borderline or abnormal ﬁndings
on HBPM with ABPM122 which is currently considered the reference
for outofofﬁce BP with the additional advantage of providing night
time BP values Furthermore most—if not all—patients should
be familiarized with selfmeasurement of BP in order to optimize
followup for which HBPM is more suitable than ABPM However
(selfmeasured) HBPM may not be feasible because of cognitive im
pairment or physical limitations or may be contraindicated
because of anxiety or obsessive patient behaviour in which case
ABPM may be more suitable Conditions considered as clinical indi
cations for outofofﬁce BP measurement for diagnostic purposes
are listed in Table 7
315 Blood pressure during exercise and laboratory stress
BP increases during dynamic and static exercise whereby the in
crease is more pronounced for systolic than for diastolic BP123 Exer
cise testing usually involves dynamic exercise either on a bicycle
ergometer or a treadmill Notably only SBP can be measured reliably
with noninvasive methods There is currently no consensus on
normal BP response during dynamic exercise testing A SBP of
≥210 mmHg for men and ≥190 mmHg for women has been
termed exercise hypertension’ in a numberof studies but other deﬁ
nitions of an exaggerated BP response to exercise have also been
used124125 Furthermore the increase of SBP at ﬁxed submaximal
exercise is related to preexercise BP age arterial stiffness and ab
dominal obesity and is somewhat greater in women than in men
and less in ﬁt than in unﬁt individuals123–127 Most—but not all—
studies have shown that an excessive rise of BP during exercise pre
dicts the development of hypertension in normotensive subjects in
dependently from BP at rest123124128 However exercise testing to
predict future hypertension is not recommended because of a
number of limitations such as lackof standardization of methodology
and deﬁnitions Furthermore there is no unanimity on the associ
ation of exercise BP with OD such as LVH after adjustment for
resting BP and other covariates as well in normotensives as in hyper
tensive patients123124 Also the results on the prognostic signiﬁcance
of exercise BP are not consistent125 which may be due to the fact that
the two haemodynamic components of BP change in opposite direc
tions during dynamic exercise systemic vascular resistance decreases
whereas cardiac output increases It is likely that the decisive prog
nostic factor is a blunted reduction of systemic vascular resistance
during exercise compatible with structural pathophysiological
changes in arteries and arterioles123129 Whether or not the
impaired arterial dilatation is translated into an excessive rise of BP
may at least partly depend on cardiac output In normotensive sub
jects and in mild hypertensive patients with adequate increase of
cardiac output an exaggerated BP response predicts a poorer long
term outcome125130 In the case of normal resting BP exercise
induced hypertension can be considered an indication for ABPM
because of its association with masked hypertension131 On the
other handwhen hypertension isassociated with cardiac dysfunction
and blunted exerciseinduced increase of cardiac output the prog
nostic signiﬁcance of exercise BP may be lost129 Finally a higher BP
during exercise may even carry a better prognosis such as in
75yearold individuals132 in patients with suspected cardiac
disease133 or with heart failure134 in whom a higher exercise BP
implies relatively preserved systolic cardiac function125 In conclu
sion the overall results question the clinical utility of BP measure
ments during exercise testing for diagnostic and prognostic
purposes in patients with hypertension However exercise testing
is useful as a general prognostic indicator using exercise capacity
and electrocardiogram (ECG) data and an abnormal BP response
may warrant ABPM
A number of mental stress tests have been applied to evoke stress
and increase BP via a problem of mathematical technical or decisio
nal nature123 However these laboratory stress tests in general do
not reﬂect reallife stress and are not well standardized have
limited reproducibility and correlations between BP responses to
the various stressors are limited In addition results on the independ
ent relationships of the BP response to mental stressors with future
hypertension are not unanimous and if signiﬁcant the additional
explained variance is usually small123135 A recent metaanalysis sug
gested that greater responsiveness to acute mental stress has an
adverse effect on future CV risk status—a composite of elevated
BP hypertensionleft ventricular mass (LVM) subclinical atheroscler
osis and clinical cardiac events136 The overall results suggest that BP
measurements during mental stress tests are currently not clinically
useful
Table 7 Clinical indications for outofofﬁce blood
pressure measurement for diagnostic purposes
Clinical indications for HBPM or ABPM
Specific indications for ABPM
• Suspicion of whitecoat hypertension
G
H
damage and at low total CV risk
• Suspicion of masked hypertension
H
N
damage or at high total CV risk
• I
• C
visits
• Autonomic postural postprandial siesta and druginduced
hypotension
• E
women
• I
• M
• Assessment of dipping status
• Suspicion of nocturnal hypertension or absence of dipping such
as in patients with sleep apnoea CKD or diabetes
• Assessment of BP variability
ABPM ¼ ambulatory blood pressure monitoring BP ¼ blood pressure CKD ¼
chronic kidney disease CV ¼ cardiovascular HBPM ¼ home blood pressure
monitoring
ESH and ESC Guidelines 2171
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 2019316 Central blood pressure
The measurement of central BP in hypertensive patients raises in
creasing interest because of both its predictive value for CV events
and the differential effect of antihypertensive drugs compared with
brachial BP The arterial pressure waveform is a composite of the
forward pressure wave created by ventricular contraction and a
reﬂected wave137 It should be analysed at the central level ie in
the ascending aorta since it represents the true load imposed on
heart brain kidney and large arteries The phenomenon of wave re
ﬂection can be quantiﬁed through the augmentation index—deﬁned
as the difference between the second and ﬁrst systolic peaks
expressed as a percentage of the pulse pressure preferably adjusted
for heart rate Owing to the variable superimposition of incoming and
reﬂected pressure waves along the arterial tree aortic systolic and
pulse pressures may be different from the conventionally measured
brachial pressure In recent years several methods including applana
tion tonometry and transfer function have been developed to esti
mate central systolic BP or pulse pressure from brachial pressure
wave They have been critically reviewed in an expert consensus
document138
Early epidemiological studies in the 2000s showed that central aug
mentation index and pulse pressure directly measured by carotid
tonometry wereindependent predictors of allcause and CV mortal
ity in patients with ESRD139 A recent metaanalysis conﬁrmed these
ﬁndings in several populations140 However the additive predictive
value of central BP beyondbrachial BP was either marginal or not stat
istically signiﬁcant in most studies140
Thus the current guidelines like previous ones2141 consider that
although the measurement of central BP and augmentation index is of
great interest for mechanistic analyses in pathophysiology pharma
cology and therapeutics more investigation is needed before recom
mending their routine clinical use The only exception may be ISH in
the young in some of these individuals increased SBP at the brachial
level may be due to high ampliﬁcation of the central pressure wave
while central BP is normal142
32 Medical history
The medical history should address the time of the ﬁrst diagnosis
of arterial hypertension current and past BP measurements and
current and past antihypertensive medications Particular attention
should be paid to indications of secondary causes of hypertension
Women should be questioned about pregnancyrelated hyperten
sion Hypertension translates into an increased risk of renal and
CV complications (CHD heart failure stroke PAD CV death) es
pecially when concomitant diseases are present Therefore a
careful history of CVDs should be taken in all patients to allow
assessment of global CV risk including concomitant diseases
such as diabetes clinical signs or a history of heart failure CHD
or PAD valvular heart disease palpitations syncopal episodes
neurological disorders with an emphasis on stroke and transient
ischaemic attack (TIA) A history of CKD should include the
type and duration of kidney disease Nicotine abuse and evidence
for dyslipidaemia should be sought A family history of premature
hypertension andor premature CVD is an important ﬁrst indica
tor of familial (genetic) predisposition to hypertension and CVD
and may trigger clinically indicated genetic tests Details on
family and medical history are summarized in Table 8
Table 8 Personal and family medical history
1 Duration and previous level of high BP including
measurements at home
2 Secondary hypertension
a) Family history of CKD (polycystic kidney)
b) History of renal disease urinary tract infection haematuria
analgesic abuse (parenchymal renal disease)
c) Drugsubstance intake eg oral contraceptives liquorice
carbenoxolone vasoconstrictive nasal drops cocaine
amphetamines gluco and mineralocorticosteroids
n
cyclosporine
d) Repetitive episodes of sweating headache anxiety
palpitations (pheochromocytoma)
e) Episodes of muscle weakness and tetany
(hyperaldosteronism)
f) Symptoms suggestive of thyroid disease
3 Risk factors
a) Family and personal history of hypertension and CVD
b) Family and personal history of dyslipidaemia
c) Family and personal history of diabetes mellitus (medications
bloodglucose levels polyuria)
d) Smoking habits
e) Dietary habits
f) Recent weight changes obesity
g) Amount of physical exercise
h) Snoring sleep apnoea (information also from partner)
i) Low birthweight
4 History and symptoms of organ damage and
cardiovascular disease
a) Brain and eyes headache vertigo impaired vision TIA
revascularization
b) Heart chest pain shortness of breath swollen ankles
myocardial infarction revascularization syncope history of
p
c) Kidney thirst polyuria nocturia haematuria
d) Peripheral arteries cold extremities intermittent
claudication painfree walking distance peripheral
revascularization
e) History of snoringchronic lung diseasesleep apnoea
f) Cognitive dysfunction
5 Hypertension management
a) Current antihypertensive medication
b) Past antihypertensive medication
c) Evidence of adherence or lack of adherence to therapy
d) E
BP ¼ blood pressure CKD ¼ chronic kidney disease CVD ¼ cardiovascular
disease TIA ¼ transient ischaemic attack
ESH and ESC Guidelines2172
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 201933 Physical examination
Physical examination aims to establish or verify the diagnosis of
hypertension establish current BP screen for secondary causes of
hypertension and reﬁne global CV risk estimation BP should be
measured as summarized in Section 311 and should be repeated
to conﬁrm the diagnosis of hypertension On at least one occasion
BP needs to be measured at both arms and differences between
the two arms in SBP 20 mmHg andor in DBP 10 mmHg—if
conﬁrmed—should trigger further investigations of vascular
abnormalities All patients should undergo auscultation of the
carotid arteries heart and renal arteries Murmurs should suggest
further investigation (carotid ultrasound echocardiography renal
vascular ultrasound depending on the location of the murmur)
Height weight and waist circumference should be measured with
the patient standing and BMI calculated Pulse palpation and
cardiac auscultation may reveal arrhythmias In all patients heart
rate should be measured while the patient is at rest An increased
heart rate indicates an increased risk of heart disease An irregular
pulse should raise the suspicion of atrial ﬁbrillation including
silent atrial ﬁbrillation Details on physical examination are summar
ized in Table 9
34 Summary of recommendations on
blood pressure measurement history and
physical examination
35 Laboratory investigations
Laboratory investigations are directed at providing evidence for the
presence of additional risk factors searchingfor secondary hyperten
sion and looking for the absence or presence of OD Investigations
should progress from the most simple to the more complicated
ones Details on laboratory investigations are summarized in
Table 10
36 Genetics
A positive family history is a frequent feature in hypertensive
patients143144 with the heritability estimated to vary between 35
and 50 in the majority of studies145 and heritability has been con
ﬁrmed for ambulatory BP146 Several rare monogenic forms of hyper
tension have been described such as glucocorticoidremediable
Table 9 Physical examination for secondary
hypertension organ damage and obesity
Signs suggesting secondary hypertension
• Features of Cushing syndrome
• S
• Palpation of enlarged kidneys (polycystic kidney)
• Auscultation of abdominal murmurs (renovascular
hypertension)
• Auscultation of precordial or chest murmurs (aortic
coarctation aortic disease upper extremity artery disease)
• Diminished and delayed femoral pulses and reduced femoral
blood pressure compared to simultaneous arm BP
(aortic coarctation aortic disease lower extremity artery disease)
• Left–right arm BP difference (aortic coarctation
subclavian artery stenosis)
Signs of organ damage
• Brain motor or sensory defects
• Retina fundoscopic abnormalities
• Heart heart rate 3rd or 4th heart sound heart murmurs
arrhythmias location of apical impulse pulmonary rales
peripheral oedema
• Peripheral arteries absence reduction or asymmetry of pulses
cold extremities ischaemic skin lesions
• Carotid arteries systolic murmurs
Evidence of obesity
• Weight and height
• Calculate BMI body weightheight 2 (kgm2)
• Waist circumference measured in the standing position at a
level midway between the lower border of the costal margin
(the lowest rib) and uppermost border of the iliac crest
BP ¼ blood pressure BMI ¼ body mass index
Blood pressure measurement history and physical
examination
Recommendations Class a Level b Ref C
It is recommended to obtain a
comprehensive medical history and
physical examination in all patients with
hypertension to verify the diagnosis
detect causes of secondary hypertension
record CV risk factors and to identify
OD and other CVDs
I C
Obtaining a family history is
recommended to investigate familial
predisposition to hypertension and
CVDs
Office BP is recommended for screening
and diagnosis of hypertension
I B 143 144
I B 3
It is recommended that the diagnosis of
hypertension be based on at least two BP
measurements per visit and on at least
two visits
I C
It is recommended that all hypertensive
patients undergo palpation of the pulse
at rest to determine heart rate and to
search for arrhythmias especially atrial
fibrillation
Outofoffice BP should be considered
to confirm the diagnosis of hypertension
identify the type of hypertension detect
hypotensive episodes and maximize
prediction of CV risk
For outofoffice BP measurements ABPM
or HBPM may be considered depending
on indicaton availability ease cost of use
and if appropriate patient preference
I B 62 63
IIa B 89 90 103
105 109
113 117
IIb C
ABPM ¼ ambulatory blood pressure monitoring BP ¼ blood pressure CV ¼
cardiovascular CVD ¼ cardiovascular disease HBPM ¼ home blood pressure
monitoring OD ¼ organ damage
aClass of recommendation
bLevel of evidence
cReference(s) supporting recommendation(s)
ESH and ESC Guidelines 2173
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 2019aldosteronism Liddle’s syndrome and others where a single gene mu
tation fully explains the pathogenesis of hypertension and dictates the
best treatment modality147 Essential hypertension is a highly hetero
geneous disorder witha multifactorial aetiology Severalgenomewide
association studies and their metaanalyses point to a total of 29 single
nucleotide polymorphisms which are associated with systolic andor
diastolic BP148 These ﬁndings might become useful contributors to
risk scores for OD
37 Searching for asymptomatic organ
damage
Owing to the importance of asymptomatic OD as an intermediate
stage in the continuum of vascular disease and as a determinant
of overall CV risk signs of organ involvement should be sought
carefully by appropriate techniques if indicated (Table 10) It should
be pointed out that a large body of evidence is now available on
the crucial role of asymptomatic OD in determining the CV risk of
individuals with and without high BP The observation that any
of four markers of OD (microalbuminuria increased pulse wave
velocity [PWV] left ventricular hypertrophy [LVH] and carotid
plaques) can predict CV mortality independently of SCORE stratiﬁ
cation is a relevant argument in favour of using assessment of OD
in daily clinical practice51–53 although more data from larger
studies in different populations would be desirable It is also note
worthy that the risk increases as the number of damaged organs
increases51
371 Heart
3711 Electrocardiography
A 12lead ECG should be part of the routine assessment of all
hypertensive patients Its sensitivity in detecting LVH is low but
nonetheless LVH detected by the SokolowLyon index (SV1 +
RV5 35 mV) the modiﬁed SokolowLyon index (largest
Swave + largest Rwave 35 mV) RaVL 11 mV or Cornell
voltage QRS duration product (244 mV*ms) has been found in
observational studies and clinical trials to be an independent pre
dictor of CV events149 Accordingly the ECG is valuable at least
in patients over 55 years of age150151 Electrocardiography can
also be used to detect patterns of ventricular overload or strain’
which indicates more severe risk149150152 ischaemia conduction
abnormalities left atrial dilatation and arrhythmias including atrial
ﬁbrillation Twentyfourhour Holter electrocardiography is indi
cated when arrhythmias and possible ischaemic episodes are sus
pected Atrial ﬁbrillation is a very frequent and common cause of
CV complications153154 especially stroke in hypertensive
patients153 Early detection of atrial ﬁbrillation would facilitate the
prevention of strokes by initiating appropriate anticoagulant
therapy if indicated
3712 Echocardiography
Although not immune from technical limitations echocardiography
is more sensitive than electrocardiography in diagnosing LVH and is
useful to reﬁne CV and renal risk155157 It may therefore help in a
more precise stratiﬁcation of overall risk and in determining
therapy158 Proper evaluation of the left ventricle (LV) in hyperten
sive patients includes linear measurements of interventricular
septal and posterior wall thickness and internal enddiastolic diam
eter While LVM measurements indexed for body size identify LVH
relative wall thickness or the walltoradius ratio (2 × posterior
wall thicknessenddiastolic diameter) categorizes geometry (con
centric or eccentric) Calculation of LVM is currently performed
according to the American Society of Echocardiography
formula159 Although the relation between LVM and CV risk is con
tinuous thresholds of 95 gm2 for women and 115 gm2 (body
surface area [BSA]) for men are widely used for estimates of clear
cut LVH159 Indexation of LVM for height in which height to the allo
metric powerof 17 or 27 has been used160161 can be considered in
overweight and obese patients in order to scale LVM to body size
and avoid underdiagnosis of LVH159 It has recently been shown
that the optimal method is to scale allometrically by body height
to the exponent 17 (gm17) and that different cutoffs for men
Table 10 Laboratory investigations
Routine tests
• Haemoglobin andor haematocrit
• Fasting plasma glucose
• Serum total cholesterol lowdensity lipoprotein cholesterol
highdensity lipoprotein cholesterol
• Fasting serum triglycerides
• Serum potassium and sodium
• Serum uric acid
• Serum creatinine (with estimation of GFR)
• Urine analysis microscopic examination urinary protein by
dipstick test test for microalbuminuria
• 12lead ECG
Additional tests based on history physical examination
and findings from routine laboratory tests
•Haemoglobin A1c (if fasting plasma glucose is >56 mmolL
(102 mgdL) or previous diagnosis of diabetes)
• Quantitative proteinuria (if dipstick test is positive) urinary
potassium and sodium concentration and their ratio
• Home and 24h ambulatory BP monitoring
• Echocardiogram
•
Exercise testing•
Holter monitoring in case of arrhythmias
• Carotid ultrasound
• Peripheral arteryabdominal ultrasound
• Pulse wave velocity
•Anklebrachial index
• Fundoscopy
Extended evaluation (mostly domain of the specialist)
• Further search for cerebral cardiac renal and vascular damage
mandatory in resistant and complicated hypertension
• Search for secondary hypertension when suggested by history
physical examination or routine and additional tests
BP ¼ blood pressure ECG ¼ electrocardiogram GFR ¼ glomerular ﬁltration rate
ESH and ESC Guidelines2174
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 2019and women should be used160 Scaling LVM by height exponent 27
could overestimate LVH in small subjects and underestimate in tall
ones160 Concentric LVH (relative wall thickness 042 with
increased LVM) eccentric LVH (relative wall thickness ≤042
with increased LVM) and concentric remodelling (relative wall
thickness 042 with normal LVM) all predict an increased inci
dence of CVD but concentric LVH is the strongest predictor of
increased risk162–164
Hypertension is associated with alterations of LV relaxation and
ﬁlling globally deﬁned as diastolic dysfunction Hypertension
induced diastolic dysfunction is associated with concentric geom
etry and can per se induce symptomssigns of heart failure even
when ejection fraction (EF) is still normal (heart failure with pre
served EF)165 The Doppler transmitral inﬂow pattern can quantify
ﬁlling abnormalities and predict subsequent heart failure and all
cause mortality166167 but is not sufﬁcient to completely stratify
the hypertensive clinical status and prognosis166167 According to
recent echocardiographical recommendations168 it should therefore
be combined with pulsed Tissue Doppler of the mitral annulus Re
duction of the Tissue Dopplerderived early diastolic velocity (e’) is
typical of hypertensive heart disease and often the septal e’ is
reduced more than the lateral e’ Diagnosis and grading of diastolic
dysfunction is based on e’ (average of septal and lateral mitral
annulus) and additional measurements including the ratio between
transmitral E and e’ (Ee’ ratio) and left atrial size168 This grading is
an important predictor of allcause mortality in a large epidemiologic
al study169 The values of e’ velocity and of Ee’ ratio are highly de
pendent on age and somewhat less on gender170 The Ee’ ratio is
able to detect an increase of LV ﬁlling pressures The prognostic
value of e’ velocity is recognized in the hypertensive setting171
and Ee’ ratio ≥ 13168 is associated with increased cardiac risk
independent of LVM and relative wall thickness in hypertensive
patients171 Determination of left atrial dilatation can provide add
itional information and is a prerequisite for the diagnosis of diastolic
dysfunction Left atrial size is best assessed by its indexed volume or
LAVi159 LAVi ≥34 mLm2 has been shown to be an independent
predictor of death heart failure atrial ﬁbrillation and ischaemic
stroke172
Normal ranges and cutoff values for hypertensive heart disease
for key echocardiographic parameters are summarized in Table 11
The most used scaling for evaluating LVH in hypertension is to
divide LVM by BSA so that the effects on LVM of body size and
obesity are largely eliminated Despite largely derived from control
study populations with the obvious possibility for bias these para
meters recommended by the American Society of Echocardiography
and the European Association of Echocardiography are used in the
majority of laboratories for echocardiography Data from large
general populations in different ethnicities will be available soon
To assess subclinical systolic dysfunction speckle tracking echo
cardiography can quantify longitudinal contractile function (longitu
dinal strain) and help to unmask early subclinical systolic
dysfunction of newly diagnosed hypertensive patients without
LVH173174 However assessment of LV systolic function in hyperten
sive heart disease does not add prognostic information to LVM at
least in the context of a normal EF
In clinical practice echocardiography should be considered in
hypertensive patients in different clinical contexts and with dif
ferent purposes in hypertensive patients at moderate total
CV risk it may reﬁne the risk evaluation by detecting LVH un
detected by ECG in hypertensive patients with ECG evidence
of LVH it may more precisely assess the hypertrophy quantita
tively and deﬁne its geometry and risk in hypertensive patients
with cardiac symptoms it may help to diagnose underlying
disease It is obvious that echocardiography including assess
ment of ascending aorta and vascular screening may be of sig
niﬁcant diagnostic value in most patients with hypertension and
should ideally be recommended in all hypertensive patients at
the initial evaluation However a wider or more restricted
use will depend on availability and cost
3713 Cardiac magnetic resonance imaging
Cardiac magnetic resonance imaging (MRI) should be considered for
assessment of LV size and mass when echocardiography is technically
not feasible and when imaging of delayed enhancement would have
therapeutic consequences175176
3714 Myocardial ischaemia
Speciﬁc procedures are reserved for diagnosis of myocardial is
chaemia in hypertensive patients with LVH177 This is particular
ly challenging because hypertension lowers the speciﬁcity of
exercise electrocardiography and perfusion scintigraphy178 An
exercise test demonstrating a normal aerobic capacity and
without signiﬁcant ECG changes has an acceptable negative pre
dictive value in patients without strong symptoms indicative of
obstructive CHD When the exercise ECG is positive or unin
terpretableambiguous an imaging test of inducible ischaemia
such as stress cardiac MRI perfusion scintigraphy or stress
echocardiography is warranted for a reliable identiﬁcation of
myocardial ischaemia178–180 Stressinduced wall motion abnor
malities are highly speciﬁc for angiographically assessed
Table 11 Cutoff values for parameters used in the
assessment of LV remodelling and diastolic function in
patients with hypertension Based on Lang et al158 and
Nagueh et al168
Parameter Abnormal if
LV mass index (gm²) >95 (women)
>115 (men)
Relative wall thickness (RWT) >042
Diastolic function
Septal e’ velocity (cmsec)
Lateral e’ velocity (cmsec)
LA volume index (mLm2)
<8
<10
≥34
LV Filling pressures
E e’ (averaged) ratio ≥13
LA ¼ left atrium LV ¼ left ventricle RWT ¼ relative wall thickness
ESH and ESC Guidelines 2175
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 2019epicardial coronary artery stenosis whereas myocardial perfu
sion abnormalities are frequently found with angiographically
normal coronary arteries associated with LVH andor coronary
microvascular disease177 The use of dual echocardiographic
imaging of regional wall motion and transthoracic Dopplerderived
coronary ﬂow reserve on the left anterior descending artery has
recently been suggested to distinguish obstructive CHD (reduced
coronary reserve plus inducible wall motion abnormalities) from
isolated coronary microcirculatory damage (reduced coronary
reserve without wall motion abnormalities)180 A coronary ﬂow
reserve ≤191 has been shown to have an independent prognostic
value in hypertension181182
372 Blood vessels
3721 Carotid arteries
Ultrasound examination of the carotid arteries with measurement of
intima media thickness (IMT) andor the presence of plaques has
been shown to predict the occurrence of both stroke and myocardial
infarction independently of traditional CV risk factors51183–186 This
holds true both for the IMT value at the carotid bifurcations (reﬂect
ing primarily atherosclerosis) and for the IMT value at the level of the
common carotid artery (reﬂecting primarily vascular hypertrophy)
The relationship between carotid IMT and CV events is a continuous
one and determining a threshold for high CV risk is rather arbitrary
Although a carotid IMT 09 mm has been taken as a conservative
estimate of existingabnormalities inthe2007Guidelines2 thethresh
old value for high CV risk was higher in the elderly patients of the Car
diovascular Health Study and in the middleaged patients of the
European Lacidipine Study on Atherosclerosis (ELSA) study (106
and 116 mm respectively)184186 Presence of a plaque can be iden
tiﬁed by an IMT ≥15 mm or byafocal increase in thickness of 05 mm
or 50 of the surrounding carotid IMT value187 Although plaque has
a strong independent predictive value for CV events51183–185188
presence of a plaque and increased carotid IMT added little to
each other for predicting CV events and reclassifying patients
into another risk category in the Atherosclerosis Risk In Commu
nities (ARIC) study185 A recent systematic review concluded that
the added predictive value of additional carotid screening may be
primarily found in asymptomatic individuals at intermediate
CV risk189
3722 Pulse wave velocity
Large artery stiffening and the wavereﬂection phenomenon have
been identiﬁed as being the most important pathophysiological
determinants of ISH and pulse pressure increase with ageing190
Carotidfemoral PWV is the gold standard’ for measuring aortic stiff
ness138 Although the relationship between aortic stiffness and
events is continuous a threshold of 12 ms has been suggested
by the 2007 ESHESC Guidelines as a conservative estimate of signiﬁ
cant alterations of aortic function in middleaged hypertensive
patients2 A recent expert consensus statement adjusted this thresh
old value to 10 ms191 by using the direct carotidtofemoral distance
and taking into account the 20 shorter true anatomical distance
travelled by the pressure wave (ie 08 × 12 ms or 10 ms) Aortic
stiffness has independent predictive value for fatal and nonfatal CV
events in hypertensive patients192193 The additive value of PWV
above and beyond traditional risk factors including SCORE and Fra
mingham risk score has been quantiﬁed in a number of
studies5152194195 In addition a substantial proportion of patients
at intermediate risk could be reclassiﬁed into a higher or lower CV
risk when arterial stiffness is measured51195196
3723 Ankle–brachial index
Ankle–brachial index (ABI) can be measured either with automated
devicesorwithacontinuouswaveDopplerunitandaBPsphygmo
manometer A low ABI (ie 09) signals PAD and in general
advanced atherosclerosis197 has predictive value for CV
events198 and was associated with approximately twice the
10year CV mortality and major coronary event rate compared
with the overall rate in each Framingham category198 Furthermore
even asymptomatic PAD as detected by a low ABI has prospective
ly been found to be associated in men with an incidence of CV
morbid and fatal events approaching 20 in 10 years198199
However ABI is more useful for detecting PAD in individuals with
a high likelihood of PAD
3724 Other methods
Although measurements of carotid IMT aortic stiffness or ABI
are reasonable for detecting hypertensive patients at high CV
risk several other methods used in the research setting for
detecting vascular OD cannot be supported for clinical use
An increase in the wall–lumen ratio of small arteries can be
measured in subcutaneous tissues obtained through gluteal biopsies
These measurements can demonstrate early alterations in diabetes
and hypertension and have a predictive value for CV morbidity and
mortality 199–202 but the invasiveness of the method makes this ap
proach unsuitable for general use Increase in coronary calcium as
quantiﬁed by highresolution cardiac computed tomography has
also been prospectively validated as a predictor of CVD and is highly
effective in restratifying asymptomatic adults into either a moderate
or a high CVD risk group203204 but the limited availability and high
cost of the necessary instrumentations present serious problems
Endothelial dysfunction predicts outcome in patients with a variety
of CVDs205 although data on hypertension are still rather scant206
Furthermore the techniques available for investigating endothelial re
sponsiveness to various stimuli are laborious time consuming and
often invasive
373 Kidney
The diagnosis of hypertensioninduced renal damage is based on
the ﬁnding of a reduced renal function andor the detection of
elevated urinary excretion of albumin207 Once detected CKD
is classiﬁed according to estimated glomerular ﬁltration rate
(eGFR) calculated by the abbreviated modiﬁcation of diet in
renal disease’ (MDRD) formula208 the CockcroftGault formula
or more recently through the Chronic Kidney Disease EPIdemi
ology Collaboration (CKDEPI) formula209 which require age
gender ethnicity and serum creatinine When eGFR is below
60 mLmin173 m2 three different stages of CKD are recognized
stage 3 with values between 30–60 mLmin173 m2 and stages 4
and 5 with values below 30 and 15 mLmin173 m2 respective
ly210 These formulae help to detect mild impairment of renal
ESH and ESC Guidelines2176
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 2019function when serum creatinine values are still within the normal
range211 A reduction in renal function and an increase in CV risk
can be inferred from the ﬁnding of increased serum levels of
cystatin C212 A slight increase (up to 20) in serum creatinine
may sometimes occur when antihypertensive therapy—particular
ly by reninangiotensin system (RAS) blockers—is instituted or in
tensiﬁed but this should not be taken as a sign of progressive
renal deterioration Hyperuricaemia is frequently seen in untreat
ed hypertensive patients (particularly in preeclampsia) and has
been shown to correlate with a reduced renal blood ﬂow and
nephrosclerosis213
While an elevated serum creatinine concentration or a low eGFR
point to diminished renal function the ﬁnding of an increased rate of
urinary albumin or protein excretion points in general to a de
rangement in glomerular ﬁltration barrier Microalbuminuria has
been shown to predict the development of overt diabetic nephro
pathy in both type 1 and type 2 diabetic patients214 while the pres
ence of overt proteinuria generally indicates the existence of
established renal parenchymatous disease215 In both diabetic and
nondiabetic hypertensive patients microalbuminuria even below
the threshold values usually considered216 has been shown to
predict CV events217–225 and continuous relationships between
CV as well as nonCV mortality and urinary albumincreatinine
ratios 39 mgg in men and 75 mgg in women have been
reported in several studies224226 Both in the general population
and in diabetic patients the concomitance of an increased urinary
protein excretion and a reduced eGFR indicates a greater risk of
CV and renal events than either abnormality alone making these
risk factors independent and cumulative227228 An arbitrary thresh
old for the deﬁnition of microalbuminuria has been established as
30 mgg of creatinine228
In conclusion the ﬁnding of an impaired renal function in a
hypertensive patient expressed as any of the abnormalities
mentioned above constitutes a very potent and frequent pre
dictor of future CV events and death218229– 233 Therefore it
is recommended in all hypertensive patients that eGFR be esti
mated and that a test for microalbuminuria be made on a spot
urine sample
374 Fundoscopy
The traditional classiﬁcation system of hypertensive retinopathy
by fundoscopy is based on the pioneering work by Keith
Wagener and Barker in 1939 and its prognostic signiﬁcance
has been documented in hypertensive patients234 Grade III
(retinal haemorrhages microaneurysms hard exudates cotton
wool spots) and grade IV retinopathy (grade III signs and papil
loedema andor macular oedema) are indicative of severe
hypertensive retinopathy with a high predictive value for mor
tality234235 Grade I (arteriolar narrowing either focal or
general in nature) and grade II (arteriovenous nicking) point
to early stage of hypertensive retinopathy and the predictive
value of CV mortality is controversially reported and overall
less stringent236237 Most of these analyses have been done by
retinal photography with interpretation by ophthalmologists
which is more sensitive than direct ophthalmoscopyfundoscopy
by general physicians238 Criticism with respect to the reprodu
cibility of grade I and grade II retinopathy has been raised since
even experienced investigators displayed high interobserver and
intraobserver variability (in contrast to advanced hypertensive
retinopathy)239240
The relationship of retinal vessel calibre to future stroke
events has been analysed in a systematic review and individual
participant metaanalysis wider retinal venular calibre predicted
stroke whereas the calibre of retinal arterioles was not asso
ciated with stroke241 Retinal arteriolar and venular narrowing
similarly to capillary rarefaction in other vascular beds242243
may be an early structural abnormality of hypertension but its
additive value to identify patients at risk for other types of
OD needs to be deﬁned243– 244 The arteriovenous ratio of
retinal arterioles and venules predicted incident stroke and
CV morbidity but criticism that concomitant changes of the
venule diameters may affect this ratio and the methodology
(digitized photographs need of core reading centre) prohibited
its widespread clinical use245–248 New technologies to assess
the wall–lumen ratio of retinal arterioles that directly
measure the vascular remodelling in early and later stages of
hypertensive disease are currently being investigated249
375 Brain
Hypertension beyond its wellknown effect on the occurrence of
clinical stroke is also associated with the risk of asymptomatic
brain damage noticed on cerebral MRI in particular in elderly
individuals250251 The most common types of brain lesions are
white matter hyperintensities which can be seen in almost all
elderly individuals with hypertension 250 – although with variable
severity – and silent infarcts the large majority of which are
small and deep (lacunar infarctions) and the frequency of
which varies between 10 and 30252 Another type of lesion
more recently identiﬁed are microbleeds seen in about 5 of
individuals White matter hyperintensities and silent infarcts are
associated with an increased risk of stroke cognitive decline and
dementia250252–254 In hypertensive patients without overt CVD
MRI showed that silent cerebrovascular lesions are even more
prevalent (44) than cardiac (21) and renal (26) subclinical
damage and do frequently occur in the absence of other signs of
organ damage255 Availability and cost considerations do not
allow the widespread use of MRI in the evaluation of elderly
hypertensives but white matter hyperintensity and silent brain
infarcts should be sought in all hypertensive patients with neural
disturbance and in particular memory loss255–257 As cognitive dis
turbances in the elderly are at least in part hypertension
related258259 suitable cognitive evaluation tests may be used in
the clinical assessment of the elderly hypertensive patient
376 Clinical value and limitations
Table 12 summarizes the CV predictive value availability reproduci
bility and costeffectiveness of procedures for detection of OD The
recommended strategies for the search for OD are summarized in
the Table
ESH and ESC Guidelines 2177
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 2019377 Summary of recommendations on the search for
asymptomatic organ damage cardiovascular disease and
chronic kidney disease
See Search for asymptomatic organ damage cardiovascular disease
and chronic kidney disease’ on page 21
38 Searching for secondary forms
of hypertension
A speciﬁc potentially reversible cause of BPelevation can be identiﬁed in
a relatively small proportion of adult patients with hypertension
However because of the overall high prevalence of hypertension sec
ondary forms can affect millions of patients worldwide If appropriately
diagnosed and treated patients with a secondary form of hypertension
might be cured or at least show an improvement in BP control and a re
duction of CV risk Consequently as a wise precaution all patients
should undergo simple screening for secondary forms of hypertension
This screening can be based on clinical history physical examination and
routine laboratory investigations (Tables 9 10 13) Furthermore a sec
ondary form ofhypertension can be indicatedbyasevere elevation in BP
sudden onset or worsening of hypertension poor BP response to drug
therapy and OD disproportionate to the duration of hypertension If the
basal workup leads to the suspicion that the patient is suffering from a
secondary form of hypertension speciﬁc diagnostic procedures may
become necessary as outlined in Table 13 Diagnostics of secondary
forms of hypertension especially in cases with a suspicion of endocrine
hypertension should preferably be performed in referral centres
4 Treatment approach
41 Evidence favouring therapeutic
reduction of high blood pressure
Evidence favouring the administration of BPlowering drugs to
reduce the risk of major clinical CV outcomes (fatal and nonfatal
stroke myocardial infarction heart failure and other CV deaths) in
hypertensive individuals results from a number of RCTs—mostly
placebocontrolled—carried out between 1965 and 1995 Their
metaanalysis260 was referred to in the 2003 edition of ESHESC
Guidelines1 Supportive evidence also comes from ﬁnding that a
BPinduced regression of OD such as LVH and urinary protein excre
tion may be accompanied by a reduction of fatal and nonfatal out
comes261262 although this evidence is obviously indirect being
derived from posthoc correlative analyses of randomized data
Randomizedtrialsbasedonhard clinicalCVoutcomesdohowever
alsohavelimitationswhichhavebeenconsideredinpreviousESHESC
Guidelines2 (i)tolimitthenumberofpatientsneededtrialscommonly
enrol highrisk patients (old age concomitant or previous disease) and
(ii) for practical reasons the duration of controlled trials is necessarily
short (in best cases between 3 and 6 years with an average time to an
endpoint of only half of this)—so that recommendations for lifelong
intervention are based on considerable extrapolation from data
obtained over periods much shorter than the life expectancy of
most patients Support for the belief that the beneﬁts measured
during the ﬁrst few years will continue over a much longer term
comes from observational studies of a few decades duration 263
The recommendations that now follow are based on available evi
dence from randomized trials and focus on important issues for
medical practice (i) when drug therapy should be initiated (ii) the
target BP to be achieved by treatment in hypertensive patients at dif
ferent CV risk levels and (iii) therapeutic strategies and choice of
drugs in hypertensive patients with different clinical characteristics
42 When to initiate antihypertensive
drug treatment
421 Recommendations of previous Guidelines
The 2007 ESHESC Guidelines2 like many other scientiﬁc guide
lines5455264 recommended the use of antihypertensive drugs in
Table 12 Predictive value availability reproducibility and cost–effectiveness of some markers of organ damage
Marker Cardiovascular predictive value Availability Reproducibility Costeffectiveness
Electrocardiography +++ ++++ ++++ ++++
Echocardiography plus Doppler ++++ +++ +++ +++
+++ ++++ ++++ ++++
Microalbuminuria +++ ++++ ++ ++++
Carotid intima–media thickness
and plaque
+++ +++ +++ +++
Arterial stiffness (pulse wave
velocity)
+++ ++ +++ +++
Ankle–brachial index +++ +++ +++ +++
Fundoscopy +++ ++++ ++ +++
Additional measurements
Coronary calcium score ++ + +++ +
Endothelial dysfunction ++ + + +
Cerebral lacunaewhite matter
lesions
++ + +++ +
Cardiac magnetic resonance ++ + +++ ++
Scores are from + to ++ + +
ESH and ESC Guidelines2178
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 2019patients with grade 1 hypertension even in the absence of other risk
factors or OD provided that nonpharmacological treatment had
proved unsuccessful This recommendation also speciﬁcally included
the elderly hypertensive patient The 2007 Guidelines2 furthermore
recommended a lower threshold for antihypertensive drug interven
tion in patients with diabetes previous CVD or CKD and suggested
treatment of these patients even when BP was in the high normal
range (130–13985–89 mmHg) These recommendations were
reappraised in a 2009 ESH Task Force document141 on the basis
of an extensive review of the evidence265 The following now sum
marizes the conclusions for the current Guidelines
422 Grade 2 and 3 hypertension and highrisk grade 1
hypertension
RCTs providing incontrovertible evidence in favour of antihyper
tensive therapy260 as referred to in Section 41 were carried out
primarily in patients with SBP ≥160 mmHg or DBP ≥100 mmHg
who would now be classiﬁed as grade 2 and 3 hypertensives—but
also included some patients with grade 1 highrisk hypertension
Despite some difﬁculty in applying new classiﬁcations to old
trials the evidence favouring drug therapy in patients with
marked BP elevation or in hypertensive patients at high total
CV risk appears overwhelming BP represents a considerable
component of overall risk in these patients and so merits
prompt intervention
423 Lowtomoderate risk grade 1 hypertension
The evidence favouring drug treatment in these individuals is scant
because no trial has speciﬁcally addressed this condition Some of
the earlier trials on mild’ hypertension used a different grading of
hypertension (based on DBP only)266–268 or included patients at
high risk268 The more recent Felodipine EVent Reduction
Search for asymptomatic organ damage cardiovascular disease and chronic kidney disease
Recommendations Class a Level b Ref C
Heart
An ECG is recommended in all hypertensive patients to detect LVH left atrial dilatation arrhythmias or concomitant
heart disease I B 149 150
151 154
In all patients with a history or physical examination suggestive of major arrhythmias longterm ECG monitoring and
in case of suspected exerciseinduced arrhythmias a stress ECG test should be considered IIa C
suspected concomitant heart disease when these are suspected IIa B
156 158
160 163
164
Whenever history suggests myocardial ischaemia a stress ECG test is recommended and if positive or ambiguous an
imaging stress test (stress echocardiography stress cardiac magnetic resonance or nuclear scintigraphy) is recommended I C –
Arteries
Ultrasound scanning of carotid arteries should be considered to detect vascular hypertrophy or asymptomatic
atherosclerosis particularly in the elderly IIa B 51 183–
185 188
Carotid–femoral PWV should be considered to detect large artery stiffening IIa B 51 138
192–195
Ankle–brachial index should be considered to detect PAD IIa B 198 199
Kidney
Measurement of serum creatinine and estimation of GFR is recommended in all hypertensive patientsd I B 228 231
233
Assessment of urinary protein is recommended in all hypertensive patients by dipstick I B 203 210
Assessment of microalbuminuria is recommended in spot urine and related to urinary creatinine excretion I B 222 223
225 228
Fundoscopy
haemorrhages exudates and papilloedema which are associated with increased CV risk IIa C
Examination of the retina is not recommended in mildtomoderate hypertensive patients without diabetes except in
young patients III C
Brain
In hypertensive patients with cognitive decline brain magnetic resonance imaging or computed tomography may be
considered for detecting silent brain infarctions lacunar infarctions microbleeds and white matter lesions IIb C
CV ¼ cardiovascular ECG ¼ electrocardiogram GFR ¼ glomerural ﬁltration rate LVH ¼ left ventricular hypertrophy MRI ¼ magnetic resonance imaging PAD ¼ peripheral
artery disease PWV ¼ pulse wave velocity
aClass of recommendation
bLevel of evidence
cReference(s) supporting recommendation(s)
dThe MDRD formula is currently recommended but new methods such as the CKDEPI method aim to improve the accuracy of the measurement
ESH and ESC Guidelines 2179
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 2019(FEVER) study switched patients from preexisting therapies to
randomized treatments and therefore could not precisely
deﬁne baseline hypertension grade it also included complicated
and uncomplicated hypertensives269 Further analyses of FEVER
have recently conﬁrmed a signiﬁcant beneﬁt attached to
moreintensive lowering of BP after exclusion of all patients
with previous CVD or diabetes and in patients with randomiza
tion SBP below the median (153 mmHg)270 Because at random
ization all patients were on a 125 mg daily dose of
hydrochlorothiazide only it is likely that these individuals—if un
treated—would be within or very close to the SBP range deﬁning
grade 1 hypertension Overall a number of trials have shown sig
niﬁcant reductions of stroke in patients at lowtomoderate CV
risk (8–16 major CV events in 10 years) with baseline BP
values close to even if not exactly within the range of grade 1
hypertension 266267270 Also a recent Cochrane Collaboration
metaanalysis (2012CD006742) limited to patients strictly
responding to grade 1 low risk criteria ﬁnds a trend towards re
duction of stroke with active therapy but the very small number
of patients retained (half of those in 266 267) makes attainment
of statistical signiﬁcance problematic
Recent guidelines have also underlined the paucity of data for
treating grade 1 hypertension271 recommending treatment only
after conﬁrming hypertension by ABPM and restricting treatment
to grade 1 hypertensive patients with signs of OD or at high total
CV risk The advantage of systematically excluding whitecoat hyper
tensives from the possible beneﬁt of treatment is unproven Further
arguments in favour of treating even lowmoderate risk grade 1
hypertensives are that (i) waiting increases total risk and high risk
is often not entirely reversible by treatment272 (ii) a large number
of safe antihypertensive drugs are now available and treatment can
be personalized in such a way as to enhance its efﬁcacy and tolerabil
ity and (iii) many antihypertensive agents are out of patent and are
therefore cheap with a good cost–beneﬁt ratio
Table 13 Clinical indications and diagnostics of secondary hypertension
Clinical indications Diagnostics
Common
causes
Clinical
history
Physical
examination
Laboratory
investigations
Firstline
test(s)
Additional
Renal parenchymal
disease
History of urinary tract
infection or obstruction
haematuria analgesic
abuse family history of
polycystic kidney disease
Abdominal masses
(in case of polycystic
kidney disease)
Presence of protein
erythrocytes or
leucocytes in the urine
decreased GFR
Renal ultrasound Detailed workup for
kidney disease
Renal artery
stenosis
Fibromuscular dysplasia
early onset hypertension
(especially in women)
Atherosclerotic stenosis
hypertension of abrupt
onset worsening or
oedema
Abdominal bruit Difference of >15 cm
in length between the
two kidneys (renal
ultrasound) rapid
deterioration in renal
function (spontaneous
or in response to RAA
blockers)
Renal Duplex Doppler
ultrasonography
Magnetic resonance
angiography spiral
computed tomography
intraarterial digital
subtraction angiography
Primary
aldosteronism
Muscle weakness
family history of early
onset hypertension and
cerebrovascular events at
age <40 years
Arrhythmias (in
case of severe
hypokalaemia)
Hypokalaemia
(spontaneous or
diureticinduced)
incidental discovery of
adrenal masses
Aldosterone–renin ratio
under standardized
conditions (correction of
hypokalaemia and
withdrawal of drugs
affecting RAA system)
sodium loading saline
suppression or captopril
test) adrenal CT scan
adrenal vein sampling
Uncommon
causes
Pheochromocytoma Paroxysmal hypertension
or a crisis superimposed
to sustained hypertension
headache sweating
palpitations and pallor
positive family history of
pheochromocytoma
Skin stigmata of
(caféaulait spots
Incidental discovery
of adrenal (or in some
cases extraadrenal)
masses
Measurement of
urinary fractionated
metanephrines
or plasmafree
metanephrines
CT or MRI of the
abdomen and pelvis
123 Ilabelled meta
iodobenzylguanidine
scanning genetic screening
for pathogenic mutations
Cushing’s syndrome Rapid weight gain
polyuria polydipsia
psychological disturbances
Typical body habitus
(central obesity
moonface buffalo
hump red striae
hirsutism)
Hyperglycaemia 24h urinary cortisol
excretion
Dexamethasone
suppression tests
CT ¼ computed tomography GFR ¼ glomerular ﬁltration rate MRI ¼ magnetic resonance imaging RAA ¼ renin–angiotensin–aldosterone
ESH and ESC Guidelines2180
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 2019424 Isolated systolic hypertension in youth
A number of young healthy males have elevated values of bra
chial SBP (140 mmHg) and normal values of brachial DBP
(90 mmHg) As mentioned in section 31 these subjects
sometimes have normal central BP No evidence is available
that they beneﬁt from antihypertensive treatment on the con
trary there are prospective data that the condition does not ne
cessarily proceed to systolicdiastolic hypertension142 On the
basis of current evidence these young individuals can only
receive recommendations on lifestyle but because available evi
dence is scanty and controversial they should be followed
closely
425 Grade 1 hypertension in the elderly
Although the 2007 ESHESC and other guidelines recommended
treating grade 1 hypertensives independently of age2273 it has
been recognized that all the trials showing the beneﬁts of antihyper
tensive treatment in the elderly have been conducted in patients with
SBP ≥160 mmHg (grades 2 and 3)141265
426 High normal blood pressure
The 2007 ESHESC Guidelines suggested initiation of antihyper
tensive drug treatment when BP is in the high normal range
(130–13985–89 mmHg) in high and very highrisk patients
because of diabetes or concomitant CV or renal disease2 The
2009 reappraisal document pointed out that evidence in favour
of this early intervention was at best scanty141265 For diabetes
the evidence is limited to (i) the small normotensive’ Appropri
ate Blood Pressure in Diabetes (ABCD) trial in which the deﬁn
ition of normotension was unusual (160 mmHg SBP) and
beneﬁt of treatment was seen only in one of several secondary
CV events274 and (ii) subgroup analyses of two trials275276 in
which results in normotensives’ (many of whom were under
treatment) were reported not to be signiﬁcantly different from
those in hypertensives’ (homogeneity test) Furthermore in
two studies in prediabetic or metabolic syndrome patients with
a baseline BP in the high normal range administration of ramipril
or valsartan was not associated with any signiﬁcant improvement
in morbid and fatal CV events compared with placebo277278
Of two trials showing CV event reduction by lowering of BP in
patients with a previous stroke one included only 16 normoten
sives279 while in a subanalysis of the other signiﬁcant beneﬁts
were restricted to patients with baseline SBP ≥140 mmHg
(most already under baseline antihypertensive therapy)280 A
review of placebocontrolled trials of antihypertensive therapy in
coronary patients showed dissimilar results in different
studies265 In most of these trials randomized drugs were added
on a background of antihypertensive drugs therefore it is inappro
priate to classify these patients as normotensive265 This consider
ation also applies to recent large metaanalyses showing the
beneﬁts of BPlowering therapy also in individuals with baseline
SBP above and below 140 mmHg since the great majority of
the individuals had been involved in trials in which antihyperten
sive agents were present at baseline281–284 It is true that two
studies have shown that a few years’ administration of antihyper
tensive agents to individuals with high normal BP can delay transi
tion to hypertension285286 but how far the beneﬁt of this early
intervention lasts—and whether it can also delay events and be
costeffective—remains to be proven
427 Summary of recommendations on initiation
of antihypertensive drug treatment
Recommendations on initiation of antihypertensive drug treatment
are summarized in Figure 2 and below
Initiation of antihypertensive drug treatment
Recommendations Class a Level b Ref C
Prompt initiation of drug treatment is recommended in individuals with grade 2 and 3 hypertension with any level of
CV risk a few weeks after or simultaneously with initiation of lifestyle changes I A 260 265
284
Lowering BP with drugs is also recommended when total CV risk is high because of OD diabetes CVD or CKD
even when hypertension is in the grade 1 range I B 260 284
Initiation of antihypertensive drug treatment should also be considered in grade 1 hypertensive patients at low to
moderate risk when BP is within this range at several repeated visits or elevated by ambulatory BP criteria and
remains within this range despite a reasonable period of time with lifestyle measures
IIa B 266 267
In elderly hypertensive patients drug treatment is recommended when SBP is ≥160 mmHg I A 141 265
Antihypertensive drug treatment may also be considered in the elderly (at least when younger than 80 years) when
SBP is in the 140–159 mmHg range provided that antihypertensive treatment is well tolerated IIb C
Unless the necessary evidence is obtained it is not recommended to initiate antihypertensive drug therapy at
high normal BP III A 265
Lack of evidence does also not allow recommending to initiate antihypertensive drug therapy in young individuals with
isolated elevation of brachial SBP but these individuals should be followed closely with lifestyle recommendations III A 142
BP ¼ blood pressure CKD ¼ chronic kidney disease CV ¼ cardiovascular CVD ¼ cardiovascular disease OD ¼ organ damage SBP ¼ systolic blood pressure
aClass of recommendation
bLevel of evidence
cReference(s) supporting recommendation(s)
ESH and ESC Guidelines 2181
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 201943 Blood pressure treatment targets
431 Recommendations of previous Guidelines
The 2007 ESHESC Guidelines2 in common with other guidelines
recommended two distinct BP targets namely 14090 in low
moderate risk hypertensives and 13080 mmHg in highrisk hyper
tensives (with diabetes cerebrovascular CV or renal disease) More
recently the European Guidelines on CVD Prevention recommended
atargetof14080 mmHg for patients with diabetes50 Acareful
review of the available evidence265 however leads to a reappraisal
of some of these recommendations141 as detailed below
432 Lowtomoderate risk hypertensive patients
In three trials266268269 reducing SBP below 140 mmHg compared
with a control group at 140 mmHg was associated with a signiﬁcant
reduction in adverse CV outcomes Although in two of these
trials268269 CV risk in the lessintensively treated group was in the
highrisk range (20 CV morbidity and mortality in 10 years) a
recent subanalysis of FEVER has shown over ten years CV
outcome reduction through lowering SBP to 137 rather than
142 mmHg in patients free of CVD and diabetes with CV risk of
about 11 and 17270
433 Hypertension in the elderly
In the large number of randomized trials of antihypertensive treatment
in the elderly (including one in hypertensive patients aged 80 years or
more)287 all showing reduction in CV events through lowering of BP
the average achieved SBP never attained values 140 mmHg265 Con
versely two recent Japanese trials of more vs lessintensive BP lower
ing were unable to observe beneﬁts by lowering average SBP to 136
and 137 mmHg rather than 145 and 142 mmHg288289 On the other
hand a subgroup analysis of elderly patients in the FEVER study
showed reduction of CV events by lowering SBP just below
140 mmHg (compared with 145 mmHg)270
434 Highrisk patients
The reappraisal of ESHESC Guidelines carried out in 2009141 has
adopted the results of an extensive review of RCT evidence265
showing that the recommendation of previous Guidelines2 to
lower BP to 13080 mmHg in patients with diabetes or a history
of CV or renal disease is not supported by RCT evidence
4341 Diabetes mellitus
Lowering BP was found to be associated with important reductions
in CV events (i) in patients with diabetes included in a number
of trials270275290–292 (ii) in two trials entirely devoted to these
patients276293 and (iii) in a recent metaanalysis294 In two
trials290293 the beneﬁcial effect was seen from DBP reductions to
between 80–85 mmHg whereas in no trial was SBP ever reduced
below 130 mmHg The only trial in patients with diabetes that
achieved SBP values justlower than 130 mmHg in the moreintensive
ly treated group was the normotensive’ ABCD study a very small
study in which CV events (only a secondary endpoint) were not con
sistently reduced274 Although being somewhat underpowered the
BP blood pressure CKD chronic kidney disease CV cardiovascular CVD cardiovascular disease DBP diastolic blood pressure HT hypertension
OD organ damage RF risk factor SBP systolic blood pressure
Other risk factors
asymptomatic organ damage
or disease
Blood Pressure (mmHg)
High normal
SBP 130–139
or DBP 85–89
Grade 1 HT
SBP 140–159
or DBP 90–99
Grade 2 HT
SBP 160–179
or DBP 100–109
Grade 3 HT
SBP ≥180
or DBP ≥110
No other RF • No BP intervention
• Lifestyle changes
for several months
• Then add BP drugs
targeting <14090
• Lifestyle changes
for several weeks
• Then add BP drugs
targeting <14090
• Lifestyle changes
• Immediate BP drugs
targeting <14090
1–2 RF • Lifestyle changes
• No BP intervention
• Lifestyle changes
for several weeks
• Then add BP drugs
targeting <14090
• Lifestyle changes
for several weeks
• Then add BP drugs
targeting <14090
• Lifestyle changes
• Immediate BP drugs
targeting <14090
≥3 RF • Lifestyle changes
• No BP intervention
• Lifestyle changes
for several weeks
• Then add BP drugs
targeting <14090
• Lifestyle changes
• BP drugs
targeting <14090
• Lifestyle changes
• Immediate BP drugs
targeting <14090
OD CKD stage 3 or diabetes • Lifestyle changes
• No BP intervention
• Lifestyle changes
• BP drugs
targeting <14090
• Lifestyle changes
• BP drugs
targeting <14090
• Lifestyle changes
• Immediate BP drugs
targeting <14090
Symptomatic CVD
CKD stage ≥4 or
diabetes with ODRFs
• Lifestyle changes
• No BP intervention
• Lifestyle changes
• BP drugs
targeting <14090
• Lifestyle changes
• BP drugs
targeting <14090
• Lifestyle changes
• Immediate BP drugs
targeting <14090
Figure 2 Initiation of lifestyle changes and antihypertensive drug treatment Targets of treatment are also indicated Colours are as in Figure 1
Consult Section 66 for evidence that in patients with diabetes the optimal DBP target is between 80 and 85 mmHg In the high normal BP
range drug treatment should be considered in the presence of a raised outofofﬁce BP (masked hypertension) Consult section 424 for lack of
evidence in favour of drug treatment in young individuals with isolated systolic hypertension
ESH and ESC Guidelines2182
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 2019much larger Action to Control Cardiovascular Risk in Diabetes
(ACCORD) study was unable to ﬁnd a signiﬁcant reduction in inci
dence of major CV events in patients with diabetes whose SBP was
lowered to an average of 119 mmHg compared with patients
whose SBP remained at an average of 133 mmHg295
4342 Previous cardiovascular events
In two studies of patients who had experienced previous cerebrovas
cular events279296 more aggressive lowering of BP although asso
ciated with signiﬁcant reductions in stroke and CV events did not
achieve average SBP values lower than 130 mmHg a third much
larger study was unable to ﬁnd outcome differences between
groups achieving SBP of 136 vs 140 mmHg297 Among several trials
in patients who had previous coronary events SBP values lower
than 130 mmHg were achieved by more intensive treatment in ﬁve
trials but with inconsistent results (a signiﬁcant reduction of CV
events in one298 a signiﬁcant reduction by one antihypertensive
agent but not by another in a second trial299 and no signiﬁcant re
duction in hard CV outcomes in three other studies)300–302
4343 Renal disease
In patients with CKD—with or without diabetes—there are two
treatment objectives (i) prevention of CV events (the most frequent
complication of CKD) and (ii) prevention or retardation of further
renal deterioration or failure Unfortunately evidence concerning
the BP target to be achieved in these patients is scanty and confused
by the uncertainty about the respective roles of reduction of BP and
speciﬁc effects of RAS blockers303 In three trials in CKD patients
almost exclusively without diabetes304–306 patients randomized to
a lower target BP (125–130 mmHg) had no signiﬁcant differences
in ESRD or death from patients randomized to a higher target
(140 mmHg) Only in a prolonged observational followup of
two of these trials was there a trend towards lower incidence of
events which was more evident in patients with proteinuria307308
The two large trials in patients with diabetic nephropathy are not in
formative on the supposed beneﬁt of a SBP target below
130 mmHg309310 since the average SBPs achieved in the groups
with more intensive treatment were 140 and 143 mmHg Only a
recent cooperative study has reported a reduction in renal events
(GFR reduction and ESRD) in children randomized to a BP target
below—rather than above—the 50th percentile311 but these
values in children can hardly be compared with adult values Further
more it should be considered that in ACCORD although eGFR at
baseline was in the normal range more intensive lowering of BP
(11967 vs 13473 mmHg) was associated with a neardoubling of
cases with eGFR 30 mLmin173 m2295 Finally recent
metaanalyses of trials investigating different BP targets in patients
with CKD failed to demonstrate deﬁnite beneﬁts from achieving
lower BP goals in terms of CV or renal clinical events312313
435 The lower the better’ vs the Jshaped curve
hypothesis
The concept that the lower the SBP and DBP achieved the better the
outcome’ rests on the direct relationship between BP and incident
outcomes down to at least 115 mmHg SBP and 75 mmHg DBP
described in a large metaanalysis of 1 million individuals free of
CVD at baseline and subsequently followed for about 14 years3—
not the usual situation for hypertension trials The concept
assumes that the BPoutcome relationship down to the lowest BP
values is also seen when the BP differences are induced by drug
therapy and that the relationship in patients with CVD can be super
imposed on that described in individuals free of CV complications In
the absence of trials that have speciﬁcally investigated low SBP ranges
(see above) the only available data in favour of the lower the better’
concept are those of a metaanalysis of randomized trials showing
that reduction of SBP to a mean of 126 mmHg compared with
131 mmHg had the same proportional beneﬁts as reduction to a
mean of 140 mmHg compared with 145 mmHg281 Of course this
was a posthoc analysis in which randomization was lost because
the splitting of the patients into the BP categories was not considered
at the randomization stage Demonstration of the lower the better’
hypothesis is also made difﬁcult by the fact that the curve relating BP
and adverse CV events may ﬂatten at low BP values and therefore
demonstration of beneﬁts requires much larger and longer studies
than those yet available This is consistent with the semilogarithmic
nature of the relationship shown in observational studies3 but it may
also raise the question of whethera small beneﬁt is worth large effort
An alternative to thelower thebetter’ concept isthe hypothesis of
a Jshaped relationship according to which the beneﬁts of reducing
SBP or DBP to markedly low values are smaller than for reductions
to more moderate values This hypothesis continues to be widely
popular for several reasons (i) common sense indicatesthat athresh
old BP must exist below which survival is impaired (ii) physiology has
shown that there is a low (as well as a high) BP threshold for organ
bloodﬂow autoregulation and this threshold can be elevated when
there is vascular disease and (iii) there is a persistent hangover
from an old belief viewing high BP as a compensatory mechanism
for preserving organ function (the essential’ nature of hyperten
sion)314 Correct investigation of the Jcurve requires randomized
comparison of three BP targets only attempted in the Hypertension
Optimal Treatment (HOT) study but in lowrisk hypertensives and
using DBP targets290 Owing to the lack of direct evidence recourse
has been made to the indirect observational approach of relating out
comes to achieved BP A number of trials have been so analysed and
their results recently reviewed314 Some of the trial analyses have
concluded that no Jcurve exists280290315 while others have con
cluded in favour of its existence316–319 although in some trials it
was also seen in placebotreated patients320321 Furthermore two
recent trials investigating more or lessintensive lowdensity lipo
protein cholesterol lowering by statins also found a Jcurve relating
BP to adverse CV events although protocols did not include
BPlowering interventions322323 The approach used to investigate
the Jcurve raises important hypotheses yet has obvious limitations
(i) it changes a randomized study into an observational one (ii) the
numbers of patients and events in the lowest BP groups are usually
very small (iii) patients in the lowest BP groups are often at increased
baseline risk and despite statistical adjustments reversecausality
cannot be excluded and (iv) the nadir’ SBP and DBP values (the
values at which risk starts to increase) are extremely different from
trial to trial even when baseline CV risk is similar314 Some trial ana
lyses have also raised the point that a Jcurve may exist for coronary
events but not for strokes—but this is not a consistent ﬁnding in
various trials317318324–326 Whether or not the underlying high
risk to patients is more important than the excessive BP reduction
ESH and ESC Guidelines 2183
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 2019should be considered The limitations of the current approach for in
vestigating the Jcurve obviously also apply to their metaanalyses327
Yet the Jcurve hypothesis is an important issue it has a pathophysio
logical rationale and deserves to be investigated in a correctly
designed trial
436 Evidence on target blood pressure from organ
damage studies
It would be of some interest to receive guidance about target BP
from OD studies but unfortunately this information must be
judged with great caution Indeed trials using OD as an endpoint
often do not have sufﬁcient statistical power to safely measure
effects on CV outcome and the data they provide on fatal and
nonfatal CV events are subject to the effects of chance For
example a study of 1100 nondiabetic hypertensive patients fol
lowed for 2 years showed that the incidence of electrocardio
graphic LVH is reduced by tighter (about 13277 mmHg) vs
lesstight BP control (about 13679 mmHg) and reported a parallel
reduction in CV events (although there were only about 40 hard
outcome events)328 On the other hand the recent Randomized
Olmesartan And Diabetes MicroAlbuminuria Prevention
(ROADMAP) study329 in diabetic patients showed a signiﬁcant re
duction of newonset microalbuminuria in more intensively
treated patients (olmesartan vs placebo) but the more intensively
treated group also had a higher incidence of CV outcomes329
Because of the small number of CV events in the two trials it
is likely that both their reduction and their increase are due to
chance effects Furthermore when analyses of OD and event
effects are made in large trials dissociation of the two types of
effects has been reported in the Losartan Intervention For
Endpoint Reduction in Hypertensives (LIFE) study LVH regression
was linearly related to the treatmentinduced BP changes (the
lower the better)330 whereas in the same trial achieved BP and
morbid and fatal CV events were related in a Jshaped
manner319 In ONngoing Telmisartan Alone and in Combination
with Ramipril Global Endpoint Trial (ONTARGET) the lowest
BP achieved by the ramipril–telmisartan combination was asso
ciated with reduced proteinuria but with a greater risk of acute
renal failure and a similar CV risk331 The clinical signiﬁcance
of treatmentinduced changes in OD is further discussed in
Section 84
437 Clinic vs home and ambulatory blood pressure
targets
No direct evidence from randomized outcome studies is yet available
about BP targets when home or ambulatory BP measurements are
used332 although some evidence is available that differences with
ofﬁce BP may not be too pronounced when ofﬁce BP is effectively
reduced333 Outofofﬁce measurements should always be evaluated
together with measurements at the clinic Notably however the ad
justment of antihypertensive therapy on the basis of a similar target
ambulatory or home BP led to lessintensive drug treatment
without a signiﬁcant difference in OD334–336 The lower cost of med
ications in the outofofﬁce BP groups was partially offset by other
costs in the home BP groups335336
438 Summary of recommendations on blood pressure
targets in hypertensive patients
Recommendations on BP targets are summarized in Figure 2 and
below
Blood pressure goals in hypertensive patients
Recommendations Class a Level b Ref C
A SBP goal <140 mmHg
I B 266 269 270a) is recommended in patients at low–moderate CV risk
b) is recommended in patients with diabetes I A 270 275 276
c) should be considered in patients with previous stroke or TIA IIa B 296 297
d) should be considered in patients with CHD IIa B 141 265
e) should be considered in patients with diabetic or nondiabetic CKD IIa B 312 313
In elderly hypertensives less than 80 years old with SBP ≥160 mmHg there is solid evidence to recommend reducing
SBP to between 150 and 140 mmHg I A 265
population SBP goals should be adapted to individual tolerability IIb C
In individuals older than 80 years and with initial SBP ≥160 mmHg it is recommended to reduce SBP to between
150 and 140 mmHg provided they are in good physical and mental conditions I B 287
A DBP target of <90 mmHg is always recommended except in patients with diabetes in whom values <85 mmHg
are recommended It should nevertheless be considered that DBP values between 80 and 85 mmHg are safe and well
tolerated
I A 269 290
293
CHD ¼ coronary heart disease CKD ¼ chronic kidney disease CV ¼ cardiovascular DBP ¼ diastolic blood pressure SBP ¼ systolic blood pressure TIA ¼ transient ischaemic
attack
aClass of recommendation
bLevel of evidence
cReference(s) supporting recommendation(s)
ESH and ESC Guidelines2184
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 20195 Treatment strategies
51 Lifestyle changes
Appropriate lifestyle changes are the cornerstone for the preven
tion of hypertension They are also important for its treatment al
though they should never delay the initiation of drug therapy in
patients at a high level of risk Clinical studies show that the
BPlowering effects of targeted lifestyle modiﬁcations can be
equivalent to drug monotherapy337 although the major drawback
is the low level of adherence over time—which requires special
action to be overcome Appropriate lifestyle changes may safely
and effectively delay or prevent hypertension in nonhypertensive
subjects delay or prevent medical therapy in grade I hypertensive
patients and contribute to BP reduction in hypertensive individuals
already on medical therapy allowing reduction of the number and
doses of antihypertensive agents338 Beside the BPlowering effect
lifestyle changes contribute to the control of other CV risk factors
and clinical conditions50
The recommended lifestyle measures that have been shown to be
capable of reducing BP are (i) salt restriction (ii) moderation of
alcohol consumption (iii) high consumption of vegetables and
fruits and lowfat and other types of diet (iv) weight reduction and
maintenance and (v) regular physical exercise339 In addition insist
ence on cessation of smoking is mandatory in order to improve CV
risk and because cigarette smoking has an acute pressor effect that
may raise daytime ambulatory BP 340–342
511 Salt restriction
There is evidence for a causal relationship between salt intake and
BP and excessive salt consumption may contribute to resistant
hypertension Mechanisms linking salt intake and BP elevation
include an increase in extracellular volume—but also in peripheral
vascular resistance due in part to sympathetic activation343 The
usual salt intake is between 9 and 12 gday in many countries
and it has been shown that reduction to about 5 gday has a
modest (1–2 mmHg) SBPlowering effect in normotensive indivi
duals and a somewhat more pronounced effect (4–5 mmHg) in
hypertensive individuals339344345 A daily intake of 5–6 g of salt
is thus recommended for the general population The effect of
sodium restriction is greater in black people older people and
in individuals with diabetes metabolic syndrome or CKD and
salt restriction may reduce the number and doses of antihyperten
sive drugs345346 The effect of reduced dietary salt on CVD events
remains unclear347–350 although the longterm followup of the
Trials of Hypertension Prevention (TOHP) trial showed a
reduced salt intake to be associated with lower risk of CV
events351 Overall there is no evidence that reducing sodium
from high to moderate intakes causes harm352
At the individual level effective salt reduction is by no means
easy to achieve Advice should be given to avoid added salt and
highsalt food A reduction in populationwide salt intake
remains a public health priority but requires a combined effort
by the food industry governments and the public in general
since 80 of salt consumption involves hidden salt’ It has been
calculated that salt reduction in the manufacturing processes of
bread processed meat and cheese margarine and cereals will
result in an increase in qualityadjusted lifeyears353
512 Moderation of alcohol consumption
The relationship between alcohol consumption BP levels and the
prevalence of hypertension is linear Regular alcohol use raises BP
in treated hypertensive subjects354 While moderate consumption
may do no harm the move from moderate to excessive drinking is
associated both with raised BP and with an increased risk of stroke
The Prevention And Treatment of Hypertension Study (PATHS)
investigated the effects of alcohol reduction on BP The intervention
group had a 1207 mmHg greater reduction in BP than the control
group at the end of the 6month period355 No studies have been
designed to assess the impact of alcohol reduction on CV endpoints
Hypertensive men who drink alcohol should be advised to limit their
consumption to no more than 20–30 g and hypertensive women to
no more than 10–20 g of ethanol per day Total alcohol consump
tion should not exceed 140 g per week for men and 80 g per week
for women
513 Other dietary changes
Hypertensive patients should be advised to eat vegetables lowfat
dairy products dietary and soluble ﬁbre whole grains and protein
from plant sources reduced in saturated fat and cholesterol Fresh
fruits are also recommended—although with caution in over
weight patients because their sometimes high carbohydrate
content may promote weight gain339356 The Mediterranean
type of diet especially has attracted interest in recent years A
number of studies and metaanalyses have reported on the CV
protective effect of the Mediterranean diet357358 Patients with
hypertension should be advised to eat ﬁsh at least twice a week
and 300–400 gday of fruit and vegetables Soy milk appeared to
lower BP when compared with skimmed cows’ milk359 Diet ad
justment should be accompanied by other lifestyle changes In
patients with elevated BP compared with the Dietary Approaches
to Stop Hypertension (DASH) diet alone the combination of the
DASH diet with exercise and weight loss resulted in greater
reductions in BP and LVM360 With regard to coffee consumption
a recent systematic review found that most of the available studies
(10 RCTs and 5 cohort studies) were of insufﬁcient quality to
allow a ﬁrm recommendation to be given for or against coffee
consumption as related to hypertension361
514 Weight reduction
Hypertension is closely correlated with excess body weight362
and weight reduction is followed by a decrease in BP In a
metaanalysis the mean SBP and DBP reductions associated with
an average weight loss of 51 kg were 44 and 36 mmHg respect
ively363 Weight reduction is recommended in overweight and
obese hypertensive patients for control of risk factors but
weight stabilisation may be a reasonable target for many of
them In patients with established CVD manifestations observa
tional data indicate a worse prognosis following weight loss This
seems to be true also in the elderly Maintenance of a healthy
ESH and ESC Guidelines 2185
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 2019body weight (BMI of about 25 kgm2) and waist circumference
(102 cm for men and 88 cm for women) is recommended
for nonhypertensive individuals to prevent hypertension and for
hypertensive patients to reduce BP It is noteworthy however
that the optimal BMI is unclear based on two large metaanalyses
of prospective observational populationbased outcome studies
The Prospective Studies Collaboration concluded that mortality
was lowest at a BMI of about 225–25 kgm2364 whereas a
more recent metaanalysis concluded that mortality was lowest
in overweight subjects 365 Weight loss can also improve the efﬁ
cacy of antihypertensive medications and the CV risk proﬁle
Weight loss should employ a multidisciplinary approach that
includes dietary advice and regular exercise Weightloss pro
grammes are not so successful and inﬂuences on BP may be over
estimated Furthermore shortterm results are often not
maintained in the long term In a systematic review of diabetic
patients366 the mean weight loss after 1–5 years was 17 kg In
prediabetic’ patients combined dietary and physical activity inter
ventions gave a 28 kg extra weight reduction after 1 year and a
further 26 kg reduction after 2 years while not impressive this
is sufﬁcient to have a protective effect against the incidence of dia
betes367 In established type 2 diabetes mellitus (DM) intentional
weight loss—according to the Action for HEalth in Diabetes
(AHEAD) study—did not reduce CV events so that a general
control of risk factors is probably more important than weight
loss per se Weight loss can also be promoted by antiobesity
drugs such as orlistat and to a greater degree by bariatic
surgery which appears to decrease CV risk in severely obese
patients368 Details are available in a recent document by the
ESH and the European Association for the Study of Obesity368
515 Regular physical exercise
Epidemiological studies suggest that regular aerobic physical activity
may be beneﬁcial for both prevention and treatment of hyperten
sion and to lower CV risk and mortality A metaanalysis of rando
mized controlled trials has shown that aerobic endurance training
reduces resting SBP and DBP by 3024 mmHg overall and even
by 6949 mmHg in hypertensive participants369 Even regular phys
ical activity of lower intensity and duration has been shown to be
associated with about a 20 decrease in mortality in cohort
studies370371 and this is also the case for measured physical
ﬁtness372 Hypertensive patients should be advised to participate
in at least 30 min of moderateintensity dynamic aerobic exercise
(walking jogging cycling or swimming) on 5–7 days per week373
Aerobic interval training has also been shown to reduce BP374
The impact on BP values of other forms of exercise such as isomet
ric resistance training (muscular force development without move
ment) and dynamic resistance exercise (force development
associated with movement) has been reviewed recently375376
Dynamic resistance training was followed by signiﬁcant BP reduc
tion as well as improvements in other metabolic parameters and
performance of resistance exercises on 2–3 days per week can
be advised Isometric exercises are not recommended since data
from only a few studies are available
516 Smoking cessation
Smoking is a major risk factor for atherosclerotic CVD Although the
rate of smoking is declining in most European countries (in which a
legalized smoking ban is effective) it is still common in many regions
and age groups partly due to educationrelated inequalities in cessa
tion of smoking377 There is evidence also on the illhealth effects of
passive smoking378 Smoking causes an acute increase in BP and heart
rate persisting for more than 15 minutes after smoking one cigar
ette340 as a consequence of stimulation of the sympathetic
nervous system at the central level and at the nerve endings379
A parallel change in plasma catecholamines and BP plus an impair
ment of the baroreﬂex have been described that are related to
smoking379–381 Studies using ABPM have shown that both normo
tensive and untreated hypertensive smokers present higher daily
BP values than nonsmokers341342382 No chronic effect of
smoking has been reported for ofﬁce BP 383 which is not lowered
by giving up smoking Beside the impact on BP values smoking is a
powerful CV risk factor and quitting smoking is probably the single
most effective lifestyle measure for the prevention of CVDs including
stroke myocardial infarction and peripheral vascular disease384–386
Therefore tobacco use status should be established at each patient
visit and hypertensive smokers should be counselled regarding
giving up smoking
Even in motivated patients programmes to stop smoking are suc
cessful (at1 year) in only 20–30 387 Where necessarysmoking ces
sation medications such as nicotine replacement therapy
bupropion or varenicline should be considered A metaanalysis of
36 trials comparing longterm cessation rates using bupropion vs
control yielded a relative success rate of 169 (153–185)388
whereas evidence of any additional effect of adding bupropion to
nicotine replacement therapy was inadequate389 The partial
nicotinereceptor agonist varenicline has shown a modest beneﬁt
over nicotine replacement therapy and bupropion388 but the US
Food & Drug Administration (FDA) has recently issued a warning
regarding the safety proﬁle of varenicline (httpwwwfdagov
DrugsDrugSafetyucm330367htm) Although these drugs have
been shown to be effective in clinical trials they are underused due
to adverse effects contraindications low acceptance high cost
and lack of reimbursement in many countries Relapse prevention
is a cornerstone in ﬁghting nicotine addiction but the ﬁeld is inad
equately studied and existing evidence is disappointing388 There is in
sufﬁcient evidence to support the use of any speciﬁc behavioural
intervention some positive results can be expected from interven
tions focussing on identifying and resolving temptation situations
as well as from strategies steering patients towards changes in beha
viours such as motivationalinterviews Extended treatment with var
enicline may prevent relapse but studies of extended treatment with
nicotine replacement are not available390
517 Summary of recommendations on adoption
of lifestyle changes
The following lifestyle change measures are recommended in all
patients with hypertension to reduce BP andor the number of CV
risk factors
ESH and ESC Guidelines2186
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 201952 Pharmacological therapy
521 Choice of antihypertensive drugs
In the 2003 and 2007 versions12 the ESHESC Guidelines reviewed
the large number of randomized trials of antihypertensive therapy
and concluded that the main beneﬁts of antihypertensive treatment
are due to lowering of BP per se and are largely independent of the
drugs employed Although metaanalyses occasionally appear claim
ing superiority of one class of agents over another for some out
comes391–393 this largely depends on the selection bias of trials
and the largest metaanalyses available do not show clinically relevant
differences between drug classes284394395 Therefore the current
Guidelines reconﬁrm that diuretics (including thiazides chlorthali
done and indapamide) betablockers calcium antagonists
angiotensinconverting enzyme (ACE) inhibitors and angiotensin re
ceptor blockers are all suitable for the initiation and maintenance of
antihypertensive treatment either as monotherapy or in some com
binations However some therapeutic issues that have recently been
raised are discussed below
5211 Betablockers
The reasons why at variance from some guidelines271 betablockers
were maintained as a possible choice for antihypertensive treatment
were summarized in the 2007 ESHESC Guidelines and further dis
cussed in the 2009 reappraisal document2141 Although acknow
ledging that the quality of the evidence was low a Cochrane
metaanalysis (substantially reproducing a 2006 metaanalysis by
the same group)396397 has reported that betablockers may be infer
ior to some—but not all—other drug classes for some outcomes
Speciﬁcally they appear to be worse than calcium antagonists (but
not diuretics and RAS blockers) for total mortality and CV events
worse than calcium antagonists and RAS blockers for stroke and
equal to calcium antagonists RAS blockers and diuretics for CHD
On the other hand the large metaanalysis by Law et al has shown
betablockerinitiated therapy to be (i) equally as effective as the
other major classes of antihypertensive agents in preventing coron
ary outcomes and (ii) highly effective in preventing CV events in
patients with a recent myocardial infarction and those with heart
failure284 A similar incidence of CV outcomes with betablockers
andor diuretics or their combinations compared with other drug
classes hasalso beenreported inthe metaanalysis of theBPlowering
treatment trialists’ collaboration394
A slightly lower effectiveness of betablockers in preventing
stroke284 has been attributed to a lesser ability to reduce central
SBP and pulse pressure398399 However a lower effectiveness in
stroke prevention is also shared by ACE inhibitors284 although
these compounds have been reported to reduce central BP better
than betablockers398 Betablockers also appear (i) to have more
sideeffects (although the difference with other drugs is less pro
nounced in double blind studies)400 and (ii) to be somewhat less ef
fective than RAS blockers and calcium antagonists in regressing or
delaying OD such as LVH carotid IMT aortic stiffness and small
artery remodelling141 Also betablockers tend to increase body
weight401 and particularly when used in combination with diuretics
to facilitate newonset diabetes in predisposed patients402 This phe
nomenon may have been overemphasized by the fact that all trial ana
lyses have been limited to patients free of diabetes or with glucose
70 mmolL ignoring the fact that a noticeable number of patients
with a diagnosis of diabetes at baseline do not have this diagnosis
reconﬁrmed at study end which obviously reduces the weight of
treatmentinduced diabetes and raises doubts about the precision
of the deﬁnition of diabetes used in the above analyses403 Some of
the limitations of traditional betablockers do not appear to be
shared by some of the vasodilating betablockers such as
celiprolol carvedilol and nebivolol—more widely used today—
which reduce central pulse pressure and aortic stiffness better than
atenolol or metoprolol404–406 and affect insulin sensitivity less than
metoprolol407408 Nebivolol has recently been shown not to
worsen glucose tolerance compared with placebo and when added
to hydrochlorothiazide409 Both carvedilol and nebivolol have been
favourably tested in RCTs although in heart failure rather than arter
ial hypertension410 Finally betablockers have recently been
reported not to increase but even reduce the risk of exacerbations
Adoption of lifestyle changes
Recommendations Class a Level bd Level be Ref C
Salt restriction to
5–6 g per day is
recommended I AB
339
344–346
351
Moderation of
alcohol consumption
to no more than
20–30 g of ethanol
per day in men and
to no more than
10–20 g of ethanol
per day in women is
recommended
I AB339 354
355
Increased
consumption of
vegetables fruits and
lowfat dairy
products is
recommended
I AB339
356–358
Reduction of weight
to BMI of 25 kgm2
and of waist
circumference to
<102 cm in men and
<88 cm in women is
recommended
unless
contraindicated
I AB339
363–365
Regular exercise ie
at least 30 min of
moderate dynamic
exercise on 5 to 7
days per week is
recommended
I AB339 369
373 376
It is recommended
to give all smokers
advice to quit
smoking and to offer
assistance
I AB384–386
BMI ¼ body mass index
aClass of recommendation
bLevel of evidence
cReference(s) supporting recommendation(s)
dBased on the effect on BP andor CV risk proﬁle
eBased on outcome studies
ESH and ESC Guidelines 2187
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 2019and to reduce mortality in patients with chronic obstructive lung
disease411
5212 Diuretics
Diuretics have remained the cornerstone of antihypertensive treat
ment since at least the ﬁrst Joint National Committee (JNC) report
in 1977412 and the ﬁrst WHO report in 1978413 and still in 2003
they were classiﬁed as the only ﬁrstchoice drug by which to start
treatment in both the JNC7264 and the WHOInternational
Society of Hypertension Guidelines55 Thewide use of thiazide diure
tics should take into account the observation in the Avoiding Cardio
vascular Events in Combination Therapy in Patients Living with
Systolic Hypertension (ACCOMPLISH) trial414 that theirassociation
with an ACE inhibitor was less effective in reducing CV events than
the association of the same ACE inhibitor with a calcium antagonist
The interesting ﬁndings of ACCOMPLISH will be discussed in Section
522 but need replication because no other randomized study has
shown a signiﬁcant superiority of a calcium antagonist over a diuretic
Therefore the evidence provided by ACCOMPLISH does not
appear to bear sufﬁcient weight to exclude diuretics from ﬁrstline
choice
It has also been argued that diuretics such as chlorthalidone or inda
pamide should be used in preference to conventional thiazide diure
tics such as hydrochlorothiazide271 The statement that There is
limited evidence conﬁrming beneﬁt of initial therapy on clinical out
comes with low doses of hydrochlorothiazide’271 is not supported
by a more extensive review of available evidence332415 Metaanalyses
claiming that hydrochlorothiazide has a lesser ability to reduce ambu
latory BP than other agents or reduces outcomes less than chlortha
lidone416417 are conﬁned to a limited number of trials and do not
include headtohead comparisons of different diuretics (no large ran
domized study is available) In the Multiple Risk Factor Intervention
Trial (MRFIT) chlorthalidone and hydrochlorothiazide were not com
pared by randomized assignment and overall chlorthalidone was used
at higher doses than hydrochlorothiazide418 Therefore no recom
mendation can be given to favour a particular diuretic agent
Spironolactone has been found to have beneﬁcial effects in heart
failure419 and although never tested in RCTs on hypertension can
be used as a third or fourthline drug (see Section 614) and helps
in effectively treating undetected cases of primary aldosteronism
Eplerenone has also shown a protective effect in heart failure and
can be used as an alternative to spironolactone420
5213 Calcium antagonists
Calcium antagonists have been cleared from the suspicion of causing
a relative excess of coronary events by the same authors who had
raised the question Some metaanalyses suggest that these agents
maybe slightly moreeffectivein preventing stroke284394421 although
it is not clear whether this can be ascribed to a speciﬁc protective
effect on the brain circulation or to a slightly better or more
uniform BP control with this class of drugs141 The question of
whether calcium antagonists may be less effective than diuretics
betablockers and ACE inhibitors in preventing incipient heart
failure is still an open one In the largest available metaanalysis284
calcium antagonists reduced newonset heart failure by about 20
compared with placebo but when compared with diuretics beta
blockers and ACE inhibitors were inferior by about 20 (which
means a 19 rather than 24 reduction) The lower effectiveness
of calcium antagonists on the onset of heart failure may also be a con
sequence of the design of the trials pointing to this conclusion which
required prevention or withdrawal of agents essential in heart failure
therapy such as diuretics betablockers and ACE inhibitors in patients
randomized to calcium antagonists422 In fact in all trials in which the
design permitted or prescribed thesimultaneous use ofdiuretics beta
blockers or ACE inhibitors269299301423 calcium antagonists were not
inferior to comparative therapies in preventing heart failure Calcium
antagonists have shown a greater effectiveness than betablockers in
slowing down progression of carotid atherosclerosis and in reducing
LV hypertrophy in several controlled studies (see sections 6114
and 6121)
5214 Angiotensinconverting enzyme inhibitors and angiotensin receptor
blockers
Both classes are among those most widely used in antihypertensive
therapy Some metaanalyses have suggested that ACE inhibitors
may be somewhat inferior to other classes in preventing
stroke284395421 and that angiotensin receptor blockers may be infer
ior to ACE inhibitors in preventing myocardial infarction424 or all
cause mortality393 The hypothesis raised by these metaanalyses
has been undermined by the results of the large ONTARGET directly
comparing outcomes under treatment with the ACE inhibitor rami
pril and the angiotensin receptor blocker telmisartan (section
5222) ONTARGET has shown telmisartan not to be statistically in
ferior to ramipril as far as incidence of major cardiac outcomes
stroke and allcause death is concerned ONTARGET has also dis
provedthe hypothesis that the peroxisome proliferatoractivated re
ceptor (PPAR) activity of telmisartan may render this compound
more effective in preventing or delaying onset of diabetes incidence
of new diabetes was nonsigniﬁcantly different between telmisartan
and ramipril in ONTARGET
Most recently the hypothesis has been raised of an association of
angiotensin receptor blockers with cancer onset425 A much larger
metaanalysis including all major randomized trials investigating all
major compounds of the class has subsequently found no evidence
of increased cancer incidence426 for which there is also no basis
from a mechanistic standpoint427 Among the wellknown ancillary
properties of ACE inhibitors and angiotensin receptor blockers
are their peculiar effectiveness in reducing proteinuria (see section
69) and improving outcomes in chronic heart failure (section 6112)
5215 Renin inhibitors
Aliskiren a direct inhibitor of renin at the site of its activation is avail
able for treating hypertensive patients both as monotherapy and
when combined with other antihypertensive agents To date available
evidenceshowsthat when used alone aliskiren lowers SBP and DBP in
younger and elderly hypertensive patients428 that it has a greater
antihypertensive effect when given in combination with a thiazide
diuretic a blocker of the RAS at other sites or a calcium antagon
ist429430 and that prolonged administration in combination treatment
can have a favourable effect (i) on asymptomatic OD such as urinary
protein excretion431 or (ii) on prognostic biomarkers for heart failure
such as Btype natriuretic peptides432
No trial is available on the effect of aliskiren on CV or renal morbid
and fatal events in hypertension A largescale trial on diabetic
patients ALiskiren Trial In Type 2 Diabetes Using Cardiorenal End
points (ALTITUDE) in which aliskiren was administered on top of an
ESH and ESC Guidelines2188
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 2019RAS blocker has recently been stopped because in these patients at
high risk of CV and renal events there was a higher incidence of
adverse events renal complications (ESRD and renal death) hyper
kalaemia and hypotension433 This treatment strategy is therefore
contraindicated in such speciﬁc conditions similar to the contra
indications for the ACE inhibitor–angiotensin receptor blockercom
bination resulting from the ONTARGET trial (see Section 522)331
Another largescale trial A Randomized Controlled Trial of Aliskiren
in the Prevention of Major Cardiovascular Events in Elderly People
(APOLLO) in which aliskiren was used alone or in combination
with a thiazide diuretic or a calcium channel blocker has also been
stopped despite no evidence of harm in the aliskirentreated
group No aliskirenbased antihypertensive trials withhard endpoints
are expected in the near future No beneﬁcial effect on mortality and
hospitalization has recently been shown by adding aliskiren to stand
ard treatment in heart failure434
5216 Other antihypertensive agents
Centrally active agents and alphareceptor blockers are also effective
antihypertensive agents Nowadays they are most often used in mul
tiple drug combinations The alphablocker doxazosin has effectively
been used as thirdline therapy in the AngloScandinavian Cardiac
Outcomes Trial (ASCOT) This will be further discussed in the
section on resistant hypertension (614)
5217 Antihypertensive agents and visittovisit blood pressure variability
Attention has recently been drawn to the association of visittovisit
variability of intraindividual BP during antihypertensive treatment
and the incidence of CV events (particularly stroke) in highrisk
patients435 In coronary hypertensive patients consistency of BP
control between visits is accompanied by lessfrequent CV morbidity
and mortality independentlyof the meanBP level436 However in the
mild hypertensive lowCVrisk patients of the ELSA trial mean
ontreatment BP rather than visittovisit BP variations predicted
both the progression of carotid atherosclerosis and the incidence
of CV events437 Thus the clinical importance of visittovisit BP vari
ability within treated individuals visavis the achieved longterm
average BP level is not yet indisputably proven
An analysis of the ASCOT trial has suggested that visittovisit BP
variability may be lower with the combination of a calcium antagonist
and an ACE inhibitor than with the combination of a betablocker
and a diuretic438 Additionally from a metaanalysis of several trials
the conclusion has been reached that visittovisit BP variability is
more pronounced in patients under betablockade than with other
drug classes439440 Yet the underlying cause of visittovisit BP vari
ability is not known—whether it is really pharmacologically driven or
rather a marker of treatment adherence Also the abovementioned
metaanalyses based their results on interindividual BPvariability (ie
the range of the BP effects of treatment in the whole group of
patients) rather than intraindividual variability The use of inter
individual BP variability as a surrogate of intraindividual variability
to classify antihypertensive agents as associated with greater or
lesser visittovisit BP variations or more or less consistent BP
control439440 seems unjustiﬁed since discrepancies have been
reported between the two measures441 Furthermore despite any
possible correlations the two types of variability are unlikely to
measure the same phenomena442 In practical terms until
intraindividual visittovisit BP variability from new largescale
trials is analysed interindividual visittovisit variability should not
be used as a criterion for antihypertensive drug choice It remains
however an interesting subject for further investigation
5218 Should antihypertensive agents be ranked in order of choice
Once it is agreed that (i) the major mechanism of the beneﬁts of anti
hypertensive therapy is lowering of BP per se (ii) the effects on cause
speciﬁc outcomes of the various agents are similar or differ by only a
minor degree (iii) the type of outcome in a given patient is unpredict
able and (iv) all classes of antihypertensive agents have their advan
tages but also contraindications (Table 14) it is obvious that any
allpurpose ranking of drugs for general antihypertensive usage is
not evidencebased141443 Rather than indulging in an allpurpose
ranking the Task Force decided to conﬁrm (with small changes)
the table published in the 2007 ESHESC Guidelines2 with the
drugs to be considered in speciﬁc conditions based on the fact that
some classes have preferentially been used in trials in speciﬁc condi
tions or have shown greater effectiveness in speciﬁc types of OD
(see Mancia et al for detailed evidence)2 (Table 15) However no evi
dence is available that different choices should be made based on age
or gender (except for caution in using RAS blockers in women with
child bearing potential because of possible teratogenic effects)444445
In any case physicians should pay attention to adverse drug
effects—even those purely subjective—as they are powerful deter
rents to treatment adherence If necessary doses or drugs should be
changed in order to combine effectiveness with tolerability
522 Monotherapy and combination therapy
5221 Pros and cons of the two approaches
The 2007 ESHESC Guidelines underlined that no matter which drug
is employed monotherapy can effectively reduce BP in only a limited
number of hypertensive patients and that most patients require the
combination of at least two drugs to achieve BP control2 Therefore
the issue is not whether combination therapy is useful but whether
it should always be preceded by an attempt to use monotherapy
or whether—and when—combination therapy may be the initial
approach
The obvious advantage of initiating treatment with monotherapy is
thatof using a single agent thus being able to ascribe effectiveness and
adverseeffectsto that agent Thedisadvantages are thatwhen mono
therapy with one agent is ineffective or insufﬁciently effective ﬁnding
an alternative monotherapy that is more effective or better tolerated
may be a painstaking process and discourage adherence Additionally
a metaanalysis of more than 40 studies has shown that combining
two agents from any two classes of antihypertensive drugs increases
the BP reduction much more than increasing the dose of one
agent446 The advantage of initiating with combination therapy is a
prompter response in a larger number of patients (potentially bene
ﬁcial in highrisk patients) a greater probability of achieving the target
BP in patients with higher BP values and a lower probability of dis
couraging patient adherence with many treatment changes Indeed
a recent survey has shown that patients receiving combination
therapy have a lower dropout rate than patients given any mono
therapy447 A further advantage is that there are physiological and
pharmacological synergies between different classes of agents that
may not only justify a greater BP reduction but also cause fewer side
effects and may provide larger beneﬁts than those offered by a single
ESH and ESC Guidelines 2189
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 2019Table 15 Drugs to be preferred in speciﬁc conditions
Condition Drug
Asymptomatic organ damage
LVH ACE inhibitor calcium antagonist ARB
Asymptomatic atherosclerosis Calcium antagonist ACE inhibitor
Microalbuminuria ACE inhibitor ARB
Renal dysfunction ACE inhibitor ARB
Clinical CV event
Previous stroke Any agent effectively lowering BP
Previous myocardial infarction BB ACE inhibitor ARB
Angina pectoris BB calcium antagonist
Heart failure Diuretic BB ACE inhibitor ARB mineralocorticoid receptor antagonists
Aortic aneurysm
Atrial fibrillation prevention
BB
Consider ARB ACE inhibitor BB or mineralocorticoid receptor antagonist
Atrial fibrillation ventricular rate control BB nondihydropyridine calcium antagonist
ESRDproteinuria ACE inhibitor ARB
Peripheral artery disease ACE inhibitor calcium antagonist
Other
ISH (elderly) Diuretic calcium antagonist
Metabolic syndrome ACE inhibitor ARB calcium antagonist
Diabetes mellitus ACE inhibitor ARB
Pregnancy Methyldopa BB calcium antagonist
Blacks Diuretic calcium antagonist
ACE ¼ angiotensinconverting enzyme ARB ¼ angiotensin receptor blocker BB ¼ betablocker BP ¼ blood pressure CV ¼ cardiovascular ESRD ¼ endstage renal disease
ISH ¼ isolated systolic hypertension LVH ¼ left ventricular hypertrophy
Table 14 Compelling and possible contraindications to the use of antihypertensive drugs
Drug Compelling Possible
Diuretics (thiazides) Gout Metabolic syndrome
Glucose intolerance
Pregnancy
Hypercalcaemia
Hypokalaemia
Betablockers Asthma
A–V block (grade 2 or 3)
Metabolic syndrome
Glucose intolerance
Athletes and physically active patients
Chronic obstructive pulmonary disease (except
for vasodilator betablockers)
Calcium antagonists (dihydropyridines) Tachyarrhythmia
Heart failure
Calcium antagonists
(verapamil diltiazem)
A–V block (grade 2 or 3 trifascicular block)
Severe LV dysfunction
Heart failure
ACE inhibitors Pregnancy
Angioneurotic oedema
Hyperkalaemia
Bilateral renal artery stenosis
Women with child bearing potential
Angiotensin receptor blockers Pregnancy
Hyperkalaemia
Bilateral renal artery stenosis
Women with child bearing potential
Mineralocorticoid receptor antagonists Acute or severe renal failure (eGFR <30 mLmin)
Hyperkalaemia
AV ¼ atrioventricular eGFR ¼ estimated glomerular ﬁltration rate LV ¼ left ventricular
ESH and ESC Guidelines2190
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 2019agent The disadvantage of initiating with drug combinations is that
one of the drugs may be ineffective
On the whole the suggestion given in the 2007 ESHESC Guide
lines2 of considering initiation with a drug combination in patients
at high risk or with markedly high baseline BP can be reconﬁrmed
When initiating with monotherapy or with a twodrug combination
doses can be stepped up if necessary to achieve the BP target if the
target is not achieved by a twodrug combination at full doses switching
to another twodrug combination can be considered or a third drug
added However in patients with resistant hypertension adding drugs
to drugs should be done with attention to results and any compound
overtly ineffective or minimally effective should be replaced rather
than retained in an automatic stepup multipledrug approach (Figure3)
5222 Preferred drug combinations
Only indirect data are available from randomized trials giving informa
tion on drug combinations effective in reducing CV outcomes Among
the large number of RCTs of antihypertensive therapy only three sys
tematically used a given twodrug combination in at least one arm the
ADVANCE trial compared an ACE inhibitor and diuretic combination
with placebo (but on top of continued background therapy)276 FEVER
compared a calcium antagonist and diuretic combination with diuretic
alone (plus placebo)269 and ACCOMPLISH compared the same ACE
inhibitor in combination with either a diuretic or a calcium antagon
ist414 In all other trials treatment was initiated by monotherapy in
either arm and another drug (and sometimes more than one drug)
was added in some patients In some trials the second drug was
chosen by the investigator among those not used in the other treat
ment arms as in Antihypertensive and LipidLowering Treatment to
Prevent Heart ATtack (ALLHAT)448
With this important reservation Table 16 shows that with the
exception of an angiotensin receptor blocker and a calcium antagonist
(never systematically used in an outcome trial) all combinations
were used in at least one active arm of placebocontrolled trials
in which the active arm was associated with signiﬁcant
beneﬁt269276287296449–454 In trials comparing different regimens all
combinations have been used in a larger or smaller proportion of
patients without major differences in beneﬁts186445448455456458–461
The only exceptions are two trials in which a large proportion of the
patients received either an angiotensin receptor blocker–diuretic com
bination or a calcium antagonist–ACE inhibitor combination423457
both of which were superior to a betablocker–diuretic combination
in reducing CV events Admittedly a betablocker–diuretic combin
ation was as effective as other combinations in several other
trials448455460461 and more effective than placebo in three
trials449453454 However the betablocker–diuretic combination
appears to elicit more cases of newonset diabetes in susceptible indivi
duals compared with other combinations462
The only trial directly comparing two combinations in all patients
(ACCOMPLISH)414 found signiﬁcant superiority of an ACE
inhibitor–calcium antagonist combination over the ACE inhibitor–
diuretic combination despite there being no BP difference between
the two arms These unexpected results deserve to be repeated
because trials comparing a calcium antagonistbased therapy with a
diureticbased therapy have never shown superiority of the
calcium antagonist Nonetheless the possibility that ACCOMPLISH
results may be due to a more effective reduction of central BP by the
association of an RAS blocker with a calcium antagonist deserves to
be investigated398399464
Choose between
Single agent
Switch
to different agent
Previous agent
at full dose
Previous combination
at full dose
Add a third drug
Full dose
monotherapy
Two drug
combination
at full doses
Switch
to different two–drug
combination
Three drug
combination
at full doses
Two–drug combination
Mild BP elevation
Lowmoderate CV risk
Marked BP elevation
Highvery high CV risk
BP blood pressure CV cardiovascular
Figure 3 Monotherapy vs drug combination strategies to achieve target BP Moving from a less intensive to a more intensive therapeutic strategy
should be done whenever BP target is not achieved
ESH and ESC Guidelines 2191
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 2019The only combination that cannot be recommended on the
basis of trial results is that between two different blockers of
the RAS Findings in ONTARGET331463 that the combination
of an ACE inhibitor and an angiotensin receptor blocker are ac
companied by a signiﬁcant excess of cases of ESRD have recent
ly been supported by the results of the ALTITUDE trial in
diabetic patients433 This trial was prematurely interrupted
because of an excess of cases of ESRD and stroke in the arm
in which the renin inhibitor aliskiren was added to preexisting
treatment using an ACE inhibitor or an angiotensin receptor
blocker It should be noted however that BP was less closely
monitored for hypotension in ALTITUDE Twodrug
Table 16 Major drug combinations used in trials of antihypertensive treatment in a stepup approach or as a randomized
combination
Trial Comparator Type of patients SBP diff (mmHg) Outcomes
ACEI and diuretic combination
PROGRESS296 Placebo Previous stroke or TIA –9 –28 strokes (P <0001)
ADVANCE276 Placebo Diabetes –56 –9 micromacro vascular events (P 004)
HYVET287 Placebo Hypertensives aged ≥80 years –15 –34 CV events (P <0001)
CAPPP455 BB + D Hypertensives +3 +5 CV events (P NS)
Angiotensin receptor blocker and diuretic combination
SCOPE450 D + placebo Hypertensives aged ≥70 years –32 –28 non fatal strokes (P 004)
LIFE457 BB + D Hypertensives with LVH –1 –26 stroke (P <0001)
Calcium antagonist and diuretic combination
FEVER269 D + placebo Hypertensives –4 –27 CV events (P <0001)
ELSA186 BB + D Hypertensives 0 NS difference in CV events
CONVINCE458 BB + D Hypertensives with risk factors 0 NS difference in CV events
VALUE456 ARB + D Highrisk hypertensives –22 –3 CV events (P NS)
ACEI and calcium antagonist combination
SystEur451 Placebo Elderly with ISH –10 –31 CV events (P <0001)
SystChina452 Placebo Elderly with ISH –9 –37 CV events (P <0004)
NORDIL461 BB + D Hypertensives +3 NS difference in CV events
INVEST459 BB + D Hypertensives with CHD 0 NS difference in CV events
ASCOT423 BB + D Hypertensives with risk factors –3 –16 CV events (P <0001)
ACCOMPLISH414 ACEI + D Hypertensives with risk factors –1 –21 CV events (P <0001)
BB and diuretic combination
Coope & Warrender453* Placebo Elderly hypertensives –18 –42 strokes (P <003)
SHEP449 Placebo Elderly with ISH –13 –36 strokes (P <0001)
STOP454 Placebo Elderly hypertensives –23 –40 CV events (P 0003)
STOP 2460 ACEI or CA Hypertensives 0 NS difference in CV events
CAPPP455 ACEI + D Hypertensives –3 –5 CV events (P NS)
LIFE457 ARB + D Hypertensives with LVH +1 +26 stroke (P <0001)
ALLHAT448 ACEI + BB Hypertensives with risk factors –2 NS difference in CV events
ALLHAT448 CA + BB Hypertensives with risk factors –1 NS difference in CV events
CONVINCE458 CA + D Hypertensives with risk factors 0 NS difference in CV events
NORDIL461 ACEI + CA Hypertensives –3 NS difference in CV events
INVEST459 ACEI + CA Hypertensives with CHD 0 NS difference in CV events
ASCOT423 ACEI + CA Hypertensives with risk factors +3
–3
–13
+16 CV events ( P <0001)
Combination of two renin–angiotensin–system blockers ACEI + ARB or RAS blocker + renin inhibitor
ONTARGET463 ACEI or ARB Highrisk patients More renal events
ALTITUDE433 ACEI or ARB Highrisk diabetics More renal events
ACEI ¼ angiotensinconvertingenzyme inhibitor ARB ¼ angiotensin receptor blocker BB ¼ betablocker CA ¼ calcium antagonist CHD ¼ coronary heart disease CV ¼ cardiovascular
D ¼ diuretic ISH ¼ isolated systolic hypertension LVH ¼ left ventricular hypertrophy NS ¼ not signiﬁcant RAS ¼ renin angiotensin system TIA ¼ transient ischaemic attack
ESH and ESC Guidelines2192
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 2019combinations most widely used are indicated in the scheme
shown in Figure 4
5223 Fixeddose or singlepill combinations
As in previous guidelines the 2013 ESHESC Guidelines favour the
use of combinations of two antihypertensive drugs at ﬁxed doses in
a single tablet because reducing the number of pills to be taken
daily improves adherence which is unfortunately low in hyperten
sion and increases the rate of BP control465466 This approach is
now facilitated by the availability of different ﬁxeddose combina
tions of the same two drugs which minimizes one of its inconve
niences namely the inability to increase the dose of one drug
independently of the other This holds also for ﬁxeddose combina
tions of three drugs (usually a blocker of the RAS a calcium antag
onist and a diuretic) which are increasingly becoming available
Availability extends to the socalled polypill (ie a ﬁxeddose com
bination of several antihypertensive drugs with a statin and a
lowdose aspirin) with the rationale that hypertensive patients
often present with dyslipidaemia and not infrequently have a high
CV risk1213 One study has shown that when combined into the
polypill different agents maintain all or most their expected
effects467 The treatment simpliﬁcation associated with this ap
proach may only be considered however if the need for each poly
pill component has been previously established141
523 Summary of recommendations on treatment
strategies and choice of drugs
Treatment strategies and choice of drugs
Recommendations Class a Level b Ref C
Diuretics (thiazides
chlorthalidone and
indapamide) betablockers
calcium antagonists ACE
inhibitors and angiotensin
receptor blockers are all
suitable and recommended
for the initiation and
maintenance of
antihypertensive treatment
either as monotherapy or in
some combinations with
each other
Some agents should be
considered as the
preferential choice in
specific conditions
because used in trials
in those conditions or because
of greater effectiveness in
specific types of OD
I A 284 332
IIa C
Initiation of antihypertensive
therapy with a twodrug
combination may be
considered in patients with
markedly high baseline BP or
at high CV risk
IIb C
Thiazide diuretics
ACE inhibitors
Betablockers Angiotensinreceptor
blockers
Other
Antihypertensives
Calcium
antagonists
ACE angiotensinconverting enzyme
Figure 4 Possible combinations of classes of antihypertensive drugs Green continuous lines preferred combinations green dashed line useful
combination (with some limitations) black dashed lines possible but less welltested combinations red continuous line not recommended com
bination Although verapamil and diltiazem are sometimes used with a betablocker to improve ventricular rate control in permanent atrial ﬁbril
lation only dihydropyridine calcium antagonists should normally be combined with betablockers
ESH and ESC Guidelines 2193
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 20196 Treatment strategies in special
conditions
61 Whitecoat hypertension
If the evidence favouring drug treatment in grade 1 hypertensives
at lowtomoderate risk is scant (see Section 423) evidence is
even weaker in whitecoat hypertensives In these individuals no
randomized trial has ever investigated whether administration of
BPlowering drugs leads to a reduction in CV morbid and fatal
events To date information is largely limited to a subgroup analysis
of the SYSTolic Hypertension in Europe (SYSTEUR) trial which con
cluded that drug treatment reduces ambulatory BP and CV morbidity
and mortality less in whitecoat than in sustained hypertensive indivi
duals based on a small number of events468
The following considerations may help orientating the therapeutic
decision in individual cases Subjects with whitecoat hypertension
may frequently have dysmetabolic risk factors and some asymptom
atic OD (see Section 313) the presence of which raises CV risk In
these higherrisk individuals with whitecoat hypertension drug
treatment may be considered in addition to appropriate lifestyle
changes Both lifestyle changes and drug treatment may be consid
ered also when normal ambulatory BP values are accompanied by ab
normal home BP values (or vice versa) because this condition is also
characterized by increased CV risk105 In the absence of additional
CV risk factors intervention may be limited to lifestyle changes
only but this decision should be accompanied by a close followup
of the patients (including periodical outofofﬁce BP monitoring)
because in whitecoat hypertensive subjects outofofﬁce BP is
often higher than in truly normotensive subjects and whitecoat
hypertensives have a greater risk of developing OD and to progress
to diabetes and sustained hypertension (see Section 313) Consid
eration should also be given to the fact that because of its high preva
lence (particularly in mildtomoderate hypertension) whitecoat
hypertension was presumably well represented in antihypertensive
drug trials that have established clinic BP reduction as the guidance
for treatment Recommendations on treatment strategies in white
coat hypertension are listed below
62 Masked hypertension
Isolated ambulatory or masked hypertension is infrequently diag
nosed because ﬁnding a normal clinic BP only exceptionally leads
to home or ambulatory BP measurements When this condition
is identiﬁed however both lifestyle measures and antihypertensive
drug treatment should be considered because masked hypertension
has consistently been found to have a CV risk very close to that
of inofﬁce and outofofﬁce hypertension109112117469 Both at
the time of treatment decision and during followup attention to
dysmetabolic risk factors and OD should be considered since these
conditions are much more common in masked hypertension than
in normotensive individuals Efﬁcacy of antihypertensive treatment
should be assessed by ambulatory andor home BP measurements
621 Summary of recommendations on treatment
strategies in whitecoat and masked hypertension
63 Elderly
In previous sections (425 and 433) we mentioned that there is
strong evidence of beneﬁts from lowering of BP by antihypertensive
treatment in the elderly limited to individuals with initial SBP of
≥160 mmHg whose SBP was reduced to values 150 but not
140 mmHg Therefore the recommendation of lowering SBP to
150 mmHg in elderly individuals with systolic BP ≥160 mmHg is
strongly evidencebased However at least in elderly individuals
younger than 80 years antihypertensive treatment may be consid
ered at SBP values 140 mmHg and aimed at values 140 mmHg
if the individuals are ﬁt and treatment is well tolerated
Direct evidence of the effect of antihypertensive treatment in elderly
hypertensives (older than 80 years) was still missing at the time the 2007
ESHESC Guidelines were prepared The subsequent publication of the
The combination of two
antagonists of the
RAS is not recommended and
should be discouraged
III A 331 433
463
Other drug combinations
should be considered and
probably are beneficial in
proportion to the extent of
BP reduction However
combinations that have been
successfully used in trials may
be preferable
IIa C
Combinations of two
antihypertensive drugs at
fixed doses in a single tablet
may be recommended and
favoured because reducing
the number of daily pills
improves adherence which is
low in patients with
hypertension
IIb B 465
ACE ¼ angiotensinconverting enzyme BP ¼ blood pressure CV ¼
cardiovascular OD ¼ organ damage RAS ¼ reninangiotensin system
aClass of recommendation
bLevel of evidence
cReference(s) supporting recommendation(s)
Treatment strategies in whitecoat and masked
hypertension
Recommendations Class a Level b
In whitecoat hypertensives without additional
risk factors therapeutic intervention should be
considered to be limited to lifestyle changes
only but this decision should be accompanied by
a close followup
IIa C
In whitecoat hypertensives with a higher CV
risk because of metabolic derangements or
asymptomatic OD drug treatment may be
considered in addition to lifestyle changes
IIb C
In masked hypertension both lifestyle measures
and antihypertensive drug treatment should be
considered because this type of hypertension
has been consistently found to have a CV
hypertension
IIa C
CV cardiovascular OD organ damage
aClass of recommendation
bLevel of evidence
ESH and ESC Guidelines2194
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 2019HYpertension in the Very Elderly Trial (HYVET) results287 comparing
active treatment (the diuretic indapamide supplemented if necessary
by the ACE inhibitor perindopril) with placebo in octogenarians with
entry SBP ≥160 mmHg reported a signiﬁcant reduction in major CV
events and allcause deaths by aiming at SBP values 150 mmHg
(mean achieved SBP 144 mmHg) HYVET deliberately recruited
patients in good physical and mental condition and excluded ill and
frail individuals who are so commonplace among octogenarians and
also excluded patients with clinically relevant orthostatic hypotension
The duration of followup was also rather short (mean 15 years)
because the trial was interrupted prematurely by the safety monitoring
board
RCTs that have shown beneﬁcial effects of antihypertensive treat
ment in the elderly have used different classes of compounds and so
there is evidence in favour of diuretics287449454470471 beta
blockers453454 calcium antagonists451452460 ACE inhibitors460
and angiotensin receptor blockers450 The three trials on isolated sys
tolic hypertension used a diuretic 449 or a calcium antagonist451452
A prospective metaanalysis compared the beneﬁts of different
antihypertensive regimens in patients younger or older than 65
years and conﬁrmed that there is no evidence that different classes
are differently effective in the younger vs the older patient444
631 Summary of recommendations on antihypertensive
treatment strategies in the elderly
64 Young adults
In young adults with moderately high BP it is almost impossible to
provide recommendations based directly on evidence from inter
vention trials since outcomes are delayed by a period of years
The results of an important observational study on 12 million
men in Sweden initially investigated at a mean age of 184 years
at the time of military conscription examination and followedup
for a median of 24 years have recently been reported472 The rela
tionship of SBP to total mortality was Ushaped with a nadir at ap
proximately 130 mmHg but the relationship with CV mortality
increased monotonically (the higher the BP the higher the risk)
In these young men (without stiff diseased arteries) the relationship
of DBP to total and CV mortality was even stronger than that of
SBP with an apparent threshold around 90 mmHg Approximately
20 of the total mortality in these young men could be explained by
their DBP Young hypertensives may sometimes present with an
isolated elevation of DBP Despite absence of RCT evidence on
the beneﬁts of antihypertensive treatment in these young indivi
duals their treatment with drugs may be considered prudent and
especially when other risk factors are present BP should be
reduced to 14090 mmHg The case may be different for young
individuals in whom brachial SBP is elevated with normal DBP
values (90 mmHg) As discussed in sections 316 and 424
these individuals sometimes have a normal central SBP and can
be followed with lifestyle measures only
65 Women
The representation of women in RCTs in hypertension is 44473 but
only 24 of all CV trials report sexspeciﬁc results474–475 A sub
group analysis by sex of 31 RCTs including individuals found similar
BP reductions for men and women and no evidence that the two
genders obtain different levels of protection from lowering of BP
or that regimens based on ACE inhibitors calcium antagonists angio
tensin receptor blockers or diureticsbetablockers were more ef
fective in one sex than the other445
In women with childbearing potential ACE inhibitors and angio
tensin receptor blockers should be avoided due to possible terato
genic effects This is the case also for aliskiren a direct renin inhibitor
although there has not been a single case report of exposure to alis
kiren in pregnancy
651 Oral contraceptives
Use of oral contraceptives (OCs) is associated with some small but
signiﬁcant increases in BP and with the development of hypertension
in about 5 of users476477 Notably these studies evaluated older
generation OCs with relatively higher oestrogen doses compared
with those currently used (containing 50 mg oestrogen ranging
most often from 20–35 mg of ethinyl estradiol and a low dose of
second or thirdgeneration progestins) The risk of developing
hypertension decreased quickly with cessation of OCs and past
users appeared to have only a slightly increased risk2 Similar
results were later shown by the Prevention of REnal and Vascular
ENdstage Disease (PREVEND) study in which second and third
generation OCs were evaluated separately478 in this study after an
initial increase urinary albumin excretion fell once OC therapy had
been stopped Drospirenone (3 mg) a newer progestin with an anti
mineralocorticoid diuretic effect combined with ethinyl estradiol at
Antihypertensive treatment strategies in the elderly
Recommendations Class a Level b Ref C
In elderly hypertensives with
SBP ≥160 mmHg there is solid
evidence to recommend reducing
SBP to between 150 and 140
mmHg
I A 141 265
In fit elderly patients <80 years
old antihypertensive treatment
may be considered at SBP values
≥140 mmHg with a target
SBP <140 mmHg if treatment is
well tolerated
IIb C
In individuals older than 80 years
with an initial SBP ≥160 mmHg it
is recommended to reduce SBP
to between 150 and 140 mmHg
provided they are in good
physical and mental conditions
I B 287
In frail elderly patients it is
recommended to leave decisions
on antihypertensive therapy to
the treating physician and based
on monitoring of the clinical
effects of treatment
I C
Continuation of welltolerated
antihypertensive treatment
should be considered when a
treated individual becomes
octogenarian
IIa C
All hypertensive agents are
recommended and can be used in
the elderly although diuretics and
calcium antagonists may be
preferred in isolated systolic
hypertension
I A 444 449
451 452
SBP systolic blood pressure
aClass of recommendation
bLevel of evidence
cReference(s) supporting recommendation(s)
ESH and ESC Guidelines 2195
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 2019various doses lowered SBP by 1–4 mmHg across the groups479 Un
fortunately there is growing evidence that drospirenone is asso
ciated with a greater risk of venous thromboembolism than
levonorgestrel (a secondgeneration synthetic progestogen)480
The association between combined OCs and the risk of myocar
dial infarction has been intensively studied and the conclusions are
controversial Earlier prospective studies consistently showed an
increased risk of acute myocardial infarction among women who
use OCs and particularly in OC users who smoke and extended
this observation to past smokers on OCs481 Two casecontrol
studies using the second and thirdgeneration OCs exist but with con
ﬂicting results482483 A largescale Swedish populationbased pro
spective study in which most of the current OC users were taking
lowdose oestrogen and second or thirdgeneration progestins did
not ﬁnd use of OCs to be associated with an increased risk of myocar
dial infarction484 Data from observational studies with progestogen
only OCs suggest no increase in risk of myocardial infarction485
Three separate metaanalyses summarizing over 30 years of
studies have shown that OC users have about a twofold increased
risk of stroke over nonusers486–488 In an Israeli populationbased
cohort study drospirenonecontaining OCs were not associated
with an increased risk of TIAs and stroke489
There are no outcome data on the newest nonoral formulations
of hormone contraception (injectable topical vaginal routes)
However transdermal patches and vaginal rings have been found
to be associated with an increased risk of venous thrombosis com
pared with agematched controls490
Although the incidence of myocardial infarction and ischaemic
stroke is low in the age group of OC users the risk of OCs is small
in absolute terms but has an important effect on women’s health
since 30–45 of women of reproductive age use OCs Current
recommendations indicate that OCs should be selected and initiated
by weighing risks and beneﬁts for the individual patient491 BP should
be evaluated using properly taken measurements and a single BP
reading is not sufﬁcient to diagnose hypertension492 Women aged
35 years and older should be assessed for CV risk factors including
hypertension It is not recommended that OCs be used in women
with uncontrolled hypertension Discontinuation of combined
OCs in women with hypertension may improve their BP
control493 In women who smoke and are over the age of 35 years
OCs should be prescribed with caution494
652 Hormone replacement therapy
Hormone replacement therapy (HRT) and selective oestrogen recep
tor modulators should not be used for primary or secondary preven
tion of CVD495 If occasionally treating younger perimenopausal
women for severe menopausal symptoms the beneﬁts should be
weighed against potential risks of HRT490496 The probability is low
that BP will increase with HRT in menopausal hypertensive women497
653 Pregnancy
Hypertensive disorders in pregnancy have been reviewed recently by
the ESC Guidelines on the management of CVD during pregnancy498
and by other organizations499 In the absence of RCTs recommenda
tions can only be guided by expert opinion While there is consensus
that drug treatment of severe hypertension in pregnancy (160 for
SBP or 110 mmHg for DBP) is required and beneﬁcial the beneﬁts
of antihypertensive therapy are uncertain for mildly to moderately ele
vatedBPinpregnancy(≤160110 mmHg) either preexisting or
pregnancyinduced except for a lower risk of developing severe hyper
tension500 International and national guidelines vary with respect to
thresholds for starting treatment and BP targets in pregnancy The sug
gestion in the 2007 ESHESC Guidelines2 of considering drug treat
ment in all pregnant women with persistent elevation of BP ≥150
95 mmHg is supported by recent US data which show an increasing
trend in the rate of pregnancyrelated hospitalizations with stroke—es
pecially during the postpartum period—from 1994 to 2007501 and by
an analysis of stroke victims with severe preeclampsia and eclampsia502
Despite lack of evidence the 2013 Task Force reconﬁrms that physi
cians should consider early initiation of antihypertensive treatment at
values ≥14090 mmHg in women with (i) gestational hypertension
(with or without proteinuria) (ii) preexisting hypertension with the
superimposition of gestational hypertension or (iii) hypertension with
asymptomatic OD or symptoms at any time during pregnancy
No additional information has been provided after publication of
the previous Guidelines2 on the antihypertensive drugs to be used in
pregnant hypertensive women therefore the recommendations to
use methyldopa labetalol and nifedipine as the only calcium antagon
ist really tested in pregnancy can be conﬁrmed Betablockers (pos
sibly causing foetal growth retardation if given in early pregnancy) and
diuretics (in preexisting reduction of plasma volume) should be used
with caution As mentioned above all agents interfering with the
reninangiotensin system (ACE inhibitors ARBs renin inhibitors)
should absolutely be avoided In emergency (preeclampsia) intra
venous labetalol is the drug of choice with sodium nitroprusside or
nitroglycerin in intravenous infusion being the other option
There is a considerable controversy regarding the efﬁcacy of
lowdose aspirin for the prevention of preeclampsia Despite a
large metaanalysis reporting a small beneﬁt of aspirin in preventing
preeclampsia503 two other very recent analyses came to opposing
conclusions Rossi and Mullin used pooled data from approximately
5000 women at high risk and 5000 at low risk for preeclampsia
and reported no effect of lowdose aspirin in the prevention of the
disease504 Bujold et al however505 pooled data from over 11 000
women enrolled in RTCs of lowdose aspirin in pregnant women
and concluded that women who initiated treatment at 16 weeks
of gestation had a signiﬁcant and marked reduction of the relative
risk for developing preeclampsia (relative risk 047) and severe pre
eclampsia (relative risk 009) compared with control505 Faced with
these discrepant data only prudent advice can be offered women at
high risk of preeclampsia (from hypertension in a previous preg
nancy CKD autoimmune disease such as systemic lupus erythema
tosus or antiphospholipid syndrome type 1 or 2 diabetes or
chronic hypertension) or with more than one moderate risk factor
for preeclampsia (ﬁrst pregnancy age ≥40 years pregnancy interval
of 10 years BMI ≥35 kgm2 at ﬁrst visit family history of pre
eclampsia and multiple pregnancy) may be advised to take 75 mg
of aspirin daily from 12 weeks until the birth of the baby provided
that they are at low risk of gastrointestinal haemorrhage
654 Longterm cardiovascular consequences in
gestational hypertension
Because of its CV and metabolic stress pregnancy provides a unique
opportunity to estimate a woman’s lifetime risk preeclampsia may
ESH and ESC Guidelines2196
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 2019be an early indicator of CVD risk A recent large metaanalysis found
that women with a history of preeclampsia have approximately
double the risk of subsequent ischaemic heart disease stroke and
venous thromboembolic events over the 5–15 years after preg
nancy506 The risk of developing hypertension is almost fourfold507
Women with earlyonset preeclampsia (delivery before 32 weeks of
gestation) with stillbirth or foetal growth retardation are considered
at highest risk Risk factors before pregnancy for the development of
hypertensive disorders are high maternal age elevated BP dyslipidae
mia obesity positive family history of CVD antiphospholipid syn
drome and glucose intolerance Hypertensive disorders have been
recognized as an important risk factor for CVD in women495 There
forelifestyle modiﬁcations and regular checkups of BPand metabolic
factors are recommended after delivery to reduce future CVD
655 Summary of recommendations on treatment
strategies in hypertensive women
66 Diabetes mellitus
High BP is a common feature of both type 1 and type 2 diabetes and
masked hypertension is not infrequent121 so that monitoring 24h
ambulatory BP in apparently normotensive patients with diabetes
may be a useful diagnostic procedure Previous sections (426 and
434) have mentioned that there is no clear evidence of beneﬁts in
general from initiating antihypertensive drug treatment at SBP
levels 140 mmHg (high normal BP) nor there is evidence of bene
ﬁts from aiming at targets 130 mmHg This is due to the lack of suit
able studies correctly investigating these issues Whether the
presence of microvascular disease (renal ocular or neural) in dia
betes requires treatment initiation and targets of lower BP values is
also unclear Microalbuminuria is delayed or reduced by treatment
but trials in diabetic populations including normotensives and hyper
tensives have been unable to demonstrate consistently that protein
uria reduction is also accompanied by a reduction in hard CV
outcomes (see also Section 69)274276329 No effect of antihyperten
sive therapy on diabetic retinopathy has been reported in normoten
sive and hypertensive patients in the Action in Diabetes and Vascular
Disease Preterax and DiamicronMR Controlled Evaluation
(ADVANCE) trial508 and in the normotensive type1 diabetics of
the DIabetic REtinopathy Candesartan Trials (DIRECT)509 Finally
antihypertensive drugs do not appear to substantially affect neur
opathy510 Therefore evidencebased recommendations are to initi
ate antihypertensive drug treatment in all patients with diabetes
whose mean SBP is ≥160 mmHg Treatment is also strongly recom
mended in diabetic patients when SBP is ≥140 mmHg with the aim
to lower it consistently to 140 mmHg As mentioned in section
4341 DBP target between 80–85 mmHg is supported by the
results of the HOT and United Kingdom Prospective Diabetes
Study (UKPDS) studies290293 How far below 140 mmHg the SBP
target should be in patients with diabetes is not clear since the
only two large trials showing CV outcome reduction in diabetes by
SBP reduction to 140 mmHg actually reduced SBP to an average
of 139 mmHg270275 Comparison of CV event reductions in
various trials indicates that for similar SBP differences the beneﬁt
of more intensive lowering of SBP becomes gradually smaller when
the SBP differences are in the lower part of the 139–130 mmHg
range314 Supportive evidence against lowering SBP 130 mmHg
comes from the ACCORD trial295aposthoc analysis of RCTs and
a nationwide registerbased observational study in Sweden which
suggest that beneﬁts do not increase below 130 mmHg326511512
The case of the diabetic patient with increased urinary protein excre
tion is discussed in Section 69
The choice of antihypertensive drugs should be based on efﬁcacy
and tolerability All classes of antihypertensive agents are useful
according to a metaanalysis394 but the individual choice should
take comorbidities into account to tailor therapy Because BP
control is more difﬁcult in diabetes324 most of the patients in all
studies received combination therapy and combination therapy
should most often be considered when treating diabetic hyperten
sives Because of a greater effect of RAS blockers on urinary
protein excretion (see Section 69)513 it appears reasonable to
have either an ACE inhibitor or an ARB in the combination
However the simultaneous administration of two RAS blockers (in
cluding the renin inhibitor aliskiren) should be avoided in highrisk
Treatment strategies in hypertensive women
Recommendations Class a Level b Ref C
Hormone therapy and selective
oestrogen receptor modulators
are not recommended and
should not be used for primary
or secondary prevention of CVD
If treatment of younger
perimenopausal women is
considered for severe menopausal
symptoms the benefits should be
weighed against potential risks
III A 495 496
Drug treatment of severe
hypertension in pregnancy
(SBP >160 mmHg or
DBP >110 mmHg) is
recommended
I C
Drug treatment may also be
considered in pregnant women
with persistent elevation of BP
≥15095 mmHg and in those with
BP ≥14090 mmHg in the
presence of gestational
hypertension subclinical OD or
symptoms
IIb C
In women at high risk of
preeclampsia provided they are
at low risk of gastrointestinal
haemorrhage treatment with
low dose aspirin from 12 weeks
until delivery may be considered
IIb B 503 504
505
In women with childbearing
potential RAS blockers are not
recommended and should be
avoided
III C
Methyldopa labetolol and
nifedipine should be considered
preferential antihypertensive drugs
in pregnancy Intravenous
labetolol or infusion of
nitroprusside should be
considered in case of emergency
(preeclampsia)
IIa B 498
BP ¼ blood pressure CVD ¼ cardiovascular disease DBP ¼ diastolic blood
pressure OD organ damage RAS ¼ renin–angiotensin system SBP ¼ systolic
blood pressure
aClass of recommendation
bLevel of evidence
cReference(s) supporting recommendation(s)
ESH and ESC Guidelines 2197
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 2019patients because of the increased risk reported in ALTITUDE and
ONTARGET433463 Thiazide and thiazidelike diuretics are useful
and are often used together with RAS blockers Calcium antagonists
have been shownto be useful especially when combined with an RAS
blocker Betablockers though potentially impairing insulin sensitiv
ity are useful for BP control in combination therapy especially in
patients with CHD and heart failure
661 Summary of recommendations on treatment
strategies in patients with diabetes
67 Metabolic syndrome
The metabolic syndrome is variably deﬁned especially because of dif
ferent deﬁnitions of central obesity although a socalled harmonized
deﬁnition was presented in 2009 514 Whether the metabolic syn
drome is a useful clinical concept is currently disputed largely
because it has been hard to prove that it adds anything to the predict
ive power of individual factors515516 High normal BP and hyperten
sion constitute a frequent possible component of the metabolic
syndrome517 although the syndrome can also be diagnosed in the
absence of a raised BP This is consistent with the ﬁnding that hyper
tension high normal BP and whitecoat hypertension are often asso
ciated with increased waist circumference and insulin resistance
Coexistence of hypertension with metabolic disturbances increases
global risk and the recommendation (Section 423) to prescribe
antihypertensive drugs (after a suitable period of lifestyle changes)
to individuals with a BP ≥14090 mmHg should be implemented
with particular care in hypertensive patients with metabolic distur
bances No evidence is available that BPlowering drugs have a bene
ﬁcial effect on CV outcomes in metabolic syndrome individuals with
high normal BP277278 As the metabolic syndrome can often be con
sidered as a prediabetic’ state agents such as RAS blockers and
calcium antagonists are preferred since they potentially improve—
or at least do not worsen—insulin sensitivity while betablockers
(with the exception of vasodilating betablockers)407–409 and diure
tics should only be considered as additional drugs preferably at low
doses If diuretics are used the association with a potassiumsparing
agent should be considered409 as there is evidence that hypokal
aemia worsens glucose intolerance518 Lifestyle changes particularly
weight loss and increased physical exercise are recommended to all
individuals with the metabolic syndrome This will improve not only
BP but also the metabolic components of the pattern and delay the
onset of diabetes369519520
671 Summary of recommendations on treatment
strategies in hypertensive patients with metabolic syndrome
Treatment strategies in patients with diabetes
Recommendations Class a Level b Ref C
While initiation of
antihypertensive drug treatment
in diabetic patients whose SBP
is ≥160 mmHg is mandatory it is
strongly recommended to start
drug treatment also when SBP is
≥140 mmHg
I A 275 276
290–293
A SBP goal <140 mmHg is
recommended in patients with
diabetes
I A 270275
276295
The DBP target in patients with
diabetes is recommended to be
<85 mmHg
I A 290 293
All classes of antihypertensive
agents are recommended and can
be used in patients with diabetes
RAS blockers may be preferred
especially in the presence of
proteinuria or microalbuminuria
I A 394 513
It is recommended that individual
drug choice takes comorbidities
into account
I C
Simultaneous administration of
two blockers of the RAS is not
recommended and should be
avoided in patients with diabetes
III B 433
DBP ¼ diastolic blood pressure RAS ¼ renin–angiotensin system SBP ¼ systolic
blood pressure
aClass of recommendation
bLevel of evidence
cReference(s) supporting recommendation(s)
Treatment strategies in hypertensive patients with
metabolic syndrome
Recommendations Class a Level b Ref C
Lifestyle changes particularly
weight loss and physical exercise
are to be recommended to all
individuals with the metabolic
syndrome These interventions
improve not only BP but the
metabolic components of the
syndrome and delay diabetes
onset
I B 369 519
520
As the metabolic syndrome can
be considered a prediabetic’
state antihypertensive agents
potentially improving or at least
not worsening insulin sensitivity
such as RAS blockers and calcium
antagonists should be considered
as the preferred drugs
Betablockers (with the exception
of vasodilating betablockers) and
diuretics should be considered only
as additional drugs preferably in
association with a
potassiumsparing agent
IIa C
It is recommended to prescribe
antihypertensive drugs with
particular care in hypertensive
patients with metabolic
disturbances when BP is ≥14090
mmHg after a suitable period of
lifestyle changes and to maintain
BP <14090 mmHg
I B 141
BP lowering drugs are not
recommended in individuals with
metabolic syndrome and
high normal BP
III A 277 278
BP ¼ blood pressure RAS ¼ renin–angiotensin system
aClass of recommendation
bLevel of evidence
cReference(s) supporting recommendation(s)
ESH and ESC Guidelines2198
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 201968 Obstructive sleep apnoea
This topic has recently been the subject of a consensus docu
ment from the ESH and the European Respiratory Society521
The association between obstructive sleep apnoea and hyper
tension is well documented particularly when nocturnal hyper
tension is concerned Obstructive sleep apnoea appears to be
responsible for a large proportion of cases of BP increase or
absence of BP reduction at nighttime Although a few prospect
ive studies have linked severe obstructive sleep apnoea to fatal
and nonfatal CV events and allcause mortality this association
appears to be closer for stroke than CHD and to be weak with
obstructive sleep apnoea of mildtomoderate severity521
Whether monitoring CV and respiratory variables during night
sleep should be employed systematically in individuals with re
sistant hypertension is open to question and no cost
effectiveness analysis has been carried out At present these
complex methods should be preceded by ABPM showing BP ab
normalities during the night or by overnight oximetry Because
of the relationship between obesity and obstructive sleep
apnoea weight loss and exercise are commonly recommended
but unfortunately no largescale controlled trials are available521
Continuous positive airway pressure therapy is a successful
procedure for reducing obstructive sleep apnoea however on
the basis of four available metaanalyses the effect of prolonged
continuous positive airway pressure therapy on ambulatory BP
is very small (1–2 mmHg reduction)522– 525 This may be due to
poor adherence to this complex procedure or a limited follow
up period but a recent study with a followup longer than 3
years has found no difference in BP or in drug usage between
sleep apnoea patients who continued or those who quitted
positive air pressure therapy526 However two recent prospect
ive studies have reported that (i) normotensive subjects with
obstructive sleep apnoea were characterized over a 12year
followup by a signiﬁcant increase in the risk of developing
hypertension527 and (ii) the risk of newonset hypertension
was lower in subjects treated with continuous positive air pres
sure528 although the beneﬁt seemed restricted to those with
daytime sleepiness527
In conclusion despite the potential health impact of
obstructive sleep apnoea welldesigned therapeutic studies are
too few The two more urgent issues to be investigated are
whether obstructive sleep apnoea really increases the CV risk
of hypertension and whether longterm therapeutic correction
of obstructive sleep apnoea leads to a reduction in BP and CV
events529
69 Diabetic and nondiabetic
nephropathy
In observational studies the relationship between BP and pro
gression of CKD and incident ESRD is direct and progressive530
Also in the Japanese male population in general high normal BP
was associated with increased prevalence of CKD531 Likewise
in a metaanalysis of intervention trials in patients with non
diabetic nephropathy the progression of CKD correlated with
achieved BP with the slowest progression observed in patients
with treated SBP in the range 110–119 mmHg532 Unfortunately
(see Section 4343) these observational data are not supported
by the results of three trials in which CKD patients were rando
mized to a lower (125–130 mmHg) or higher (140 mmHg)
BP target 304–306 no difference in renal failure or death was
found between the two arms except in the observational
followup of two of these trials in which the groups initially ran
domized to the lower BP had fewer cases of ESRD or death
provided that proteinuria was present307308313 In patients
with diabetic or nondiabetic renal disease SBP should be
lowered to 140 mmHg and when overt proteinuria is
present values 130 mmHg may be pursued provided that
changes in eGFR are monitored
In patients with ESRD under dialysis a recent metaanalysis
showed a reduction in CV events CV death and allcause mor
tality by lowering of SBP and DBP533 However no information
on the absolute BP values achieved was provided and reduction
of mortality was seen in patients with heart failure only Hence a
recommendation on a precise BP target cannot be provided
Reduction of proteinuria (both microalbuminuria and overt
proteinuria) is widely considered as a therapeutic target since
observational analyses of data from RCTs have reported that
changes in urinary protein excretion are predictors of adverse
renal and CV events534–536 Once again solid evidence is
lacking from trials comparing CV or renal outcomes in groups
randomized to more or less aggressive reductions of proteinuria
Several RCTs have clearly indicated that RAS blockade is more
effective in reducing albuminuria than either placebo or other
antihypertensive agents in diabetic nephropathy nondiabetic
nephropathy and patients with CVD513537 and is also effective
in preventing incident microalbuminuria329538 None of these
trials had sufﬁcient statistical power to evaluate effects on CV
outcomes
Achieving BP targets usually requires combination therapy
and RAS blockers should be combined with other antihyperten
sive agents A subanalysis of the ACCOMPLISH trial has
reported that the association of an ACE inhibitor with a
calcium antagonist rather than a thiazide diuretic is more ef
fective in preventing doubling serum creatinine and ESRD
though less effective in preventing proteinuria539 As reported
in Section 66 combination of two RAS blockers though poten
tially more effective in reducing proteinuria is not generally
recommended433463 Mineralocorticoid receptor antagonists
cannot be recommended in CKD especially in combination
with an RAS blocker because of the risk of excessive reduction
in renal function and hyperkalemia540 Loop diuretics should
replace thiazides if serum creatinine is 15 mgdL or eGFR is
30 mLmin173 m2
ESH and ESC Guidelines 2199
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 2019691 Summary of recommendations on therapeutic
strategies in hypertensive patients with nephropathy
692 Chronic kidney disease stage 5D
Hypertension is a ubiquitous ﬁnding in haemodialysis patients and has
major implications for survival Detailed recommendations on how
to manage high BP in patients on haemodialysis are available in guide
lines issued by nephrological scientiﬁc societies and only few general
considerations will be made here Firstly accurate measurement of
BP is essential for the management of haemodialysis patients
However a prehaemodialysis BP may not reﬂect the average BP
experienced by the patient Thus the question of how and where the
measurements should be made is of particular importance with clear
evidence for the superiority of selfmeasured BP at home over pre
haemodialysis BP values Secondly the BP to be pursued by treatment
in patients on haemodialysis has not been clearly established in this
context A distinct difﬁculty is that large alterations in sodium and
water balance make BP particularly variable and that the extent of BP
reductions may depend on the presence of complications such as car
diomyopathy rather that druginduced BP control Thirdly all antihy
pertensive drugs except diuretics can be used in the haemodialysis
patients with doses determined by the haemodynamic instability and
the ability of the drug to be dialysed Drugs interfering with homeostatic
adjustments to volume depletion (already severely impaired in renal in
sufﬁciency) should be avoided to minimize hypotension during the fast
and intensive reduction of blood volume associated with the dialytic
manoeuvres
RCTs are rare in haemodialysis and should be encouraged Longer
or more frequent dialysis may solve the haemodynamic problems
associated with salt restriction and short dialysis time541
610 Cerebrovascular disease
6101 Acute stroke
BP management during the acute phase of stroke is a matter of con
tinuing concern The results of a small trial called Controlling Hyper
tension and Hypertension Immediately PostStroke (CHHIPS)
suggested a beneﬁcial impact in administering lisinopril or atenolol
in patients with acute stroke and a SBP 160 mmHg542 The same
was the case for the Acute Candesartan Cilexetil Therapy in
Stroke Survival (ACCESS) study543 which suggested beneﬁts of can
desartan given for 7 days afteracute stroke This latter hypothesis was
properly tested in the AngiotensinReceptor Blocker Candesartan
for Treatment of Acute STroke (SCAST) trial involving more than
2000 acute stroke patients544 SCAST was neutral for functional out
comes and CV endpoints including recurrent stroke and could not
identify any subgroup with signiﬁcant beneﬁt A recent review gives
a useful update of this difﬁcult area545
6102 Previous stroke or transient ischaemic attack
Sections 426 and 4342 have mentioned data from three major
placebocontrolled RCTs of antihypertensive treatment in patients
with a recent (but not acute) stroke or TIA279296297 which provide
somewhat conﬂicting evidence No evidence isyet available that recur
rent stroke is prevented by initiating therapy when BP is in the high
normal range nor is there evidence for reducing SBP to 130 mmHg
As prevention of stroke is the most consistent beneﬁt of antihyper
tensive therapy and has been observed in almost all large RCTs using
different drug regimens all regimens are acceptable for stroke preven
tion provided that BP is effectively reduced546 Metaanalyses and
metaregression analyses suggest that calcium antagonists may have
a slightly greater effectiveness on stroke prevention284395421 but
the two successful trials in secondarystroke prevention used a diuretic
ora diureticincombinationwithanACEinhibitor279296 Greatercere
brovascular protective effects have also been reported for ARBs vs a
variety of other drugs in single trials and metaanalyses547548
6103 Cognitive dysfunction and white matter lesions
The importance of hypertension in predicting vascular dementia has
been conﬁrmed in a recent carefully conducted observational study
in Japan549 but evidence on the effects of lowering of BP is scanty and
confusing Little information was added by a cognition substudy of
HYVET in hypertensive octogenarians because of the inadequate
duration of followup and an accompanying metaanalysis showed
very limited beneﬁt550 Trials are urgently needed on preventing cog
nitive dysfunction and on delaying dementia when cognitive dysfunc
tion has begun Although white matter lesions (hyperintensities at
MRI) are known to be associated with increased risk of stroke cog
nitive decline and dementia (see Section 375) almost no informa
tion is available as to whether antihypertensive treatment can
modify their evolution A small substudy of PROGRESS and a
recent prospectively observational study suggest that preventing
white matter hyperintensities by lowering BP is possible551552 but
this suggestion requires veriﬁcation in a large RCT
Therapeutic strategies in hypertensive patients with
nephropathy
Recommendations Class a Level b Ref C
Lowering SBP to <140 mmHg
should be considered IIa B 303 313
When overt proteinuria is
present SBP values <130 mmHg
may be considered provided that
changes in eGFR are monitored
IIb B 307 308 313
RAS blockers are more effective
in reducing albuminuria than other
antihypertensive agents and are
indicated in hypertensive patients
in the presence of
microalbuminuria or overt
proteinuria
I A 513 537
Reaching BP goals usually requires
combination therapy and it is
recommended to combine
RAS blockers with other
antihypertensive agents
I A 446
Combination of two RAS
blockers though potentially more
effective in reducing proteinuria is
not recommended
III A 331 433
463
Aldosterone antagonists cannot
be recommended in CKD
especially in combination with a
RAS blocker because of
the risk of excessive reduction in
renal function and of
hyperkalaemia
III C
BP ¼ blood pressure CKD ¼ chronic kidney disease eGFR ¼ estimated
glomerular ﬁltration rate RAS ¼ renin–angiotensin system SBP ¼ systolic blood
pressure
aClass of recommendation
bLevel of evidence
cReference(s) supporting recommendation(s)
ESH and ESC Guidelines2200
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 20196104 Summary of recommendations on therapeutic
strategies in hypertensive patients with cerebrovascular
disease
611 Heart disease
6111 Coronary heart disease
Several risk factors contribute to CHD but the level of BP over a large
and continuous range is one of the important factors with a steeper as
sociation above a SBP of about 140 mmHg The Effect of Potentially
Modiﬁable Risk Factors associated with Myocardial Infarction in 52
Countries (INTERHEART) study showed that about 50 of the
populationattributable risk ofa myocardial infarction canbe accounted
for by lipids with hypertension accounting for about 25553 Several
risk factors for CHD and particularly SBP and DBP are strongly
related to BMI554 a ﬁnding emphasizing the urgency of halting the
present inexorable rise of obesity in the general population
Sections 426 and 4342 mentioned that RCTs of antihypertensive
treatment do not provide consistent evidence that SBP target should
be 130 mmHg in hypertensive patients with overt CHD nor is
there consistent evidence that antihypertensive treatment should be
initiated with high normal BP On the contrary a number of the correla
tive analyses raising suspicion about the existence of a Jcurve relation
ship between achieved BP and CV outcomes included a high proportion
of CHD patients317318322323 and it is not unreasonable that if a Jcurve
occurs it may occur particularly in patients with obstructive coronary
disease The recommendation to lower SBP to 140 mmHg is indir
ectly strengthened by a posthoc analysis of the INternational VErapamil
SRT Trandolapril (INVEST) study (examining all patients with CHD)
showing that outcome incidence is inversely related to consistent SBP
control (ie 140 mmHg) throughout followup visits436
As to which drugs are better in hypertensive patients there is evi
dence for greater beneﬁts from betablockers after a recent myocar
dial infarction284 a condition in which ACE inhibitors have also been
successfully tested555556 Later on all antihypertensive agents can be
used284 Betablockers and calcium antagonists are to be preferred at
least for symptomatic reasons in cases of angina
6112 Heart failure
Hypertension is the leading attributable risk factor for developing
heart failure which is today a hypertensionrelated complication
almost as common as stroke557 Preventing heart failure is the
largest beneﬁt associated with BPlowering drugs395 including in the
very elderly287 This has been observed using diuretics betablockers
ACE inhibitors and ARBs with calcium antagonists apparently being
less effective in comparative trials at least in those trials in which
they replaced diuretics395 In ALLHAT448 an ACE inhibitor was
found to be less effective than a diuretic but the study design
implied initial diuretic withdrawal and the small excess of early heart
failure episodes may have resulted from this withdrawal In the Preven
tion Regimen for Effectively Avoiding Secondary Strokes (PROFESS)
and Telmisartan Randomised AssessmeNt Study in ACE iNtolerant
subjects with cardiovascular Disease (TRANSCEND) trials297558 an
ARB did not reduce hospitalizations for heart failure below those
occurring on placebo (in which treatment consisted of nonRAS
blocking agents) and in ONTARGET463 an ARB appeared (non
signiﬁcantly) less effective than an ACE inhibitor
Whilst a history of hypertension is common in patients with heart
failure a raised BP can disappear when heart failure with LV systolic
dysfunction develops No RCT has been carried out in these patients
with the speciﬁc intent of testing the effects of reducing BP (in most
trials of antihypertensive therapy heart failure patients have usually
been excluded) In these patients evidence in favour of the administra
tion of betablockers ACE inhibitors ARBs and mineralocorticoid re
ceptor antagonists has been obtained from trials in which these agents
were aimed at correcting cardiac overstimulation by the sympathetic
system and the RAS rather than at lowering of BP (and indeed in a
number of these trials BP changes were not reported)411 In a
metaanalysis of 10 prospective observational studies of heart failure
patients a higher SBP was found to be associated with better out
comes559
Hypertension is more common in heart failure patients with pre
served LV ejection fraction However in outcome trials speciﬁcally in
cluding these patients few had uncontrolled hypertension probably
because they received a large background therapy of BPlowering
agents In one of these trials Irbesartan in Heart Failure with Preserved
Systolic Function (IPRESERVE)560 the angiotensin receptor blocker
irbesartan failed to lessen CV events compared with placebo
However randomized therapy was added to optimize existing antihy
pertensive therapy (including 25 of ACE inhibitors) and initial BP was
only 13676 mmHg thus further strengthening the question as to
whether lowering SBP much below 140 mmHg is of any further beneﬁt
6113 Atrial ﬁbrillation
Hypertension is the most prevalent concomitant condition in patients
with atrial ﬁbrillation in both Europe and the USA561 Evenhighnormal
Therapeutic strategies in hypertensive patients with
cerebrovascular disease
Recommendations Class a Level b Ref C
It is not recommended to
intervene with BPlowering
therapy during the first week after
acute stroke irrespective of BP
level although clinical judgement
should be used in the face of very
high SBP values
III B 544 545
Antihypertensive treatment is
recommended in hypertensive
patients with a history of stroke
or TIA even when initial SBP is in
the 140–159 mmHg range
I B 280 296
In hypertensive patients with a
history of stroke or TIA a SBP
goal of <140 mmHg should be
considered
IIa B 280 296
297
In elderly hypertensives with
previous stroke or TIA SBP
values for intervention and goal
may be considered to be
somewhat higher
IIb B 141 265
All drug regimens are
recommended for stroke
prevention provided that BP is
effectively reduced
I A 284
BP ¼ blood pressure SBP ¼ systolic blood pressure TIA ¼ transientischaemic attack
aClass of recommendation
bLevel of evidence
cReference(s) supporting recommendation(s)
ESH and ESC Guidelines 2201
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 2019BP is associated with the development of atrial ﬁbrillation562 and
hypertension is likely to be a reversible causative factor154 The rela
tionships of hypertension and antihypertensive therapy to atrial ﬁbril
lation have recently been discussed by a position paper of an ESH
working group563
Hypertensive patients with atrial ﬁbrillation should be assessed for
the risk of thromboembolism by the score mentioned in the recent
ESC Guidelines561 and unless contraindications exist the majority
of them should receive oral anticoagulation therapy to prevent
stroke and other embolic events564565 Current therapy is based
on vitamin K antagonistsbut newer drugseither direct thrombin inhi
bitors (dabigatran) or factor Xa inhibitors (rivaroxaban apixaban)
have been shown to be noninferior and sometimes superior to war
farin561563 They are promising newcomers in this therapeutic ﬁeld
although their value outside clinical trials remains to be demon
strated In patients receiving anticoagulant therapy good control of
BP has the added advantage of reducing bleeding events566
Most patients show a high ventricular rate when in atrial ﬁbrilla
tion565 Betablockers and nondihydropyridine calcium antagonists
are hence recommended as antihypertensive agents in patients
with atrial ﬁbrillation and high ventricular rate
The consequences of atrial ﬁbrillation include increased overall
mortality stroke heart failure and hospitalizations thereforepreven
tion or retardation of new atrial ﬁbrillation is desirable154 Secondary
analyses oftrials in patients with LVHand hypertensionhave found that
ARBs (losartan valsartan) are better in preventing ﬁrst occurrence of
atrial ﬁbrillation than betablocker (atenolol) or calcium antagonist
(amlodipine) therapy consistent with similar analyses in patients with
heart failure567–571 This ﬁnding has not been conﬁrmed in some
morerecent trials in highriskpatientswith establishedatherosclerotic
disease such as PRoFESS and TRANSCEND297558 and irbesartan did
not improve survival in the Atrial Fibrillation Clopidogrel Trial with
Irbesartan for Prevention of Vascular Events(ACTIVE I) trial in patients
with established atrial ﬁbrillation572 ARBs have not prevented recur
rences of paroxysmal or persistent atrial ﬁbrillation [CAndesartan in
the Prevention of Relapsing Atrial Fibrillation (CAPRAF)573 Gruppo
Italiano perloStudiodella Sopravvivenza nell’Infarto MiocardicoAtrial
Fibrillation (GISSIAF)574 and ANgioTensin II Antagonist In Paroxys
mal Atrial Fibrillation (ANTIPAF)575 trials] Given the heterogeneity
of the available data it has been suggested that the beneﬁcial effects
of ARBs may be limited to the prevention of incident atrial ﬁbrillation
inhypertensivepatientswithstructuralheartdiseasesuchasLVhyper
trophy or dysfunction or high risk in general but no history of atrial ﬁb
rillation568576 In patients with heart failure betablockers and
mineralocorticoid antagonists may also prevent atrial ﬁbrillation577578
The suggestion is indirectly supported by the results of a general prac
tice database in the UK with approximately 5 million patient records
reporting that ACE inhibitors and ARBs were associated with a lower
risk of atrial ﬁbrillation compared with calcium antagonists579 This has
been shown also for betablockers in heart failure Hence these agents
may be considered as the preferred antihypertensive agents in hyper
tensive patients with cardiac OD to prevent incident atrial ﬁbrillation
6114 Left ventricular hypertrophy
The 2009 ESH reappraisal document summarized the evidence on
why LVH especially of the concentric type is associated with a
CVD risk higher than 20 in 10 years (ie high CV risk)141 A
number of smaller studies but in particular the LIFE study330
reported that LVH reduction is closely related to BP reduction For
similar BP reductions ARBs ACE inhibitors and calcium antagonists
have been found in randomized comparative studies to be more ef
fective than betablockers580 In the LIFE study which selected only
hypertensive patients with LVH the therapeutically induced reduc
tion of LVM was signiﬁcantly associated with CV event reduction261
This topic is further discussed in Section 84
6115 Summary of recommendations on therapeutic
strategies in hypertensive patients with heart disease
Therapeutic strategies in hypertensive patients with
heart disease
Recommendations Class a Level b Ref C
In hypertensive patients with
CHD a SBP goal <140 mmHg
should be considered
IIa B 141 265
In hypertensive patients with a
recent myocardial infarction
betablockers are recommended
In case of other CHD all
antihypertensive agents can be
used but betablockers and
calcium antagonists are to be
preferred for symptomatic
reasons (angina)
I A 284
Diuretics betablockers ACE
inhibitors angiotensin receptor
blockers andor mineralocorticoid
receptor antagonists are
recommended in patients with
heart failure or severe LV
dysfunction to reduce mortality
and hospitalization
I A 411
In patients with heart failure and
preserved EF there is no evidence
that antihypertensive therapy per
se or any particular drug is
beneficial However in these
patients as well as in patients
with hypertension and systolic
dysfunction lowering SBP to
around 140 mmHg should be
considered Treatment guided by
relief of symptoms (congestion
with diuretics high heart rate
with betablockers etc) should
also be considered
IIa C
ACE inhibitors and angiotensin
receptor blockers (and
betablockers and
mineralocorticoid receptor
antagonists if heart
failure coexists) should be
considered as antihypertensive
agents in patients at risk of new
or recurrent atrial fibrillation
IIa C
It is recommended that all
patients with LVH receive
antihypertensive agents
I B 458
In patients with LVH initiation of
treatment with one of the agents
that have shown a greater ability
to regress LVH should be
considered ie ACE inhibitors
angiotensin receptor blockers and
calcium antagonists
IIa B 580
ACE ¼ angiotensinconverting enzyme CHD ¼ coronary heart disease EF ¼
ejection fraction LV ¼ left ventricle LVH ¼ left ventricular hypertrophy SBP ¼
systolic blood pressure
aClass of recommendation
bLevel of evidence
cReference(s) supporting recommendation(s)
ESH and ESC Guidelines2202
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 2019612 Atherosclerosis arteriosclerosis and
peripheral artery disease
6121 Carotid atherosclerosis
The 2007 ESHESC Guidelines concluded that progression of carotid
atherosclerosis can be delayed by lowering BP2 but calcium antago
nists have a greater efﬁcacy than diuretics and betablockers186 and
ACE inhibitors more than diuretics581 Very few data are available on
whethercalcium antagonists have a greatereffect on carotid IMTthan
RAS blockers
6122 Increased arterial stiffness
All antihypertensive drugs reduce arterial stiffness since the re
duction of BP unloads the stiff components of the arterial wall
leading to a passive decrease of PWV A recent metaanalysis
and metaregression analysis of RCTs documented that ACE inhi
bitors and ARBs reduce PWV582583 However owing to the lack
of highquality and properly powered RTCs it is not clear
whether they are superior to other antihypertensive agents in
their effect on arterial stiffness The ability of RAS blockers to
reduce arterial stiffness as assessed by PWV seems to be inde
pendent of their ability to reduce BP582–584 However although
the amlodipinevalsartan combination decreased central SBP
more effectively than the amlodipineatenolol combination in
the Amlodipine–Valsartan Combination Decreases Central Systol
ic Blood Pressure more Effectively than the Amlodipine–Atenolol
Combination (EXPLOR) trial both combinations decreased PWV
by 095 ms with no signiﬁcant differences over the trial 24week
duration399 Also in a randomized study in mildtomoderate
hypertension the vasodilating betablocker nebivolol decreased
central pulse pressure to a larger extent than the nonvasodilating
betablocker metoprolol after 1 year of treatment although no
signiﬁcant changes in the augmentation index or carotidfemoral
PWV were detected with either drug406 Improvement of arterial
stiffness with treatment has been documented over the long
term585 A relationship between a reduction of arterial stiffness
and reduced incidence of CV events has been reported in only
one study on a limited number of patients with advanced renal
disease586
6123 Peripheral artery disease
A prospective observational analysis of the UKPDS shows that the in
cidence of PADrelated amputation and death in patients with dia
betes is strongly and inversely associated with the SBP achieved by
treatment315587 The choice of the antihypertensive agent is less im
portant than actual BP control in patients with PAD199 ACE inhibi
tors have shown beneﬁt in a subgroup analysis of more than 4000
patients with PADenrolled in the Heart Outcomes PreventionEvalu
ation (HOPE) study588 but the arm receiving the ACE inhibitor had a
lower BP than the comparative arm
There has been concern that the use of betablockers in
patients with PAD may worsen the symptoms of claudication
Two metaanalyses of studies published in PAD patients with
mildtomoderate limb ischaemia did not conﬁrm the intake of
betablockers to be associated with exacerbation of PAD
symptoms589590
The incidence of renal artery stenosis is increased in patients with
PAD Thus this diagnosis must be kept in mind when resistant hyper
tension is encountered in these patients587
6124 Summary of recommendations on therapeutic
strategies in hypertensive patients with atherosclerosis
arteriosclerosis and peripheral artery disease
613 Sexual dysfunction
Sexual dysfunction is moreprevalent in hypertensive than normoten
sive individuals but available information mostly concerns men
Erectile dysfunction is considered to be an independent CV risk
factor and an early diagnostic indicator for asymptomatic or clinical
OD591 Hence a full history should include sexual dysfunction Life
style modiﬁcation may ameliorate erectile function592 Compared
with older antihypertensive drugs newer agents (ARBs ACE inhibi
tors calcium antagonists and vasodilating betablockers) have
neutral or even beneﬁcial effects on erectile function593
Phosphodiesterase5 inhibitors may be safely administered to
hypertensives even those on multiple drug regimens (with the pos
sible exception of alphablockers and in absence of nitrate adminis
tration)594 and may improve adherence to antihypertensive
Therapeutic strategies in hypertensive patients with
atherosclerosis arteriosclerosis and peripheral artery
disease
Recommendations Class a Level b Ref C
In the presence of carotid
atherosclerosis prescription of
calcium antagonists and ACE
inhibitors should be considered as
these agents have shown a greater
efficacy in delaying atherosclerosis
progression than diuretics and
betablockers
IIa B 186 581
In hypertensive patients with a
PWV above 10 ms all
antihypertensive drugs should be
considered provided that a BP
reduction to <14090 mmHg is
consistently achieved
IIa B 138 582
586
Antihypertensive therapy is
recommended in hypertensive
patients with PAD to achieve a
goal of <14090 mmHg
because of their high risk of
myocardial infarction stroke
heart failure and CV death
I A 284
Though a careful follow up is
necessary betablockers may be
considered for the treatment of
arterial hypertension in
patients with PAD since their use
does not appear to be associated
with exacerbation of PAD
symptoms
IIb A 589 590
ACE ¼ angiotensinconverting enzyme BP ¼ blood pressure CV ¼
cardiovascular PAD ¼ peripheral artery disease PWV ¼ pulse wave velocity
aClass of recommendation
bLevel of evidence
cReference(s) supporting recommendation(s)
ESH and ESC Guidelines 2203
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 2019therapy595 Studies on the effects of hypertension and antihyperten
sive therapy on female sexual dysfunction are in their infancy and
should be encouraged596
614 Resistant hypertension
Hypertension is deﬁnedas resistance to treatment when atherapeut
ic strategy that includes appropriate lifestyle measures plus a diuretic
and two otherantihypertensive drugs belonging to different classesat
adequate doses (but not necessarily including a mineralocorticoid re
ceptor antagonist) fails to lower SBP and DBP values to 140 and
90 mmHg respectively Depending on the population examined
and the level of medical screening the prevalence of resistant hyper
tension has been reported to range from 5–30 of the overall hyper
tensive population with ﬁgures less than 10 probably representing
the true prevalence Resistant hypertension is associated with a high
risk of CV and renal events597–600
Resistant hypertension can be real or only apparent or spurious A
frequent causeofspuriousresistant hypertensionisfailuretoadhere to
the prescribed treatment regimen a notoriously common phenom
enon that is responsible for the poor rate of BP control in the hyper
tensive population worldwide Lack of BP control may however
also depend on (i) persistence of an alerting reaction to the
BPmeasuring procedure with an elevation of ofﬁce (although not of
outofofﬁce) BP (ii) use of small cuffs on large arms with inadequate
compressionofthevesseland(iii)pseudohypertensioniemarkedar
terial stiffening (more common in the elderly especially with heavily
calciﬁed arteries) which prevents occlusion of the brachial artery
True resistant hypertension may originate from (i) lifestyle factors
such as obesity or large weight gains excessive alcohol consumption
(even in the form of binge drinking) and high sodium intake which
may oppose the BPlowering effect of antihypertensive drugs via sys
temic vasoconstriction sodium and water retention and for obesity
the sympathostimulating effect of insulin resistance and increased
insulin levels (ii) chronic intake of vasopressor or sodiumretaining
substances (iii) obstructive sleep apnoea (usually but not invariably
associated with obesity)521 possibly because nocturnal hypoxia
chemoreceptor stimulation and sleep deprivation may have a long
lasting vasoconstrictor effect (iv) undetected secondary forms of
hypertension and (v) advanced and irreversible OD particularly
when it involves renal function or leads to a marked increase in arteri
olar wall–lumen ratio or reduction of large artery distensibility
A correct diagnostic approach to resistant hypertension requires
detailed information on the patient’s history (including lifestyle
characteristics) a meticulous physical examination and laboratory
tests to detect associated risk factors OD and alterations of
glucose metabolism as well as of advanced renal dysfunction
opposing—via sodium retention—the effect of BPlowering drugs
The possibility of a secondary cause of hypertension should always
be considered primary aldosteronism may be more frequent than
was believed years ago601 and renal artery stenoses of an athero
sclerotic nature have been shown to be quite common in the
elderly Finally ABPM should be performed regularly not only to
exclude spurious resistance but also to quantify to a better degree
the BP elevation and the subsequent effect of the treatment
modiﬁcations598602
In clinical practice identiﬁcation of low adherence to treatment
may present special difﬁculties because (i) information provided by
the patient may be misleading and (ii) methods to objectively
measureadherenceto treatment havelittle applicability indaytoday
medicine An unhealthy lifestyle may represent a clue as may a
patient’s expression of negative feelings about medicines in general
Ultimately physicians may have to consider stopping all current
drugs and restart with a simpler treatment regimen under close
medical supervision This approach may also avoid futile use of inef
fective drugs Although hospitalization for hypertension is regarded
as inappropriate in most European countries a few days in hospital
may be necessary to check the BP effect of antihypertensive drugs
under strict control
Although resistant hypertension mayshowa BP reduction if the di
uretic dose is further increased (see below) most patients with this
condition require the administration of more than three drugs Sub
group analyses of largescale trials and observational studies have
provided evidence that all drug classes with mechanisms of action
partially or totally different from those of the existing three drug regi
mens can lower BP in at least some resistant hypertensive indivi
duals603 A good response has been reported to the use of
mineralocorticoid receptor antagonists ie spironolactone even at
low doses (25–50 mgday) or eplerenone the alpha1blocker dox
azosin and a further increase in diuretic dose604–608 loop diuretic re
placing thiazides or chlorthalidone if renal function is impaired Given
that blood volume may be elevated in refractory hypertension609
amiloride may add its effect to that of a previously administered thia
zide or thiazidelike diuretic although its use may favour hyperkalae
mia and is not indicated in patients with marked reduction of eGFR
The BP response to spironolactone or eplerenone may be accounted
for by the elevated plasma aldosterone levels frequently accompany
ing resistant hypertension either because aldosterone secretion
escapes the early reduction associated with RAS blockade610 or
because of undetected primary aldosteronism
At variance from an earlier report611 endothelin antagonists have
not been found to effectively reduce clinic BP in resistant hyperten
sion and their use has also been associated with a considerable rate
of sideeffects612 New BPlowering drugs (nitric oxide donors vaso
pressin antagonists neutral endopeptidase inhibitors aldosterone
synthase inhibitors etc) are all undergoing early stages of investiga
tion613 No other novel approach to drug treatment of resistant
hypertensive patients is currently available
6141 Carotid baroreceptor stimulation
Chronic ﬁeld electrical stimulation of carotid sinus nerves via
implanted devices has recently been reported to reduce SBP and
DBP in resistant hypertensive individuals614–616 The reduction was
quite marked when initial BP values were very high and the effect
included ambulatory BP and persisted for up to 53 months615
However longerterm observations have so far involved only a
restricted number of patients and further data on larger numbers
of individuals with an elevation of BP unresponsive to multiple drug
treatments are necessary to conﬁrm the persistent efﬁcacy of the
procedure Although only a few remediable sideeffects of a local
nature (infection nerve damage pain of glossopharyngeal nerve
origin etc) have so far been reported a larger database is also
needed to conclusively establish its safety Ongoing technical
improvements to reduce the inconvenience represented by the
ESH and ESC Guidelines2204
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 2019surgical implantation of the stimulating devices and to prolong the
duration of the battery providing the stimulation are being tested
6142 Renal denervation
A growing nondrug therapeutic approach to resistant hypertension
is bilateral destruction of the renal nerves travelling along the renal
artery by radiofrequency ablation catheters of various design percu
taneously inserted through the femoral artery617–621 The rationale
for renal denervation lays in the importance of sympathetic inﬂu
ences on renal vascular resistance renin release and sodium re
absorption the increased sympathetic tone to the kidney and
other organs displayed by hypertensive patients622–624 and the
pressor effect of renal afferent ﬁbres documented in experimental
animals625626 The procedurehas beenshownto induce a marked re
duction in ofﬁce BP which has been found to be sustained after one
year and in a small number of patients two and three years following
the denervation procedure Limited reductions have been observed
on ambulatory and home BP and need of antihypertensive drugs627
while some evidence of additional beneﬁt such as decrease of arterial
stiffening reversal of LVH and diastolic dysfunction renal protection
and improvement of glucose tolerance has been obtained628–630
Except for the rare problems related to the catheterization proced
ure (local haematoma vessel dissection etc) no major complications
or deterioration of renal function have been reported
At present the renal denervation method is promising but in need
of additional data from properly designed longterm comparison
trials to conclusively establish its safety and persistent efﬁcacy vs
the best possible drug treatments Understanding what makes
renal denervation effective or ineffective (patient characteristics or
failure to achieve renal sympathectomy) will also be important to
avoid the procedure in individuals unlikely to respond A position
paper of the ESH on renal denervation should be consulted for
more details631
6143 Other invasive approaches
Research in this area is ongoing and new invasive procedures are
under study Examples are creation of a venousarterial ﬁstula and
neurovascular decompression by surgical interventions which has
been found to lower BP in a few cases of severe resistant hyperten
sion (presumably by reducing central sympathetic overactivity)
with however an attenuation of the effect after 2 years632 New
catheters are also available to shorten the renal ablation procedure
and to achieve renal denervation by means other than radiofre
quency eg by ultrasounds
Overall renal denervation and carotid baroreceptor stimulation
should be restricted to resistant hypertensive patients at particularly
high risk after fully documenting the inefﬁcacy of additional antihy
pertensive drugs to achieve BP control For either approach it will
be of fundamental importance to determine whether the BP reduc
tions are accompanied by a reduced incidence of CV morbid and fatal
events given the recent evidence from the FEVER and Valsartan Anti
hypertensive Longterm Use Evaluation (VALUE) studies that in
patients under multidrug treatment CV risk (i) was greater than in
patients on initial randomized monotherapy and (ii) did not decrease
as a result of a fall in BP633634 This raises the possibility of risk irrever
sibility which should be properly studied
6144 Followup in resistant hypertension
Patients with resistant hypertension should be monitored closely
Ofﬁce BP should be measured at frequent intervals and ambulatory
BP at least once a year Frequent home BP measures can also be con
sidered and measures of organ structure and function (particularly of
the kidney) instituted on a yearly basis Although mineralocorticoid re
ceptor antagonists at low doses have been associated with relatively
few sideeffects their use should prompt frequent assessment of
serum potassium and serum creatinine concentrations because
these patients may undergo acutely or chronically an impairment of
renal function especially if there is concomitant treatment with a
RAS blocker Until more evidence is available on thelongterm efﬁcacy
and safety of renal denervation and baroreceptor stimulation imple
mentation of these procedures should be restricted to experienced
operators and diagnosis and followup restricted to hypertension
centres631
6145 Summary of recommendations on therapeutic
strategies in patients with resistant hypertension
Therapeutic strategies in patients with resistant
hypertension
Recommendations Class a Level b Ref C
In resistant hypertensive patients
it is recommended that physicians
check whether the drugs included
in the existing multiple drug
regimen have any BP lowering
effect and withdraw them if their
effect is absent or minimal
I C
Mineralocorticoid receptor
antagonists amiloride and the
alpha1blocker doxazosin should
be considered if no
contraindication exists
IIa B 604 606
607 608
In case of ineffectiveness of drug
treatment invasive procedures
such as renal denervation and
baroreceptor stimulation may be
considered
IIb C
Until more evidence is available
on the longterm efficacy and
safety of renal denervation and
baroreceptor stimulation it is
recommended that these
procedures remain in the hands
of experienced operators and
diagnosis and followup restricted
to hypertension centers
It is recommended that the
invasive approaches are
considered only for truly resistant
hypertensive patients with clinic
values ≥160 mmHg SBP or
≥110 mmHg DBP and with BP
elevation confirmed by ABPM
I
I
C
C

ABPM ¼ ambulatory blood pressure monitoring BP ¼ blood pressure DBP ¼
diastolic blood pressure SBP ¼ systolic blood pressure
aClass of recommendation
bLevel of evidence
cReference(s) supporting recommendation(s)
ESH and ESC Guidelines 2205
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 2019615 Malignant hypertension
Malignant hypertension is a hypertensive emergency clinically
deﬁned as the presence of very high BP associated with ischaemic
OD (retina kidney heart or brain) Although its frequency is very
low the absolute number of new cases has not changed much over
the past 40 years The survival rate 5 years after diagnosis of malignant
hypertension has improved signiﬁcantly (it was close to zero 50 years
ago) possibly as a result of earlier diagnosis lower BP targets and
availability of new classes of antihypertensive agents635 OD may
regress—at least partially—under treatment636 although longterm
prognosis remains poor especially when renal function is severely
reduced637 Because of its low incidence no good controlled study
has been conducted with recent agents Current treatment is
founded on agents that can be administered by intravenous infusion
and titrated and so can act promptly but gradually in order to avoid
excessive hypotension and further ischaemic OD Labetalol sodium
nitroprusside nicardipine nitrates and furosemide are among the
intravenous agents most usually employed but in these severely ill
patients treatment should be individualized by the physician
When diuretics are insufﬁcient to correct volume retention ultraﬁl
tration and temporary dialysis may help
616 Hypertensive emergencies
and urgencies
Hypertensive emergencies are deﬁned as large elevations in SBP or DBP
(180 mmHg or 120 mmHg respectively) associated with impend
ingorprogressive ODsuchas majorneurological changeshypertensive
encephalopathy cerebral infarction intracranial haemorrhage acute LV
failure acute pulmonary oedema aortic dissection renal failure or
eclampsia Isolated large BP elevations without acute OD (hypertensive
urgencies)—often associated with treatment discontinuation or reduc
tion as well as with anxiety—should not be considered an emergency
but treated by reinstitution or intensiﬁcation of drug therapy and treat
ment of anxiety Suspicions have recently been raised on the possible
damaging effect of maximum vs predominant BP values435 However
this requires more information and overtreatment should be avoided
Treatment of hypertensive emergencies depends on the type of
associated OD and ranges from no lowering or extremely cautious
lowering of BP in acute stroke (see Section 610) to prompt and ag
gressive BP reduction in acute pulmonary oedema or aortic dissec
tion In most other cases it is suggested that physicians induce a
prompt but partial BP decrease aiming at a 25 BP reduction
during the ﬁrst hours and proceed cautiously thereafter Drugs to
be used initially intravenously and subsequently orally are those
recommended for malignant hypertension (see Section 615) All
suggestions in this area except those for acute stroke are based
on experience because of the lack of any RCTs comparing aggressive
vs conservative lowering of BP and the decision on how to proceed
should be individualized
617 Perioperative management
of hypertension
Presence of hypertension is one of the common reasons for postpon
ing necessary surgery but it is arguable whether this is necessary638
StratifyingtheoverallCVriskofthesurgerycandidate maybemoreim
portant639 The question of whether antihypertensive therapy should
be maintained immediately before surgery is frequently debated
Sudden withdrawal of clonidine or betablockers should be avoided
because of potential BP or heart rate rebounds Both types of agent
can be continued over surgery and when patients are unable to take
oralmedicationsbetablockerscanbegivenparenterallyand clonidine
transdermally Diuretics should be avoided on the day of surgery
because of potential adverse interaction with surgerydependent
ﬂuid depletion ACE inhibitors and ARBs may also be potentiated by
surgerydependent ﬂuid depletion and it has been suggested that
they should not be taken on the day of surgery and restarted after
ﬂuid repletion has been assured Postsurgery BP elevation when it
occurs is frequently caused by anxiety and pain after awakening and
disappears after treating anxiety and pain All these suggestions are
based on experience only (Class IIb Level C)
618 Renovascular hypertension
Renovascular artery stenosis secondary to atherosclerosis is relative
ly frequent especially in the elderly population but rarely progresses
to hypertension or renal insufﬁciency640 It is still debated whether
patients with hypertension or renal insufﬁciency beneﬁt from inter
ventions mostly percutaneous renal artery stenting While there is
convincing (though uncontrolled) information favouring this proced
ure in younger (mostly female) patients with uncontrolled hyperten
sion in ﬁbromuscular hyperplasia (82–100 success restenosis in
10–11)641 (Class IIa Level B) the matter is highly controversial
in atherosclerotic renovascular hypertension Two retrospective
studies have reported improvements (though not in mortality) in
patients with bilateral renal artery stenosis complicated by recurrent
episodes of acute heart failure642 In all other conditions with renal
artery stenosis uncertainties continue regarding the beneﬁt of angio
plasty and stenting despite several controlled trials Two RCTs and
21 cohort studies published before 2007 showed no uniform
pattern of beneﬁt The more recent Angioplasty and STenting for
Renal Artery Lesions (ASTRAL) trial including 806 patients rando
mized between angioplasty and stenting plus medical therapy vs
medical therapy alone did not provide any evidence of clinically
meaningful beneﬁt on BP renal function or CV events643 Although
no ﬁnal conclusions can be drawn from ASTRAL because of some
limitations in its design (patients with a strong indication for interven
tion wereexcluded fromrandomization) and lackof statisticalpower
intervention is at present not recommended in atherosclerotic renal
artery stenosis if renal function has remained stable over the past 6–
12 months and if hypertension can be controlled by an acceptable
medical regimen (Class III Level B) Suitable medical regimens can
include RAS blockers except in bilateral renal artery stenosis or in
unilateral artery stenosis with evidence of functional importance by
ultrasound examinations or scintigraphy
619 Primary aldosteronism
In documented unilateral primary aldosteronism caused either by
aldosteroneproducing adenoma or unilateral adrenal hyperplasia
the treatment of choice is unilateral laparoscopic adrenalectomy
whereas treatment with mineralocorticoid receptor antagonists is
indicated in patients with bilateral adrenal disease (idiopathic
adrenal hyperplasia and bilateral adenoma) Glucocorticoidremedi
able aldosteronism is treated with a low dose of a longacting gluco
corticoid eg dexamethasone
Surgical treatment in patients with unilateral primary aldosteron
ism shows improvement of postoperative serum potassium concen
trations in nearly 100 of patients644 when diagnosis of—and
indication for—adrenalectomy are based on adrenal venous
ESH and ESC Guidelines2206
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 2019sampling Hypertension is cured (deﬁned as BP 14090 mmHg
without antihypertensive medication) in about 50 (range 35–
60) of patients with primary aldosteronism after unilateral adrena
lectomy Cure is more likely in patients having no more than one
ﬁrstdegree relative with hypertension preoperative use of two
antihypertensive drugs at most younger age shorter duration of
hypertension and no vascular remodelling645646
Mineralocorticoid receptor antagonists (spironolactone eplere
none) are indicated in patients presenting with bilateral adrenal
disease and in those who for various reasons do not undergo
surgery for unilateral primary aldosteronism The starting dose for spir
onolactone should be 125–25 mg daily in a single dose the lowest ef
fective dose should be found very gradually titrating upwards to a dose
of 100 mg daily or more The incidence of gynaecomasty with spirono
lactone is doserelated whereas the exact incidence of menstrual distur
bances in premenopausal women with spironolactone is unknown A
small dose of a thiazide diuretic triamterene or amiloride can be added
to avoid a higher dose of spironolactone which may cause sideeffects
Eplerenone is a newer selective mineralocorticoid receptor antag
onist without antiandrogen and progesterone agonist effects thus redu
cing the rate of sideeffects it has 60 of the antagonist potency of
spironolactone Because of its shorter duration of action multiple
daily dosing is required (with a starting dose of 25 mg twice daily) In
a recent 16week doubleblind randomized study comparing the anti
hypertensive effect of eplerenone (100–300 mg once daily) and spir
onolactone (75–225 mg once daily) spironolactone was signiﬁcantly
superior to eplerenone in reducing BP in primary aldosteronism647
7 Treatment of associated risk
factors
71 Lipidlowering agents
Patients with hypertension and especially those with type 2 diabetes
or metabolic syndrome often have atherogenic dyslipidemia charac
terized by elevated triglycerides and LDLcholesterol with a low
HDLcholesterol1213648 The beneﬁt of adding a statin to antihyper
tensive treatment was well established by the AngloScandinavian
Cardiac Outcomes Trial—Lipid Lowering Arm (ASCOTLLA)
study649 as summarized in the 2007 ESHESC Guidelines2 The
lack of statistically signiﬁcant beneﬁt in the ALLHAT study can be
attributed to insufﬁcient lowering of total cholesterol (11 in
ALLHAT compared with 20 in ASCOT)650 Further analyses of
the ASCOT data have shown that the addition of a statin to the
amlodipinebased antihypertensive therapy can reduce the incidence
of the primary CV outcome even more markedly than the addition of
a statin to the atenololbased therapy651 The beneﬁcial effect of
statin administration to patients without previous CV events [target
ing a lowdensity lipoprotein cholesterol value 30 mmolL
(115 mgdL)] has been strengthened by the ﬁndings of the Justiﬁca
tion for the Use of Statins in Primary Prevention an Intervention
Trial Evaluating Rosuvastatin (JUPITER) study652 showing thatlower
ing lowdensity lipoprotein cholesterol by 50 in patients with base
line values 34 mmolL (130 mgdL) but with elevated Creactive
protein reduced CV events by 44 This justiﬁes use of statins in
hypertensive patients who have a high CV risk
As detailed in the recent ESCEAS Guidelines653 when overt CHD
is present there is clear evidence that statins should be administered
to achieve lowdensity lipoprotein cholesterol levels 18 mmolL
(70 mgdL)654 Beneﬁcial effects of statin therapy have also been
shown in patients with a previous stroke with lowdensity lipopro
tein cholesterol targets deﬁnitely lower than 35 mmolL (135 mg
dL)655 Whether they also beneﬁt from a target 18 mmolL
(70 mgdL) is open to future research This is the case also for hyper
tensive patients with a lowmoderate CV risk in whom evidence of
the beneﬁcial effects of statin administration is not clear656
72 Antiplatelet therapy
In secondary CV prevention a large metaanalysis published in 2009
showed that aspirin administration yielded an absolute reduction in
CV outcomes much larger than the absolute excess of major bleed
ings657 In primary prevention however the relationship between
beneﬁt and harm is different as the absolute CV event reduction is
small and only slightly greater than the absolute excess in major
bleedings A more favourable balance between beneﬁt and harm of
aspirin administration has been investigated in special groups of
primary prevention patients Studies on diabetes have so far failed
to establish a favourable beneﬁt–harm ratio whereas a substudy
of the HOT trial in which hypertensive patients were classiﬁed on
the basis of eGFR at randomization showed aspirin administration
to be associated with a signiﬁcant trend for a progressive reduction
in major CV events and death the lower the baseline eGFR values
This reduction was particularly marked in hypertensive patients
with eGFR 45 mLmin173 m2 In this group of patients the risk
of bleeding was modest compared with the CV beneﬁt658 Aspirin
therapy should be given only when BP is well controlled
In conclusion the prudent recommendations of the 2007 ESH
ESC Guidelines can be reconﬁrmed2 antiplatelet therapy particular
ly lowdose aspirin should be prescribed to controlled hypertensive
patients with previous CV events and considered in hypertensive
patients with reduced renal function or a high CV risk Aspirin is
not recommended in lowtomoderate risk hypertensive patients
in whom absolute beneﬁt and harm are equivalent It is noteworthy
that a recent metaanalysis has shown lower incidences of cancer
and mortality in the aspirin (but not the warfarin) arm of primary pre
vention trials659 If conﬁrmed this additional action of aspirin may
lead to a more liberal reconsideration of its use Lowdose aspirin
in the prevention of preeclampsia is discussed in Section 653
73 Treatment of hyperglycaemia
The treatment of hyperglycaemiafor preventionof CV complications
in patients with diabetes has been evaluated in a number of studies
For patients with type 1 diabetes the Diabetes Control and Compli
cations (DCCT) study convincingly showed that intensive insulin
therapy was superior for vascular protection and reduction of
events compared with standard treatment660661 In type 2 diabetes
several largescale studies have aimed at investigating whether a tight
glycaemic control based on oral drugs andor insulin is superior to
lesstight control for CV prevention In UKPDS tighter glycaemic
control could prevent microvascular—but not macrovascular—
complications662 except in a subgroup with obesity treated with
metformin663 The appropriate target for a glycaemic control has
been explored recently in the ADVANCE664 ACCORD665 and Vet
erans’ Affairs Diabetes Trial (VADT)666 studies which randomized
one study arm to very low HbA1c targets (65 or 60) None of
these individual studies showed a signiﬁcant reduction of the com
posite endpoint of combined CVD events but a number of later
metaanalyses have documented that more intensive glycaemic
ESH and ESC Guidelines 2207
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 2019control is likely to reduce nonfatal coronary events and myocardial
infarction as well as nephropathy but not stroke or allcause or CV
mortality667–669 However especially in ACCORD the lower HbA1c
target arm was associated with an excess of hypoglycaemic episodes
and allcause mortality Based on these data the American Diabetol
ogy Association and the European Association for the Study of Dia
betes (EASD)670 have jointly taken a similar prudent attitude
recommending that physicians individualize treatment targets and
avoid overtreatment of fragile higherrisk patients by restricting
more stringent control of hyperglycaemia to younger patients with
recent diabetes absent or minor vascular complications and long life
expectancy (HbA1c target 70) while considering a lessstringent
HbA1c of 75–80 or even higher in more complicated and fragile
patients particularly in elderly patients with cognitive problems
and a limited capacity for self care670671 The ESCEASD Guidelines
for the treatment of diabetes should be consulted for moredetails672
74 Summary of recommendations on
treatment of risk factors associated with
hypertension
8 Followup
81 Followup of hypertensive patients
After the initiation of antihypertensive drug therapy it is important to
see the patient at 2 to 4week intervals to evaluate the effects on BP
and to assess possible sideeffects Some medications will have an
effect within days or weeks but a continued delayed response may
occur during the ﬁrst 2 months Once the target is reached a visit
interval of a few months is reasonable and evidence has been
obtained that no difference exists in BP control between 3 and
6month intervals673 Depending on the local organization of
health resources many of the later visits may be performed by non
physician health workers such as nurses674 For stable patients
HBPM and electronic communication with the physician (SMS
email social media or automated telecommunication of home BP
readings) may also provide an acceptable alternative675–677 It is
nevertheless advisable to assess risk factors and asymptomatic OD
at least every 2 years
82 Followup of subjects with high normal
blood pressure and whitecoat
hypertension
Individuals with high normal BPor whitecoat hypertension frequent
ly have additional risk factors including asymptomatic OD with a
higher chance of developing ofﬁce or sustained hypertension re
spectively285351678–681 (see Section 313) Even if untreated they
should be scheduled for regular followup (at least annual visits) to
measure ofﬁce and outofofﬁce BP as well as to check the CV risk
proﬁle Regular annual visits should also serve the purpose of reinfor
cing recommendations on lifestyle changes which represent the ap
propriate treatment in many of these patients
83 Elevated blood pressure
at control visits
Patients and physicians have a tendency to interpret an uncon
trolled BP at a given visit as due to occasional factors and thus
to downplay its clinical signiﬁcance This should be avoided and
the ﬁnding of an elevated BP should always lead physicians to
search for the cause(s) particularly the most common ones
such as poor adherence to the prescribed treatment regimen per
sistence of a whitecoat effect and occasional or moreregular
consumption of drugs or substances that raise BP or oppose
the antihypertensive effect of treatment (eg alcohol non
steroidal antiinﬂammatory drugs) This may require tactful but
stringent questioning of the patient (and hisher relatives) as
well as repeated measurements of BP to attenuate the initial alert
ing response to the BPmeasuring procedures If ineffective treat
ment is regarded as the reason for inadequate BP control the
treatment regimen should be modiﬁed without delay to avoid clin
ical inertia—major contribution to poor BP control world
wide682683 Consideration should be given to the evidence that
visittovisit BP variability may be a determinant of CV risk inde
pendently of the mean BP levels achieved during longterm treat
ment and that thus CV protection may be greater in patients
with consistent BP control throughout visits
Treatment of risk factors associated with hypertension
Recommendations Class a Level b Ref C
It is recommended to use statin
therapy in hypertensive patients
at moderate to high CV risk
targeting a lowdensity
lipoprotein cholesterol value
<30 mmolL (115 mgdL)
I A 649 652
When overt CHD is present it is
recommended to administer
statin therapy to achieve
lowdensity lipoprotein
cholesterol levels <18 mmolL
(70 mgdL)
I A 654
Antiplatelet therapy in particular
lowdose aspirin is recommended
in hypertensive patients with
previous CV events
I A 657
Aspirin should also be
considered in hypertensive
patients with reduced renal
function or a high CV risk
provided that BP is well
controlled
IIa B 658
Aspirin is not recommended for
CV prevention in lowmoderate
risk hypertensive patients in
whom absolute benefit
and harm are equivalent
III A 657
In hypertensive patients with
diabetes a HbA1c target of <70
is recommended with antidiabetic
treatment
I B 670
In more fragile elderly patients
with a longer diabetes duration
more comorbidities and at high
risk treatment to a HbA1c target
of <75–80 should be
considered
IIa C
BP ¼ blood pressure CHD ¼ coronary heart disease CV ¼ cardiovascular
HbA1c ¼ glycated haemoglobin
aClass of recommendation
bLevel of evidence
cReference(s) supporting recommendation(s)
ESH and ESC Guidelines2208
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 201984 Continued search for asymptomatic
organ damage
Several studies have shown that the regression of asymptomatic OD
occurring during treatment reﬂects the treatmentinduced reduction
of morbid and fatal CV events thereby offering valuable information
onwhetherpatientsaremoreorlesseffectivelyprotectedbythetreat
ment strategies adopted This has been shown for the treatment
induced regression of electrocardiographic LVH (voltage or strain
criteria) the echocardiographic LVH and the echocardiographically
derived measures of LVM and left atrial size150151261684–686 Lower
incidence of CV events and slower progression of renal disease
have also been repeatedly associated with treatmentinduced reduc
tion in urinary protein excretion in both diabetic and
nondiabetic patients227262535536687688 but especially for microal
buminuria discordant results havealso been reported329331 This has
also been the case in a recent subanalysis of the ACCOMPLISH trial
in which the combination of an ACE inhibitorand acalcium antagonist
was more effective than an ACE inhibitor–diuretic combination in
preventing the doubling of serum creatinine or ESRD while reducing
proteinuria to a lesser degree539 A recent analysis of the ELSA study
has on the other hand failed to consistently document a predictive
value for CV events of treatmentinduced reductions in carotid
IMT (possibly because the changes are minimal and their impact
masked by large betweensubject differences)188 This conclusion is
supported by metaanalyses689–691 though some of them have
been discussed692 Evidence on the predictive power of treatment
induced changes in other measures of OD (eGFR PWV and ABI) is
either limited or absent On the whole it appears reasonable to
search for at least some asymptomatic OD not only for the initial
stratiﬁcation of CV risk but also during followup A cost
effectiveness analysis of which signs of OD should best be assessed
in the followup of hypertensive patients has never been done As
sessment of urinary protein excretion can be reliably quantiﬁed in a
morning urine sample and has a low cost wide availability and
ability to show a treatmentinduced effect within a few months
Also the low cost and wide availability suggest regular repetition
of an ECG although detection of its LVHdependent change is
less sensitive Treatmentinduced changes are also slow for echo
cardiographic measures of LVM which also carries the disadvan
tage of reduced availability higher cost extratime and need of
reﬁned expertise for proper assessment The information available
on assessment of OD during antihypertensive treatment is sum
marized in Figure 5 In addition followup measurements should
include lipid proﬁle blood glucose serum creatinine and serum po
tassium and regardless of their greater or smaller ability to accur
ately and quickly detect regression with treatment all measures of
OD may provide useful information on the progression of
hypertensiondependent abnormalities as well as on the appear
ance of conditions requiring additional therapeutic interventions
such as arrhythmias myocardial ischaemia stenotic plaques and
heart failure
85 Can antihypertensive medications be
reduced or stopped
In some patients in whom treatment is accompanied by an effective
BP control for an extended period it may be possible to reduce the
number and dosage of drugs This may be particularly the case if BP
control is accompanied by healthy lifestyle changes such as weight
loss exercise habits and a lowfat and lowsalt diet which remove en
vironmental pressor inﬂuences Reduction of medications should be
made gradually and the patient should frequently be checked because
of the risk of reappearance of hypertension
9 Improvement of blood pressure
control in hypertension
Despite overwhelming evidence that hypertension is a major CV risk
factor and that BPlowering strategies substantially reduce the risk
studies performed outside Europe and in several European coun
tries16683 consistently show that (i) a noticeable proportion of
hypertensive individuals are unaware of this condition or if aware
do not undergo treatment693694 (ii) target BP levels are seldom
achieved regardless of whether treatment is prescribed or patients
are followed by specialists or general practitioners695696 (iii)
failure to achieve BP control is associated with persistence of an ele
vated CV risk 697698 and (iv) the rate of awareness of hypertension
and BP control is improving slowly or not at all—and this is the
case also in secondary prevention699700 Because in clinical trials
antihypertensive treatment can achieve BP control in the majority
of the patients701 these data reﬂect the wide gap that exists
between the antihypertensive treatment potential and reallife
ECG electrocardiogram echo echocardiogram eGFR estimated
y OD organ damage
Marker of
organ damage
Sensitivity
for changes Time to change Prognostic value
of changes
LVHECG Low Moderate
(>6 months) Yes
LVHecho Moderate Moderate
(>6 months) Yes
LVHcardiac
magnetic
resonance
High Moderate
(>6 months) No data
eGFR Moderate Very slow
(years) No data
Urinary
protein
excretion
High Fast
(weeks–months) Moderate
Carotid wall
thickness Very low Slow
(>12 months) No
Pulse wave
velocity High Fast
(weeks–months) Limited data
Ankle
brachial
index
Low No data No data
Figure 5 Sensitivity to detect treatmentinduced changes time
to change and prognostic value of change by markers of asymptom
atic OD
ESH and ESC Guidelines 2209
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 2019practice As a consequence high BP remains a leading cause of death
and CV morbidity in Europe as elsewhere in theworld702 Thusthere
is a strong need to detect and treat more hypertensive patients as
well as improve the efﬁcacy of ongoing treatment
Overall three main causes of the low rate of BP control in real life
havebeenidentiﬁed (i) physicianinertia703 (ii) patient lowadherence
to treatment704705 and (iii) deﬁciencies of healthcare systems in their
approach to chronic diseases however delayed initiation of treat
ment when OD is irreversible or scarcely reversible is also likely to
be an important factor272 Physician inertia (ie lack of therapeutic
action when the patient’s BP is uncontrolled) is generated by
several factors doubts about the risk represented by high BP particu
larly in the elderly fear of a reduction in vital organ perfusion when BP
is reduced (the Jcurve phenomenon) and concern about side
effects Several physicians also maintain a sceptical attitude towards
guidelines because of their multiplicity and origin from different
sources (international and national scientiﬁc societies governmental
agencies local hospitals etc) which make their recommendations
sometimes inconsistent Recommendations are also often perceived
as unrealistic when applied to the environment where physicians
operate706
Low adherence to treatment is an even more important cause of
poor BP control because it involves a large number of patients and
its relationship with persistence of elevated BP values and high CV
risk has been fully documented704–710 Nonadherence has been
classiﬁed into discontinuers’ (patients who discontinue treatment)
and bad users’ [ie those who take treatment irregularly because
of delays in drug(s) intake or repeated short interruptions of the pre
scribed therapeutic strategy] Discontinuers represent a greater
problem because their behaviour is normally intentional and once
discontinued treatment resumption is more difﬁcult Bad users
however are at higher risk of becoming discontinuers and thus
their identiﬁcation is important
Low adherence is extremely common for lifestyle changes but im
portantly extends to drug prescriptions for which it develops quite
rapidly after 6 months more than onethird and after 1 year about
half of the patients may stop their initial treatment furthermore on
a daily basis 10 of patients forget to take their drug704705 For
hypertension (and other chronic diseases) investigating adherence
to treatment is now facilitated by electronic methods of measuring
adherence and by the availability of administrative databases that
provide information for the entire population709711
Several approaches have been proposed to reduce physician
inertia unawareness of hypertension and nonadherence to treat
ment Physician training programmes notably reduce inertia al
though perhaps with less than expected beneﬁts712–714 and
there is consensus that making simple informative material avail
able in the lay press the physician’s ofﬁce pharmacies schools
and other public places may have a favourable effect on information
and motivation by interested individuals715 Emphasis should be
placed on the importance of measuring and reporting BP values
even at visits not connected with hypertension or problems of a
CV nature in order to collate information on BP status over the
years Adherence to treatment can also be improved by simpliﬁca
tion of treatment716 and use of selfmeasured BP at home66 an
additional favourable effect might be gained through the use of tel
emetry for transmission of recorded home values9899
Health providers should facilitate guidelines implementation as a
means of educating physicians about recent scientiﬁc data rather
than primarily as an instrument to contain cost They should also
foster a multidisciplinary approach to CV prevention which could
mean that physicians receive the same motivating message from dif
ferent perspectives The mostserious attempt by a healthcare system
to improve the diagnostic and treatment aspects of hypertension has
been done in the UK based on the payperperformance principle
ie to give incentives to physicians rewarding the appropriate diagno
sis and care of chronic diseases including hypertension The impact
on the quality and outcomes of care for hypertension is uncertain
An early report showed that the implementation was associated
with an increased rate of BP monitoring and control among general
practitioners717 whereas later reports showed that the trend was
not sustained Furthermore no statistically signiﬁcant changes in
the cumulative incidence of major hypertensionrelated adverse out
comes or mortality have been observed after implementation of
payforperformance for the subgroups of already treated and
newly treated patients718719
A list of the interventions associated with improved patient adher
ence to treatment in shown in Table 17
10 Hypertension disease
management
While there is strong evidence that antihypertensive treatment has a
protective effect (see Section 41) it is less clear how care for
Table 17 Methods to improve adherence to physicians’
recommendations
Patient level
Information combined with motivational strategies
(see Section 516 on smoking cessation)
Group sessions
Selfmonitoring of blood pressure
Selfmanagement with simple patientguided systems
Complex interventionsa
Drug treatment level
Reminder packaging
Health system level
home visits telemonitoring of home blood pressure social
support computeraided counselling and packaging)
Interventions directly involving pharmacists
Reimbursement strategies to improve general practitioners’
involvement in evaluation and treatment of hypertension
aAlmost all of the interventionsthatwere effectivefor longterm carewere complex
including combinations of more convenient care information reminders
selfmonitoring reinforcement counselling family therapy psychological therapy
crisis intervention manual telephone followup supportive care worksite and
pharmacybased programmes
ESH and ESC Guidelines2210
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 2019hypertensive patients should be organized and delivered in the com
munity720 However there seems to be little doubt that for effective
disease management a multidisciplinary approach is required This
means the involvement of a variety of healthcare providers720–722
the general practitioner who should take care of the majority of
hypertensive patients medical specialists from various ﬁelds depend
ing on the nature of the hypertension and the difﬁculty posed by its
treatment speciﬁcally trained nurses to closely follow the patient
during his or her lifetime treatment and pharmacists who handle phy
sicians’ prescriptions and often have to deal directly with the patients’
problems and reply to his or her questions In an ideal setting all
health care providers should cooperate in a successful lifetime inter
vention against this condition In a review of the results of 13 studies
interpretation of disease management programmes resulted in a sig
niﬁcantly greater SBP and DBP reduction compared with controls
The effect was equivalent to an about 5 mmHg and 4 mmHg
greater effect on SBP and DBP respectively723
101 Team approach in disease
management
Wide variations exist in the organization of healthcare systems across
Europe but in most countries hypertension is usually diagnosed and
managed in primary care (ie by general practitioners) In some coun
tries practicebased specialists take care of more complex examina
tions (ultrasounds etc) and the more difﬁculttotreat cases while in
other countries only hospitalbased specialists and hypertension
units are available for referral In a few countries specially educated
and trained nurses assist physicians in the prescription consultation
referral and even hospital admission of individuals with raised BP In
most countries however nurses have little or no rolesharing with
physicians
Several studies are available to show that teambased care can
reduce BP by several mmHg more than standard care724 with a
greater SBP reduction of about 10 mmHg (median value) and an ap
proximately 22 greater rate of BP control in a metaanalysis from
37 comparisons between teambased and standardtreatment
groups725 Compared with standard care teambased care has
been found to be effective if it involves nurses andor pharmacists
either within a clinic or in the community724 The beneﬁcial effect
of the involvement of pharmacists and nurses in the management
of hypertension has been obtained when their task involved patient
education behavioural and medical counselling assessment of adher
ence to treatment and for pharmacists interaction with physicians in
the area of guidelinebased therapy724726727 In a review of 33 RCTs
published between 2005 and 2009 BP targets were more commonly
achieved when interactions included a stepcare treatment algorithm
administeredby nurses as well asthe involvement of nurses in patient
monitoring by telephone726728729 Clearly teambased strategies
offer an important potential method for improvement of antihyper
tensive treatment compared with strategies involving physicians
alone Physicians nurses and pharmacists should all be represented
and general practitioners should interact when needed with specia
lists from various areas such as internists cardiologists nephrolo
gists endocrinologists and dieticians The contribution of nurses
may be particularly important for implementation of lifestyle
changes for which longterm adherence is notoriously extremely
low Details on how team work for hypertension management may
be organized are available in a recent publication on ESH Excellence
Centres730
102 Mode of care delivery
Care is normally delivered on a facetoface basis ie during an ofﬁce
visit in the primary care setting in a specialist’s ofﬁce or in hospital
Other methods for the delivery of care are however available
such as telephone interviews and advanced telemedicine (including
videoconferences) Telephone contacts are effective in changing
patientbehaviours with the additional potential advantage thatcom
pared with facetoface contact726 (i) more patients can be reached
(ii) little or no time or working hours are lost and (iii) contacts can be
more frequent with a greater chance of addressing patients’ con
cerns inatimely mannertailoring treatment and ultimatelyimproving
adherence It is nevertheless important to emphasize that these new
models of care delivery do not represent a substitute for ofﬁce visits
but rather offer a potentially useful addition to the strategy of estab
lishing a good relationship between the patient and the healthcare
providers
103 The role of information and
communication technologies
Studies using communication technologies have shown that there are
many new ways by which healthcare teams can communicate with
patients with the theoretical advantage of timely and effective adjust
ment of care plans Home BP telemonitoring represents an appropri
ate example several studies have shown that electronic transmission
of selfmeasured BP can lead to better adherence to treatment
regimen and more effective BP control677728731732 Other examples
include the use of smart phones cell phones Bluetooth texting per
sonal electronic health records and patient portals all aimed at
favouring selfmonitoring of treatment efﬁcacy adherence to pre
scription and feedback to healthcare personnel It should be noted
however that for no such device has effectiveness been proven in
an RCT thus their advantage over classical medical approaches
remains to be established723724731–734
The impact of information and communication technologies in
general and of computerized decisionsupport systems in particular
on patient risk management and safety is analysed in detail in the
eHealth for Safety report published by the European Commission
in 2007 (reviewepracticeenenlibrary302671) The report main
tains that these systems can (i) prevent medical errors and adverse
events (ii) initiate rapid responses to an event enable its tracking
and provide feedback to learn from (iii) provide information that
can ease diagnostic and therapeutic decisions and (iv) favour involve
ment of the patient in the decisionmaking process with an advantage
to his or her cooperation and adherence735
Connecting the patient’s health records to a variety of electronic
health records (from different providers pharmacies laboratories
hospitals or insurers) may foster the development of tailored tools
for the individual patient enhancing his or her engagement in care
and disease prevention and improving health outcomes and patient
satisfaction Further developments are the incorporation of compu
terized technology that may help in the decisionmaking process to
manage high BP
ESH and ESC Guidelines 2211
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 201911 Gaps in evidence and need for
future trials
Based on the review of the evidence available for the 2013 Guidelines
on hypertension it is apparent that several therapeutic issues are still
open to question and would beneﬁt from further investigation
(1) Should antihypertensive drug treatment be given to all patients
with grade 1 hypertension when their CV risk is
lowtomoderate
(2) Should elderly patients with a SBP between 140 and 160 mmHg
be given antihypertensive drug treatments
(3) Should drug treatment be given to subjects with whitecoat
hypertension Can this condition be differentiated into patients
needing or not needing treatment
(4) Should antihypertensive drug treatment be started in the high
normal BP range and if so in which patients
(5) What are the optimal ofﬁce BP values (ie the most protective
and safe) for patients to achieve by treatment in different demo
graphic and clinical conditions
(6) Do treatment strategies based on control of outofofﬁce BP
provide an advantage (reduced clinical morbidity and mortality
fewer drugs fewer sideeffects) over strategies based on con
ventional (ofﬁce) BP control
(7) What are the optimal outofofﬁce (home and ambulatory) BP
values to be reached with treatment and should targets be
lower or higher in high risk hypertensives
(8) Does central BP add to CV event prediction in untreated and
treated hypertensive patients
(9) Do invasive procedures for treatment of resistant hypertension
compare favourably with the best drug treatment and provide
longterm BP control and reduction of morbid and fatal events
(10) Do treatmentinduced changes in asymptomatic OD predict
outcome Which measures—or combinations of measures—
are most valuable
(11) Are lifestyle measures known to reduce BP capable of reducing
morbidity and mortality in hypertensive patients
(12) Does a treatmentinduced reduction of 24h BP variability add
to CV protection by antihypertensive treatment
(13) Does BP reduction substantially lower CV risk in resistant
hypertension
While RCTs remain the gold standard’ for solving therapeutic issues
it is equally clear that it would be unreasonable to expectthatall these
questions can realistically be answered by RCTs in a foreseeable
future Approaching some of these questions such as those of the re
duction of CV morbid and fatal events by treating grade 1 hyperten
sive individuals at low risk for CVD or the CV event reduction of
lifestyle measures would require trials involving many thousands of
individuals for a very extended period and may also raise ethical pro
blems Others such as the beneﬁt of drug treatment for whitecoat
hypertensives or the additional predictive power of central vs per
ipheral BP may requirehuge investigational efforts for small prospect
ive beneﬁts It appears reasonable at least for the next years to focus
RCTs upon important—as well as moreeasily approachable—issues
like the optimal BP targets to be achieved by treatment the BP values
to be treated and achieved in elderly hypertensive individuals clinical
reduction of morbidity and fatal events by new approaches to
treating resistant hypertension and the possible beneﬁts of treating
highrisk individuals with high normal BP Other important issues
eg the predictive value of outofofﬁce BP and that of OD can be
approached more realistically by adding these measurements to
the design of some of the RCTs planned in the near future
APPENDIX
Task Force members afﬁliations
Giuseppe Mancia (Chairperson)1 Robert Fagard (Chairperson)2
Krzysztof Narkiewicz (Section Coordinator)3 Josep Redon (Section
Coordinator)4 Alberto Zanchetti (Section Coordinator)5 Michael
Bo¨hm6 Thierry Christiaens7RenataCifkova8 Guy De Backer9
Anna Dominiczak10 Maurizio Galderisi11 Diederick E Grobbee12
Tiny Jaarsma13 Paulus Kirchhof14 Sverre E Kjeldsen15Ste´phane
Laurent16 Athanasios J Manolis17 Peter M Nilsson18LuisMiguel
Ruilope19 Roland E Schmieder20 Per Anton Sirnes21 Peter
Sleight22 Margus Viigimaa23BernardWaeber24 Faiez Zannad25
1Centro di Fisiologia Clinica e Ipertensione Universita` Milano
Bicocca IRCSS Istituto Auxologico ItalianoMilano Italy 2Hyperten
sion and Cardiovascular Rehab Unit KU Leuven University Leuven
Belgium 3Department of Hypertension and Diabetology Medical
University of Gdansk Gdansk Poland 4University of Valencia
INCLIVA Research Institute and CIBERobn Madrid 5University of
Milan Istituto Auxologico Italiano Milan Italy 6Klinik fu¨r Innere
Medizin III Universitaetsklinikum des Saarlandes HomburgSaar
Germany 7General Practice and Family Health Care Ghent Univer
sity Ghent Belgium 8Centre for Cardiovascular Prevention Charles
University Medical School I and Thomayer Hospital Prague Czech
Republic Centre 9Department of Public Health University Hospital
Ghent Belgium 10College of Medical Veterinary and Life Sciences
University of Glasgow Glasgow UK 11Cardioangiology with CCU
Department of Translational Medical Science Federico II University
Hospital Naples Italy 12University Medical CentreUtrecht Utrecht
Netherlands 13Department of Social and Welfare Studies Facultyof
Health Sciences University of Linko¨ping Linko¨ping Sweden
14Centre for Cardiovascular Sciences University of Birmingham
and SWBH NHS Trust Birmingham UK and Department of Cardio
vascular Medicine Universityof Mu¨nsterGermany 15Department of
Cardiology University of Oslo Ullevaal Hospital Oslo Norway
16Department of Pharmacology and INSERM U970 European Hos
pital Georges Pompidou Paris France 17Cardiology Department
Asklepeion General Hospital Athens Greece 18Department of
Clinical Sciences Lund University Scania University Hospital
Malmo Sweden 19Hypertension Unit Hospital 12 de Octubre
Madrid Spain 20Nephrology and Hypertension University Hospital
Erlangen Germany 21Cardiology Practice Ostlandske Hjertesenter
Moss Norway 22Nufﬁeld Department of Medicine John Radcliffe
Hospital Oxford UK 23Heart Health Centre North Estonia
Medical Centre Tallinn University of Technology Tallinn Estonia
24Physiopathologie Clinique Centre Hospitalier Universitaire
Vaudois Lausanne Switzerland 25INSERM Centre d’Investigation
Clinique 9501 and U 1116 Universite´ de Lorraine and CHU
Nancy France
ESH and ESC Guidelines2212
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 2019References
1 2003 European Society of HypertensionEuropean Society of Cardiology guide
lines for the management of arterial hypertensionJ Hypertens2003211011–1053
2 Mancia G De Backer G Dominiczak A Cifkova R Fagard R Germano G Grassi G
Heagerty AM Kjeldsen SE Laurent S Narkiewicz K Ruilope L Rynkiewicz A
Schmieder RE Boudier HA Zanchetti A 2007 Guidelines for the Management
of Arterial Hypertension The Task Force for the Management of Arterial Hyper
tension of the European Society of Hypertension (ESH) and of the European
Society of Cardiology (ESC) J Hypertens 2007251105–1187
3 Lewington S Clarke R Qizilbash N Peto R Collins R Agespeciﬁc relevance of
usual blood pressure to vascular mortality a metaanalysis of individual data for
one million adults in 61 prospective studies Lancet 20023601903–1913
4 Britton KA Gaziano JM Djousse L Normal systolic blood pressure and risk of heart
failure in US male physicians Eur J Heart Fail 2009111129–1134
5 Kalaitzidis RG Bakris GL Prehypertension is it relevant for nephrologists Kidney
Int 201077194–200
6 Asia Paciﬁc Cohort Studies Collaboration Blood pressure and cardiovascular
disease in the Asia Paciﬁc region J Hypertens 200321707–716
7 Brown DW Giles WH Greenlund KJ Blood pressure parameters and risk of fatal
stroke NHANES II mortality study Am J Hypertens 200720338–341
8 Franklin SS Gustin WIV Wong ND Larson MG Weber MA Kannel WB Levy D
Haemodynamic patterns of agerelated changes in blood pressure The Framing
ham Heart Study Circulation 199796308–315
9 Vishram JK Borglykke A Andreasen AH Jeppesen J Ibsen H Jørgensen T Broda G
Palmieri L Giampaoli S Donfrancesco C Kee F Mancia G Cesana G Kuulasmaa K
Sans S Olsen MH on behalf of the MORGAM ProjectImpact of Age on the Import
ance of Systolic and Diastolic Blood Pressures for Stroke Risk The MOnica Risk
Genetics Archiving and Monograph (MORGAM) Project Hypertension 201260
1117–1123
10 Benetos A Safar M Rudnichi A Smulyan H Richard JL Ducimetieere P Guize L
Pulse pressure a predictor of longterm cardiovascular mortality in a French
male population Hypertension 1997301410–1415
11 Kannel WB Wolf PA McGee DL Dawber TR McNamara P Castelli WP Systolic
blood pressure arterial rigidity risk of stroke The Framingham study JAMA 1981
2451225–1229
12 Kannel WB Risk stratiﬁcation in hypertension new insights from the Framingham
Study Am J Hypertens 2000133S–10S
13 Thomas F Rudnichi A Bacri AM Bean K Guize L Benetos A Cardiovascular mor
tality in hypertensive men according to presence of associated risk factors Hyper
tension 2001371256–1261
14 Pickering G Hypertension Deﬁnitions natural histories and consequences Am J
Med 197252570–583
15 Lurbe E Cifkova R Cruickshank JK Dillon MJ Ferreira I Invitti C Kuznetsova T
Laurent S Mancia G MoralesOlivas F Rascher W Redon J Schaefer F
Seeman T Stergiou G Wuhl E Zanchetti A Management of high blood pressure
in children and adolescents recommendations of the European Society of Hyper
tension J Hypertens 2009271719–1742
16 Pereira M Lunet N Azevedo A Barros H Differences in prevalence awareness
treatment and control of hypertension between developing and developed coun
tries J Hypertens 200927963–975
17 DanonHersch N MarquesVidal P Bovet P Chiolero A Paccaud F Pecoud A
Hayoz D Mooser V Waeber G Vollenweider P Prevalence awareness treatment
and control of high blood pressure in a Swiss city general population the CoLaus
study Eur J Cardiovasc Prev Rehabil 20091666–72
18 Altun B Arici M Nergizoglu G Derici U Karatan O Turgan C Sindel S Erbay B
Hasanoglu E Caglar S Prevalence awareness treatment and control of hyperten
sion in Turkey (the PatenT study) in 2003 J Hypertens 2005231817–1823
19 Tugay Aytekin N Pala K Irgil E Akis N Aytekin H Distribution of blood pressures
in Gemlik District northwest Turkey Health Soc Care Community 200210
394–401
20 Efstratopoulos AD Voyaki SM Baltas AA Vratsistas FA Kirlas DE Kontoyannis JT
Sakellariou JG Triantaphyllou GB Alokrios GA Lianas DN Vasilakis EA
Fotiadis KN Kastritsea EE Prevalence awareness treatment and control of hyper
tension in Hellas Greece the Hypertension Study in General Practice in Hellas
(HYPERTENSHELL) national study Am J Hypertens 20061953–60
21 Macedo ME Lima MJ Silva AO Alcantara P Ramalhinho V Carmona J Prevalence
awareness treatment and control of hypertension in Portugal the PAP study
J Hypertens 2005231661–1666
22 Psaltopoulou T Orfanos P Naska A Lenas D Trichopoulos D Trichopoulou A
Prevalence awareness treatment and control of hypertension in a general popu
lation sample of 26913 adults in the Greek EPIC study Int J Epidemiol 200433
1345–1352
23 Saraﬁdis PA Lasaridis A Gousopoulos S Zebekakis P Nikolaidis P Tziolas I
Papoulidou F Prevalence awareness treatment and control of hypertension in
employees of factories of Northern Greece the Naoussa study J Hum Hypertens
200418623–629
24 Panagiotakos DB Pitsavos CH Chrysohoou C Skoumas J Papadimitriou L
Stefanadis C Toutouzas PK Status and management of hypertension in Greece
role of the adoption of a Mediterranean diet the Attica study J Hypertens 2003
211483–1489
25 Banegas JR Graciani A de la CruzTroca JJ Le´onMunoz LM GuallarCastillo`nP
Coca A Ruilope LM RodriguezArtalejo F Achievement of cardiometabolic
targets in aware hypertensive patients in Spain a nationwide populationbased
study Hypertension 201260898–905
26 Primatesta P Poulter NR Improvement in hypertension management in England
results from the Health Survey for England 2003 J Hypertens 2006241187–1192
27 Meisinger C Heier M Volzke H Lowel H Mitusch R Hense HW Ludemann J Re
gional disparities of hypertension prevalence and management within Germany
J Hypertens 200624293–299
28 Agyemang C UjcicVoortman J Uitenbroek D Foets M Droomers M Prevalence
and management of hypertension among Turkish Moroccan and native Dutch
ethnic groups in Amsterdam the Netherlands The Amsterdam Health Monitor
Survey J Hypertens 2006242169–2176
29 Agyemang C Bindraban N Mairuhu G Montfrans G Koopmans R Stronks K
Prevalence awareness treatment and control of hypertension among Black Suri
namese South Asian Surinamese and White Dutch in Amsterdam The Nether
lands the SUNSET study J Hypertens 2005231971–1977
30 Scheltens T Bots ML Numans ME Grobbee DE Hoes AW Awareness treatment
and control of hypertension the ’rule of halves’ in an era of riskbased treatment of
hypertension J Hum Hypertens 20072199–106
31 Zdrojewski T Szpakowski P Bandosz P Pajak A Wiecek A
KrupaWojciechowska B Wyrzykowski B Arterial hypertension in Poland in
2002 J Hum Hypertens 200418557–562
32 Cifkova R Skodova Z Lanska V Adamkova V Novozamska E Jozifova M
Plaskova M Hejl Z Petrzilkova Z Galovcova M Palous D Prevalence awareness
treatment and control of hypertension in the Czech Republic Results of two na
tionwide crosssectional surveys in 19971998 and 20002001 Czech Post
MONICA Study J Hum Hypertens 200418571–579
33 Scuteri A Najjar SS Orru M Albai G Strait J Tarasov KV Piras MG Cao A
Schlessinger D Uda M Lakatta EG Age and genderspeciﬁc awareness treatment
and control of cardiovascular risk factors and subclinical vascular lesions in a
founder population the SardiNIA Study Nutr Metab Cardiovasc Dis 200919
532–541
34 Kastarinen M Antikainen R Peltonen M Laatikainen T Barengo NC Jula A
Salomaa V Jousilahti P Nissinen A Vartiainen E Tuomilehto J Prevalence aware
ness and treatment of hypertension in Finland during 1982–2007 J Hypertens 2009
271552–1559
35 Falaschetti E Chaudhury M Mindell J PoulterN Continued improvement in hyper
tension management in England results from the Health Survey for England 2006
Hypertension 200953480–486
36 Erem C Hacihasanoglu A Kocak M Deger O Topbas M Prevalence of prehyper
tension and hypertension and associated risk factors among Turkish adults
Trabzon Hypertension Study J Public Health (Oxf) 20093147–58
37 Costanzo S Di Castelnuovo A Zito F Krogh V Siani A Arnout J Cappuccio FP
Miller MA van Dongen M de Lorgeril M de Gaetano G Donati MB Iacoviello L
Prevalence awareness treatment and control of hypertension in healthy unrelated
malefemale pairs of European regions the dietary habit proﬁle in European com
munities with different risk of myocardial infarction the impact of migration as a
model of geneenvironment interaction project J Hypertens 2008262303–2311
38 Cooper RS Using public health indicators to measure the success of hypertension
control Hypertension 200749773–774
The CME text 2013 ESHESC Guidelines for the management of arterial hypertension’ is accredited by the European Board for Accreditation in Cardiology (EBAC) EBAC works accord
ing to the quality standards of the European Accreditation Council for Continuing Medical Education (EACCME) which is an institution of the European Union of Medical Specialists
(UEMS) In compliance with EBACEACCME Guidelines all authors participating in this programme have disclosed any potential conﬂicts of interest that might cause a bias in the
article The Organizing Committee is responsible for ensuring that all potential conﬂicts of interest relevant to the programme are declared to the participants prior to the CME activities
CME questions for this article are available at European Heart Journal httpwwwoxfordelearningcomeurheartj and European Society of Cardiology httpwwwescardio
orgguidelines
ESH and ESC Guidelines 2213
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 201939 WolfMaier K Cooper RS Banegas JR Giampaoli S Hense HW Joffres M
Kastarinen M Poulter N Primatesta P RodriguezArtalejo F Stegmayr B
Thamm M Tuomilehto J Vanuzzo D Vescio F Hypertension prevalence and
blood pressure levels in 6 European countries Canada and the United States
JAMA 20032892363–2369
40 Redon J Olsen MH Cooper RS Zurriaga O MartinezBeneito MA Laurent S
Cifkova R Coca A Mancia G Stroke mortality trends from 1990 to 2006 in 39
countries from Europe and Central Asia implications for control of high blood
pressure Eur Heart J 2011321424–1431
41 Pyorala K De Backer G Graham I PooleWilson P Wood D Prevention of coron
ary heart disease in clinical practice Recommendations of the Task Force of the
European Society of Cardiology European Atherosclerosis Society and European
Society of Hypertension Eur Heart J 1994151300–1331
42 D’Agostino RB Sr Vasan RS Pencina MJ Wolf PA Cobain M Massaro JM
Kannel WB General cardiovascular risk proﬁle for use in primary care the Fra
mingham Heart Study Circulation 2008117743–753
43 Conroy RM Pyorala K Fitzgerald AP Sans S Menotti A De Backer G De
Bacquer D Ducimetiere P Jousilahti P Keil U Njolstad I Oganov RG
Thomsen T TunstallPedoe H Tverdal A Wedel H Whincup P Wilhelmsen L
Graham IM Estimation of tenyear risk of fatal cardiovascular disease in Europe
the SCORE project Eur Heart J 200324987–1003
44 Woodward M Brindle P TunstallPedoe H Adding social deprivation and family
history to cardiovascular risk assessment the ASSIGN score from the Scottish
Heart Health Extended Cohort (SHHEC) Heart 200793172–176
45 HippisleyCox J Coupland C Vinogradova Y Robson J Minhas R Sheikh A
Brindle P Predicting cardiovascular risk in England and Wales prospective deriv
ation and validation of QRISK2 BMJ 20083361475–1482
46 Assmann G Cullen P Schulte H Simple scoring scheme for calculating the risk of
acute coronary events based on the 10year followup of the prospective cardio
vascular Munster (PROCAM) study Circulation 2002105310–315
47 Ridker PM Paynter NP Rifai N Gaziano JM Cook NR Creactive protein and par
ental history improveglobal cardiovascular risk prediction the Reynolds Risk Score
for men Circulation 20081182243–2251 2244p following 2251
48 Ridker PM Buring JE Rifai N Cook NR Development and validation of improved
algorithms for the assessment of global cardiovascular risk in women the Reynolds
Risk Score JAMA 2007297611–619
49 Cooney MT Dudina AL Graham IM Value and limitations of existing scores for the
assessment of cardiovascular risk a review for physicians J Am Coll Cardiol 200954
1209–1227
50 Perk J De Backer G Gohlke H Graham I Reiner Z Verschuren M Albus C
Benlian P Boysen G Cifkova R Deaton C Ebrahim S Fisher M Germano G
Hobbs R Hoes A Karadeniz S Mezzani A Prescott E Ryden L Scherer M
Syvanne M Scholte Op Reimer WJ Vrints C Wood D Zamorano JL Zannad F
European Guidelines on cardiovascular disease prevention in clinical practice
(version 2012) The Fifth Joint Task Force of the European Society of Cardiology
and Other Societies on Cardiovascular Disease Prevention in Clinical Practice
(constituted by representatives of nine societies and by invited experts) Developed
with the special contribution of the European Association for Cardiovascular Pre
vention & Rehabilitation (EACPR) Eur Heart J 2012331635–1701
51 Sehestedt T Jeppesen J Hansen TW Wachtell K Ibsen H TorpPedersen C
Hildebrandt P Olsen MH Risk prediction is improved by adding markers of subclin
ical organ damage to SCORE Eur Heart J 201031883–891
52 Sehestedt T Jeppesen J Hansen TW Rasmussen S Wachtell K Ibsen H
TorpPedersen C Olsen MH Thresholds for pulse wave velocity urine albumin
creatinine ratio and left ventricular mass index using SCORE Framingham and
ESHESC risk charts J Hypertens 2012301928–1936
53 Volpe M Battistoni A Tocci G Agabiti Rosei E Catapano AL Coppo R del Prato S
Gentile S Mannarino E Novo S Prisco D Mancia G Cardiovascular risk assess
ment beyond systemic coronary risk estimation a role for organ damage
markers J Hypertens 2012301056–1064
54 Guidelines Subcommittee 1999 World Health OrganizationInternational Society
of Hypertension Guidelines for the Management of Hypertension J Hypertens
199917151–183
55 World Health Organization International Society of Hypertension Writing Group
World Health Organization (WHO)International Society of Hypertension (ISH)
statement on management of hypertension J Hypertens 2003211983–1992
56 O’Brien E Waeber B Parati G Staessen J Myers MG Blood pressure measuring
devices recommendations of the European Society of Hypertension BMJ 2001
322531–536
57 Clark CE Taylor RS Shore AC Ukoumunne OC Compbell JL Association of a dif
ference in systolic blood pressure between arms with vascular disease and mortal
ity a systematic review and metaanalysis Lancet 2012379905–914
58 Fedorowski A Stavenow L Hedblad B Berglund G Nilsson PM Melander O
Orthostatic hypotension predicts allcause mortality and coronary events in
middleaged individuals (The Malmo Preventive Project) Eur Heart J 201031
85–91
59 Fagard RH De Cort P Orthostatic hypotension is a more robust predictor of car
diovascular eventsthan nighttime reverse dipping in elderlyHypertension201056
56–61
60 Trazzi S Mutti E Frattola A Imholz B Parati G Mancia G Reproducibility of non
invasive and intraarterial blood pressure monitoring implications for studies on
antihypertensive treatment J Hypertens 19919115–119
61 Myers MG Godwin M Dawes M Kiss A Tobe SW Kaczorowski J Measurement of
blood pressure in the ofﬁce recognizing the problem and proposing the solution
Hypertension 201055195–200
62 Julius S Palatini P Kjeldsen SE Zanchetti A Weber MA McInnes GT Brunner HR
Mancia G Schork MA Hua TA Holzhauer B Zappe D Majahalme S Jamerson K
Koylan N Usefulness of heart rate to predict cardiac events in treated patients with
highrisk systemic hypertension Am J Cardiol 2012109685–692
63 Benetos A Rudnichi A Thomas F Safar M Guize L Inﬂuence of heart rate on mor
tality in a French population role of age gender and blood pressure Hypertension
19993344–52
64 O’Brien E Asmar R Beilin L Imai Y Mancia G Mengden T Myers M Padﬁeld P
Palatini P Parati G Pickering T Redon J Staessen J Stergiou G Verdecchia P Prac
tice guidelines of the European Society of Hypertension for clinic ambulatory and
self blood pressure measurement J Hypertens 200523697–701
65 O’Brien E Parati G Stergiou G Asmar R Beilin L Bilo G Clement D de la Sierra A
de Leeuw P Dolan E Fagard R Graves J Head G Imai Y Kario K Lurbe E
Mallion JM Mancia G Mengden T Myers M Ogedegbe G Ohkubo T
Omboni S Palatini P Redon J Ruilope LL Shennan A Staessen JA van
Montfrans G Verdecchia P Waeber B Wang J Zanchetti A Zhang Y on behalf
of the European Society of Hypertension Working Group on Blood Pressure Mon
itoring European Society of Hypertension position paper on ambulatory blood
pressure monitoring J Hypertens 2013 in press
66 Parati G Stergiou GS Asmar R Bilo G de Leeuw P Imai Y Kario K Lurbe E
Manolis A Mengden T O’Brien E Ohkubo T Padﬁeld P Palatini P Pickering TG
Redon J Revera M Ruilope LM Shennan A Staessen JA Tisler A Waeber B
Zanchetti A Mancia G European Society of Hypertension practice guidelines for
home blood pressure monitoring J Hum Hypertens 201024779–785
67 Parati G Stergiou GS Asmar R Bilo G de Leeuw P Imai Y Kario K Lurbe E
Manolis A Mengden T O’Brien E Ohkubo T Padﬁeld P Palatini P Pickering TG
Redon J Revera M Ruilope LM Shennan A Staessen JA Tisler A Waeber B
Zanchetti A Mancia G European Society of Hypertension Working Group on
Blood Pressure Monitoring European Society of Hypertension guidelines for
blood pressure monitoring at home a summary report of the Second International
Consensus Conference on Home Blood Pressure Monitoring J Hypertens 200826
1505–1526
68 Mancia G Omboni S Parati G Trazzi S Mutti E Limited reproducibility of hourly
blood pressure values obtained by ambulatory blood pressure monitoring implica
tions for studies on antihypertensive drugs J Hypertens 1992101531–1535
69 Di Rienzo M GrassiG Pedotti A Mancia G Continuousvs intermittent blood pres
sure measurements in estimating 24hour average blood pressure Hypertension
19835264–269
70 Stergiou GS Kollias A Destounis A Tzamouranis D Automated blood pressure
measurement in atrial ﬁbrillation a systematic review and metaanalysis
J Hypertens 2012302074–2082
71 Fagard R Brguljan J Thijs L Staessen J Prediction of the actual awake and asleep
blood pressures by various methods of 24 h pressure analysis J Hypertens 1996
14557–563
72 Octavio JA Contreras J Amair P Octavio B Fabiano D Moleiro F Omboni S
Groppelli A Bilo G Mancia G Parati G Timeweighted vs conventional quantiﬁ
cation of 24h average systolic and diastolic ambulatory blood pressures
J Hypertens 201028459–464
73 Omboni S Parati G Palatini P Vanasia A Muiesan ML Cuspidi C Mancia G Repro
ducibility and clinical value of nocturnal hypotension prospective evidence from
the SAMPLE study Study on Ambulatory Monitoring of Pressure and Lisinopril
Evaluation J Hypertens 199816733–738
74 Stenehjem AE Os I Reproducibility of blood pressure variability whitecoat effect
and dipping pattern in untreated uncomplicated and newly diagnosed essential
hypertension Blood Press 200413214–224
75 Mancia G Short and longterm blood pressure variability present and future
Hypertension 201260512–517
76 Kario K Pickering TG Umeda Y Hoshide S Hoshide Y Morinari M Murata M
Kuroda T Schwartz JE Shimada K Morning surge in blood pressure as a predictor
of silent and clinical cerebrovascular disease in elderly hypertensives a prospective
study Circulation 20031071401–1406
77 Head GA Chatzivlastou K Lukoshkova EV Jennings GL Reid CM A novel measure
of the power of the morning blood pressure surge from ambulatory blood pressure
recordings Am J Hypertens 2010231074–1081
ESH and ESC Guidelines2214
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 201978 White WB Blood pressure load and target organ effects in patients with essential
hypertension J Hypertens 19919(Suppl 8)S39–41
79 Li Y Wang JG Dolan E Gao PJ Guo HF Nawrot T Stanton AV Zhu DL O’Brien E
Staessen JA Ambulatory arterial stiffness index derived from 24hour ambulatory
blood pressure monitoring Hypertension 200647359–364
80 Parati G Schillaci G What are the real determinants of the ambulatory arterial stiff
ness index J Hypertens 201230472–476
81 Verdecchia P Angeli F Mazzotta G Garofoli M Ramundo E Gentile G
Ambrosio G Reboldi G Daynight dip and earlymorning surge in blood pressure
in hypertension prognostic implications Hypertension 20126034–42
82 Gaborieau V Delarche N Gosse P Ambulatory blood pressure monitoring vs self
measurement of blood pressure at home correlation with target organ damage
J Hypertens 2008261919–1927
83 Bliziotis IA Destounis A Stergiou GS Home vs ambulatory and ofﬁce blood pres
sure in predicting target organ damage in hypertension a systematic review and
metaanalysis J Hypertens 2012301289–1299
84 Staessen JA Thijs L Fagard R O’Brien ET Clement D de Leeuw PW Mancia G
Nachev C Palatini P Parati G Tuomilehto J Webster J Predicting cardiovascular
risk using conventional vs ambulatory blood pressure in older patients with systolic
hypertension Systolic Hypertension in Europe Trial Investigators JAMA 1999282
539–546
85 Clement DL De Buyzere ML De Bacquer DA de Leeuw PW Duprez DA
Fagard RH Gheeraert PJ Missault LH Braun JJ Six RO Van Der Niepen P
O’Brien E Ofﬁce vs Ambulatory Pressure Study Investigators Prognostic value
of ambulatory bloodpressure recordings in patients with treated hypertension
N Engl J Med 20033482407–2415
86 Dolan E Stanton A Thijs L Hinedi K Atkins N McClory S Den Hond E
McCormack P Staessen JA O’Brien E Superiority of ambulatory over clinic
blood pressure measurement in predicting mortality the Dublin outcome study
Hypertension 200546156–161
87 Sega R Facchetti R Bombelli M Cesana G Corrao G Grassi G Mancia G Prognos
tic value of ambulatory and home blood pressures compared with ofﬁce blood
pressure in the general population followup results from the Pressioni Arteriose
Monitorate e Loro Associazioni (PAMELA) study Circulation 2005111
1777–1783
88 Conen D Bamberg F Noninvasive 24h ambulatory blood pressure and cardiovas
cular disease a systematic review and metaanalysis J Hypertens 200826
1290–1299
89 Boggia J Li Y Thijs L Hansen TW Kikuya M BjorklundBodegard K Richart T
Ohkubo T Kuznetsova T TorpPedersen C Lind L Ibsen H Imai Y Wang J
Sandoya E O’Brien E Staessen JA Prognostic accuracy of day vs night ambulatory
blood pressure a cohort study Lancet 20073701219–1229
90 Fagard RH Celis H Thijs L Staessen JA Clement DL De Buyzere ML De
Bacquer DA Daytime and nighttime blood pressure as predictors of death and
causespeciﬁc cardiovascular eventsin hypertensionHypertension20085155–61
91 Fagard RH Thijs L Staessen JA Clement DL De Buyzere ML De Bacquer DA
Prognostic signiﬁcance of ambulatory blood pressure in hypertensive patients
with history of cardiovascular disease Blood Press Monit 200813325–332
92 Minutolo R Agarwal R Borrelli S Chiodini P Bellizzi V Nappi F Cianciaruso B
Zamboli P Conte G Gabbai FB De Nicola L Prognostic role of ambulatory
blood pressure measurement in patients with nondialysis chronic kidney disease
Arch Intern Med 20111711090–1098
93 de la Sierra A Banegas JR Segura J Gorostidi M Ruilope LM Ambulatory blood
pressuremonitoring and development ofcardiovasculareventsinhighrisk patients
included in the Spanish ABPM registry the CARDIORISC Event study J Hypertens
201230713–719
94 Hansen TW Li Y Boggia J Thijs L Richart T Staessen JA Predictive role of the
nighttime blood pressure Hypertension 2011573–10
95 Fagard RH Thijs L Staessen JA Clement DL De Buyzere ML De Bacquer DA
Nightday blood pressure ratio and dipping pattern as predictors of death and car
diovascular events in hypertension J Hum Hypertens 200923645–653
96 Mancia G Bombelli M Facchetti R Madotto F Corrao G Trevano FQ Grassi G
Sega R Longterm prognostic value of blood pressure variability in the general
population results of the Pressioni Arteriose Monitorate e Loro Associazioni
Study Hypertension 2007491265–1270
97 Kario K Pickering TG Matsuo T Hoshide S Schwartz JE Shimada K Stroke prog
nosis and abnormal nocturnal blood pressure falls in older hypertensivesHyperten
sion 200138852–857
98 Parati G Omboni S Role of home blood pressure telemonitoring in hypertension
management an update Blood Press Monit 201015285–295
99 Stergiou GS Nasothimiou EG Hypertension Does home telemonitoring improve
hypertension management Nature Rev Nephrol 20117493–495
100 Kikuya M Ohkubo T Metoki H Asayama K Hara A Obara T Inoue R Hoshi H
Hashimoto J Totsune K Satoh H Imai Y Daybyday variability of blood pressure
and heart rate athome as a novel predictorof prognosis the Ohasama studyHyper
tension 2008521045–1050
101 Stergiou GS Bliziotis IA Home blood pressure monitoring in the diagnosis and
treatment of hypertension a systematic review Am J Hypertens 201124123–134
102 Stergiou GS Siontis KC Ioannidis JP Home blood pressure as a cardiovascular
outcome predictor it’s time to take this method seriously Hypertension 201055
1301–1303
103 Ward AM Takahashi O Stevens R Heneghan C Home measurement of blood
pressure and cardiovascular disease systematic review and metaanalysis of pro
spective studies J Hypertens 201230449–456
104 FagardRH VanDen BroekeC De CortP Prognostic signiﬁcance ofblood pressure
measured in the ofﬁce at home and during ambulatory monitoring in older patients
in general practice J Hum Hypertens 200519801–807
105 Mancia G Facchetti R Bombelli M Grassi G Sega R Longterm risk of mortality
associated with selective and combined elevation in ofﬁce home and ambulatory
blood pressure Hypertension 200647846–853
106 Mancia G Bertinieri G Grassi G Parati G Pomidossi G Ferrari A Gregorini L
Zanchetti A Effects of bloodpressure measurement by the doctor on patient’s
blood pressure and heart rate Lancet 19832695–698
107 Parati G Ulian L Santucciu C Omboni S Mancia G Difference between clinic and
daytime blood pressure is not a measure of the whitecoat effect Hypertension
1998311185–1189
108 Mancia G Zanchetti A Whitecoat hypertension misnomers misconceptions and
misunderstandings What should we do next J Hypertens 1996141049–1052
109 Fagard RH Cornelissen VA Incidence of cardiovascular events in whitecoat
masked and sustained hypertension vs true normotension a metaanalysis
J Hypertens 2007252193–2198
110 Staessen JA O’Brien ET Amery AK Atkins N Baumgart P De Cort P Degaute JP
Dolenc P De Gaudemaris R Enstrom I et al Ambulatory blood pressure in normo
tensive and hypertensive subjects results from an international database
J Hypertens Suppl 199412S1–12
111 Dolan E Stanton A Atkins N Den Hond E Thijs L McCormack P Staessen J
O’Brien E Determinants of whitecoat hypertension Blood Press Monit 20049
307–309
112 Pierdomenico SD Cuccurullo F Prognostic value of whitecoat and masked hyper
tension diagnosed by ambulatory monitoring in initially untreated subjects an
updated meta analysis Am J Hypertens 20112452–58
113 Franklin SS Thijs L Hansen TW Li Y Boggia J Kikuya M BjorklundBodegard K
Ohkubo T Jeppesen J TorpPedersen C Dolan E Kuznetsova T
StolarzSkrzypek K Tikhonoff V Malyutina S Casiglia E Nikitin Y Lind L
Sandoya E KaweckaJaszcz K Imai Y Wang J Ibsen H O’Brien E Staessen JA Sig
niﬁcance of whitecoat hypertension in older persons with isolated systolic hyper
tension a metaanalysis using the International Database on Ambulatory Blood
Pressure Monitoring in Relation to Cardiovascular Outcomes population Hyper
tension 201259564–571
114 Sega R Trocino G Lanzarotti A Carugo S Cesana G Schiavina R Valagussa F
Bombelli M Giannattasio C Zanchetti A Mancia G Alterations of cardiacstructure
in patients with isolated ofﬁce ambulatory or home hypertension Data from the
general population (Pressione Arteriose Monitorate E Loro Associazioni
[PAMELA] Study) Circulation 20011041385–1392
115 Mancia G Bombelli M Facchetti R Madotto F QuartiTrevano F Grassi G Sega R
Increased longterm risk of newonset diabetes mellitus in whitecoat and masked
hypertension J Hypertens 2009271672–1678
116 Mancia G Bombelli M Facchetti R Madotto F QuartiTrevano F Polo Friz H
Grassi G Sega R Longterm risk of sustained hypertension in whitecoat or
masked hypertension Hypertension 200954226–232
117 Bobrie G Clerson P Menard J PostelVinay N Chatellier G Plouin PF Masked
hypertension a systematic review J Hypertens 2008261715–1725
118 Ogedegbe G Agyemang C Ravenell JE Masked hypertension evidence of the need
to treat Current Hypertens Rep 201012349–355
119 Lurbe E Torro I Alvarez V Nawrot T Paya R RedonJ Staessen JA Prevalence per
sistence and clinical signiﬁcance of masked hypertension in youth Hypertension
200545493–498
120 Lurbe E Redon J Kesani A Pascual JM Tacons J Alvarez V Batlle D Increase in noc
turnal blood pressure and progression to microalbuminuria in type 1 diabetes N
Engl J Med 2002347797–805
121 Wijkman M Lanne T Engvall J Lindstrom T Ostgren CJ Nystrom FH Masked noc
turnal hypertension a novel marker of risk in type 2 diabetes Diabetologia 200952
1258–1264
122 Hodgkinson J Mant J Martin U Guo B Hobbs FD Deeks JJ Heneghan C
Roberts N McManus RJ Relative effectiveness of clinic and home blood pressure
monitoring compared with ambulatory blood pressure monitoring in diagnosis of
hypertension systematic review BMJ 2011342d3621
ESH and ESC Guidelines 2215
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 2019123 Fagard R Grassi G Blood pressure response to acute physical and mental stress In
Mancia G Grassi G Kjeldsen SE (editors) Manual of Hypertension of the European
Society of Hypertension Informa Healthcare London UK 2008 p184–189
124 Le VV Mitiku T Sungar G Myers J Froelicher V The blood pressure response to
dynamic exercise testing a systematic review Prog Cardiovasc Dis 200851
135–160
125 Smith RG Rubin SA Ellestad MH Exercise hypertension an adverse prognosis
J Am Soc Hyper 20093366–373
126 Huot M Arsenault BJ Gaudreault V Poirier P Perusse L Tremblay A Bouchard C
Despres JP Rheaume C Insulin resistance low cardiorespiratory ﬁtness and
increasedexercise blood pressure contribution ofabdominal obesityHypertension
2011581036–1042
127 Sung J Choi SH Choi YH Kim DK Park WH The relationship between arterial
stiffness and increase in blood pressure during exercise in normotensive
persons J Hypertens 201230587–591
128 Holmqvist L Mortensen L Kanckos C Ljungman C Mehlig K Manhem K Exercise
blood pressure and the risk of future hypertension J Hum Hypertens 201226
691–695
129 Fagard RH Pardaens K Staessen JA Thijs L Prognostic value of invasive haemo
dynamic measurements at rest and during exercise in hypertensive men Hyperten
sion 19962831–36
130 Kjeldsen SE Mundal R Sandvik L Erikssen G Thaulow E Erikssen J Supine and ex
ercise systolic blood pressure predict cardiovascular death in middleaged men
J Hypertens 2001191343–1348
131 Sharman JE Hare JL Thomas S Davies JE Leano R Jenkins C Marwick TH Asso
ciation of masked hypertension and left ventricular remodeling with the hyperten
sive response to exercise Am J Hypertens 201124898–903
132 Hedberg P Ohrvik J Lonnberg I Nilsson G Augmented blood pressure response
to exercise is associated with improved longterm survival in older people Heart
2009951072–1078
133 Gupta MP Polena S Coplan N Panagopoulos G Dhingra C Myers J Froelicher V
Prognostic signiﬁcance of systolic blood pressure increases in men during exercise
stress testing Am J Cardiol 20071001609–1613
134 Corra U Giordano A Mezzani A Gnemmi M Pistono M Caruso R Giannuzzi P
Cardiopulmonary exercise testing and prognosis in heart failure due to systolic
left ventricular dysfunction a validation study of the European Society of Cardi
ology Guidelines and Recommendations (2008) and further developments Eur J
Prev Cardiol 20121932–40
135 Carroll D Phillips AC Der G Hunt K Benzeval M Blood pressure reactions to
acute mental stress and future blood pressure status data from the 12year follow
up of the West of Scotland Study Psychosom Med 201173737–742
136 Chida Y Steptoe A Greater cardiovascular responses to laboratory mental stress
are associated with poor subsequent cardiovascular risk status a metaanalysis of
prospective evidence Hypertension 2010551026–1032
137 Nichols WW O’Rourke MFMcDonald’s blood ﬂow in arteries Theoretical experimen
tal and clinical principles Fifth Edition Oxford Oxford University Press 2005 p 624
138 Laurent S Cockcroft J Van Bortel L Boutouyrie P Giannattasio C Hayoz D
Pannier B Vlachopoulos C Wilkinson I StruijkerBoudier H Expert consensus
document on arterial stiffness methodological issues and clinical applications
Eur Heart J 2006272588–2605
139 Safar ME Blacher J Pannier B Guerin AP Marchais SJ Guyonvarc’h PM
London GM Central pulse pressure and mortality in endstagerenal diseaseHyper
tension 200239735–738
140 Vlachopoulos C Aznaouridis K O’Rourke MF Safar ME Baou K Stefanadis C Pre
diction of cardiovascular events and allcause mortality with central haemodynam
ics a systematic review and metaanalysis Eur Heart J 2010311865–1871
141 Mancia G Laurent S AgabitiRosei E Ambrosioni E Burnier M Caulﬁeld MJ
Cifkova R Clement D Coca A Dominiczak A Erdine S Fagard R Farsang C
Grassi G Haller H Heagerty A Kjeldsen SE Kiowski W Mallion JM Manolis A
Narkiewicz K Nilsson P Olsen MH Rahn KH Redon J Rodicio J Ruilope L
Schmieder RE StruijkerBoudier HA van Zwieten PA Viigimaa M Zanchetti A Re
appraisal of European guidelines on hypertension management a European Society
of Hypertension Task Force document J Hypertens 2009272121–2158
142 O’Rourke MF Adji A Guidelines on guidelines focus on isolated systolic hyprten
sion in youth J Hypertens 2013 31649–654
143 Hunt SC Williams RR Barlow GK A comparison of positive family history deﬁni
tions for deﬁning risk of future disease J Chronic Dis 198639809–821
144 Friedman GD Selby JV Quesenberry CP Jr Armstrong MA Klatsky AL Precursors
of essential hypertension body weight alcohol and salt use and parental history of
hypertension Prev Med 198817387–402
145 Luft FC Twins in cardiovascular genetic research Hypertension 200137350–356
146 Fagard R Brguljan J Staessen J Thijs L Derom C Thomis M Vlietinck R Heritability
of conventional and ambulatory blood pressures A study in twins Hypertension
199526919–924
147 Lifton RP Gharavi AG Geller DS Molecular mechanisms of human hypertension
Cell 2001104545–556
148 Ehret GB Munroe PB Rice KM Bochud M Johnson AD Chasman DI Smith AV
Tobin MD Verwoert GC Hwang SJ Pihur V Vollenweider P O’Reilly PF
Amin N BraggGresham JL Teumer A Glazer NL Launer L Zhao JH
Aulchenko Y Heath S Sober S Parsa A Luan J Arora P Dehghan A Zhang F
Lucas G Hicks AA Jackson AU Peden JF Tanaka T Wild SH Rudan I Igl W
Milaneschi Y Parker AN Fava C Chambers JC Fox ER Kumari M Go MJ van
der Harst P Kao WH Sjogren M Vinay DG Alexander M Tabara Y
ShawHawkins S Whincup PH Liu Y Shi G Kuusisto J Tayo B Seielstad M
Sim X Nguyen KD Lehtimaki T Matullo G Wu Y Gaunt TR
OnlandMoret NC Cooper MN Platou CG Org E Hardy R Dahgam S
Palmen J Vitart V Braund PS Kuznetsova T Uiterwaal CS Adeyemo A
Palmas W Campbell H Ludwig B Tomaszewski M Tzoulaki I Palmer ND
Aspelund T Garcia M Chang YP O’Connell JR Steinle NI Grobbee DE
Arking DE Kardia SL Morrison AC Hernandez D Najjar S McArdle WL
Hadley D Brown MJ Connell JM Hingorani AD Day IN Lawlor DA Beilby JP
Lawrence RW Clarke R Hopewell JC Ongen H Dreisbach AW Li Y Young JH
Bis JC Kahonen M Viikari J Adair LS Lee NR Chen MH Olden M Pattaro C
Bolton JA Kottgen A Bergmann S Mooser V Chaturvedi N Frayling TM
Islam M Jafar TH Erdmann J Kulkarni SR Bornstein SR Grassler J Groop L
Voight BF Kettunen J Howard P Taylor A Guarrera S Ricceri F Emilsson V
Plump A Barroso I Khaw KT Weder AB Hunt SC Sun YV Bergman RN
Collins FS Bonnycastle LL Scott LJ Stringham HM Peltonen L Perola M
Vartiainen E Brand SM Staessen JA Wang TJ Burton PR Artogas MS Dong Y
Snieder H Wang X Zhu H Lohman KK Rudock ME Heckbert SR Smith NL
Wiggins KL Doumatey A Shriner D Veldre G Viigimaa M Kinra S
Prabhakaran D Tripathy V Langefeld CD Rosengren A Thelle DS Corsi AM
Singleton A Forrester T Hilton G McKenzie CA Salako T Iwai N Kita Y
Ogihara T Ohkubo T Okamura T Ueshima H Umemura S Eyheramendy S
Meitinger T Wichmann HE Cho YS Kim HL Lee JY Scott J Sehmi JS Zhang W
Hedblad B Nilsson P Smith GD Wong A Narisu N Stancakova A Raffel LJ
Yao J Kathiresan S O’Donnell CJ Schwartz SM Ikram MA Longstreth WT Jr
Mosley TH Seshadri S Shrine NR Wain LV Morken MA Swift AJ Laitinen J
Prokopenko I Zitting P Cooper JA Humphries SE Danesh J Rasheed A
Goel A Hamsten A Watkins H Bakker SJ van Gilst WH Janipalli CS Mani KR
Yajnik CS Hofman A MattaceRaso FU Oostra BA Demirkan A Isaacs A
Rivadeneira F Lakatta EG Orru M Scuteri A AlaKorpela M Kangas AJ
Lyytikainen LP Soininen P Tukiainen T Wurtz P Ong RT Dorr M Kroemer HK
Volker U Volzke H Galan P Hercberg S Lathrop M Zelenika D Deloukas P
Mangino M Spector TD Zhai G Meschia JF Nalls MA Sharma P Terzic J
Kumar MV Denniff M ZukowskaSzczechowska E Wagenknecht LE
Fowkes FG Charchar FJ Schwarz PE Hayward C Guo X Rotimi C Bots ML
Brand E Samani NJ Polasek O Talmud PJ Nyberg F Kuh D Laan M Hveem K
Palmer LJ van der Schouw YT Casas JP Mohlke KL Vineis P Raitakari O
Ganesh SK Wong TY Tai ES Cooper RS Laakso M Rao DC Harris TB
Morris RW Dominiczak AF Kivimaki M Marmot MG Miki T Saleheen D
Chandak GR Coresh J Navis G Salomaa V Han BG Zhu X Kooner JS
Melander O Ridker PM Bandinelli S Gyllensten UB Wright AF Wilson JF
Ferrucci L Farrall M Tuomilehto J Pramstaller PP Elosua R Soranzo N
Sijbrands EJ Altshuler D Loos RJ Shuldiner AR Gieger C Meneton P
Uitterlinden AG Wareham NJ Gudnason V Rotter JI Rettig R Uda M
Strachan DP Witteman JC Hartikainen AL Beckmann JS Boerwinkle E
Vasan RS Boehnke M Larson MG Jarvelin MR Psaty BM Abecasis GR
Chakravarti A Elliott P van Duijn CM NewtonCheh C Levy D Caulﬁeld MJ
Johnson T Genetic variants in novel pathwaysinﬂuence blood pressure and cardio
vascular disease risk Nature 2011478103–109
149 Levy D Salomon M D’Agostino RB Belanger AJ Kannel WB Prognostic implica
tions of baseline electrocardiographic features and their serial changes in subjects
with left ventricular hypertrophy Circulation 1994901786–1793
150 Okin PM Devereux RB Jern S Kjeldsen SE Julius S Nieminen MS Snapinn S
Harris KE Aurup P Edelman JM Wedel H Lindholm LH Dahlof B Regression of
electrocardiographic left ventricular hypertrophy during antihypertensive treat
ment and the prediction of major cardiovascular events JAMA 2004292
2343–2349
151 Fagard RH Staessen JA Thijs L Celis H Birkenhager WH Bulpitt CJ de Leeuw PW
Leonetti G Sarti C Tuomilehto J Webster J Yodfat Y Prognostic signiﬁcance of
electrocardiographicvoltages and their serial changesin elderly with systolic hyper
tension Hypertension 200444459–464
152 Okin PM Oikarinen L Viitasalo M Toivonen L Kjeldsen SE Nieminen MS
Edelman JM Dahlof B Devereux RB Prognostic value of changes in the electrocar
diographic strain pattern during antihypertensivetreatment the Losartan Interven
tion for EndPoint Reduction in Hypertension Study (LIFE) Circulation 2009119
1883–1891
ESH and ESC Guidelines2216
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 2019153 Kirchhof P Bax J BlomstromLundquist C Calkins H Camm AJ Cappato R
Cosio F Crijns H Diener HC Goette A Israel CW Kuck KH Lip GY Nattel S
Page RL Ravens U Schotten U Steinbeck G Vardas P Waldo A
Wegscheider K Willems S Breithardt G Early and comprehensive management
of atrial ﬁbrillation executive summary of the proceedings from the 2nd
AFNETEHRA consensus conference ’research perspectives in AF’ Eur Heart J
2009302969–2977c
154 Kirchhof P Lip GY Van Gelder IC Bax J Hylek E Kaab S Schotten U
Wegscheider K Boriani G Ezekowitz M Diener H Heidbuchel H Lane D
Mont L Willems S Dorian P Vardas P Breithardt G Camm AJ Comprehensive
risk reductionin patientswith atrialﬁbrillation Emerging diagnosticand therapeutic
options Executive summary of the report from the 3rd AFNETEHRA consensus
conference Thromb Haemost 20111061012–1019
155 Reichek N Devereux RB Left ventricular hypertrophy relationship of anatomic
echocardiographic and electrocardiographic ﬁndings Circulation 198163
1391–1398
156 Levy D Garrison RJ Savage DD Kannel WB Castelli WP Prognostic implications
of echocardiographically determined left ventricular mass in the Framingham Heart
Study N Engl J Med 19903221561–1566
157 Tsiouﬁs C Kokkinos P Macmanus C Thomopoulos C Faselis C Doumas M
Stefanadis C Papademetriou V Left ventricular hypertrophy as a determinant of
renal outcome in patients with high cardiovascular risk J Hypertens 201028
2299–2308
158 Cuspidi C Ambrosioni E Mancia G Pessina AC Trimarco B Zanchetti A Role of
echocardiography and carotid ultrasonography in stratifying risk in patients with es
sential hypertension the Assessment of Prognostic Risk Observational Survey
J Hypertens 2002201307–1314
159 Lang RM Bierig M Devereux RB Flachskampf FA Foster E Pellikka PA Picard MH
Roman MJ Seward J Shanewise J Solomon S Spencer KT St John Sutton M
Stewart W Recommendations for chamber quantiﬁcation Eur J Echocardiogr
2006779–108
160 Chirinos JA Segers P De Buyzere ML Kronmal RA Raja MW De Bacquer D
Claessens T Gillebert TC St JohnSutton M Rietzschel ER Left ventricular
mass allometric scaling normative values effect of obesity and prognostic per
formance Hypertension 20105691–98
161 Armstrong AC Gidding S Gjesdal O Wu C Bluemke DA Lima JA LV mass
assessed by echocardiography and CMR cardiovascular outcomes and medical
practice JACC Cardiovasc Imaging 20125837–848
162 Koren MJ Devereux RB Casale PN Savage DD Laragh JH Relation of left ventricu
lar mass and geometry to morbidity and mortality in uncomplicated essential
hypertension Ann Intern Med 1991114345–352
163 Verdecchia P Schillaci G Borgioni C Ciucci A Battistelli M Bartoccini C
Santucci A Santucci C Reboldi G Porcellati C Adverse prognostic signiﬁcance
of concentric remodeling of the left ventricle in hypertensive patients with
normal left ventricular mass J Am Coll Cardiol 199525871–878
164 Muiesan ML Salvetti M Monteduro C Bonzi B Paini A Viola S Poisa P Rizzoni D
Castellano M AgabitiRosei E Left ventricular concentric geometry during treat
ment adversely affects cardiovascular prognosis in hypertensive patients Hyperten
sion 200443731–738
165 Hogg K Swedberg K McMurray J Heart failure with preserved left ventricular sys
tolic function epidemiology clinical characteristics and prognosis J Am Coll Cardiol
200443317–327
166 Aurigemma GP Gottdiener JS Shemanski L Gardin J Kitzman D Predictive value
of systolic and diastolic function for incident congestive heart failure in the elderly
the cardiovascular health study J Am Coll Cardiol 2001371042–1048
167 Bella JN Palmieri V Roman MJ Liu JE Welty TK Lee ET Fabsitz RR Howard BV
Devereux RB Mitral ratio of peak early to late diastolic ﬁlling velocity as a predictor
of mortality in middleaged and elderly adults the Strong Heart Study Circulation
20021051928–1933
168 Nagueh SF Appleton CP Gillebert TC Marino PN Oh JK Smiseth OA
Waggoner AD Flachskampf FA Pellikka PA Evangelisa A Recommendations for
the evaluation of left ventricular diastolic function by echocardiography Eur J Echo
cardiogr 200910165–193
169 Redﬁeld MM Jacobsen SJ Burnett JC Jr Mahoney DW Bailey KR Rodeheffer RJ
Burden of systolic and diastolic ventricular dysfunction in the community appreci
ating the scope of the heart failure epidemic JAMA 2003289194–202
170 De Sutter J DeBacker J Van de Veire N Velghe A De Buyzere M Gillebert TC
Effects of age gender and left ventricular mass on septal mitral annulus velocity
(E’) and the ratio of transmitral early peak velocity to E’ (EE’) Am J Cardiol 2005
951020–1023
171 Sharp AS Tapp RJ Thom SA Francis DP Hughes AD Stanton AV Zambanini A
O’Brien E Chaturvedi N Lyons S Byrd S Poulter NR Sever PS Mayet J Tissue
Doppler EE’ ratio is a powerful predictor of primary cardiac events in a hyperten
sive population an ASCOT substudy Eur Heart J 201031747–752
172 Abhayaratna WP Seward JB Appleton CP Douglas PS Oh JK Tajik AJ Tsang TS
Left atrial size physiologic determinants and clinical applications J Am Coll Cardiol
2006472357–2363
173 MorAvi V Lang RM Badano LP Belohlavek M Cardim NM Derumeaux G
Galderisi M Marwick T Nagueh SF Sengupta PP Sicari R Smiseth OA
Smulevitz B Takeuchi M Thomas JD Vannan M Voigt JU Zamorano JL Current
and evolving echocardiographic techniques for the quantitative evaluation of
cardiac mechanics ASEEAE consensus statement on methodology and indications
endorsed by the Japanese Society of Echocardiography Eur J Echocardiogr 201112
167–205
174 Galderisi M Lomoriello VS Santoro A Esposito R Olibet M Raia R Di Minno MN
Guerra G Mele D Lombardi G Differences of myocardial systolic deformation and
correlates of diastolic function in competitive rowers and young hypertensives a
speckletracking echocardiography study J Am Soc Echocardiogr 201023
1190–1198
175 Codella NC Lee HY Fieno DS Chen DW HurtadoRua S Kochar M Finn JP
Judd R Goyal P Schenendorf J Cham MD Devereux RB Prince M Wang Y
Weinsaft JW Improved left ventricular mass quantiﬁcation with partial voxel inter
polation in vivo and necropsy validation of a novel cardiac MRI segmentation algo
rithm Circ Cardiovasc Imaging 20125137–146
176 Parsai C O’Hanlon R Prasad SK Mohiaddin RH Diagnostic and prognostic value of
cardiovascular magnetic resonance in nonischaemic cardiomyopathies
J Cardiovasc Magn Reson 20121454
177 Picano E Palinkas A Amyot R Diagnosis of myocardial ischemia in hypertensive
patients J Hypertens 2001191177–1183
178 Chin D Battistoni A Tocci G Passerini J ParatiG Volpe M Noninvasive diagnostic
testing for coronaryartery disease in the hypertensive patient potential advantages
of a risk estimationbased algorithm Am J Hypertens 2012251226–1235
179 Schulman DS Francis CK Black HR Wackers FJ Thallium201 stress imaging in
hypertensive patients Hypertension 19871016–21
180 Sicari R Nihoyannopoulos P Evangelista A Kasprzak J Lancellotti P Poldermans D
Voigt JU Zamorano JL Stress Echocardiography Expert Consensus Statement Ex
ecutive Summary European Association of Echocardiography (EAE) (a registered
branch of the ESC) Eur Heart J 200930278–289
181 Greenwood JP Maredia N Younger JF Brown JM Nixon J Everett CC
Bijsterveld P Ridgway JP Radjenovic A Dickinson CJ Ball SG Plein S Cardiovascu
lar magnetic resonance and singlephoton emission computed tomography for
diagnosis of coronary heart disease (CEMARC) a prospective trial Lancet 2012
379453–460
182 Cortigiani L Rigo F Galderisi M Gherardi S Bovenzi F Picano E Sicari R Diagnostic
and prognostic value of Doppler echocardiographic coronary ﬂow reserve in the
left anterior descending artery in hypertensive and normotensive patients [cor
rected] Heart 2011971758–1765
183 Bots ML Hoes AW Koudstaal PJ Hofman A Grobbee DE Common carotid
intimamedia thickness and risk of stroke and myocardial infarction the Rotterdam
Study Circulation 1997961432–1437
184 O’Leary DH Polak JF Kronmal RA Manolio TA Burke GL Wolfson SK Jr
Carotidartery intima and media thickness as a risk factor for myocardial infarction
and stroke in older adults Cardiovascular Health Study Collaborative Research
Group N Engl J Med 199934014–22
185 Nambi V Chambless L Folsom AR He M Hu Y Mosley T Volcik K Boerwinkle E
Ballantyne CM Carotid intimamedia thickness and presence or absence of plaque
improves prediction of coronary heart disease risk the ARIC (Atherosclerosis Risk
In Communities) study J Am Coll Cardiol 2010551600–1607
186 Zanchetti A Bond MG Hennig M Neiss A Mancia G Dal Palu C Hansson L
Magnani B Rahn KH Reid JL Rodicio J Safar M Eckes L Rizzini P Calcium antag
onist lacidipine slows down progression of asymptomatic carotid atherosclerosis
principal results of the European Lacidipine Study on Atherosclerosis(ELSA) a ran
domized doubleblind longterm trial Circulation 20021062422–2427
187 Touboul PJ Hennerici MG Meairs S Adams H Amarenco P Desvarieux M
Ebrahim S Fatar M Hernandez Hernandez R Kownator S Prati P Rundek T
Taylor A Bornstein N Csiba L Vicaut E Woo KS Zannad F Mannheim intima
media thickness consensus Cerebrovasc Dis 200418346–349
188 Zanchetti A Hennig M Hollweck R Bond G Tang R Cuspidi C Parati G
Facchetti R Mancia G Baseline values but not treatmentinduced changes in
carotid intimamedia thickness predict incident cardiovascular events in treated
hypertensivepatients ﬁndings in the European Lacidipine Studyon Atherosclerosis
(ELSA) Circulation 20091201084–1090
189 Peters SA den Ruijter HM Bots ML Moons KG Improvements in risk stratiﬁcation
for the occurrence of cardiovascular disease by imaging subclinical atherosclerosis
a systematic review Heart 201298177–184
190 Safar ME Levy BI StruijkerBoudier H Current perspectives on arterial stiffness
and pulse pressure in hypertension and cardiovascular diseases Circulation 2003
1072864–2869
ESH and ESC Guidelines 2217
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 2019191 Van Bortel LM Laurent S Boutouyrie P Chowienczyk P Cruickshank JK De
Backer T Filipovsky J Huybrechts S MattaceRaso FU Protogerou AD
Schillaci G Segers P Vermeersch S Weber T Expert consensus document on
the measurement of aortic stiffness in daily practice using carotidfemoral pulse
wave velocity J Hypertens 201230445–448
192 Laurent S Boutouyrie P Asmar R Gautier I Laloux B Guize L Ducimetiere P
Benetos A Aortic stiffness is an independent predictor of allcause and cardiovas
cular mortality in hypertensive patients Hypertension 2001371236–1241
193 Vlachopoulos C Aznaouridis K Stefanadis C Prediction of cardiovascular events
and allcause mortality with arterial stiffness a systematic review and metaanalysis
J Am Coll Cardiol 2010551318–1327
194 Boutouyrie P Tropeano AI Asmar R Gautier I Benetos A Lacolley P Laurent S
Aortic stiffness is an independent predictor of primary coronary events in hyper
tensive patients a longitudinal study Hypertension 20023910–15
195 MattaceRaso FU van der Cammen TJ Hofman A van Popele NM Bos ML
Schalekamp MA Asmar R Reneman RS Hoeks AP Breteler MM Witteman JC Ar
terial stiffness and risk of coronary heart disease and stroke the Rotterdam Study
Circulation 2006113657–663
196 Mitchell GF Hwang SJ Vasan RS Larson MG Pencina MJ Hamburg NM Vita JA
Levy D Benjamin EJ Arterial stiffness and cardiovascular events the Framingham
Heart Study Circulation 2010121505–511
197 Feringa HH Bax JJ van Waning VH Boersma E Elhendy A Schouten O
Tangelder MJ van Sambeek MH van den Meiracker AH Poldermans D The long
term prognostic value of the resting and postexercise anklebrachial index Arch
Intern Med 2006166529–535
198 Fowkes FG Murray GD Butcher I Heald CL Lee RJ Chambless LE Folsom AR
Hirsch AT Dramaix M deBacker G Wautrecht JC Kornitzer M Newman AB
Cushman M SuttonTyrrell K Lee AJ Price JF d’Agostino RB Murabito JM
Norman PE Jamrozik K Curb JD Masaki KH Rodriguez BL Dekker JM
Bouter LM Heine RJ Nijpels G Stehouwer CD Ferrucci L McDermott MM
Stoffers HE Hooi JD Knottnerus JA Ogren M Hedblad B Witteman JC
Breteler MM Hunink MG Hofman A Criqui MH Langer RD Fronek A
Hiatt WR Hamman R Resnick HE Guralnik J Ankle brachial index combined
with Framingham Risk Score to predict cardiovascular events and mortality a
metaanalysis JAMA 2008300197–208
199 De Buyzere ML Clement DL Management of hypertension in peripheral arterial
disease Prog Cardiovasc Dis 200850238–263
200 Park JB Schiffrin EL Small artery remodeling is the most prevalent (earliest) form
of target organ damage in mild essential hypertension J Hypertens 200119
921–930
201 Schoﬁeld I Malik R Izzard A Austin C Heagerty A Vascular structural and func
tional changes in type 2 diabetes mellitus evidence for the roles of abnormal myo
genic responsiveness and dyslipidemia Circulation 20021063037–3043
202 Rizzoni D Porteri E Boari GE De Ciuceis C Sleiman I Muiesan ML Castellano M
Miclini M AgabitiRosei E Prognostic signiﬁcance of smallartery structure in
hypertension Circulation 20031082230–2235
203 Greenland P Alpert JS Beller GA Benjamin EJ Budoff MJ Fayad ZA Foster E
Hlatky MA Hodgson JM Kushner FG Lauer MS Shaw LJ Smith SC Jr Taylor AJ
Weintraub WS Wenger NK Jacobs AK 2010 ACCFAHA guideline for assess
ment of cardiovascular risk in asymptomatic adults a report of the American
College of Cardiology FoundationAmerican Heart Association Task Force on
Practice Guidelines Circulation 2010122e584–e636
204 PerroneFilardi P Achenbach S Mo¨hlenkamp S Reiner Z Sambuceti G Schuijf JD
Van der Wall E Kaufmann PA Knuuti J Schroeder S Zellweger MJ Cardiac com
puted tomography and myocardial perfusion scintigraphy for risk stratiﬁcation in
asymptomatic individuals without known cardiovascular disease a position state
ment of the Working Group on Nuclear Cardiology and Cardiac CT of the Euro
pean Society of Cardiology Eur Heart J 2011321986–1993
205 Lerman A Zeiher AM Endothelial function cardiac events Circulation 2005111
363–368
206 Versari D Daghini E Virdis A Ghiadoni L Taddei S Endothelial dysfunction as a
target for prevention of cardiovascular disease Diabetes Care 200932(Suppl 2)
S314–321
207 Stevens LA Coresh J Greene T Levey AS Assessing kidneyfunction measured and
estimated glomerular ﬁltration rate N Engl J Med 20063542473–2483
208 Hallan S Asberg A Lindberg M Johnsen H Validation of the Modiﬁcation of Diet in
Renal Disease formula for estimating GFR with special emphasis on calibration of
the serum creatinine assay Am J Kidney Dis 20044484–93
209 Matsushita K Mahmodi BK Woodward M Emberson JM Jafar JH Jee SH
Polkinghorne KR Skankar A Smith DH Tonelli M Warnock DG Wen CP
Coresh J Gansewoort DG Emmaljarn BR LeveyAS Comparison of risk prediction
using the CKDEPI equation and the MDRD study equation for estmated glomeru
lar ﬁltration rate JAMA 20123071941–1951
210 Levey AS Eckardt KU Tsukamoto Y Levin A Coresh J Rossert J De Zeeuw D
Hostetter TH Lameire N Eknoyan G Deﬁnition and classiﬁcation of chronic
kidney disease a position statement from Kidney Disease Improving Global Out
comes (KDIGO) Kidney Int 2005672089–2100
211 Moe S Drueke T Cunningham J Goodman W Martin K Olgaard K Ott S
Sprague S Lameire N Eknoyan G Deﬁnition evaluation and classiﬁcation of
renal osteodystrophy a position statement from Kidney Disease Improving
Global Outcomes (KDIGO) Kidney Int 2006691945–1953
212 Shlipak MG Katz R Sarnak MJ Fried LF Newman AB StehmanBreen C Seliger SL
Kestenbaum B Psaty B Tracy RP Siscovick DS Cystatin C and prognosis for car
diovascular and kidney outcomes in elderly persons without chronic kidney
disease Ann Intern Med 2006145237–246
213 Culleton BF Larson MG Wilson PW Evans JC Parfrey PS Levy D Cardiovascular
disease and mortality in a communitybased cohort with mild renal insufﬁciency
Kidney Int 1999562214–2219
214 Parving HH Initiation and progression of diabetic nephropathy N Engl J Med 1996
3351682–1683
215 Ruilope LM Rodicio JL Clinical relevanceofproteinuria and microalbuminuriaCurr
Opin Nephrol Hypertens 19932962–967
216 Redon J Williams B Microalbuminuria in essential hypertension redeﬁning the
threshold J Hypertens 200220353–355
217 Jensen JS FeldtRasmussen B Strandgaard S Schroll M BorchJohnsen K Arterial
hypertension microalbuminuria and risk of ischemic heart disease Hypertension
200035898–903
218 de Leeuw PW Ruilope LM Palmer CR Brown MJ Castaigne A Mancia G
Rosenthal T Wagener G Clinical signiﬁcance of renal function in hypertensive
patients at high risk results from the INSIGHT trial Arch Intern Med 2004164
2459–2464
219 Sarnak MJ Levey AS Schoolwerth AC Coresh J Culleton B Hamm LL
McCullough PA Kasiske BL Kelepouris E Klag MJ Parfrey P Pfeffer M Raij L
Spinosa DJ Wilson PW Kidney disease as a risk factor for development of cardio
vascular disease a statement from the American Heart Association Councils on
Kidney in Cardiovascular Disease High Blood Pressure Research Clinical Cardi
ology and Epidemiology and Prevention Circulation 20031082154–2169
220 Gerstein HC Mann JF Yi Q Zinman B Dinneen SF Hoogwerf B Halle JP Young J
Rashkow A Joyce C Nawaz S Yusuf S Albuminuria and risk of cardiovascular
events death and heart failure in diabetic and nondiabetic individuals JAMA 2001
286421–426
221 Wachtell K Ibsen H Olsen MH BorchJohnsen K Lindholm LH Mogensen CE
Dahlof B Devereux RB Beevers G de Faire U Fyhrquist F Julius S Kjeldsen SE
Kristianson K LederballePedersen O Nieminen MS Okin PM Omvik P
Oparil S Wedel H Snapinn SM Aurup P Albuminuria and cardiovascular risk in
hypertensive patients with left ventricular hypertrophy the LIFE study Ann Intern
Med 2003139901–906
222 Jager A Kostense PJ Ruhe HG Heine RJ Nijpels G Dekker JM Bouter LM
Stehouwer CD Microalbuminuria and peripheral arterial disease are independent
predictors of cardiovascular and allcause mortality especially among hypertensive
subjects ﬁveyear followup of the Hoorn Study Arterioscler Thromb Vac Biol 1999
19617–624
223 Bigazzi R Bianchi S Baldari D Campese VM Microalbuminuria predicts cardiovas
cular events and renal insufﬁciency in patients with essential hypertension
J Hypertens 1998161325–1333
224 National Kidney Foundation KDOQI clinical practice guidelines on hypertension
and antihypertensive agents in chronic kidney disease Executive summary Am J Kid
Dis 200443 (Suppl 1)S16–S33
225 Arnlov J Evans JC Meigs JB Wang TJ Fox CS Levy D Benjamin EJ D’Agostino RB
Vasan RS Lowgrade albuminuria and incidence of cardiovascular disease events in
nonhypertensive and nondiabetic individuals the Framingham Heart Study Circula
tion 2005112969–975
226 Hillege HL Fidler V Diercks GF van Gilst WH de Zeeuw D van Veldhuisen DJ
Gans RO Janssen WM Grobbee DE de Jong PE Urinary albumin excretion pre
dicts cardiovascular and noncardiovascular mortality in general population Circula
tion 20021061777–1782
227 Ninomiya T Perkovic V de Galan BE Zoungas S Pillai A Jardine M Patel A Cass A
Neal B Poulter N Mogensen CE Cooper M Marre M Williams B Hamet P
Mancia G Woodward M MacMahon S Chalmers J Albuminuria and kidney func
tion independently predict cardiovascular and renal outcomes in diabetes J Am Soc
Nephrol 2009201813–1821
228 Matsushita K van der Velde M Astor BC Woodward M Levey AS de Jong PE
Coresh J Gansevoort RT Association of estimated glomerular ﬁltration rate and
albuminuria with allcause and cardiovascular mortality in general population
cohorts a collaborative metaanalysis Lancet 20103752073–2081
229 Zanchetti A Hansson L Dahlof B Elmfeldt D Kjeldsen S Kolloch R Larochelle P
McInnes GT Mallion JM Ruilope L Wedel H Effects of individual risk factors on the
incidence of cardiovascular events in the treated hypertensive patients of the
Hypertension Optimal Treatment Study HOT Study Group J Hypertens 2001
191149–1159
ESH and ESC Guidelines2218
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 2019230 Ruilope LM Salvetti A Jamerson K Hansson L Warnold I Wedel H Zanchetti A
Renal function and intensive lowering of blood pressure in hypertensive partici
pants of the hypertension optimal treatment (HOT) study J Am Soc Nephrol
200112218–225
231 De Leeuw PW Thijs L Birkenhager WH Voyaki SM Efstratopoulos AD
Fagard RH Leonetti G Nachev C Petrie JC Rodicio JL Rosenfeld JJ Sarti C
Staessen JA Prognostic signiﬁcance of renal function in elderly patients with iso
lated systolic hypertension results from the SystEur trial J Am Soc Nephrol 2002
132213–2222
232 Segura J Ruilope LM Zanchetti A On the importance of estimating renal function
for cardiovascular risk assessment J Hypertens 2004221635–1639
233 Rahman M Pressel S Davis BR Nwachuku C Wright JT Jr Whelton PK Barzilay J
Batuman V Eckfeldt JH Farber MA Franklin S Henriquez M Kopyt N Louis GT
Saklayen M Stanford C Walworth C Ward H Wiegmann T Cardiovascular out
comes in highrisk hypertensive patients stratiﬁed by baseline glomerular ﬁltration
rate Ann Intern Med 2006144172–180
234 Breslin DJ Gifford RW Jr Fairbairn JF 2nd Kearns TP Prognostic importance of
ophthalmoscopic ﬁndings in essential hypertension JAMA 1966195335–338
235 FrantR Groen J Prognosis of vascular hypertension a 9 yearfollowup studyof 418
cases Arch Intern Med (Chic) 195085727–750
236 Wong TY Mitchell P Hypertensive retinopathy N Engl J Med 2004351
2310–2317
237 Sairenchi T Iso H Yamagishi K Irie F Okubo Y Gunji J Muto T Ota H Mild retin
opathy is a risk factor for cardiovascular mortality in Japanese with and without
hypertension the Ibaraki Prefectural Health Study Circulation 2011124
2502–2511
238 Mollentze WF Stulting AA Steyn AF Ophthalmoscopy vs nonmydriatic fundus
photography in the detection of diabetic retinopathy in black patients S Afr Med J
199078248–250
239 Dimmitt SB West JN Eames SM Gibson JM Gosling P Littler WA Usefulness of
ophthalmoscopy in mild to moderate hypertension Lancet 198911103–1106
240 van den Born BJ Hulsman CA Hoekstra JB Schlingemann RO van Montfrans GA
Value of routine funduscopy in patients with hypertension systematic review BMJ
200533173
241 McGeechan K Liew G Macaskill P Irwig L Klein R Klein BE Wang JJ Mitchell P
Vingerling JR de Jong PT Witteman JC Breteler MM Shaw J Zimmet P
Wong TY Prediction of incident stroke events based on retinal vessel caliber a sys
tematic review and individualparticipant metaanalysis Am J Epidemiol 2009170
1323–1332
242 Antonios TF Singer DR Markandu ND Mortimer PS MacGregor GA Rarefaction
of skin capillaries in borderline essential hypertension suggests an early structural
abnormality Hypertension 199934655–658
243 Noon JP Walker BR Webb DJ Shore AC Holton DW Edwards HV Watt GC
Impaired microvascular dilatation and capillary rarefaction in young adults with a
predisposition to high blood pressure J Clin Invest 1997991873–1879
244 Cuspidi C Meani S Salerno M Fusi V Severgnini B Valerio C Catini E Esposito A
Magrini F Zanchetti A Retinal microvascular changes and target organ damage in
untreated essential hypertensives J Hypertens 2004222095–2102
245 Hubbard LD Brothers RJ King WN Clegg LX Klein R Cooper LS Sharrett AR
Davis MD Cai J Methods for evaluation of retinal microvascular abnormalities
associated with hypertensionsclerosis in the Atherosclerosis Risk in Communities
Study Ophthalmology 19991062269–2280
246 Ikram MK de Jong FJ Vingerling JR Witteman JC Hofman A Breteler MM de
Jong PT Areretinal arteriolaror venular diameters associated with markers forcar
diovascular disorders The Rotterdam Study Invest Ophthalmol Vis Sci 200445
2129–2134
247 Wong TY Knudtson MD Klein R Klein BE Meuer SM Hubbard LD Computer
assisted measurement of retinal vessel diameters in the Beaver Dam Eye Study
methodology correlation between eyes and effect of refractive errorsOphthalmol
ogy 20041111183–1190
248 Sun C Liew G Wang JJ Mitchell P Saw SM Aung T Tai ES Wong TY Retinal vas
cular caliber blood pressure and cardiovascular risk factors in an Asian population
the Singapore Malay Eye Study Invest Ophthalmol Vis Sci 2008491784–1790
249 Lehmann MV Schmieder RE Remodeling of retinal small arteries in hypertension
Am J Hypertens 2011241267–1273
250 Longstreth WT Jr Manolio TA Arnold A Burke GL Bryan N Jungreis CA
Enright PL O’Leary D Fried L Clinical correlates of white matter ﬁndings on
cranial magnetic resonance imaging of 3301 elderly people The Cardiovascular
Health Study Stroke 1996271274–1282
251 de Leeuw FE de Groot JC Oudkerk M Witteman JC Hofman A van Gijn J
Breteler MM Hypertension and cerebral white matter lesions in a prospective
cohort study Brain 2002125765–772
252 Vermeer SE Longstreth WT Jr Koudstaal PJ Silent brain infarcts a systematic
review Lancet Neurology 20076611–619
253 Wong TY Klein R Sharrett AR Couper DJ Klein BE Liao DP Hubbard LD
Mosley TH Cerebral white matter lesions retinopathy and incident clinical
stroke JAMA 200228867–74
254 Buyck JF Dufouil C Mazoyer B Maillard P Ducimetiere P Alperovitch A
Bousser MG Kurth T Tzourio C Cerebral white matter lesions are associated
with the risk of stroke but not with other vascular events the 3City Dijon
Study Stroke 2009402327–2331
255 KearneySchwartz A Rossignol P Bracard S Felblinger J Fay R Boivin JM
Lecompte T Lacolley P Benetos A Zannad F Vascular structure and function is
correlated to cognitive performance and white matter hyperintensities in older
hypertensive patients with subjective memory complaints Stroke 200940
1229–1236
256 Henskens LH van Oostenbrugge RJ Kroon AA Hofman PA Lodder J de
Leeuw PW Detection of silent cerebrovascular disease reﬁnes risk stratiﬁcation
of hypertensive patients J Hypertens 200927846–853
257 Stewart R Xue QL Masaki K Petrovitch H Ross GW White LR Launer LJ Change
in blood pressure and incident dementia a 32year prospective study Hypertension
200954233–240
258 Skoog I Lernfelt B Landahl S Palmertz B Andreasson LA Nilsson L Persson G
Oden A Svanborg A 15year longitudinal study of blood pressure and dementia
Lancet 19963471141–1145
259 Kilander L Nyman H Boberg M Hansson L Lithell H Hypertension is related to
cognitive impairment a 20year followup of 999 men Hypertension 199831
780–786
260 Collins R MacMahon S Blood pressure antihypertensive drug treatment and the
risks of stroke and of coronary heart disease Br Med Bull1994 50272–298
261 Devereux RB Wachtell K Gerdts E Boman K Nieminen MS Papademetriou V
Rokkedal J Harris K Aurup P Dahlof B Prognostic signiﬁcance of left ventricular
mass change during treatment of hypertension JAMA 20042922350–2356
262 Ibsen H Olsen MH Wachtell K BorchJohnsen K Lindholm LH Mogensen CE
Dahlof B Devereux RB de Faire U Fyhrquist F Julius S Kjeldsen SE
LederballePedersen O Nieminen MS Omvik P Oparil S Wan Y Reduction in al
buminuria translates to reduction in cardiovascular events in hypertensive patients
losartan intervention for endpoint reduction in hypertension study Hypertension
200545198–202
263 Sytkowski PA D’Agostino RB Belanger AJ Kannel WB Secular trends in longterm
sustained hypertension longterm treatment and cardiovacsular mortality The
Framngham Heart Study 1950 to 1990 Circulation 199693697–703
264 Chobanian AV Bakris GL Black HR Cushman WC GreenLA Izzo JL Jr Jones DW
Materson BJ Oparil S Wright JT Jr RoccellaEJ Seventh report of the Joint National
Committee on Prevention Detection Evaluation and Treatment of High Blood
Pressure Hypertension 2003421206–1252
265 Zanchetti A Grassi G Mancia G When should antihypertensive drug treatment be
initiated and to what levels should systolic blood pressure be lowered A critical
reappraisal J Hypertens 200927923–934
266 Medical Research Council Working Party MRC trial on treatment of mild hyper
tension principal results Br Med J 198529197–104
267 Management Committee The Australian therapeutic trial in mild hypertension
Lancet 198011261–1267
268 Hypertension Detection and Followup Program Cooperative Group The effect
of treatment on mortality in mild hypertension results of the Hypertension
Detection and Followup Program N Engl J Med 1982307976–980
269 Liu L Zhang Y Liu G Li W Zhang X Zanchetti A The Felodipine Event Reduction
(FEVER) Study a randomized longterm placebocontrolled trial in Chinese hyper
tensive patients J Hypertens 2005232157–2172
270 Zhang Y Zhang X Liu L Zanchetti A Is a systolic blood pressure target
140 mmHg indicated in all hypertensives Subgroup analyses of ﬁndings from
the randomized FEVER trial Eur Heart J 2011321500–1508
271 National Institute for Health and Clinical Excellence Hypertension (CG127) clinical
management of primary hypertension in adults httpwwwniceorgukguidance
CG127
272 Zanchetti A Bottom blood pressure or bottom cardiovascular risk How far can
cardiovascular risk be reduced J Hypertens 2009271509–1520
273 Aronow WS Fleg JL Pepine CJ Artinian NT Bakris G Brown AS Ferdinand KC
Ann Forciea M Frishman WH Jaigobin C Kostis JB Mancia G Oparil S Ortiz E
Reisin E Rich MW Schocken DD Weber MA Wesley DJ ACCFAHA 2011
expert consensus document on hypertension in the elderly a report of the Ameri
can College of Cardiology Foundation Task Force on Clinical Expert Consensus
documents developed in collaboration with the American Academy of Neurology
American Geriatrics Society American Society for Preventive Cardiology Ameri
can Society of Hypertension American Society of Nephrology Association of
Black Cardiologists and European Society of Hypertension J Am Coll Cardiol
2011572037–2114
ESH and ESC Guidelines 2219
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 2019274 Schrier RW Estacio RO Esler A Mehler P Effects of aggressive blood pressure
control in normotensive type 2 diabetic patients on albuminuria retinopathy and
strokes Kidney Int 2002611086–1097
275 Heart Outcomes Prevention Evaluation Study InvestigatorsEffects of ramipril on
cardiovascular and microvascular outcomes in people with diabetes mellitus
results of the HOPE study and MICROHOPE substudy Lancet 2000355
253–259
276 ADVANCE Collaborative Group Effects of a ﬁxed combination of perindopril and
indapamide on macrovascular and microvascular outcomes in patients with type 2
diabetes mellitus (the ADVANCE trial) a randomised controlled trial Lancet 2007
370829–840
277 DREAM Trial Investigators Effects of ramipril and rosiglitazone on cardiovascular
and renal outcomes in people with impaired glucose tolerance or impaired fasting
glucose results of the Diabetes REduction Assessment with ramipril and rosiglita
zone Medication (DREAM) trial Diabetes Care 2008311007–1014
278 The NAVIGATOR study Group Effect of Valsartan on the Incidence of Diabetes
and Cardiovascular Events N Eng J Med 20103621477–1490
279 PATS Collaborating Group Poststroke antihypertensive treatment study A pre
liminary result Chin Med J (Engl) 1995108710–717
280 Arima H Chalmers J Woodward M Anderson C Rodgers A Davis S MacMahon S
Neal B Lower target blood pressures are safe and effective for the prevention of
recurrent stroke the PROGRESS trial J Hypertens 2006241201–1208
281 Czernichow S Zanchetti A Turnbull F Barzi F Ninomiya T Kengne AP Lambers
Heerspink HJ Perkovic V Huxley R Arima H Patel A Chalmers J
Woodward M MacMahon S Neal B The effects of blood pressure reduction
and of different blood pressurelowering regimens on major cardiovascular
events according to baseline blood pressure metaanalysis of randomized trials
J Hypertens 2011294–16
282 Thompson AM Hu T Eshelbrenner CL Reynolds K He J Bazzano LA Antihyper
tensive treatment and secondary prevention of cardiovascular disease events
among persons without hypertension a metaanalysis JAMA 2011305913–922
283 Sipahi I Swamiinathan A Natesan V Debanne SM Simon DI Fang JC Effect of anti
hypertensive therapy on incident stroke in cohorts with prehypertensive blood
pressure levels a metaanalysis of randomized controlled trials Stroke 201243
432–440
284 Law MR Morris JK Wald NJ Use of blood pressure lowering drugs in the preven
tion of cardiovascular disease metaanalysis of 147 randomised trials in the context
of expectations from prospective epidemiological studies BMJ 2009338b1665
285 Julius S Nesbitt SD Egan BM Weber MA Michelson EL Karioti N Black HR
Grimm RHJ Messerli EH Oparil S Schork MA Feasibility of treating prehyperten
sion with an angiotensin receptor blocker N Engl J Med 20063541685–1697
286 Luders S Schrader J Berger J Unger T Zidek W Bohn M Middeke M Motz W
Lubcke C Gansz A Brokamp L Schmieder RE Trenkwalder P Haller H
Dominiak P The PHARAO Study prevention of hypertension with the angiotensin
converting enzyme inhibitor ramipril in patients with high normal blood pressure a
prospective randomized controlled prevention trial of the German Hypertension
League J Hypertens 2008261487–1496
287 Beckett NS Peters R Fletcher AE Staessen JA Liu L Dumitrascu D StoyanovskyV
Antikainen RL Nikitin Y Anderson C Belhani A Forette F Rajkumar C Thijs L
Banya W Bulpitt CJ Treatment of hypertension in patients 80 years of age or
older N Engl J Med 20083581887–1898
288 JATOS Study Group Principal results of the Japanese trial to assess optimal systolic
blood pressure in elderly hypertensive patients (JATOS) Hypertens Res 200831
2115–2127
289 Ogihara T Saruta T Rakugi H Matsuoka H Shimamoto K Shimada K Imai Y
Kikuchi K Ito S Eto T Kimura G Imaizumi T Takishita S Ueshima H Target
blood pressure for treatment of isolated systolic hypertension in the elderly Val
sartan in Elderly Isolated Systolic Hypertension Study Hypertension 201056
196–202
290 Hansson L Zanchetti A Carruthers SG Dahlof B Elmfeldt D Julius S Menard J
Rahn KH Wedel H Westerling S Effects of intensive bloodpressure lowering
and lowdose aspirin in patients with hypertension principal results of the Hyper
tension Optimal Treatment (HOT) randomised trial HOT Study Group Lancet
19983511755–1762
291 Curb JD Pressel SL Cutler JA Savage PJ Applegate WB Black H Camel G
Davis BR Frost PH Gonzalez N Guthrie G Oberman A Rutan GH Stamler J
Effect of diureticbased antihypertensive treatment on cardiovascular disease
risk in older diabetic patients with isolated systolic hypertension Systolic Hyper
tension in the Elderly Program Cooperative Research Group JAMA 1996276
1886–1892
292 Tuomilehto J Rastenyte D Birkenhager WH Thijs L Antikainen R Bulpitt CJ
Fletcher AE Forette F Goldhaber A Palatini P Sarti C Fagard R Effects of calcium
channel blockade in older patients with diabetes and systolic hypertension Systolic
Hypertension in Europe Trial Investigators N Engl J Med 1999340677–684
293 UK Prospective Diabetes Study Group Tight blood pressure control and risk of
macrovascular and microvascular complications in type 2 diabetes UKPDS 38 Br
Med J 1998317703–713
294 Reboldi G Gentile G Angeli F Ambrosio G Mancia G Verdecchia P Effects of in
tensive blood pressure reduction on myocardial infarction and stroke in diabetes a
metaanalysis in 73913 patients J Hypertens 2011291253–1269
295 The ACCORD Study Group Effects of intensive bloodpressure control in type 2
diabetes mellitus N Engl J Med 20103621575–1585
296 PROGRESS Collaborative Group Randomised trial of a perindoprilbased
bloodpressurelowering regimen among 6105 individuals with previous stroke
or transient ischaemic attack Lancet 20013581033–1041
297 Yusuf S Diener HC Sacco RL Cotton D Ounpuu S Lawton WA Palesch Y
Martin RH Albers GW Bath P Bornstein N Chan BP Chen ST Cunha L
Dahlof B De Keyser J Donnan GA Estol C Gorelick P Gu V Hermansson K
Hilbrich L Kaste M Lu C Machnig T Pais P Roberts R Skvortsova V Teal P
Toni D VanderMaelen C Voigt T Weber M Yoon BW Telmisartan to prevent re
current stroke and cardiovascular events N Engl J Med 20083591225–1237
298 The European Trial on reduction of cardiac events with Perindopril in stable cor
onary artery disease Investigators Efﬁcacy of perindopril in reduction of cardiovas
cular events among patients with stable coronary artery disease randomised
doubleblind placebocontrolled multicentre trial (the EUROPA study) Lancet
2003362782–788
299 Nissen SE Tuzcu EM Libby P Thompson PD Ghali M Garza D Berman L Shi H
Buebendorf E Topol EJ Effect of antihypertensive agents on cardiovascular events
in patients with coronary disease and normal blood pressure the CAMELOT study
a randomized controlled trial JAMA 20042922217–2225
300 Pitt B Byington RP Furberg CD Hunninghake DB Mancini GB Miller ME Riley W
Effect of amlodipine on the progression of atherosclerosis and the occurrence of
clinical events PREVENT Investigators Circulation 20001021503–1510
301 PooleWilson PA Lubsen J Kirwan BA van Dalen FJ Wagener G Danchin N
Just H Fox KA Pocock SJ Clayton TC Motro M Parker JD Bourassa MG
Dart AM Hildebrandt P Hjalmarson A Kragten JA Molhoek GP Otterstad JE
SeabraGomes R SolerSoler J Weber S Effect of longacting nifedipine on mor
tality and cardiovascular morbidity in patients with stable angina requiring treat
ment (ACTION trial) randomised controlled trial Lancet 2004364849–857
302 The PEACE Trial Investigators Angiotensinconvertingenzyme inhibition in stable
coronary artery disease N Engl J Med 20043512058–2068
303 Lewis JB Blood pressure control in chronic kidney disease is less really more JAm
Soc Nephrol 2010211086–1092
304 Klahr S Levey AS Beck GJ Caggiula AW Hunsicker L Kusek JW Striker G The
effects of dietary protein restriction and bloodpressure control on the progres
sion of chronic renal disease Modiﬁcation of Diet in Renal Disease Study Group
N Engl J Med 1994330877–884
305 Wright JT Jr Bakris G Greene T Agodoa LY Appel LJ Charleston J Cheek D
DouglasBaltimore JG Gassman J Glassock R Hebert L Jamerson K Lewis J
Phillips RA Toto RD Middleton JP Rostand SG Effect of blood pressure lowering
and antihypertensive drug class on progression of hypertensive kidney disease
results from the AASK trial JAMA 20022882421–2431
306 Ruggenenti P Perna A Loriga G Ganeva M EneIordache B Turturro M Lesti M
Perticucci E Chakarski IN Leonardis D Garini G Sessa A Basile C Alpa M
Scanziani R Sorba G Zoccali C Remuzzi G Bloodpressure control for renopro
tection in patients with nondiabetic chronic renal disease (REIN2) multicentre
randomised controlled trial Lancet 2005365939–946
307 Sarnak MJ Greene T Wang X Beck G Kusek JW Collins AJ Levey AS The effect of
a lower target blood pressure on the progression of kidney disease longterm
followup of the modiﬁcation of diet in renal disease study Ann Intern Med 2005
142342–351
308 Appel LJ Wright JT Jr Greene T Agodoa LY Astor BC Bakris GL Cleveland WH
Charleston J Contreras G Faulkner ML Gabbai FB Gassman JJ Hebert LA
Jamerson KA Kopple JD Kusek JW Lash JP Lea JP Lewis JB Lipkowitz MS
Massry SG Miller ER Norris K Phillips RA Pogue VA Randall OS Rostand SG
Smogorzewski MJ Toto RD Wang X Intensive bloodpressure control in hyper
tensive chronic kidney disease N Engl J Med 2010363918–929
309 Lewis EJ Hunsicker LG Clarke WR Berl T Pohl MA Lewis JB Ritz E Atkins RC
Rohde R Raz I Renoprotective effect of the angiotensinreceptor antagonist irbe
sartan in patients with nephropathy due to type 2 diabetes N Engl J Med 2001345
851–860
310 Brenner BM Cooper ME de Zeeuw D Keane WF Mitch WE Parving HH
Remuzzi G Snapinn SM Zhang Z Shahinfar S Effects of losartan on renal and car
diovascular outcomes in patients with type 2 diabetes and nephropathy N Engl J
Med 2001345861–869
311 The ESCAPE Trial Group Strict bloodpressure control and progression of renal
failure in children N Engl J Med 20093611639–1650
312 Arguedas JA Perez MI Wright JM Treatment blood pressure targets for hyperten
sion Cochrane Database Syst Rev 2009CD004349
ESH and ESC Guidelines2219a
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 2019313 Upadhyay A Earley A Haynes SM Uhlig K Systematic review blood pressure
target in chronic kidney disease and proteinuria as an effect modiﬁer Ann Intern
Med 2011154541–548
314 Zanchetti A Blood pressure targets of antihypertensive treatment up and down
the Jshaped curve Eur Heart J 2010312837–2840
315 Adler AI Stratton IM Neil HA Yudkin JS Matthews DR Cull CA Wright AD
Turner RC Holman RR Association of systolic blood pressure with macrovascular
and microvascular complications of type 2 diabetes (UKPDS 36) prospective ob
servational study BMJ 2000321412–419
316 Berl T Hunsicker LG Lewis JB Pfeffer MA Porush JG Rouleau JL Drury PL
Esmatjes E Hricik D Pohl M Raz I Vanhille P Wiegmann TB Wolfe BM
Locatelli F Goldhaber SZ Lewis EJ Impact of achieved blood pressure on cardio
vascular outcomes in the Irbesartan Diabetic Nephropathy Trial J Am Soc Nephrol
2005162170–2179
317 Messerli FH Mancia G Conti CR Hewkin AC Kupfer S Champion A Kolloch R
Benetos A Pepine CJ Dogma disputed can aggressively lowering blood pressure
in hypertensive patients with coronary artery disease be dangerous Ann Intern
Med 2006144884–893
318 Sleight P Redon J Verdecchia P Mancia G Gao P Fagard R Schumacher H
Weber M Bohm M Williams B Pogue J Koon T Yusuf S Prognostic value of
blood pressure in patients with high vascular risk in the Ongoing Telmisartan
Alone and in combination with Ramipril Global Endpoint Trial study J Hypertens
2009271360–1369
319 Okin PM Hille DA Kjeldsen SE Dahlof B Devereux RB Impact of lower achieved
blood pressure on outcomes in hypertensive patients J Hypertens 201230
802–810
320 Boutitie F Gueyfﬁer F Pocock S Fagard R Boissel JP Jshaped relationship between
blood pressure and mortality in hypertensive patients new insights from a
metaanalysis of individualpatient data Ann Intern Med 2002136438–448
321 Fagard RH Staessen JA Thijs L Celis H Bulpitt CJ de Leeuw PW Leonetti G
Tuomilehto J Yodfat Y Ontreatment diastolic blood pressure and prognosis in
systolic hypertension Arch Intern Med 20071671884–1891
322 Bangalore S Messerli FH Wun C Zuckerman AL DeMicco D Kostis JB LaRosa JC
Treating to New Targets Steering Committee and Investigators JCurve revisited
an analysis of the Treating to New Targets (TNT) Trial J Am Coll Cardiol 200953
A217
323 Bangalore S Qin J Sloan S Murphy SA Cannon CP What isthe optimal blood pres
sure in patients after acute coronary syndromes Relationship of blood pressure
and cardiovascular events in the PRavastatin OR atorVastatin Evaluation and Infec
tion TherapyThrombolysis In Myocardial Infarction (PROVE ITTIMI) 22 trial Cir
culation 20101222142–2151
324 Mancia G Schumacher H Redon J Verdecchia P Schmieder R Jennings G Yusoff K
Ryden L Liu GL Teo K Sleight P Yusuf S Blood pressure targets recommended by
guidelines and incidence of cardiovascular and renal events in the Ongoing Telmi
sartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTAR
GET) Circulation 20111241727–1736
325 Ovbiagele B Diener HC Yusuf S Martin RH Cotton D Vinisko R Donnan GA
Bath PM Level of systolic blood pressure within the normal range and risk of recur
rent stroke JAMA 20113062137–2144
326 Redon J Mancia G Sleight P Schumacher H Gao P Pogue J Fagard R Verdecchia P
Weber M Bohm M Williams B Yusoff K Teo K Yusuf S Safety and efﬁcacy of low
blood pressures among patients with diabetes subgroup analyses from the
ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril
Global Endpoint Trial) J Am Coll Cardiol 20125974–83
327 Bangalore S Kumar S Lobach I Messerli FH Blood pressure targets in subjects with
type 2 diabetes mellitusimpaired fasting glucose observations from traditional and
bayesian randomeffects metaanalyses of randomized trials Circulation 2011123
2799–2810
328 Verdecchia P Staessen JA Angeli F de Simone G Achilli A Ganau A Mureddu G
Pede S Maggioni AP Lucci D Reboldi G Usual vs tight control of systolic blood
pressure in nondiabetic patients with hypertension (CardioSis) an openlabel
randomised trial Lancet 2009374525–533
329 Haller H Ito S Izzo JL Jr Januszewicz A Katayama S Menne J Mimran A
Rabelink TJ Ritz E Ruilope LM Rump LC Viberti G ROADMAP Trial Investigators
Olmesartan for the delay or prevention of microalbuminuria in type 2 diabetes N
Engl J Med 2011364907–917
330 Okin PM Devereux RB Jern S Kjeldsen SE Julius S Nieminen MS Snapinn S
Harris KE Aurup P Edelman JM Dahlof B Regression of electrocardiographic
left ventricular hypertrophy by losartan vs atenolol The Losartan Intervention
for Endpoint reduction in Hypertension (LIFE) Study Circulation 2003108
684–690
331 Mann JF Schmieder RE McQueen M Dyal L Schumacher H Pogue J Wang X
Maggioni A Budaj A Chaithiraphan S Dickstein K Keltai M Metsarinne K
Oto A Parkhomenko A Piegas LS Svendsen TL Teo KK Yusuf S Renal outcomes
with telmisartan ramipril or both in people at high vascular risk (the ONTARGET
study) a multicentre randomised doubleblind controlled trial Lancet 2008372
547–553
332 Zanchetti A Mancia G Longing for clinical excellence a critical outlook into the
NICE recommendations on hypertension management is nice always good
J Hypertens 201230660–668
333 Mancia G Parati G Bilo G Gao P Fagard R Redon J Czuriga I Pola`k M Ribeiro JM
Sanchez R Trimarco B Verdecchia P van Mieghem W Teo K Sleight P Yusuf S
Ambulatory Blood Pressure Values in the Ongoing Telmisartan Alone and in Com
bination with Ramipril Global Endpoint Trial (ONTARGET) Hypertension 201260
1400–1406
334 Staessen JA Byttebier G Buntinx F Celis H O’Brien ET FagardR Antihypertensive
treatment based on conventional or ambulatory blood pressure measurement A
randomized controlled trial Ambulatory Blood Pressure Monitoring and Treat
ment of Hypertension Investigators JAMA 19972781065–1072
335 Staessen JA Den Hond E Celis H Fagard R Keary L Vandenhoven G O’Brien ET
Antihypertensive treatment based on blood pressure measurement at home or in
the physician’s ofﬁce a randomized controlled trial JAMA 2004291955–964
336 Verberk WJ Kroon AA Lenders JW Kessels AG van Montfrans GA Smit AJ van
der Kuy PH Nelemans PJ Rennenberg RJ Grobbee DE Beltman FW Joore MA
Brunenberg DE Dirksen C Thien T de Leeuw PW Selfmeasurement of blood
pressure at home reduces the need for antihypertensive drugs a randomized con
trolled trial Hypertension 2007501019–1025
337 Elmer PJ Obarzanek E Vollmer WM SimonsMorton D Stevens VJ Young DR
Lin PH Champagne C Harsha DW Svetkey LP Ard J Brantley PJ Proschan MA
Erlinger TP Appel LJ Effects of comprehensive lifestyle modiﬁcation on diet
weight physical ﬁtness and blood pressure control 18month results of a rando
mized trial Ann Intern Med 2006144485–495
338 Frisoli TM Schmieder RE Grodzicki T Messerli FH Beyond salt lifestyle modiﬁca
tions and blood pressure Eur Heart J 2011323081–3087
339 Dickinson HO Mason JM Nicolson DJ Campbell F Beyer FR Cook JV Williams B
Ford GA Lifestyle interventions to reduce raised blood pressure a systematic
review of randomized controlled trials J Hypertens 200624215–233
340 Groppelli A Omboni S Parati G Mancia G Blood pressure and heart rate response
to repeated smoking before and after betablockade and selective alpha 1 inhib
ition J Hypertens 19908(Suppl 5)S35–40
341 Groppelli A Giorgi DM Omboni S Parati G Mancia G Persistent blood pressure
increase induced by heavy smoking J Hypertens 199210495–499
342 Mann SJ James GD Wang RS Pickering TG Elevation of ambulatory systolic blood
pressure in hypertensive smokers A casecontrol study JAMA 1991265
2226–2228
343 Guild SJ McBryde FD Malpas SC Barrett CJ High dietary salt and angiotensin II
chronically increase renal sympathetic nerve activity a direct telemetric study
Hypertension 201259614–620
344 Pimenta E Gaddam KK Oparil S Aban I Husain S Dell’Italia LJ Calhoun DA Effects
of dietary sodium reduction on blood pressure in subjects with resistant hyperten
sion results from a randomized trial Hypertension 200954475–481
345 Graudal NA HubeckGraudal T Jurgens G Effects of lowsodium diet vs high
sodium diet on blood pressure renin aldosterone catecholamines cholesterol
and triglyceride (Cochrane Review) Am J Hypertens 2012251–15
346 He FJ MacGregor GA How far should salt intake be reduced Hypertension 2003
421093–1099
347 BibbinsDomingo K Chertow GM Coxson PG Moran A Lightwood JM
Pletcher MJ Goldman L Projected effect of dietary salt reductions on future car
diovascular disease N Engl J Med 2010362590–599
348 He FJ MacGregor GA Salt reduction lowers cardiovascular risk metaanalysis of
outcome trials Lancet 2011378380–382
349 Taylor RS Ashton KE Moxham T Hooper L Ebrahim S Reduced dietary salt for
the prevention of cardiovascular disease a metaanalysis of randomized controlled
trials (Cochrane review) Am J Hypertens 201124843–853
350 He FJ Burnier M Macgregor GA Nutrition in cardiovascular disease salt in hyper
tension and heart failure Eur Heart J 2011323073–3080
351 Cook NR Cutler JA Obarzanek E Buring JE Rexrode KM Kumanyika SK Appel LJ
Whelton PK Long term effects of dietary sodium reduction on cardiovascular
disease outcomes observational followup of the trials of hypertension prevention
(TOHP) BMJ 2007334885–888
352 O’Donnell MJ Mente A Smyth A Yusuf S Salt intake and cardiovascular disease
why are the data inconsistent Eur Heart J 2013341034–1040
353 Cobiac LJ Vos T Veerman JL Costeffectiveness of interventions to reduce dietary
salt intake Heart 2010961920–1925
354 Puddey IB Beilin LJ Vandongen R Regular alcohol use raises blood pressure in
treated hypertensive subjects A randomised controlled trial Lancet 19871
647–651
355 Cushman WC Cutler JA Hanna E Bingham SF Follmann D Harford T Dubbert P
Allender PS Dufour M Collins JF Walsh SM Kirk GF Burg M Felicetta JV
Hamilton BP Katz LA Perry HM Jr Willenbring ML Lakshman R Hamburger RJ
ESH and ESC Guidelines 2219b
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 2019Prevention and Treatment of Hypertension Study (PATHS) effects of an
alcohol treatment program on blood pressure Arch Intern Med 1998158
1197–1207
356 Mente A de Koning L Shannon HS Anand SS A systematic review of the evidence
supporting a causal link between dietary factors and coronary heart disease Arch
Intern Med 2009169659–669
357 Soﬁ F Abbate R Gensini GF Casini A Accruing evidence on beneﬁts of adherence
to the Mediterranean diet on health an updated systematic review and
metaanalysis Am J Clin Nutr 2010921189–1196
358 Estruch R Ros E SalasSalvado´ J Covas MI Corella D Aro´sFGo´mezGracia E
RuizGutie´rrez V Fiol M Lapetra J LamuelaRaventos RM SerraMajem L
Pinto´ X Basora J Mun˜oz MA Sorlı´ JV Martı´nez JA Martı´nezGonza´lez MA the
PREDIMED Study Investigators Primary Prevention of Cardiovascular Disease
with a Mediterranean Diet N Eng J Med 20133681279–1290
359 Rivas M Garay RP Escanero JF Cia P Jr Cia P Alda JO Soy milk lowers blood pres
sure in men and women with mild to moderate essential hypertension J Nutr 2002
1321900–1902
360 Blumenthal JA Babyak MA Hinderliter A Watkins LL Craighead L Lin PH
Caccia C Johnson J Waugh R Sherwood A Effects of the DASH diet al one and
in combination with exercise and weight loss on blood pressure and cardiovascular
biomarkers in men and women with high blood pressure the ENCORE study Arch
Intern Med 2010170126–135
361 Stessen M Kuhle C Hensrad D Erwin PJ Murad MH The effect of coffee consump
tion on blood pressure and the development of hypertension a systematic review
and metaanalysis J Hypertens 2012302245–2254
362 Romero R Bonet J de la Sierra A Aguilera MT Undiagnosed obesity in hyperten
sion clinical and therapeutic implications Blood Press 200716347–353
363 Neter JE Stam BE Kok FJ Grobbee DE Geleijnse JM Inﬂuence of weight reduction
on blood pressure a metaanalysis of randomized controlled trials Hypertension
200342878–884
364 Prospective Studies Collaboration Bodymass index and causespeciﬁc mortality
in 900 000 adults collaborative analyses of 57 prospective studies Lancet 2009
37310831096
365 Flegal KM Kit BK Orpana H Graubard BI Association of allcause mortality with
overweight and obesity using standard body mass index categories A systematic
review and metaanalysis JAMA 201330971–82
366 Shaw K Gennat H O’Rourke P Del Mar C Exercise for overweight or obesity
Cochrane Database Syst Rev 2006CD003817
367 Norris SL Zhang X Avenell A Gregg E Schmid CH Lau J Longterm non
pharmacological weight loss interventions for adults with prediabetes Cochrane
Database Syst Rev 2005CD005270
368 Jordan J Yumuk V Schlaich M Nilsson PM ZahorskaMarkiewicz B Grassi G
Schmieder RE Engeli S Finer N Joint statement of the European Association for
the Study of Obesity and the European Society of Hypertension obesity and difﬁ
cult to treat arterial hypertension J Hypertens 2012301047–1055
369 Cornelissen VA Fagard RH Effects of endurance training on blood pressure blood
pressureregulating mechanisms and cardiovascular risk factorsHypertension2005
46667–675
370 Leitzmann MF Park Y Blair A BallardBarbash R Mouw T Hollenbeck AR
Schatzkin A Physical activity recommendations and decreased risk of mortality
Arch Intern Med 20071672453–2460
371 Rossi A Dikareva A Bacon SL Daskalopoulou SS The impact of physical activity on
mortality in patients with high blood pressure a systematic review J Hypertens
2012301277–1288
372 Fagard RH Physical activity ﬁtness mortality J Hypertens 2012301310–1312
373 Fagard RH Exercise therapy in hypertensive cardiovascular disease Prog Cardiovasc
Dis 201153404–411
374 MolmenHansen HE Stolen T Tjonna AE Aamot IL Ekeberg IS Tyldum GA
Wisloff U Ingul CB Stoylen A Aerobic interval training reduces blood pressure
and improves myocardial function in hypertensive patients Eur J Prev Cardiol
201219151–160
375 Cornelissen VA FagardRH Coeckelberghs E VanheesL Impact of resistance train
ing on blood pressure and other cardiovascular risk factors a metaanalysis of ran
domized controlled trials Hypertension 201158950–958
376 Vanhees L Geladas N Hansen D Kouidi E Niebauer J Reiner Z Cornelissen V
Adamopoulos S Prescott E Bo¨rjesson M BjarnasonWehrens B Bjo¨rnstad HH
CohenSolal A Conraads V Corrado D De Sutter J Doherty P Doyle F
Dugmore D Ellingsen Ø Fagard R Giada F Gielen S Hager A Halle M
Heidbu¨chel H Jegier A Mazic S McGee H Mellwig KP Mendes M Mezzani A
Pattyn N Pelliccia A Piepoli M Rauch B SchmidtTrucksa¨ss A Takken T van
Buuren F Vanuzzo D Importance of characteristics and modalities of physical ac
tivity and exercise in the management of cardiovascular health in individuals with
cardiovascular risk factors recommendations from the EACPR Part II Eur J Prev
Cardiol 2012191005–1033
377 Huisman M Kunst AE Mackenbach JP Inequalities in the prevalence of smoking in
the European Union comparing education and income Prev Med 200540
756–764
378 Yarlioglues M Kaya MG Ardic I Calapkorur B Dogdu O Akpek M Ozdogru M
Kalay N Dogan A Ozdogru I Oguzhan A Acute effects of passive smoking on
blood pressure and heart rate in healthy females Blood Press Monit 201015
251–256
379 Grassi G Seravalle G Calhoun DA Bolla GB Giannattasio C Marabini M Del Bo A
Mancia G Mechanisms responsible for sympathetic activation by cigarette smoking
in humans Circulation 199490248–253
380 Narkiewicz K van de Borne PJ Hausberg M Cooley RL Winniford MD
Davison DE Somers VK Cigarette smoking increases sympathetic outﬂow in
humans Circulation 199898528–534
381 Mancia G Groppelli A Di Rienzo M Castiglioni P Parati G Smoking impairs bar
oreﬂex sensitivity in humans Am J Physiol 1997273H1555–1560
382 Bang LE Buttenschon L Kristensen KS Svendsen TL Do we undertreat hyperten
sive smokers A comparison between smoking and nonsmoking hypertensives
Blood Press Monit 20005271–274
383 Primatesta P Falaschetti E Gupta S Marmot MG Poulter NR Association between
smoking and blood pressure evidence from the health survey for England Hyper
tension 200137187–193
384 Doll R Peto R Wheatley K Gray R Sutherland I Mortality in relation to smoking
40 years’ observations on male British doctors BMJ 1994309901–911
385 Rosenberg L Kaufman DW Helmrich SP Shapiro S The risk of myocardial infarc
tion after quitting smoking in men under 55 years of age N Engl J Med 1985313
1511–1514
386 Manson JE Tosteson H RidkerPM SatterﬁeldS Hebert P O’ConnorGT Buring JE
Hennekens CH The primary prevention of myocardial infarction N Engl J Med
19923261406–1416
387 Lancaster T Stead L Physician advice for smoking cessation Cochrane Database Syst
Rev 2004CD000165
388 Cahill K Stead LF Lancaster T Nicotine receptor partial agonists for smoking ces
sation Cochrane Database Syst Rev 2010CD006103
389 Hughes JR Stead LF Lancaster T Antidepressants for smoking cessation Cochrane
Database Syst Rev 2007CD000031
390 Hajek P Stead LF West R Jarvis M Lancaster T Relapse prevention interventions
for smoking cessation Cochrane Database Syst Rev 2009CD003999
391 Psaty BM Lumley T Furberg CD Schellenbaum G Pahor M Alderman MH
Weiss NS Health outcomes associated with various antihypertensive therapies
used as ﬁrstline agents a network metaanalysis JAMA 20032892534–2544
392 Costanzo P PerroneFilardi P Petretta M Marciano C Vassallo E Gargiulo P
Paolillo S Petretta A Chiariello M Calcium channel blockers and cardiovascular
outcomes a metaanalysis of 175634 patients J Hypertens 2009271136–1151
393 van Vark LC Bertrand M Akkerhuis KM Brugts JJ Fox K Mourad JJ Boersma E
Angiotensinconverting enzyme inhibitors reduce mortality in hypertension a
metaanalysis of randomized clinical trials of reninangiotensinaldosterone
system inhibitors involving 158 998 patients Eur Heart J 2012332088–2097
394 Blood Pressure Lowering Treatment Trialists’ Collaboration Effects of different
blood pressurelowering regimens on major cardiovascular events in individuals
with and without diabetes mellitus results of prospectively designed overviews
of randomized trials Arch Intern Med 20051651410–1419
395 Blood Pressure Lowering Treatment Trialists’ Collaboration Effects of different
bloodpressurelowering regimens on major cardiovascular events results of
prospectivelydesigned overviews of randomised trials Lancet 2003362
1527–1535
396 Wiyonge CS Bradley HA Volmink J Mayosi BM Mbenin A Opie LH Cochrane
Database Syst Rev 2012Nov 1411CD002003doi
397 Bradley HA Wiyonge CS Volmink VA Mayosi BM Opie LH How strong is the evi
dence for use of betablockers as ﬁrst line therapy for hypertension J Hypertens
2006242131–2141
398 Williams B Lacy PS Thom SM Cruickshank K Stanton A Collier D Hughes AD
Thurston H O’Rourke M Differential impact of blood pressurelowering drugs
on central aortic pressure and clinical outcomes principal results of the Conduit
Artery Function Evaluation (CAFE) study Circulation 20061131213–1225
399 Boutouyrie P Achouba A Trunet P Laurent S Amlodipinevalsartan combination
decreases central systolic blood pressure more effectively than the
amlodipineatenolol combination the EXPLOR study Hypertension 201055
1314–1322
400 Silvestri A Galetta P Cerquetani E Marazzi G Patrizi R Fini M Rosano GM Report
of erectile dysfunction after therapy with betablockers is related to patient knowl
edge of sideeffects and is reversed by placebo Eur Heart J 2003241928–1932
401 Sharma AM Pischon T Hardt S Kruz I Luft FC Hypothesis Betaadrenergic recep
tor blockers and weight gain A systematic analysisHypertension 200137250–254
402 Elliott WJ Meyer PM Incident diabetes in clinical trials of antihypertensive drugs a
network metaanalysis Lancet 2007369201–207
ESH and ESC Guidelines2219c
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 2019403 Zanchetti A Hennig M Baurecht H Tang R Cuspidi C Carugo S Mancia G Preva
lence and incidence of the metabolic syndrome in the European Lacidipine Studyon
Atherosclerosis (ELSA) and its relation with carotid intimamedia thickness
J Hypertens 2007252463–2470
404 Boutouyrie P Bussy C Hayoz D Hengstler J Dartois N Laloux B Brunner H
Laurent S Local pulse pressure and regression of arterial wall hypertrophy
during longterm antihypertensive treatment Circulation 20001012601–2606
405 Dhakam Z Yasmin McEniery CM Burton T Brown MJ Wilkinson IB A compari
son of atenolol and nebivolol in isolated systolic hypertension J Hypertens 200826
351–356
406 Kampus P Serg M Kals J Zagura M Muda P Karu K Zilmer M Eha J Differential
effects of nebivolol and metoprolol on central aortic pressure and left ventricular
wall thickness Hypertension 2011571122–1128
407 Bakris GL Fonseca V Katholi RE McGill JB Messerli FH Phillips RA Raskin P
Wright JT Jr Oakes R Lukas MA Anderson KM Bell DS Metabolic effects of car
vedilol vs metoprolol in patients with type 2 diabetes mellitus and hypertension a
randomized controlled trial JAMA 20042922227–2236
408 Celik T Iyisoy A Kursaklioglu H Kardesoglu E Kilic S Turhan H Yilmaz MI
Ozcan O Yaman H Isik E Fici F Comparative effects of nebivolol and metoprolol
on oxidative stress insulin resistance plasma adiponectin and soluble Pselectin
levels in hypertensive patients J Hypertens 200624591–596
409 Stears AJ Woods SH Watts MM Burton TJ Graggaber J Mir FA Brown MJ A
doubleblind placebocontrolled crossover trial comparing the effects of amilor
ide and hydrochlorothiazide on glucose tolerance in patients with essential hyper
tension Hypertension 201259934–942
410 McMurray JJ Adamopoulos S Anker SD Auricchio A Bohm M Dickstein K Falk V
Filippatos G Fonseca C GomezSanchez MA Jaarsma T Kober L Lip GY
Maggioni AP Parkhomenko A Pieske BM Popescu BA Ronnevik PK Rutten FH
Schwitter J Seferovic P Stepinska J Trindade PT Voors AA Zannad F Zeiher A
ESC Guidelines for the diagnosis and treatment of acute and chronic heart
failure 2012 The Task Force for the Diagnosis and Treatment of Acute and
Chronic Heart Failure 2012 of the European Society of Cardiology Developed
in collaboration with the Heart Failure Association (HFA) of the ESC Eur Heart J
2012331787–1847
411 Rutten FH Zuithoff NP Halk F Grobbee DE Hoes AW BetaBlockers may reduce
mortality and risk of exacerbations in patients with chronic obstructive pulmonary
disease Arch Intern Med 2010170880–887
412 Report of the Joint National Committee on Detection Evaluation and Treatment
of High Blood Pressure A cooperative study JAMA 1977237255–261
413 Arterial hypertension Report of a WHO expert committee World Health Organ
Tech Rep Ser 19787–56
414 Jamerson K Weber MA Bakris GL Dahlof B Pitt B Shi V Hester A Gupte J
Gatlin M Velazquez EJ Benazepril plus amlodipine or hydrochlorothiazide for
hypertension in highrisk patients N Engl J Med 20083592417–2428
415 Zanchetti A Hypertension metaanalyses ﬁrstrankevidence or second hand infor
mation Nat Rev Cardiol 201114249–251
416 Messerli FH Makani H Benjo A Romero J Alviar C Bangalore S Antihypertensive
efﬁcacy of hydrochlorothiazide as evaluated by ambulatory blood pressure moni
toring A metaanalysed of randomized trials J Am Coll Cardiol 201157590–600
417 Roush GC Halford TR Guddati AK Chlortalidone compared with hydrochlor
othiazide in reducing cardiovascular events systematic review and network
metaanalyses Hypertension 2012591110–1117
418 Dorsch MP Gillespie BW Erickson SR Bleske BE Weder AB Chlortalidone
reduces cardiovascular events compared with hydrochlorothiazide a retrospect
ive cohort analysis Hypertension 201157689–694
419 Pitt B Zannad F Remme WJ Cody R Castaigne A Perez A Palensky J Wittes J The
effect of spironolactone on morbidity and mortality in patients with severe heart
failure Randomized Aldactone Evaluation Study Investigators N Engl J Med 1999
341709–717
420 Zannad F McMurray JJ Krum H van Veldhuisen DJ Swedberg K Shi H Vincent J
Pocock SJ Pitt B EMPHASISHF Study Group Eplerenone in patients with systolic
heart failure and mild symptoms N Engl J Med 201136411–21
421 Verdecchia P Reboldi G Angeli F Gattobigio R Bentivoglio M Thijs L Staessen JA
Porcellati C AngiotensinConverting Enzyme Inhibitors and Calcium Channel
Blockers for Coronary Heart Disease and Stroke Prevention Hypertension 2005
46386–392
422 Zanchetti A Calcium channel blockers in hypertension in Black HR Elliott WJ
(eds) Hypertension a companion to Braunwald Heart Disease Elsevier 2012 chapt
22204–218
423 Dalhof B Sever PS Poulter NR Wedel H Beevers DG aulﬁeld M Collins R
Kjeldsen SE Kristinsson A McInnes GT Mehlsen J Neminen M O’Brien E
Ostergren J Prevention of cardiovascular events with an antihypertensive
regimen of amlodipine adding perindopril as required vs atenolol adding bendro
ﬂumethiazide as required in the AngloScandinavian Cardiac Outcomes Trial
Blood Pressure Lowering Arm (ASCOTBPLA) a multicentre randomised con
trolled trial Lancet 2005 366895–906
424 Strauss MH Hall AS Do angiotensin receptor blockers increase the risk of myocar
dial infarction Angiotensin Receptor Blockers May increase risk of Myocardial In
farction Unraveling the ARBMI Paradox Circulation 2006114838–854
425 Sipahi I Debanne SM Rowland DY Simon DI Fang JC Angiotensinreceptor block
ade and risk of cancer metaanalysis of randomised controlled trials The Lancet On
cology 201011627–636
426 ARB Trialists collaboration Effects of telmisartan irbesartan valsartan candesar
tan and losartan on cancers in 15 trials enrolling 138769 individuals J Hypertens
201129623–635
427 Volpe M Azizi M Danser AH Nguyen G Ruilope LM Twisting arms to angiotensin
receptor blockersantagonists the turn of cancer Eur Heart J 20113219–22
428 Gradman AH Schmieder RE Lins RL Nussberger J Chiang Y Bedigian MP Aliski
ren a novel orally effective renin inhibitor provides dosedependent antihyperten
sive efﬁcacy and placebolike tolerability in hypertensive patients Circulation 2005
1111012–1018
429 O’Brien E Barton J Nussberger J Mulcahy D Jensen C Dicker P Stanton A Alis
kiren reduces blood pressure and suppresses plasma renin activity in combination
with athiazide diuretican angiotensinconvertingenzyme inhibitor oran angioten
sin receptor blocker Hypertension 200749276–284
430 Littlejohn TW 3rd Trenkwalder P Hollanders G Zhao Y Liao W Longterm
safety tolerability and efﬁcacy of combination therapy with aliskiren and amlodi
pine in patients with hypertension Curr Med Res Opin 200925951–959
431 Parving HH Persson F Lewis JB Lewis EJ Hollenberg NK Aliskiren combined with
losartan in type 2 diabetes and nephropathy N Engl J Med 20083582433–2446
432 Seed A Gardner R McMurray J Hillier C Murdoch D MacFadyen R Bobillier A
Mann J McDonagh T Neurohumoral effects of the new orallyactive renin inhibitor
aliskiren in chronic heart failure Eur J Heart Fail 200791120–1127
433 Parving HH Brenner BM McMurray JJV de Zeeuw D Haffer SM Solomon SD Car
diorenal endpoints in a trial of aliskiren for type 2 diabetes N Engl J Med
20123672204–2213
434 Gheorghiade M Bo¨hm M Greene SJ Fonarow GC Lewis EF Zannad F
Solomon SD Baschiera F Botha J Hua TA Gimpelewicz CR Jaumon X
Lesogor A Maggioni AP for the ASTRONAUT Investigators and Coordinators
Effect of Aliskiren on Postdischarge Mortality and Heart Failure Readmissions
Among Patients Hospitalized for Heart Failure The ASTRONAUT Randomized
Trial JAMA 20133091125–1135
435 Rothwell PM Howard SC Dolan E O’Brien E Dobson JE Dahlof B Sever PS
Poulter NR Prognostic signiﬁcance of visittovisit variability maximum systolic
blood pressure and episodic hypertension Lancet 2010375895–905
436 Mancia G Messerli F Bakris G Zhou Q Champion A Pepine CJ Blood pressure
control and improved cardiovascular outcomes in the International Verapamil
SRTrandolapril Study Hypertension 200750299–305
437 Mancia G Facchetti R Parati G Zanchetti A VisittoVisit Blood Pressure Variabil
ity Carotid Atherosclerosis and Cardiovascular Events in the European Lacidipine
Study on Atherosclerosis Circulation 2012126569–578
438 Rothwell PM Howard SC Dolan E O’Brien E Dobson JE Dahlof B Poulter NR
Sever PS Effects of beta blockers and calciumchannel blockers on
withinindividual variability in blood pressure and risk of stroke Lancet Neurology
20109469–480
439 Webb AJ Fischer U Mehta Z Rothwell PM Effects of antihypertensivedrug class
on interindividual variation in blood pressure and risk of stroke a systematic
review and metaanalysis Lancet 2010375906–915
440 Webb AJ Rothwell PM Effect of dose and combination of antihypertensives on
interindividual blood pressure variability a systematic review Stroke 201142
2860–2865
441 Mancia G Facchetti R Parati G Zanchetti A Visittovisit blood pressure variability
in the European Lacidipine Study on Atherosclerosis methodological aspects and
effects of antihypertensive treatment J Hypertens 2012301241–1251
442 Zanchetti A Wars war games and dead bodies on the battleﬁeld variations on the
theme of blood pressure variability Stroke 2011422722–2724
443 Mancia G Zanchetti A Choice of antihypertensivedrugs in the European Society of
HypertensionEuropean Society of Cardiology guidelines speciﬁc indications
rather than ranking for general usage J Hypertens 200826164–168
444 Blood Pressure Lowering Treatment Trialists’ Collaboration Effects of different
regimens to lower blood pressure on major cardiovascular events in older and
younger adults metaanalysis of randomised trials BMJ 20083361121–1123
445 Blood Pressure Lowering Treatment Trialists’ Collaboration Do men and women
respond differently to blood pressurelowering treatment Results of prospective
ly designed overviews of randomized trials Eur Heart J 2008292669–2680
446 Wald DS Law M Morris JK Bestwick JP Wald NJ Combination therapy vs mono
therapy in reducing blood pressure metaanalysis on 11000 participants from 42
trials Am J Med 2009122290–300
ESH and ESC Guidelines 2219d
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 2019447 Corrao G Parodi A Zambon A Heiman F Filippi A Cricelli C Merlino L Mancia G
Reduced discontinuation of antihypertensive treatment by twodrug combination
as ﬁrst step Evidence from daily life practice J Hypertens 2010281584–1590
448 ALLHAT ofﬁcers and coordinators for the ALLHAT Collaborative Research
Group Major outcomes in highrisk hypertensive patients randomized to
angiotensinconverting enzyme inhibitor or calcium channel blocker vs diuretic
The Antihypertensive and LipidLowering Treatment to Prevent Heart Attack
Trial (ALLHAT) JAMA 20022882981–2997
449 SHEP Cooperative Research Group Prevention of stroke by antihypertensive
drug treatment in older persons with isolated systolic hypertension Final results
of the Systolic Hypertension in the Elderly Program (SHEP) JAMA 1991265
3255–3264
450 Lithell H Hansson L Skoog I Elmfeldt D Hofman A Olofsson B Trenkwalder P
Zanchetti A The Study on Cognition and Prognosis in the Elderly (SCOPE) prin
cipal results of a randomized doubleblind intervention trial J Hypertens 200321
875–886
451 Staessen JA FagardR Thijs L CelisH Arabidze GG Birkenhager WH Bulpitt CJ de
Leeuw PW Dollery CT Fletcher AE Forette F Leonetti G Nachev C O’Brien ET
Rosenfeld J Rodicio JL Tuomilehto J Zanchetti A Randomised doubleblind com
parison of placebo and active treatment for older patients with isolated systolic
hypertension The Systolic Hypertension in Europe (SystEur) Trial Investigators
Lancet 1997350757–764
452 Liu L Wang JG Gong L Liu G Staessen JA Comparison of active treatment and
placebo in older Chinese patients with isolated systolic hypertension Systolic
Hypertension in China (SystChina) Collaborative Group J Hypertens 199816
1823–1829
453 Coope J Warrender TS Randomised trial of treatment of hypertension in elderly
patients in primary care BMJ 19862931145–1151
454 Dahlof B Lindholm LH Hansson L Schersten B Ekbom T Wester PO Morbidity
and mortality in the Swedish Trial in Old Patients with Hypertension
(STOPHypertension) Lancet 19913381281–1285
455 Hansson L Lindholm LH Niskanen L Lanke J Hedner T Niklason A
Luomanmaki K Dahlof B de Faire U Morlin C Karlberg BE Wester PO
Bjorck JE Effect of angiotensinconvertingenzyme inhibition compared with con
ventional therapy on cardiovascular morbidity and mortality in hypertension the
Captopril Prevention Project (CAPPP) randomised trial Lancet 1999353
611–616
456 Julius S Kjeldsen SE Weber M Brunner HR Ekman S Hansson L Hua T Laragh J
McInnes GT Mitchell L Plat F Schrok A Smith B Zanchetti A VALUE trial group
Outcomes inhypertensive patients at high cardiovascular risk treated with regi
mens based on valsartan or amlodipine the VALUE randomised trial Lancet
20043632022–2031
457 Dahlof B Devereux RB Kjeldsen SE Julius S Beevers G de Faire U Fyhrquist F
Ibsen H Kristiansson K LederballePedersen O Lindholm LH Nieminen MS
Omvik P Oparil S Wedel H LIFE Study Group Cardiovascular morbidity and mor
tality in the Losartan Intervention For Endpoint reduction in hypertension study
(LIFE) a randomised trial against atenolol Lancet 2002359995–1003
458 Black HR Elliott WJ Grandits G Grambsch P Lucente T White WB Neaton JD
Grimm RH Jr Hansson L Lacourcie`re Y Muller J Sleight P Weber MA Williams G
Wittes J Zanchetti A Anders RJ CONVINCE Trial group Principal results of the
Controlled Onset Verapamil Investigation of Cardiovascular End Points (CON
VINCE) trial JAMA 20032892073–2082
459 Pepine CJ Handberg EM CooperDeHoff RM Marks RG Kowey P Messerli FH
Mancia G Cangiano JL GarciaBarreto D Keltai M Erdine S Bristol HA
Kolb HR Bakris GL Cohen JD Parmley WW INVEST investigators A calcium an
tagonist vs a noncalcium antagonist hypertension treatment strategy for patients
with coronary artery disease The International VerapamilTrandolapril Study
(INVEST) a randomized controlled trial JAMA 20032902805–2816
460 Hansson L Lindholm LH Ekbom T Dahlof B Lanke J Schersten B Wester PO
Hedner T de Faire U Randomised trial of old and new antihypertensive drugs in
elderly patients cardiovascular mortality and morbidity the Swedish Trial in Old
Patients with Hypertension2 study Lancet 19993541751–1756
461 Hansson L Hedner T LundJohansen P Kjeldsen SE Lindholm LH Sylversten JO
Lanke J de Faire U Dalhof B Karlberg BE Randomised trial of effects of calcium
antagonists compared with diuretics and betablockers on cardiovascular morbid
ity and mortality in hypertension the Nordic Diltiazem (NORDIL) study Lancet
2000356359–365
462 Mancia G Grassi G Zanchetti A Newonset diabetes and antihypertensive drugs
J Hypertens 2006243–10
463 ONTARGET Investigators Telmisartan ramipril or both in patients at high risk for
vascular events N Engl J Med 20083581547–1559
464 Matsui Y Eguchi K O’Rourke MF Ishikawa J Miyashita H Shimada K Kario K Dif
ferential effects between a calcium channel blocker and a diuretic when used in
combination with angiotensin II receptor blocker on central aortic pressure in
hypertensive patients Hypertension 200954716–723
465 Gupta AK Arshad S Poulter NR Compliance safety and effectiveness of ﬁxed
dose combinations of antihypertensive agents a metaanalysis Hypertension
201055399–407
466 Claxton AJ Cramer J Pierce C A systematic review of the association between
dose regimens and medication compliance Clin Ther 2001231296–1310
467 Indian Polycap Study (TIPS) Effects of a polypill (Polycap) on risk factors in
middleaged individuals without cardiovascular disease (TIPS) a phase II double
blind randomised trial Lancet 20093731341–1351
468 Fagard RH Staessen JA Thijs L Gasowski J Bulpitt CJ Clement D de Leeuw PW
Dobovisek J Jaaskivi M Leonetti G O’Brien E Palatini P Parati G Rodicio JL
Vanhanen H Webster J Response to antihypertensive therapy in older patients
with sustained and nonsustained systolic hypertension Systolic Hypertension in
Europe (SystEur) Trial Investigators Circulation 20001021139–1144
469 Bjorklund K Lind L Zethelius B Andren B Lithell H Isolated ambulatory hyperten
sion predicts cardiovascular morbidity in elderly men Circulation 2003107
1297–1302
470 Amery A Birkenhager W Brixko P Bulpitt C Clement D Deruyttere M De
Schaepdryver A Dollery C Fagard R Forette F Handy R Joossens JV Lund
Johansen P Petrie J Tuomilehto J Mortality and morbidity results from the Euro
pean Working Party on High Blood Pressure in the Elderly trial Lancet 19851
1349–1354
471 Medical Research Council trial of treatment of hypertension in older adults prin
cipal results MRC Working Party BMJ 1992304405–412
472 Sundstrom J Neovius M Tynelius P Rasmussen F Association of blood pressure in
late adolescence with subsequent mortality cohort study of Swedish male con
scripts BMJ 2011342d643473
473 Melloni C Berger JS Wang TY Gunes F Stebbins A Pieper KS Dolor RJ
Douglas PS Mark DB Newby LK Representation of women in randomized clinical
trials of cardiovascular disease prevention Circulation Cardiovascular quality and out
comes 20103135–142
474 Blauwet LA Hayes SN McManus D Redberg RF Walsh MN Low rate of sex
speciﬁc result reporting in cardiovascular trials Mayo Clin Proc 200782166–170
475 Gueyfﬁer F Boutitie F Boissel JP Pocock S Coope J Cutler J Ekbom T Fagard R
Friedman L Perry M Prineas R Schron E Effect of antihypertensive drug treatment
on cardiovascular outcomes in women and men A metaanalysis of individual
patient data from randomized controlled trials The INDANA Investigators Ann
Intern Med 1997126761–767
476 Dong W Colhoun HM Poulter NR Blood pressure in women using oral contra
ceptives results from the Health Survey for England 1994 J Hypertens 199715
1063–1068
477 ChasanTaber L Willett WC Manson JE Spiegelman D Hunter DJ Curhan G
Colditz GA Stampfer MJ Prospective study of oral contraceptives and hyperten
sion among women in the United States Circulation 199694483–489
478 Atthobari J Gansevoort RT Visser ST de Jong PE de Jongvan den Berg LT The
impact of hormonal contraceptives on blood pressure urinary albumin excretion
and glomerular ﬁltration rate Br J Clin Pharmacol 200763224–231
479 Oelkers WH Drospirenone in combination with estrogens for contraception and
hormone replacement therapy Climacteric 20058(Suppl 3)19–27
480 Martinez F Ramirez I PerezCampos E Latorre K Lete I Venous and pulmonary
thromboembolism and combined hormonal contraceptives Systematic review
and metaanalysis Eur J Contracept Reprod Health Care 2012177–29
481 Stampfer MJ Colditz GA Willett WC Speizer FE Hennekens CH A prospective
studyof moderatealcohol consumption and the risk of coronary disease and stroke
in women N Engl J Med 1988319267–273
482 Dunn N Thorogood M Faragher B de Caestecker L MacDonald TM McCollum C
Thomas S Mann R Oral contraceptives and myocardial infarction results of the
MICA casecontrol study BMJ 19993181579–1583
483 Tanis BC van den Bosch MA Kemmeren JM Cats VM Helmerhorst FM Algra A
van der Graaf Y Rosendaal FR Oral contraceptives and the risk of myocardial in
farction N Engl J Med 20013451787–1793
484 Margolis KL Adami HO Luo J Ye W Weiderpass E A prospective study of oral
contraceptive use and risk of myocardial infarction among Swedish women Fertility
and Sterility 200788310–316
485 Chakhtoura Z Canonico M Gompel A Scarabin PY PluBureau G Progestogen
only contraceptives and the risk of acute myocardial infarction a metaanalysis
J Clin Endocrinol Metab 2011961169–1174
486 Gillum LA Mamidipudi SK Johnston SC Ischemic stroke risk with oral contracep
tives A metaanalysis JAMA 200028472–78
487 Chan WS Ray J Wai EK Ginsburg S Hannah ME Corey PN Ginsberg JS Risk of
stroke in women exposed to lowdose oral contraceptives a critical evaluation
of the evidence Arch Intern Med 2004164741–747
488 Baillargeon JP McClish DK Essah PA Nestler JE Association between the current
use of lowdose oral contraceptives and cardiovascular arterial disease a
metaanalysis J Clin Endocrinol Metab 2005903863–3870
ESH and ESC Guidelines2219e
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 2019489 Gronich N Lavi I Rennert G Higher risk of venous thrombosis associated with
drospirenonecontaining oral contraceptives a populationbased cohort study
CMAJ 2011183e1319–e1325
490 Lidegaard O Nielsen LH Skovlund CW Lokkegaard E Venousthrombosis in users
of nonoral hormonal contraception followup study Denmark 2001–10 BMJ
2012344e2990doi101136bmj
491 Shufelt CL Bairey Merz CN Contraceptive hormone use and cardiovascular
disease J Am Coll Cardiol 200953221–231
492 World Health Organization Medical eligibility criteria for contraceptive use 3rd ed
Geneva World Health Organization 2004
493 Lubianca JN Moreira LB Gus M Fuchs FD Stopping oral contraceptives an effect
ive blood pressurelowering intervention in women with hypertension J Hum
Hypertens 200519451–455
494 ACOG Committee on practice bulletin Gynecology ACOG practice bulletin No
73 Use of hormonal contraception in women with coexisting medical conditions
Obstet Gynecol 20061071453–1472
495 Mosca L Benjamin EJ Berra K Bezanson JL Dolor RJ LloydJones DM Newby LK
Pina IL Roger VL Shaw LJ Zhao D Beckie TM Bushnell C D’Armiento J
KrisEtherton PM Fang J Ganiats TG Gomes AS Gracia CR Haan CK
Jackson EA Judelson DR Kelepouris E Lavie CJ Moore A Nussmeier NA
Oﬁli E Oparil S Ouyang P Pinn VW Sherif K Smith SC Jr Sopko G
ChandraStrobos N Urbina EM Vaccarino V Wenger NK Effectivenessbased
guidelines for the prevention of cardiovascular disease in women 2011 update a
guideline from the American Heart Association J Am Coll Cardiol 201157
1404–1423
496 Collins P Rosano G Casey C Daly C Gambacciani M Hadji P Kaaja R Mikkola T
Palacios S Preston R Simon T Stevenson J StrambaBadiale M Management of car
diovascular risk in the perimenopausal woman a consensus statement of Euro
pean cardiologists and gynaecologists Eur Heart J 2007282028–2040
497 Mueck AO Seeger H Effect of hormone therapy on BP in normotensive and hyper
tensive postmenopausal women Maturitas 200449189–203
498 RegitzZagrosek V Blomstrom Lundqvist C Borghi C Cifkova R Ferreira R
Foidart JM Gibbs JS GohlkeBaerwolf C Gorenek B Iung B Kirby M Maas AH
Morais J Nihoyannopoulos P Pieper PG Presbitero P RoosHesselink JW
Schaufelberger M Seeland U Torracca L Bax J Auricchio A Baumgartner H
ESC Guidelines on the management of cardiovascular diseases during pregnancy
the Task Force on the Management of Cardiovascular Diseases during Pregnancy
of the European Society of Cardiology (ESC) Eur Heart J 2011323147–3197
499 Hypertension in pregnancy The management of hypertensive disorders during
pregnancy NICE Clinical Guidelines No 107 National Collaborating Centre for
Women’s and Children’s Health (UK) London RCOG Press August 2010
500 Abalos E Duley L SteynDW HendersonSmart DJ Antihypertensive drug therapy
for mild to moderate hypertension during pregnancy Cochrane Database Syst Rev
2001CD002252
501 Kuklina EV Tong X Bansil P George MG Callaghan WM Trends in pregnancy hos
pitalizations that included a stroke in the United States from 1994 to 2007 reasons
for concern Stroke 2011422564–2570
502 Martin JN Jr Thigpen BD Moore RC Rose CH Cushman J May W Stroke and
severe preeclampsia and eclampsia a paradigm shift focusing on systolic blood
pressure Obstet Gynecol 2005105246–254
503 Duley L HendersonSmart D Knight M King J Antiplatelet drugs for prevention of
preeclampsia and its consequences systematic review BMJ 2001322329–333
504 Rossi AC Mullin PM Prevention of preeclampsia with lowdose aspirin or vitamins
C and E in women at high or low risk a systematic review with metaanalysis Eur J
Obstet Gynecol Reprod Biol 20111589–16
505 Bujold E Roberge S Lacasse Y Bureau M Audibert F Marcoux S Forest JC
Giguere Y Prevention of preeclampsia and intrauterine growth restriction with
aspirin started in early pregnancy a metaanalysis Obstet Gynecol 2010116
402–414
506 Bellamy L Casas JP Hingorani AD Williams DJ Preeclampsia and risk of cardio
vascular disease and cancer in later life systematic review and metaanalysis BMJ
2007335974
507 McDonald SD Malinowski A Zhou Q Yusuf S Devereaux PJ Cardiovascular se
quelae of preeclampsiaeclampsia a systematic review and metaanalyses Am
Heart J 2008156918–930
508 Beulens JW Patel A Vingerling JR Cruickshank JK Hughes AD Stanton A Lu J
McG Thom SA Grobbee DE Stolk RP Effects of blood pressure lowering and in
tensive glucose control on the incidence and progression of retinopathy in patients
with type 2 diabetes mellitus a randomised controlled trial Diabetologia 200952
2027–2036
509 Chaturvedi N Porta M Klein R Orchard T Fuller J Parving HH Bilous R Sjolie AK
Effect of candesartan on prevention (DIRECTPrevent 1) and progression
(DIRECTProtect 1) of retinopathy in type 1 diabetes randomised placebo
controlled trials Lancet 20083721394–1402
510 Watkins PJ Edmonds ME Diabetic autonomic failure Oxford University Press 1999
511 Cederholm J Gudbjornsdottir S Eliasson B Zethelius B EegOlofsson K
Nilsson PM Blood pressure and risk of cardiovascular disease in type 2 diabetes
further ﬁndings from the Swedish National Diabetes Register (NDRBPII)
J Hypertens 2012302020–2030
512 CooperDeHoff RM Gong Y Handberg EM Bavry AA Denardo SJ Bakris GL
Pepine CJ Tight blood pressure control and cardiovascular outcomes among
hypertensives patients with diabetes and coronary artery disease JAMA 2010
30461–68
513 Schmieder RE Hilgers KF Schlaich MP Schmidt BM Reninangiotensin system and
cardiovascular risk Lancet 20073691208–1219
514 Alberti KG EckelRH Grundy SM Zimmet PZ Cleeman JI DonatoKA Fruchart JC
James WP Loria CM Smith SC Jr Harmonizing the metabolic syndrome a joint
interim statement of the International Diabetes Federation Task Force on Epidemi
ology and Prevention National Heart Lung and Blood Institute American Heart
Association World Heart Federation International Atherosclerosis Society and
International Association for the Study of Obesity Circulation 2009120
1640–1645
515 Benetos A Thomas F Pannier B Bean K Jego B Guize L Allcause and cardiovas
cular mortality using the different deﬁnitions of metabolic syndrome Am J Cardiol
2008102188–191
516 Nilsson PM EngstromG Hedblad B The metabolic syndrome and incidence ofcar
diovascular disease in nondiabetic subjects a populationbased study comparing
three different deﬁnitions Diabet Med 200724464–472
517 Mancia G Bombelli M Corrao G Facchetti R Madotto F Giannattasio C
Trevano FQ Grassi G Zanchetti A Sega R Metabolic syndrome in the Pressioni
Arteriose Monitorate E Loro Associazioni (PAMELA) study daily life blood pres
sure cardiac damage and prognosis Hypertension 20074940–47
518 Shaﬁ T Appel LJ Miller ER 3rd Klag MJ Parekh RS Changes in serum potassium
mediate thiazideinduced diabetes Hypertension 2008521022–1029
519 Tuomilehto J Lindstrom J Eriksson JG Valle TT Hamalainen H IlanneParikka P
KeinanenKiukaanniemi S Laakso M Louheranta A Rastas M Salminen V
Uusitupa M Prevention of type 2 diabetes mellitus by changes in lifestyle among
subjects with impaired glucose tolerance N Engl J Med 20013441343–1350
520 Knowler WC BarrettConnor E Fowler SE Hamman RF Lachin JM Walker EA
Nathan DM Reduction in the incidence of type 2 diabetes with lifestyle interven
tion or metformin N Engl J Med 2002346393–403
521 Parati G Lombardi C Hedner J Bonsignore MR Grote L Tkacova R Levy P Riha R
Bassetti C Narkiewicz K Mancia G McNicholas WT Position paper on the man
agement of patients with obstructive sleep apnea and hypertension joint recom
mendations by the European Society of Hypertension by the European
Respiratory Society and by the members of European COST (Cooperation in Sci
entiﬁc and Technological research) ACTION B26 on obstructive sleep apnea
J Hypertens 201230633–646
522 Bazzano LA Khan Z Reynolds K He J Effect of nocturnal nasal continuous positive
airway pressure on blood pressure in obstructive sleep apnea Hypertension 2007
50417–423
523 Alajmi M Mulgrew AT Fox J Davidson W Schulzer M Mak E Ryan CF Fleetham J
Choi P Ayas NT Impact of continuous positive airway pressure therapy on blood
pressure in patients with obstructive sleep apnea hypopnea a metaanalysis of ran
domized controlled trials Lung 200718567–72
524 Mo L He QY [Effect of longterm continuous positive airway pressure ventilation
on blood pressure in patients with obstructive sleep apnea hypopnea syndrome a
metaanalysis of clinical trials] Zhonghua yi xue za zhi 2007871177–1180
525 Haentjens P Van Meerhaeghe A Moscariello A De Weerdt S Poppe K Dupont A
Velkeniers B The impact of continuous positive airway pressure on blood pressure
in patients with obstructive sleep apnea syndrome evidence from a metaanalysis
of placebocontrolled randomized trials Arch Intern Med 2007167757–764
526 Kasiakogias A Tsouﬁs C Thomopoulos C Aragiannis D Alchanatis M
Tousoulis D Papademetriou V Floras JS Stefanadis C Effects of continuous posi
tive airway pressure in hypertensive patients with obstructive sleep apnea a 3year
followup J Hypertens 201331352–360
527 Barbe F DuranCantolla J SanchezdelaTorre M MartinezAlonso M
Carmona C Barcelo A Chiner E Masa JF Gonzalez M Marin JM GarciaRio F
Diaz de Atauri J Teran J Mayos M de la Pena M Monasterio C del Campo F
Montserrat JM Effect of continuous positive airway pressure on the incidence of
hypertension and cardiovascular events in nonsleepy patients with obstructive
sleep apnea a randomized controlled trial JAMA 20123072161–2168
528 Marin JM Agusti A Villar I Forner M Nieto D Carrizo SJ Barbe F Vicente E Wei Y
Nieto FJ Jelic S Association between treated and untreated obstructive sleep
apnea and risk of hypertension JAMA 20123072169–2176
529 Zanchetti A What should be learnt about the management of obstructive sleep
apnea in hypertension J Hypertens 201230669–670
530 Klag MJ Whelton PK Randall BL Neaton JD Brancati FL Stamler J Endstage renal
disease in AfricanAmerican and white men 16year MRFIT ﬁndings JAMA 1997
2771293–1298
ESH and ESC Guidelines 2219f
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 2019531 Yano Y Fujimoto S Sato Y Konta T Iseki K Moriyama T Yamagata K Tsuruya K
Yoshida H Asahi K Kurahashi I Ohashi Y Watanabe T Association between pre
hypertension and chronic kidney disease in the Japanese general population Kidney
Int 201281293–299
532 Jafar TH Stark PC Schmid CH Landa M Maschio G de Jong PE de Zeeuw D
Shahinfar S Toto R Levey AS Progression of chronic kidney disease the role of
blood pressure control proteinuria and angiotensinconverting enzyme inhibition
a patientlevel metaanalysis Ann Intern Med 2003139244–252
533 Heerspink HJ Ninomiya T Zoungas S de Zeeuw D Grobbee DE Jardine MJ
Gallagher M Roberts MA Cass A Neal B Perkovic V Effect of lowering blood pres
sure on cardiovascular events and mortality in patients on dialysis a systematic
review and metaanalysis of randomised controlled trials Lancet 2009373
1009–1015
534 Lea J Greene T Hebert L Lipkowitz M Massry S Middleton J Rostand SG Miller E
Smith W Bakris GL The relationship between magnitude of proteinuria reduction
and risk of endstage renal disease results of the African American study of kidney
disease and hypertension Arch Intern Med 2005165947–953
535 de Zeeuw D Remuzzi G Parving HH Keane WF Zhang Z Shahinfar S Snapinn S
Cooper ME Mitch WE Brenner BM Albuminuria a therapeutic target for cardio
vascular protection in type 2 diabetic patients with nephropathy Circulation 2004
110921–927
536 Schmieder RE Mann JF Schumacher H Gao P Mancia G Weber MA McQueen M
Koon T Yusuf S Changes in albuminuria predict mortality and morbidity in patients
with vascular disease J Am Soc Nephrol 2011221353–1364
537 Kunz R Friedrich C Wolbers M Mann JF Metaanalysis effect of monotherapy and
combination therapy with inhibitors of the renin angiotensin system on proteinuria
in renal disease Ann Intern Med 200814830–48
538 Ruggenenti P Fassi A Ilieva AP Iliev IP Chiurchiu C Rubis N Gherardi G
EneIordache B Gaspari F Perna A Cravedi P Bossi A Trevisan R Motterlini N
Remuzzi G Effects of verapamil addedon trandolapril therapy in hypertensive
type 2 diabetes patients with microalbuminuria the BENEDICTB randomized
trial J Hypertens 201129207–216
539 Bakris GL Seraﬁdis PA Weir MR Dalhof B Pitt B Jamerson K Velazquez EJ
StaikosByrne L Kelly RY Shi V Chiang YT Weber MA ACCOMPLISH Trial Inves
tigators Renal outcomes with different ﬁxeddose combination therapies in
patients with hypertension at high risk for cardiovascular events (ACCOMPLISH)
a prespeciﬁed secondary analysis of randomised controlled trial Lancet 2010375
1173–1181
540 Pisoni R Acelajado MC Cartmill FR Dudenbostel T Dell’Italia LJ Coﬁeld SS
Oparil S Calhoun DA Longterm effects of aldosterone blockade in resistant
hypertension associated with chronic kidney disease J Hum Hypertens 201226
502–506
541 Levin NW Kotanko P Eckardt KU Kasiske BL Chazot C Cheung AK Redon J
Wheeler DC Zoccali C London GM Blood pressure in chronic kidney disease
stage 5Dreport from a Kidney Disease Improving Global Outcomes controver
sies conference Kidney Int 201077273–284
542 Potter JF Robinson TG Ford GA Mistri A James M Chernova J Jagger C Control
ling hypertension and hypotension immediately poststroke (CHHIPS) a rando
mised placebocontrolled doubleblind pilot trialLancet Neurology 2009848–56
543 Schrader J Luders S Kulschewski A Berger J Zidek W Treib J Einhaupl K
Diener HC Dominiak P The ACCESS Study evaluation of Acute Candesartan
Cilexetil Therapy in Stroke Survivors Stroke 2003341699–1703
544 Sandset EC Bath PM Boysen G Jatuzis D Korv J Luders S Murray GD Richter PS
Roine RO Terent A Thijs V Berge E The angiotensinreceptor blocker candesar
tan for treatment of acute stroke (SCAST) a randomised placebocontrolled
doubleblind trial Lancet 2011377741–750
545 Fuentes Patarroyo SX Anderson C Blood Pressure Lowering in Acute Phase of
Stroke Latest Evidence and Clinical Implication Ther Adv Chronic Dis 20123
163–171
546 Gueyfﬁer F Boissel JP Boutitie F Pocock S Coope J Cutler J Ekbom T Fagard R
Friedman L Kerlikowske K Perry M Prineas R Schron E Effect of antihypertensive
treatment in patients having already suffered from stroke Gathering the evidence
The INDANA (INdividual Data ANalysis of Antihypertensive intervention trials)
Project Collaborators Stroke 1997282557–2562
547 Schrader J Luders S Kulschewski A Hammersen F Plate K Berger J Zidek W
Dominiak P Diener HC MOSES Study Group Morbidity and mortality after
stroke eprosartan compared with nitrendipine for secondary prevention principal
results of a prospective randomized controlled study (MOSES) Stroke 200536
1218–1226
548 Reboldi G Angeli F Cavallini C Gentile G Mancia G Verdecchia P Comparison
between angiotensinconverting enzyme inhibitors and angiotensin receptor
blockers on the risk of myocardial infarction stroke and death a metaanalysis
J Hypertens 2008 261282–1289
549 Ninomiya T Ohara T Hirakawa Y Yoshida D Doi Y Hata J Kanba S Iwaki T
Kiyohara Y Midlife and latelife blood pressure and dementia in Japanese elderly
the Hisayama study Hypertension 20115822–28
550 Peters R Beckett N Forette F Tuomilehto J Clarke R Ritchie C Waldman A
Walton I Poulter R Ma S Comsa M Burch L Fletcher A Bulpitt C Incident demen
tia and blood pressure lowering in the Hypertension in the Very Elderly Trial cog
nitive function assessment (HYVETCOG) a doubleblind placebo controlled
trial Lancet Neurology 20087683–689
551 Dufouil C Godin O Chalmers J Coskun O McMahon S TzourioMazoyer N
Bousser MG Anderson C Mazoyer B Tzourio C Severe cerebral white matter
hypersensities predict severe cognitive decline in patients with cerebrovascular
disease history Stroke 2009402219–2221
552 Godin O Tsourio C Maillard P Mazoyer B Dufouil C Antihypertensive treatment
and change in blood pressure are associated with the progression of white matter
lesion volumes the ThreeCity (3C)Dijon Magnetic Resonance Imaging Study Cir
culation 2011123266–273
553 Yusuf S Hawken S Ounpuu S Dans T Avezum A Lanas F McQueen M Budaj A
Pais P Varigos J Liu L INTERHEART Study Investigators Effect of potentially modi
ﬁable risk factors associated with myocardial infarction in 52 countries (the INTER
HEART study) casecontrol study Lancet 2004364937–952
554 Prospective Study Collaboration Bodymass index and causespeciﬁc mortality in
900 000 adults collaborative analyses of 57 prospective studies Lancet 2009373
1083–1096
555 Borghi C Bacchelli S Degli Esposti D Bignamini A Magnani B Ambrosioni E Effects
of the administration of an angiotensin converting enzyme inhibitor during the
acute phase of myocardial infarction in patients with arterial hypertension SMILE
Study Investigators Survival of Myocardial Infarction Long Term Evaluation Am J
Hypertens 199912665–672
556 Gustafsson F Kober L TorpPedersen C Hildebrand P Ottesen MM Sonne B
Carlsen J Longterm prognosis after acute myocardial infarction in patients with
a history of arterial hypertension Eur Heart J 19984588–594
557 Tocci G Sciarretta S Volpe M Development of heart failure in recenthypertension
trials J Hypertens 2008261477–1486
558 Telmisartan Randomized Assessment Study in ACE intolerant subjects with cardio
vascular disease (TRANSCEND) Investigators Effects of the angiotensinreceptor
blocker telmisartan on cardiovascular events in highrisk patients intolerant to
angiotensinconverting enzyme inhibitors a randomised controlled trial Lancet
20083721174–1183
559 Raphael CE Whinnett ZI Davies JE Fontana M Ferenczi EA Manisty CH Mayet J
Francis DP Quantifying the paradoxical effect of higher systolic blood pressure on
mortality in chronic heart failure Heart 20099556–62
560 Massie BM Carson PE McMurray JJ Komajda M McKelvie R Zile MR Anderson S
Donovan M Iverson E Staiger C Ptaszynska A Irbesartan in patients with heart
failure and preserved ejection fraction N Engl J Med 20083592456–2467
561 Camm AJ Kirchhof P Lip GY Schotten U Savelieva I Ernst S Van Gelder IC
AlAttar N Hindricks G Prendergast B Heidbuchel H Alﬁeri O Angelini A
Atar D Colonna P De Caterina R De Sutter J Goette A Gorenek B Heldal M
Hohloser SH Kolh P Le Heuzey JY Ponikowski P Rutten FH Guidelines for the
management of atrial ﬁbrillation the Task Force for the Management of Atrial Fib
rillation of the European Society of Cardiology (ESC) Eur Heart J 201031
2369–2429
562 Grundvold I Skretteberg PT Liestol K Erikssen G Kjeldsen SE Arnesen H
Erikssen J Bodegard J Upper normal blood pressures predict incident atrial ﬁbril
lation in healthy middleaged men a 35year followup studyHypertension201259
198–204
563 Manolis AJ Rosei EA Coca A Cifkova R Erdine SE Kjeldsen S Lip GY
Narkiewicz K Parati G Redon J Schmieder R Tsiouﬁs C Mancia G Hypertension
and atrial ﬁbrillation diagnostic approach prevention and treatment Position
paper of the Working Group ’Hypertension Arrhythmias and Thrombosis’ of
the European Society of Hypertension J Hypertens 201230239–252
564 Hart RG Pearce LA Aquilar MI Metaanalysis antithrombotic therapy to prevent
stroke in patients who have nonvalvular atrial ﬁbrillation Ann Intern Med 2007146
857–867
565 Camm AJ Lip GY De Caterina R Savelieva I Atar D Hohnloser SH Hindricks G
Kirchhof P 2012 focused update of the ESC Guidelines for the management of atrial
ﬁbrillation An update of the 2010 ESC Guidelines for the management of atrial
ﬁbrillationEur Heart J 2012332719–274
566 Arima H Anderson C Omae T Woodward M MacMahon S Mancia G
Bousser MG Tzourio C Rodgers A Neal B Chalmers J Effects of blood pressure
lowering on intracranial and extracranial bleeding in patients on antithrombotic
therapy the PROGRESS trial Stroke 2012431675–1677
567 Wachtell K Lehto M Gerdts E Olsen MH Hornestam B Dahlof B Ibsen H Julius S
Kjeldsen SE Lindholm LH Nieminen MS Devereux RB Angiotensin II receptor
blockade reduces newonset atrial ﬁbrillation and subsequent stroke compared
ESH and ESC Guidelines2219g
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 2019with atenolol the Losartan Intervention For End Point Reduction in Hypertension
(LIFE) study J Am Coll Cardiol 200545712–719
568 Schmieder RE Kjeldsen SE Julius S McInnes GT Zanchetti A Hua TA Reduced
incidence of newonset atrial ﬁbrillation with angiotensin II receptor blockade
the VALUE trial J Hypertens 200826403–411
569 Cohn JN Tognoni G A randomized trial of the angiotensinreceptor blocker val
sartan in chronic heart failure N Engl J Med 20013451667–1675
570 Vermes E Tardif JC Bourassa MG Racine N Levesque S White M Guerra PG
Ducharme A Enalapril decreases the incidence of atrial ﬁbrillation in patients
with left ventricular dysfunction insight from the Studies Of Left Ventricular Dys
function (SOLVD) trials Circulation 20031072926–2931
571 Ducharme A Swedberg K Pfeffer MA CohenSolal A Granger CB Maggioni AP
Michelson EL McMurray JJ Olsson L Rouleau JL Young JB Olofsson B Puu M
Yusuf S Prevention of atrial ﬁbrillation in patients with symptomatic chronic
heart failure by candesartan in the Candesartan in Heart failure Assessment of Re
duction in Mortality and morbidity (CHARM) program Am Heart J 2006152
86–92
572 The Active I Investigators Irbesartan in patients with atrial ﬁbrillation N Engl J Med
2011364928–938
573 Tveit A Grundvold I Olufsen M Seljeﬂot I Abdelnoor M Arnesen H Smith P Can
desartan in the prevention of relapsing atrial ﬁbrillation Int J Cardiol 2007120
85–91
574 The GISSIAF Investigators Valsartan for prevention of recurrent atrial ﬁbrillation
N Engl J Med 20093601606–1617
575 Goette A Schon N Kirchhof P Breithardt G Fetsch T Hausler KG Klein HU
Steinbeck G Wegscheider K Meinertz T Angiotensin IIantagonist in paroxysmal
atrialﬁbrillation (ANTIPAF) trialCirculation Arrhythmia and Electrophysiology 20125
43–51
576 Schneider MP Hua TA Bohm M Wachtell K Kjeldsen SE Schmieder RE Preven
tion of atrial ﬁbrillation by reninangiotensin system inhibition a metaanalysis JAm
Coll Cardiol 2010552299–2307
577 Nasr IA Bouzamondo A Hulot JS Dubourg O Le Heuzey JY Lechat P Prevention
of atrial ﬁbrillation onset by betablocker treatment in heart failure a metaanalysis
Eur Heart J 200728457–462
578 Swedberg K Zannad F McMurray JJ Krum H van Veldhuisen DJ Shi H Vincent J
Pitt BEMPHASISHF Study Investigators Eplerenone and atrial ﬁbrillation in mild
systolic heart failure results from the EMPHASISHF (Eplerenone in Mild Patients
Hospitalization And SurvIval Study in Heart Failure) studyJ Am Coll Cardiol 201259
1598–1603
579 Schaer BA Schneider C Jick SS Conen D Osswald S Meier CR Risk for incident
atrial ﬁbrillation in patients who receive antihypertensive drugs a nested case
control study Ann Intern Med 201015278–84
580 Fagard RH Celis H Thijs L Wouters S Regression of left ventricular mass by anti
hypertensive treatment a metaanalysis of randomized comparative studiesHyper
tension 2009541084–1091
581 Zanchetti A Crepaldi G Bond MG Gallus G Veglia F Mancia G Ventura A
Baggio G Sampieri L Rubba P Sperti G Magni A Different effects of antihyperten
sive regimens based on fosinopril or hydrochlorothiazide with or without lipid low
ering by pravastatin on progression of asymptomatic carotid atherosclerosis
principal results of PHYLLIS a randomized doubleblind trial Stroke 200435
2807–2812
582 Ong KT Delerme S Pannier B Safar ME Benetos A Laurent S Boutouyrie P Aortic
stiffness is reduced beyond blood pressure lowering by shortterm and longterm
antihypertensive treatment a metaanalysis of individual data in 294 patients
J Hypertens 2011291034–1042
583 Shahin Y Khan JA Chetter I Angiotensin converting enzyme inhibitors effect on
arterial stiffness and wave reﬂections a metaanalysis and metaregression of ran
domised controlled trials Atherosclerosis 201222118–33
584 Karalliedde J Smith A DeAngelis L Mirenda V Kandra A Botha J Ferber P
Viberti G Valsartan improves arterial stiffness in type 2 diabetes independently
of blood pressure lowering Hypertension 2008511617–1623
585 Ait Oufella H Collin C Bozec E Ong KT Laloux B Boutouyrie P Laurent S Long
term reduction in aortic stiffness a 53 year followup in routine clinical practice
J Hypertens 2010282336–2340
586 Guerin AP Blacher J Pannier B Marchais SJ Safar ME London GM Impact of aortic
stiffness attenuation on survival of patients in endstage renal failure Circulation
2001103987–992
587 Singer DR Kite A Management of hypertension in peripheral arterial disease does
the choice of drugs matter Eur J Vasc Endovasc Surg 200835701–708
588 The Heart Outcomes Prevention Evaluation Study Investigators Effects of an
angiotensinconvertingenzyme inhibitor ramipril on cardiovascular events in
highrisk patients N Engl J Med 2000342145–153
589 Paravastu SC Mendonca DA da Silva A Beta blockers for peripheral arterial
disease Eur J Vasc Endovasc Surg 20093866–70
590 Radack K Deck C Betaadrenergic blocker therapy does not worsen intermittent
claudication in subjects with peripheral arterial disease A metaanalysis of rando
mized controlled trials Arch Intern Med 19911511769–1776
591 Dong JY Zhang YH Qin LQ Erectile dysfunction and risk of cardiovascular disease
metaanalysis of prospective cohort studies J Am Coll Cardiol 2011581378–1385
592 Gupta BP Murad MH Clifton MM Prokop L Nehra A Kopecky SL The effect of
lifestyle modiﬁcation and cardiovascular risk factor reduction on erectile dysfunc
tion a systematic review and metaanalysis Arch Intern Med 20111711797–1803
593 Manolis A Doumas M Sexual dysfunction the ’prima ballerina’ of hypertension
related qualityoflife complications J Hypertens 2008262074–2084
594 Pickering TG Shepherd AM Puddey I Glasser DB Orazem J Sherman N
Mancia G Sildenaﬁl citrate for erectile dysfunction in men receiving multiple anti
hypertensive agents a randomized controlled trial Am J Hypertens 200417
1135–1142
595 Scranton RE Lawler E Botteman M Chittamooru S Gagnon D Lew R Harnett J
Gaziano JM Effect of treating erectile dysfunction on management of systolic
hypertension Am J Cardiol 2007100459–463
596 Ma R Yu J Xu D Yang L Lin X Zhao F Bai F Effect of felodipine with irbesartan or
metoprolol on sexual function and oxidative stress in women with essential hyper
tension J Hypertens 201230210–216
597 Fagard RH Resistant hypertension Heart 201298254–261
598 De la Sierra A Segura J Banegas JR Gorostidi M de la Cruz JJ Armario P Oliveras A
Ruilope LM Clinical features of 8295 patients with resistant hypertension classiﬁed
on the basis of ambulatory blood pressure monitoring Hypertension 201157
171–174
599 Daugherty SL Powers JD Magid DJ Tavel HM Masoudi FA Maragolis KL
O’Connor PJ Selby JV Ho PM Incidence and prognosis of resistant hypertension
in hypertensive patients Circulation 20121251635–1642
600 Persell SD Prevalence of resistant hypertension in the United States 2003–2008
Hypertension 2011571076–1080
601 Mantero F Mattarello MJ Albiger NM Detecting and treating primary aldosteron
ism primary aldosteronism Exp Clin Endocrinol Diabetes 2007115171–174
602 Redon J Campos C Narciso ML Rodicio JL Pascual JM Ruilope LM Prognostic
value of ambulatory blood pressure monitoring in refractory hypertension a pro
spective study Hypertension 199831712–718
603 Yakovlevitch M Black HR Resistant hypertension in a tertiary care clinic Arch Intern
Med 19911511786–1792
604 Zannad F Aldosterone antagonist therapy in resistant hypertension J Hypertens
200725747–750
605 Lane DA Shah S Beevers DG Lowdose spironolactone in the management of re
sistant hypertension a surveillance study J Hypertens 200725891–894
606 Vaclavik J Sedlak R Plachy M Navratil K Plasek J Jarkovsky J Vaclavik T Husar R
Kocianova E Taborsky M Addition of spironolactone in patients with resistant ar
terial hypertension (ASPIRANT) a randomized doubleblind placebocontrolled
trial Hypertension 2011571069–1075
607 Chapman N Chang CL Dahlof B Sever PS Wedel H Poulter NR Effect of doxa
zosin gastrointestinal therapeutic system as thirdline antihypertensive therapy on
blood pressure and lipids in the AngloScandinavian Cardiac Outcomes Trial Circu
lation 200811842–48
608 Bobrie G Frank M Azizi M Peyrard S Boutouyrie P Chatellier G Laurent S
Menard J Plouin PF Sequential nephron blockade vs sequential reninangiotensin
system blockade in resistant hypertension a prospective randomized open
blinded endpoint study J Hypertens 2012301656–1664
609 Gaddam KK Nishizaka MK PrattUbunama MN Pimenta E Aban I Oparil S
Calhoun DA Characterization of resistant hypertension association between re
sistant hypertension aldosterone and persistent intravascular volume expansion
Arch Intern Med 20081681159–1164
610 Lijnen P Staessen J Fagard R Amery A Increase in plasma aldosterone during pro
longed captopril treatment Am J Cardiol 1982491561–1563
611 Weber MA Black H Bakris G Krum H Linas S Weiss R Linseman JV Wiens BL
Warren MS Lindholm LH A selective endothelinreceptor antagonist to reduce
blood pressure in patients with treatmentresistant hypertension a randomised
doubleblind placebocontrolled trial Lancet 20093741423–1431
612 Bakris GL Lindholm LH Black HR Krum H Linas S Linseman JV Arterburn S
Sager P Weber M Divergent results using clinic and ambulatory blood pressures
report of a darusentanresistant hypertension trial Hypertension 201056
824–830
613 Laurent S Schlaich M Esler M New drugs procedures and devices for hyperten
sion Lancet 2012380591–600
614 Bisognano JD Bakris G Nadim MK Sanchez L Kroon AA Schafer J de Leeuw PW
Sica DA Baroreﬂex activation therapy lowers blood pressure in patients with re
sistant hypertension results from the doubleblind randomized placebo
controlled rheos pivotal trial J Am Coll Cardiol 201158765–773
615 Bakris GL Nadim MK Haller H Lovett EG Schafer JE Bisognano JD Baroreﬂex
activation therapy provides durable beneﬁt in patients with resistant hypertension
ESH and ESC Guidelines 2219h
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 2019results of longterm followup in the Rheos Pivotal Trial J Am Soc Hypertens 20126
152–158
616 Hoppe UC Brandt MC Wachter R Beige J Rump LC Kroon AA Cates AW
Lovett EG Haller H Minimally invasive system for baroreﬂex activation therapy
chronically lowers blood pressure with pacemakerlike safety proﬁle results
from the Barostim Neo trial J Am Soc Hypertens 20126270–276
617 Krum H Schlaich M Whitbourn R Sobotka PA Sadowski J Bartus K Kapelak B
Walton A Sievert H Thambar S Abraham WT Esler M Catheterbased renal sym
pathetic denervation for resistant hypertension a multicentre safety and
proofofprinciple cohort study Lancet 20093731275–1281
618 Simplicity HTN1 Investigators Catheterbased renal sympathetic denervation for
resistant hypertension durability of blood pressure reduction out to 24 months
Hypertension 201157911–917
619 Simplicity HTNInvestigators Renal sympathetic denervation in patients with
treatmentresistant hypertension (The Symplicity HTN2 Trial) a randomised
controlled trial Lancet 20103761903–1909
620 Krum H Barman N Schlaich M Sobotka P Esler M Mahfoud F Bo¨hm M Dunlap M
Sadowski J Bartus K Kapelak B RochaSingh KJ Katholi RE Witkowski A Kadziela J
Januswewicz A Prejbisz A Walton AS Sievert H Id D Wunderlich N
Whitbourn R Rump LC Vonend O Saleh A Thambar S Nanra R Zeller T
Erglis A Sagic D Boskovic S Brachmann J Schmidt M Wenzel UO Bart BA
Schmieder RE SCheinert D Borgel J Straley C Longterm follow up of catheter
based renal sympathetic denervation for resistant hypertension conﬁrms durable
blood pressure reduction J Am Coll Cardiol 201259(13s1)E1704E1704 doi
101016S07351097(12)617057
621 Geisler BP Egan BM Cohen JT Garner AM Akehurst RL Esler MD Pietsch JB
Costeffectiveness and clinical effectiveness of catheterbased renal denervation
for resistant hypertension J Am Coll Cardiol 2012601271–1277
622 Esler M Lambert G Jenningis G Regional norepinephrine turnover in human
hypertension Clin Exp Hypertens 198911(Suppl 1)75–89
623 Grassi G Cattaneo BM Seravalle G Lanfranchi A Mancia G Baroreﬂex Control of
sympathetic nerve activity in essential and secondary hypertension Hypertension
19983168–72
624 Grassi G Seravalle G Dell’Oro R Turri C Bolla GB Mancia G Adrenergic and
reﬂex abnormalities in obesityrelated hypertension Hypertension 2000
36538–542
625 Stella A Zanchetti A Functional role of renal afferents Physiol Rev 199171
659–682
626 DiBona GF Kopp UC Neural control of renal function Physiol Rev 199777
75–197
627 Doumas M Anyfanti P Bakris G Should ambulatory blood pressure monitoring be
mandatory for future studies in resistant hypertensiona perspective Hypertension
201230874–876
628 Brandt MC Mahfoud F Reda S Schirmer SH Erdmann E Bo¨hm M Hoppe UC
Renal sympathetic denervation reduces left ventricular hypertrophy and improves
cardiac function in patients with resistant hypertension J Am Coll Cardiol 201259
901–909
629 Mahfoud F Schlaich M Kindermann I Ukena C Cremers B Brandt MC Hoppe UC
Vonend O Rump LC Sobotka PA Krum H Esler M Bo¨hm M Effect of renal sym
pathetic denervation on glucose metabolism in patients with resistant hyperten
sion a pilot study Circulation 20111231940–1946
630 Mahfoud F Cremers B Janker J Link B Vonend O Ukena C Linz D Schmieder R
Rump LC Kindermann I Sobotka PA Krum H Scheller B Schlaich M Laufs U
Bo¨hm M Renal haemodynamics and renal function after catheterbased renal sym
pathetic denervation in patients with resistant hypertension Hypertension 201260
419–424
631 Schmieder RE Redon J Grassi G Kjeldsen SE Mancia G Narkiewicz K Parati G
Ruilope L van de Borne P Tsiouﬁs C ESH position paper renal denervation an
interventional therapy of resistant hypertension J Hypertens 201230837–841
632 Frank H Heusser K Geiger H Fahlbuscg R Naraghi R Schobel HP Temporary re
duction of blood pressure and sympathetic nerve activity in hypertensive patients
after microvascular decompression Stroke 20094047–51
633 Zhang Y Zhang X Liu L Wang Y Tang X Zanchetti A FEVER Study Group Higher
cardiovascular risk and impaired beneﬁt of antihypertensve treatment in hyperten
sive patients requiring additional drugs on top of randomized therapy is adding
drugs always beneﬁcial J Hypertens 2012302202–2212
634 Weber MA Julius S Kjeldsen SE Jia Y Brunner HR Zappe DH Hua TA
McInnes GT Schork A Mancia G Zanchetti A Cardiovascular outcomes in hyper
tensive patients comparing singleagent therapy with combination therapy
J Hypertens 2012302213–2222
635 Lane DA Lip GY Beevers DG Improving survival of malignant hypertension
patients over 40 years Am J Hypertens 2009221199–1204
636 Gosse P Coulon P Papaioannou G Litalien J Lemetayer P Impact of malignant ar
terial hypertension on the heart J Hypertens 201129798–802
637 Gonzalez R Morales E Segura J Ruilope LM Praga M Longterm renal survival in
malignant hypertension Nephrol Dial Transplant 2010253266–3272
638 Casadei B Abuzeid H Is there a strong rationale for deferring elective surgery in
patients with poorly controlled hypertension J Hypertens 20052319–22
639 Manolis AJ Erdine S Borghi C Tsiouﬁs K Perioperative screening and management
of hypertensive patients European Society of Hypertension Scientiﬁc Newsletter 2010
112
640 Pearce JD Craven BL Craven TE Piercy KT Stafford JM Edwards MS Hansen KJ
Progression of atherosclerotic renovascular disease A prospective population
based study J Vasc Surg 200644955–962
641 Saﬁan RD Textor SC Renalartery stenosis N Engl J Med 2001344431–442
642 Gray BH Olin JW Childs MB Sullivan TM Bacharach JM Clinical beneﬁt of renal
arteryangioplasty with stenting for the controlof recurrent and refractory congest
ive heart failure Vasc Med 20027275–279
643 Wheatley K Ives N Gray R Kalra PA Moss JG Baigent C Carr S Chalmers N
Eadington D Hamilton G Lipkin G Nicholson A Scoble J Revascularization vs
medical therapy for renalartery stenosis N Engl J Med 20093611953–1962
644 Funder JW Carey RM Fardella C GomezSanchez CE Mantero F Stowasser M
Young WF Jr Montori VM Case detection diagnosis and treatment of patients
with primary aldosteronism an endocrine society clinical practice guideline J Clin
Endocrinol Metab 2008933266–3281
645 Sawka AM Young WF Thompson GB Grant CS Farley DR Leibson C van
Heerden JA Primary aldosteronism factors associated with normalization of
blood pressure after surgery Ann Intern Med 2001135258–261
646 Rossi GP Bolognesi M Rizzoni D Seccia TM Piva A Porteri E Tiberio GA
Giulini SM AgabitiRosei E Pessina AC Vascular remodeling and durationof hyper
tension predict outcome of adrenalectomy in primary aldosteronism patients
Hypertension 2008511366–1371
647 Parthasarathy HK Menard J White WB Young WF Jr Williams GH Williams B
Ruilope LM McInnes GT Connell JM MacDonald TM A doubleblind randomized
study comparing the antihypertensive effect of eplerenone and spironolactone in
patients with hypertension and evidence of primary aldosteronism J Hypertens
201129980–990
648 Chapman MJ Ginsberg HN Amarenco P Andreotti F Bore´n J Catapano AL
Descamps OS Fisher E Kovanen PT Kuivenhoven JA Lesnik P Masana L
Nordestgaard BG Ray KK Reiner Z Taskinen MR Tokgo¨zoglu L
TybjærgHansen A Watts GF and for the European Atherosclerosis Society Con
sensus Panel Triglyceriderich lipoproteins and highdensity lipoprotein choles
terol in patients at high risk of cardiovascular disease evidence and guidance for
management Eur Heart J 2011321345–1361
649 Sever PS Dahlof B Poulter NR Wedel H Beevers G Caulﬁeld M Collins R
Kjeldsen SE Kristinsson A McInnes GT Mehlsen J Nieminen M O’Brien E
Ostergren J ASCOT Investigators Prevention of coronary and stroke events
with atorvastatin in hypertensive patients who have average or lowerthanaverage
cholesterol concentrations in the AngloScandinavian Cardiac Outcomes Trial
Lipid Lowering Arm (ASCOTLLA) a multicentre randomised controlled trial
Lancet 20033611149–1158
650 ALLHAT ofﬁcers and coordinators for the ALLHAT collaborative research group
The antihypertensive and lipid lowering treatment to prevent heart attack trial
Major outcomes in moderately hypercholesterolemic hypertensive patients ran
domized to pravastatin vs usual care The Antihypertensive and LipidLowering
Treatment to Prevent Heart Attack Trial (ALLHATLLT) JAMA 2002288
2998–3007
651 Sever PS Poulter NR Dahlof B Wedel H ASCOT Investigators Antihypertensive
therapy and the beneﬁts of atorvastatin in the AngloScandinavian Cardiac Out
comes Trial lipidlowering arm extension J Hypertens 200927947–954
652 Ridker PM Danielson E Fonseca FA Genest J Gotto AM Jr Kastelein JJ Koenig W
Libby P Lorenzatti AJ MacFadyen JG Nordestgaard BG Shepherd J Willerson JT
Glynn RJ JUPITER Study Group Rosuvastatin to prevent vascular events in men
and women with elevated Creactive protein N Engl J Med 20083592195–2207
653 Reiner Z Catapano AL De Backer G Graham I Taskinen MR Wiklund O
Agewall S Alegria E Chapman J Durrington P Erdine S Halcox J Hobbs R
Kjekshus J Perrone Filardi P Riccardi G Storey RF Wood D ESCEAS Guidelines
for the management of dyslipidaemias The Task Force for the management of dys
lipidaemias of the European Society of Cardiology ESC) and the European Athero
sclerosis Society (EAS) Eur Heart J 2011321769–1818
654 Baigent C Blackwell L Emberson J Holland LE Reith C Bhala N Peto R Barnes EH
Keech A Simes J Collins R Efﬁcacy and safety of more intensive lowering of LDL
cholesterol a metaanalysis of data from 170000 participants in 26 randomised
trials Lancet 20103761670–1681
655 Amarenco P Bogousslavsky J Callahan A 3rd Goldstein LB Hennerici M
Rudolph AE Sillesen H Simunovic L Szarek M Welch KM Zivin JA Stroke Preven
tion by aggressive reduction in cholesterol levels (SPARCL) investigators High
dose atorvastatin after stroke or transient ischemic attack N Engl J Med 2006
355549–559
ESH and ESC Guidelines2219i
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 2019656 Taylor F Ward K Moore TH Burke M Davey Smith G Casas JP Ebrahim S Statins
for the primary prevention of cardiovascular disease Cochrane Database Syst Rev
2011 Jan 19CD004816
657 Baigent C Blackwell L Collins R Emberson J Godwin J Peto R Buring J
Hennekens C Kearney P Meade T Patrono C Roncaglioni MC Zanchetti A
Aspirin in the primary and secondary prevention of vascular disease collaborative
metaanalysis of individual participant data from randomised trials Lancet 2009
3731849–1860
658 Jardine MJ Ninomiya T Perkovic V Cass A Turnbull F Gallagher MP Zoungas S
Lambers Heerspink HJ Chalmers J Zanchetti A Aspirin is beneﬁcial in hyperten
sive patients with chronic kidney disease a posthoc subgroup analysis of a rando
mized controlled trial J Am Coll Cardiol 201056956–965
659 Rothwell PM Price JF Fowkes FG Zanchetti A Roncaglioni MC Tognoni G Lee R
Belch JF Wilson M Mehta Z Meade TW Shortterm effects of daily aspirin on
cancer incidence mortality and nonvascular death analysis of the time course
of risks and beneﬁts in 51 randomised controlled trials Lancet 2012379
1602–1612
660 Nathan DM Cleary PA Backlund JY Genuth SM Lachin JM Orchard TJ Raskin P
Zinman B Intensive diabetes treatment and cardiovascular disease in patients with
type 1 diabetes N Engl J Med 20053532643–2653
661 Polak JF Backlund JY Cleary PA Harrington AP O’Leary DH Lachin JM
Nathan DM DCCTEDIC Research GroupProgression of carotid artery intima
media thickness during 12 years in the Diabetes Control and Complications
TrialEpidemiology of Diabetes Interventions and Complications (DCCTEDIC)
study Diabetes 201160607–613
662 UK Prospective Diabetes Study (UKPDS ) Group Intensive bloodglucose control
with sulphonylureas or insulin compared with conventional treatment and risk of
complications in patients with type 2 diabetes (UKPDS 33) Lancet 1998352
837–853
663 UK Prospective Diabetes Study (UKPDS) GroupEffect of intensive bloodglucose
control with metformin on complications in overweight patients with type 2 dia
betes (UKPDS 34) Lancet 1998352854–865
664 ADVANCE Collaborative Group Intensive blood glucose control and vascular
outcomes in patients with type 2 diabetes N Engl J Med 20083582560–2572
665 Gerstein HC Miller ME Genuth S IsmailBeigi F Buse JB Goff DC Jr Probstﬁeld JL
Cushman WC Ginsberg HN Bigger JT Grimm RH Jr Byington RP Rosenberg YD
Friedewald WT Longterm effects of intensive glucose lowering on cardiovascular
outcomes N Engl J Med 2011364818–828
666 Duckworth W Abraira C Moritz T Reda D Emanuele N Reaven PD Zieve FJ
Marks J Davis SN Hayward R Warren SR Goldman S McCarren M Vitek ME
Henderson WG Huang GD Glucose control and vascular complications in veter
ans with type 2 diabetes N Engl J Med 2009360129–139
667 Ray KK Seshasai SR Wijesuriya S Sivakumaran R Nethercott S Preiss D Erqou S
Sattar N Effect of intensive control of glucose on cardiovascular outcomes and
death in patients with diabetes mellitus a metaanalysis of randomised controlled
trials Lancet 20093731765–1772
668 Turnbull FM Abraira C Anderson RJ Byington RP Chalmers JP Duckworth WC
Evans GW Gerstein HC Holman RR Moritz TE Neal BC Ninomiya T Patel AA
Paul SK Travert F Woodward M Intensive glucose control and macrovascular out
comes in type 2 diabetes Diabetologia 2009522288–2298
669 Hemmingsen B Lund SS Gluud C Vaag A Almdal T Hemmingsen C Wetterslev J
Intensive glycaemic control for patients with type 2 diabetes systematic review
with metaanalysis and trial sequential analysis of randomised clinical trials BMJ
2011343d6898
670 Inzucchi SE Bergenstal RM Buse JB Diamant M Ferrannini E Nauck M Peters AL
Tsapas A Wender R Matthews DR Management of hyperglycaemia in type 2 dia
betes a patientcentreed approach Position statement of the American Diabetes
Association (ADA) and the European Association for the Study of Diabetes
(EASD) Diabetologia 2012551577–1596
671 Ferrannini E Solini A SGLT2 inhibition in diabetes mellitus rationale and clinical
prospects Nature Rev Endocrinol 20128495–502
672 ESCEASD Guidelines on diabetes prediabetes and cardiovascular diseases Eur
Heart J 2013doi101093eurheartjeht108
673 Birtwhistle RV Godwin MS Delva MD Casson RI Lam M MacDonald SE Seguin R
Ruhland L Randomised equivalence trial comparing three month and six month
follow up of patients with hypertension by family practitioners BMJ 2004328204
674 Clark CE Smith LF Taylor RS Campbell JL Nurse led interventions to improve
control of blood pressure in people with hypertension systematic review and
metaanalysis BMJ 2010341c3995
675 Niiranen TJ Hanninen MR Johansson J Reunanen A Jula AM Homemeasured
blood pressure is a stronger predictor of cardiovascular risk than ofﬁce blood pres
sure the FinnHome study Hypertension 2010551346–1351
676 Bray EP Holder R Mant J McManus RJ Does selfmonitoring reduce blood pres
sure Metaanalysis with metaregression of randomized controlled trials Ann
Med 201042371–386
677 McManus RJ Mant J Bray EP Holder R Jones MI Greenﬁeld S Kaambwa B
Banting M Bryan S Little P Williams B Hobbs FD Telemonitoring and self
management in the control of hypertension (TASMINH2) a randomised con
trolled trial Lancet 2010376163–172
678 Gupta AK McGlone M Greenway FL Johnson WD Prehypertension in disease
free adults a marker for an adverse cardiometabolic risk proﬁle Hypertens Res
201033905–910
679 Thompson AM Hu T Eshelbrenner CL Reynolds K He J Bazzano LA Antihyper
tensive treatment and secondary prevention of cardiovascular disease events
among persons without hypertension a metaanalysis JAMA 2011305913–922
680 Sacks FM Svetkey LP Vollmer WM Appel LJ Bray GA Harsha D Obarzanek E
Conlin PR Miller ER 3rd SimonsMorton DG Karanja N Lin PH Effects on
blood pressure of reduced dietary sodium and the Dietary Approaches to Stop
Hypertension (DASH) diet DASHSodium Collaborative Research Group N
Engl J Med 20013443–10
681 Viera AJ Bangura F Mitchell CM Cerna A Sloane P Do physicians tell patients they
have prehypertension J Am Board Family Med 201124117–118
682 Faria C Wenzel M Lee KW Coderre K Nichols J Belletti DA A narrative review of
clinical inertia focus on hypertension J Am Soc Hypert 20093267–276
683 Kearney PM Whelton M Reynolds K Whelton PK He J Worldwide prevalence of
hypertension a systematic review J Hypertens 20042211–19
684 Muiesan ML Salvetti M Paini A Monteduro C Galbassini G Bonzi B Poisa P
Belotti E Agabiti Rosei C Rizzoni D Castellano M Agabiti Rosei E Inappropriate
left ventricular mass changes during treatment adversely affects cardiovascular
prognosis in hypertensive patients Hypertension 2007491077–1083
685 Okin PM Oikarinen L Viitasalo M Toivonen L Kjeldsen SE Nieminen MS
Edelman JM Dahlof B Devereux RB Serial assessment of the electrocardiographic
strain pattern for prediction of newonset heart failure during antihypertensive
treatment the LIFE study Eur J Heart Fail 201113384–391
686 Gerdts E Wachtell K Omvik P Otterstad JE Oikarinen L Boman K Dahlof B
Devereux RB Left atrial size and risk of major cardiovascular events during antihy
pertensivetreatmentlosartan intervention forendpoint reduction in hypertension
trial Hypertension 200749311–316
687 Olsen MH Wachtell K Ibsen H Lindholm LH Dahlof B Devereux RB Kjeldsen SE
Oikarinen L Okin PM Reductions in albuminuria and in electrocardiographic left
ventricular hypertrophy independently improve prognosis in hypertension the
LIFE study J Hypertens 200624775–781
688 Atkins RC Briganti EM Lewis JB Hunsicker LG Braden G Champion de
Crespigny PJ DeFerrari G Drury P Locatelli F Wiegmann TB Lewis EJ Proteinuria
reduction and progression to renal failure in patients with type 2 diabetes mellitus
and overt nephropathy Am J Kidney Dis 200545281–287
689 Costanzo P PerroneFilardi P Vassallo E Paolillo S Cesarano P Brevetti G
Chiariello M Does carotid intimamedia thickness regression predict reduction
of cardiovascular events A metaanalysis of 41 randomized trials J Am Coll
Cardiol 2010562006–2020
690 Goldberger ZD Valle JA Dandekar VK Chan PS Ko DT Nallamothu BK Are
changes in carotid intimamedia thickness related to risk of nonfatal myocardial in
farction A critical review and metaregression analysis Am Heart J 2010160
701–714
691 Lorenz MW Polak JF Kavousi M Mathiesen EB Voelzke H Tuomainen TP
Sander D Plichart Catapano AL Robertson CM Kiechi S Rundek T
Desvarieaux M Lind L Schmid C DasMahapatra P Gao L Wiegelbauer K
Bots ML Thompson SG PROGIMT Study Group Carotid intimamedia tickness
progression to predict cardiovascular events in the general population (the
PROGIMT collaborative project) a metaanalysis of individuial participant data
Lancet3792053–2062
692 Bots ML Taylor AJ Kastelein JJ Peters SA den Ruijter HM Tegeler CH
Baldassarre D Stein JH O’Leary DH REvkin JH Grobbee DE Rate of exchange
in carotid intimamedia thickness and vascular events metaanalyses can not
solve all the issues A point of view J Hypertens 2012301690–1696
693 Burt VL Cutler JA Higgins M Horan MJ Labarthe D Whelton P Brown C
Roccella EJ Trends in the prevalence awareness treatment and control of hyper
tension in the adult US population Data from the Health Examination Surveys
1960 to 1991 Hypertension 19952660–69
694 Reiner Z Sonicki Z TedeschiReiner E Physicians’ perception knowledge and
awareness of cardiovacsulr risk factors and adherence to prevention guidelines
the PERCRODOC survey Atherosclerosis 2010 213598–603
695 Amar J Chamontin B Genes N Cantet C Salvador M Cambou JP Why is hyper
tension so frequently uncontrolled in secondary prevention J Hypertens 200321
1199–1205
696 Mancia G Ambrosioni E Agabiti Rosei E Leonetti G Trimarco B Volpe M Blood
pressure control and risk of stroke in untreated and treated hypertensive patients
screened from clinical practice results of the ForLife study J Hypertens 200523
1575–1581
ESH and ESC Guidelines 2219j
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 2019697 Benetos A Thomas F Bean KE Guize L Why cardiovascular mortality is higher in
treated hypertensives vs subjects of the same age in the general population
J Hypertens 2003211635–1640
698 Redon J CeaCalvo L Lozano JV MartiCanales JC Llisterri JL Aznar J
GonzalezEsteban J Differences in blood pressure control and stroke mortality
across Spain the Prevencion de Riesgo de Ictus (PREVICTUS) study Hypertension
200749799–805
699 Kotseva K Wood D De Backer G De Bacquer D Pyorala K Keil U Cardiovascular
prevention guidelines in daily practice a comparison of EUROASPIRE I II and III
surveys in eight European countries Lancet 2009373929–940
700 Bhatt DL Steg PG Ohman EM Hirsch AT Ikeda Y Mas JL Goto S Liau CS
Richard AJ Rother J Wilson PW International prevalence recognition and treat
ment of cardiovascular risk factors in outpatients with atherothrombosis JAMA
2006295180–189
701 CooperDeHoff RM Handberg EM Mancia G Zhou Q Champion A Legler UF
Pepine CJ INVEST revisited review of ﬁndings from the International Verapamil
SRTrandolapril Study Expert Rev Cardiovasc Ther 200971329–1340
702 Ezzati M Lopez AD Rodgers A Vander Hoorn S Murray CJ Selected major risk
factors and global and regional burden of disease Lancet 20023601347–1360
703 Banegas JR Segura J Ruilope LM Luque M GarciaRobles R Campo C
RodriguezArtalejo F Tamargo J Blood pressure control and physician manage
ment of hypertension in hospital hypertension units in Spain Hypertension 2004
431338–1344
704 Corrao G Zambon A Parodi A Poluzzi E Baldi I Merlino L Cesana G Mancia G
Discontinuation of and changes in drug therapy for hypertension among newly
treated patients a populationbased study in Italy J Hypertens 200826819–824
705 Lee JK Grace KA Taylor AJ Effect of a pharmacy care program on medication ad
herence and persistence blood pressureand lowdensity lipoproteincholesterol a
randomized controlled trial JAMA 20062962563–2571
706 Gale NK Greenﬁeld S Gill P Gutridge K Marshall T Patient and general practition
er attitudes to taking medication to prevent cardiovascular disease after receiving
detailed information on risks and beneﬁts of treatment a qualitative study BMC
Family Practice 20111259
707 Shanti M Maribel S Hypertension World Health Organization 2003 p 98–104
708 KrouselWood M Joyce C Holt E Muntner P Webber LS Morisky DE
Frohlich ED Re RN Predictors of decline in medication adherence results from
the cohort study of medication adherence among older adults Hypertension
201158804–810
709 Corrao G Parodi A Nicotra F Zambon A Merlino L Cesana G Mancia G Better
compliance to antihypertensive medications reduces cardiovascular risk
J Hypertens 201129610–618
710 Mazzaglia G Ambrosioni E Alacqua M Filippi A Sessa E Immordino V Borghi C
Brignoli O Caputi AP Cricelli C Mantovani LG Adherence to antihypertensive
medications and cardiovascular morbidity among newly diagnosed hypertensive
patients Circulation 20091201598–1605
711 Vrijens B Vincze G Kristanto P Urquhart J Burnier M Adherence to prescribed
antihypertensive drug treatments longitudinal study of electronically compiled
dosing histories BMJ 20083361114–1117
712 Redon J Coca A Lazaro P Aguilar MD Cabanas M Gil N SanchezZamorano MA
Aranda P Factors associated with therapeutic inertia in hypertension validation of
a predictive model J Hypertens 2010281770–1777
713 Luders S Schrader J Schmieder RE Smolka W Wegscheider K Bestehorn K Im
provement of hypertension management by structured physician education and
feedback system cluster randomized trial Eur J Cardiovasc Prev Rehabil 201017
271–279
714 De Rivas B Barrios V Redon J Calderon A Effectiveness of an Interventional
Program to Improve Blood Pressure Control in Hypertensive Patients at High
Risk for Developing Heart Failure HEROIC study J Clin Hypertens (Greenwich)
201012335–344
715 Guthrie B Inkster M Fahey T Tackling therapeutic inertia role of treatment data in
quality indicators BMJ 2007335542–544
716 Claxton AJ Cramer J Pierce C A systematic review of the associations between
dose regimens and medication compliance Clin Ther 2001231296–1310
717 Ashworth M Medina J Morgan M Effect of social deprivation on blood pressure
monitoring and control in England a survey of data from the quality and outcomes
framework BMJ 2008337a2030
718 Serumaga B RossDegnan D Avery AJ Elliott RA Majumdar SR Zhang F
Soumerai SB Effect of pay for performance on the management and outcomes
of hypertension in the United Kingdom interrupted time series study BMJ 2011
342d108
719 Campbell SM Reeves D Kontopantelis E Sibbald B Roland M Effects of pay for
performance on the quality of primary care in England N Engl J Med 2009361
368–378
720 Fahey T Schroeder K Ebrahim S Educational and organisational interventions used
to improve the management of hypertension in primary care a systematic review
Br J Gen Pract 200555875–882
721 Weingarten SR Henning JM Badamgarav E Knight K Hasselblad V Gano A Jr
Ofman JJ Interventions used in disease management programmes for patients
with chronic illnesswhich ones work Metaanalysis of published reports BMJ
2002325925
722 Carter BL Bosworth HB Green BB The hypertension team the role of the
pharmacist nurse and teamwork in hypertension therapy J Clin Hypertens (Green
wich) 20121451–65
723 Chodosh J Morton SC Mojica W Maglione M Suttorp MJ Hilton L Rhodes S
Shekelle P Metaanalysis chronic disease selfmanagement programs for older
adults Ann Intern Med 2005143427–438
724 Carter BL Rogers M Daly J Zheng S James PA The potency of teambased care
interventions for hypertension a metaanalysis Arch Intern Med 2009169
1748–1755
725 Walsh JM McDonald KM Shojania KG Sundaram V Nayak S Lewis R Owens DK
Goldstein MK Quality improvement strategies for hypertension management a
systematic review Med Care 200644646–657
726 Glynn LG Murphy AW Smith SM Schroeder K Fahey T Interventions used to
improve control of blood pressure in patients with hypertension Cochrane Data
base Syst Rev 2010CD005182
727 Machado M Bajcar J Guzzo GC Einarson TR Sensitivity of patient outcomes to
pharmacist interventions Part II Systematic review and metaanalysis in hyperten
sion management Ann Pharmacother 2007411770–1781
728 Morak J Kumpusch H Hayn D ModreOsprian R Schreier G Design and evalu
ation of a telemonitoring concept based on NFCenabled mobile phones and
sensor devices IEEE transactions on information technology in biomedicine a publication
of the IEEE Engineering in Medicine and Biology Society 20121617–23
729 Canzanello VJ Jensen PL Schwartz LL Wona JB Klein LK Inferred blood pressure
control with a physiciannurse team and home BP measurement Mayo Clin Proc
20058031–36
730 Stergiou G Myers MG Reid JL Burnier M Narkiewicz K Viigimaa M Mancia G
Settingup a blood pressure and vascular protection clinic requirements of the
European Society of Hypertension J Hypertens 2010281780–1781
731 Shea K Chamoff B Telehomecare communication and selfcare in chronic condi
tions moving toward a shared understanding Worldviews on evidencebased nursing
Sigma Theta Tau International Honor Society of Nursing 20129109–116
732 Parati G Omboni S Albini F Piantoni L Giuliano A Revera M Illyes M Mancia G
Home blood pressure telemonitoring improves hypertension control in general
practice The TeleBPCare study J Hypertens 200927198–203
733 Neumann CL Menne J Rieken EM Fischer N Weber MH Haller H Schulz EG
Blood pressure telemonitoring is useful to achieve blood pressure control in inad
equately treated patients with arterial hypertension J Hum Hypertens 201125
732–738
734 Omboni S Guarda A Impact of home blood pressure telemonitoring and blood
pressure control a metaanalysis of randomized controlled studies Am J Hypertens
201124989–998
735 Russell M Roe B Beech R Russell W Service developments for managing people
with longterm conditions using case management approaches an example from
the UK International J Integrated Care 20099e02
ESH and ESC Guidelines2219k
Downloaded from httpsacademicoupcomeurheartjarticleabstract34282159451304 by guest on 28 October 2019

《香当网》用户分享的内容，不代表《香当网》观点或立场，请自行判断内容的真实性和可靠性！
该内容是文档的文本内容，更好的格式请下载文档

2013管理指南动脉高血压

相关文档

2013“全国高血压日”宣传教育活动工作总结

镇高血压病管理实施方案

高血压病人自我管理小组计划

软件过程管理指南

高血压护理

项目管理中的质量指南

难治性高血压的处理

高血压工作计划12篇高血压计划书

《2020ACR痛风管理指南》

工程项目代建管理指南

APQC知识管理实施指南

《高血压健康教育》

高血压用药教育（全）

SOAP病史1-高血压

减盐防控高血压知识

高血压常识（完整版）

＊＊医院20＊＊年度高血压或者健康管理项目工作报告

浅谈街道居民高血压、糖尿病管理

2021年卫生院高血压病管理项目工作总结

公司安全管理工作指南

该用户的其他文档

相关pdf

相关ppt