ESH2013欧洲高血压指南

ESH AND ESC GUIDELINES

2013ESH/ESC 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)

Authors/Task Force Members:Giuseppe Mancia (Chairperson)(Italy)*,Robert Fagard (Chairperson)(Belgium)*,Krzysztof Narkiewicz (Section co-ordinator)(Poland),Josep Redon (Section co-ordinator)(Spain),Alberto Zanchetti (Section co-ordinator)

(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 (Germany/UK),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 Scienti?c 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 Cau?eld (UK),Antonio Coca (Spain),Michael Hecht Olsen (Denmark),Roland E.Schmieder (Germany),Costas Tsiou?s (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 (Germany/UK),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,

35,20121Milano,Italy.Tel:+390392333357,Fax:+39039322274.Email:giuseppe.mancia@unimib.it .Chairperson ESC:Professor Robert Fagard,Hypertension &Cardiovascular Rehab.Unit,KU Leuven University,Herestraat 49,3000Leuven,Belgium.Tel:+3216348707,Fax:+3216343766,Email:robert.fagard@uzleuven.be

These guidelines also appear in the Journal of Hypertension ,doi:10.1097/https://www.wendangku.net/doc/1614079067.html, and in Blood Pressure ,doi:10.3109/08037051.2013.812549.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 ESH/ESC 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:journals.permissions@https://www.wendangku.net/doc/1614079067.html,.

European Heart Journal

doi:10.1093/eurheartj/eht151

Document Reviewers:Denis L.Clement(ESH Review Co-ordinator)(Belgium),Antonio Coca(ESH Review

Co-ordinator)(Spain),Thierry C.Gillebert(ESC Review Co-ordinator)(Belgium),Michal Tendera(ESC Review

Co-ordinator)(Poland),Enrico Agabiti Rosei(Italy),Ettore Ambrosioni(Italy),Stefan D.Anker(Germany), Johann Bauersachs(Germany),Jana Brguljan Hitij(Slovenia),Mark Caul?eld(UK),Marc De Buyzere(Belgium), Sabina De Geest(Switzerland),Genevie`ve Anne Derumeaux(France),Serap Erdine(Turkey),Csaba Farsang (Hungary),Christian Funck-Brentano(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),Zˇeljko Reiner(Croatia),Lars Ryde′n(Sweden),Yuriy Sirenko(Ukraine), Alice Stanton(Ireland),Harry Struijker-Boudier(Netherlands),Costas Tsiou?s(Greece),Philippe van de Borne (Belgium),Charalambos Vlachopoulos(Greece),Massimo Volpe(Italy),David A.Wood(UK).

The af?liations 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 https://www.wendangku.net/doc/1614079067.html, and https://www.wendangku.net/doc/1614079067.html,/guidelines

------------------------------------------------------------------------------------------------------------------------------------------------------Keywords Hypertension?Guidelines?Antihypertensive treatment?Blood pressure?Blood pressure

measurement?Cardiovascular risk?Cardiovascular complications?Device therapy?Follow-up

?Lifestyle?Organ damage

Table of Contents

Abbreviations and acronyms (4)

1Introduction (5)

1.1Principles (5)

1.2New aspects (5)

2Epidemiological aspects (6)

2.1Relationship of blood pressure to cardiovascular and renal

damage (6)

2.2De?nition and classi?cation of hypertension (7)

2.3Prevalence of hypertension (7)

2.4Hypertension and total cardiovascular risk (7)

2.4.1Assessment of total cardiovascular risk (7)

2.4.2Limitations (8)

2.4.3Summary of recommendations on total cardiovascular

risk assessment (9)

3Diagnostic evaluation (9)

3.1Bood pressure measurement (10)

3.1.1Of?ce or clinic blood pressure (10)

3.1.2Out-of-of?ce blood pressure (10)

3.1.3White-coat(or isolated of?ce)hypertension

and masked(or isolated ambulatory)hypertension (12)

3.1.4Clinical indications for out-of-of?ce blood pressure..12

3.1.5Blood pressure during exercise and laboratory stress.13

3.1.6Central blood pressure (14)

3.2Medical history (15)

3.3Physical examination (15)

3.4Summary of recommendations on blood pressure

measurement,history,and physical examination (15)

3.5Laboratory investigations (16)

3.6Genetics (16)

3.7Searching for asymptomatic organ damage (16)

3.7.1Heart (16)

3.7.2Blood vessels (18)

3.7.3Kidney (18)

3.7.4Fundoscopy (19)

3.7.5Brain (19)

3.7.6Clinical value and limitations (20)

3.7.7Summary of recommendations on the search for

asymptomatic organ damage,cardiovascular disease,and

chronic kidney disease (20)

3.8Searching for secondary forms of hypertension (21)

4Treatment approach (21)

4.1Evidence favouring therapeutic reduction of high blood

pressure (21)

4.2When to initiate antihypertensive drug treatment (22)

4.2.1Recommendations of previous Guidelines (22)

4.2.2Grade2and3hypertension and high-risk grade1

hypertension (22)

4.2.3Low-to-moderate risk,grade1hypertension (22)

4.2.4Isolated systolic hypertension in youth (22)

4.2.5Grade1hypertension in the elderly (22)

4.2.6High normal blood pressure (23)

4.2.7Summary of recommendations on initiation

of antihypertensive drug treatment (23)

4.3Blood pressure treatment targets (24)

4.3.1Recommendations of previous Guidelines (24)

4.3.2Low-to-moderate risk hypertensive patients (24)

4.3.3Hypertension in the elderly (24)

4.3.4High-risk patients (24)

ESH and ESC Guidelines

Page2of72

hypothesis (25)

4.3.6Evidence on target blood pressure from organ damage

studies (26)

4.3.7Clinic vs.home and ambulatory blood pressure

targets (26)

4.3.8Summary of recommendations on blood pressure

targets in hypertensive patients (26)

5Treatment strategies (27)

5.1Lifestyle changes (27)

5.1.1Salt restriction (27)

5.1.2Moderation of alcohol consumption (27)

5.1.3Other dietary changes (27)

5.1.4Weight reduction (27)

5.1.5Regular physical exercise (28)

5.1.6Smoking cessation (28)

5.1.7Summary of recommendations on adoption of lifestyle

changes (28)

5.2Pharmacological therapy (29)

5.2.1Choice of antihypertensive drugs (29)

5.2.2Monotherapy and combination therapy (31)

5.2.3Summary of recommendations on treatment

strategies and choice of drugs (35)

6Treatment strategies in special conditions (36)

6.1White-coat hypertension (36)

6.2Masked hypertension (36)

6.2.1Summary of recommendations on treatment

strategies in white-coat and masked hypertension (36)

6.3Elderly (36)

6.3.1Summary of recommendations on antihypertensive

treatment strategies in the elderly (37)

6.4Young adults (37)

6.5Women (37)

6.5.1Oral contraceptives (37)

6.5.2Hormone replacement therapy (38)

6.5.3Pregnancy (38)

6.5.4Long-term cardiovascular consequences in gestational

hypertension (38)

6.5.5Summary of recommendations on treatment

strategies in hypertensive women (39)

6.6Diabetes mellitus (39)

6.6.1Summary of recommendations on treatment

strategies in patients with diabetes (40)

6.7Metabolic syndrome (40)

6.7.1Summary of recommendations on treatment

strategies in hypertensive patients with metabolic syndrome40

6.8Obstructive sleep apnoea (41)

6.9Diabetic and non-diabetic nephropathy (41)

6.9.1Summary of recommendations on therapeutic

strategies in hypertensive patients with nephropathy (41)

6.9.2Chronic kidney disease stage5D (42)

6.10Cerebrovascular disease (42)

6.10.1Acute stroke (42)

6.10.2Previous stroke or transient ischaemic attack (42)

6.10.4Summary of recommendations on therapeutic

strategies in hypertensive patients with cerebrovascular

disease (43)

6.11Heart disease (43)

6.11.1Coronary heart disease (43)

6.11.2Heart failure (43)

6.11.3Atrial?brillation (44)

6.11.4Left ventricular hypertrophy (44)

6.11.5Summary of recommendations on therapeutic

strategies in hypertensive patients with heart disease (44)

6.12Atherosclerosis,arteriosclerosis,and peripheral artery

disease (45)

6.12.1Carotid atherosclerosis (45)

6.12.2Increased arterial stiffness (45)

6.12.3Peripheral artery disease (45)

6.12.4Summary of recommendations on therapeutic

strategies in hypertensive patients with atherosclerosis,

arteriosclerosis,and peripheral artery disease (45)

6.13Sexual dysfunction (45)

6.14Resistant hypertension (46)

6.14.1Carotid baroreceptor stimulation (46)

6.14.2Renal denervation (47)

6.14.3Other invasive approaches (47)

6.14.4Follow-up in resistant hypertension (47)

6.14.5Summary of recommendations on therapeutic

strategies in patients with resistant hypertension (47)

6.15Malignant hypertension (48)

6.16Hypertensive emergencies and urgencies (48)

6.17Perioperative management of hypertension (48)

6.18Renovascular hypertension (48)

6.19Primary aldosteronism (48)

7Treatment of associated risk factors (49)

7.1Lipid-lowering agents (49)

7.2Antiplatelet therapy (49)

7.3Treatment of hyperglycaemia (49)

7.4Summary of recommendations on treatment of risk factors

associated with hypertension (50)

8Follow-up (50)

8.1Follow-up of hypertensive patients (50)

8.2Follow-up of subjects with high normal blood pressure and

white-coat hypertension (50)

8.3Elevated blood pressure at control visits (51)

8.4Continued search for asymptomatic organ damage (51)

8.5Can antihypertensive medications be reduced or stopped?51 9Improvement of blood pressure control in hypertension (52)

10Hypertension disease management (52)

10.1Team approach in disease management (53)

10.2Mode of care delivery (53)

10.3The role of information and communication technologies53 11Gaps in evidence and need for future trials (54)

APPENDIX:Task Force members af?liations (54)

References (55)

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 angiotensin-converting enzyme

ACTIVE I Atrial Fibrillation Clopidogrel Trial with Irbesartan

for Prevention of Vascular Events

ADVANCE Action in Diabetes and Vascular Disease:Preterax

and Diamicron-MR Controlled Evaluation AHEAD Action for HEAlth in Diabetes

ALLHAT Antihypertensive and Lipid-Lowering Treatment to

Prevent Heart ATtack

ALTITUDE ALiskiren Trial In Type2Diabetes Using

Cardio-renal 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 Anglo-Scandinavian Cardiac Outcomes Trial ASCOT-LLA Anglo-Scandinavian Cardiac Outcomes Trial—

Lipid Lowering Arm

ASTRAL Angioplasty and STenting for Renal Artery Lesions A-V atrioventricular

BB beta-blocker

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 Post-Stroke

CKD chronic kidney disease

CKD-EPI Chronic Kidney Disease—EPIdemiology collabor-

ation

CONVINCE Controlled ONset Verapamil INvestigation of CV

Endpoints

CT computed tomography

CV cardiovascular

CVD cardiovascular disease

D diuretic DBP diastolic blood pressure

DCCT Diabetes Control and Complications Study DIRECT DIabetic REtinopathy Candesartan Trials

DM diabetes mellitus

DPP-4dipeptidyl peptidase4

EAS European Atherosclerosis Society

EASD European Association for the Study of Diabetes ECG electrocardiogram

EF ejection fraction

eGFR estimated glomerular?ltration rate

ELSA European Lacidipine Study on Atherosclerosis ESC European Society of Cardiology

ESH European Society of Hypertension

ESRD end-stage renal disease

EXPLOR Amlodipine–Valsartan Combination Decreases

Central Systolic Blood Pressure more Effectively

than the Amlodipine–Atenolol Combination FDA U.S.Food and Drug Administration

FEVER Felodipine EVent Reduction study

GISSI-AF Gruppo Italiano per lo Studio della Sopravvivenza

nell’Infarto Miocardico-Atrial 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 intima-media thickness

I-PRESERVE Irbesartan in Heart Failure with Preserved Systolic

Function

INTERHEART Effect of Potentially Modi?able Risk Factors asso-

ciated with Myocardial Infarction in52Countries INVEST INternational VErapamil SR/T Trandolapril

ISH Isolated systolic hypertension

JNC Joint National Committee

JUPITER Justi?cation for the Use of Statins in Primary Preven-

tion:an Intervention Trial Evaluating Rosuvastatin LAVi left atrial volume index

LIFE Losartan Intervention For Endpoint Reduction in

Hypertensives

LV left ventricle/left ventricular

LVH left ventricular hypertrophy

LVM left ventricular mass

MDRD Modi?cation 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

PPAR peroxisome proliferator-activated 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 renin-angiotensin-aldosterone

RAS renin-angiotensin system

RCT randomized controlled trials

RF risk factor

ROADMAP Randomized Olmesartan And Diabetes MicroAl-

buminuria Prevention

SBP systolic blood pressure

SCAST Angiotensin-Receptor 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 STOP-2The 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 Long-term Use

Evaluation

WHO World Health Organization

1Introduction

1.1Principles

The2013guidelines 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 in2003and 2007.1,2Publication of a new document6years 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 re?nements,modi?cations and expansion of the previous recommendations necessary.

The2013ESH/ESC guidelines continue to adhere to some funda-mental principles that inspired the2003and2007guidelines,namely (i)to base recommendations on properly conducted studies identi-?ed from an extensive review of the literature,(ii)to consider,as the highest priority,data from randomized,controlled trials(RCTs) and their meta-analyses,but not to disregard—particularly when dealing with diagnostic aspects—the results of observational and other studies of appropriate scienti?c calibre,and(iii)to grade the level of scienti?c evidence and the strength of recommendations on major diagnostic and treatment issues as in European guidelines on other diseases,according to ESC recommendations(Tables1and2). While it was not done in the2003and2007guidelines,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?elds 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 the2013 guidelines on hypertension have been appointed by the ESH and ESC,based on their recognized expertise and absence of major con-?icts of interest[their declaration of interest forms can be found on the ESC website(https://www.wendangku.net/doc/1614079067.html,/guidelines)and ESH website (https://www.wendangku.net/doc/1614079067.html,)].Each member was assigned a speci?c writing task,which was reviewed by three co-ordinators and then by two chairmen,one appointed by ESH and another by ESC.The text was?nalized over approximately18months,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 by42European reviewers,half selected by ESH and half by ESC.It can thus be con?-dently stated that the recommendations issued by the2013ESH/ESC guidelines on hypertension largely re?ect 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.

1.2New aspects

Because of new evidence on several diagnostic and therapeutic aspects of hypertension,the present guidelines differ in many respects from the previous ones.2Some of the most important differ-ences are listed below:

(1)Epidemiological data on hypertension and BP control in Europe.

(2)Strengthening of the prognostic value of home blood pressure

monitoring(HBPM)and of its role for diagnosis and manage-ment of hypertension,next to ambulatory blood pressure mon-itoring(ABPM).

(3)Update of the prognostic signi?cance of night-time BP,white-

coat hypertension and masked hypertension.

(4)Re-emphasis 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 Page5of72

(5)Update of the prognostic signi?cance 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 evidence-based

criteria and no drug treatment of high normal BP.

(9)Target BP for treatment.More evidence-based criteria and

uni?ed target systolic blood pressure(SBP)(,140mmHg)in both higher and lower CV risk patients.

(10)Liberal approach to initial monotherapy,without any all-ranking

purpose.

(11)Revised schema for priorital two-drug 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 OD-guided therapy.

(18)New approaches to chronic management of hypertensive

disease.

2Epidemiological aspects

2.1Relationship 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 studies.3The results,reported in detail in the2003and2007ESH/ ESC guidelines,1,2can be summarized as follows:

(1)Of?ce 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 end-stage renal disease(ESRD).3–5This is true at all ages and in all ethnic groups.6,7

(2)The relationship with BP extends from high BP levels to rela-

tively low values of110–115mmHg for SBP and70–75mmHg for diastolic BP(DBP).SBP appears to be a better predictor of events than DBP after the age of50years,8,9and in elderly individuals pulse pressure(the difference between SBP and DBP values)has been reported to have a possible additional prognostic role.10This 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

out-of-of?ce BP values,such as those obtained by ABPM and HBPM(see Section3.1.2).

(4)The relationship between BP and CV morbidity and mortality is

modi?ed by the concomitance of other CV risk factors.

Metabolic risk factors are more common when BP is high than when it is low.12,13

2.2De?nition and classi?cation

of hypertension

The continuous relationship between BP and CV and renal events makes the distinction between normotension and hypertension dif-?cult when based on cut-off BP values.This is even more so because,in the general population,SBP and DBP values have a uni-modal distribution.14In practice,however,cut-off BP values are uni-versally used,both to simplify the diagnostic approach and to facilitate the decision about treatment.The recommended classi?cation is un-changed from the2003and2007ESH/ESC guidelines(Table3). Hypertension is de?ned as values≥140mmHg SBP and/or ≥90mmHg DBP,based on the evidence from RCTs that in patients with these BP values treatment-induced BP reductions are bene?cial (see Sections4.1and4.2).The same classi?cation is used in young, middle-aged 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-?cation 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 adolescents.15

2.3Prevalence of hypertension

Limited comparable data are available on the prevalence of hyperten-sion and the temporal trends of BP values in different European coun-tries.16Overall 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 decade.17–37

Owing to the dif?culty of obtaining comparable results among countries and over time,the use of a surrogate of hypertension status has been suggested.38Stroke 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 reported.39The 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 clear-cut increase in death rates from stroke.40

2.4Hypertension 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.In1994,the ESC,ESH and European Atherosclerosis Society(EAS)developed joint recommendations on prevention of coronary heart disease(CHD)in clinical practice,41and emphasized that prevention of CHD should be related to quanti?cation of total (or global)CV risk.This approach is now generally accepted and had already been integrated into the2003and2007ESH/ESC guide-lines for the management of arterial hypertension.1,2The 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 factors may potentiate each other,leading to a total CV risk that is greater than the sum of its individual components. Finally,in high-risk individuals,antihypertensive treatment strategies (initiation and intensity of treatment,use of drug combinations,etc.: see Sections4,5,6and7),as well as other treatments,may be differ-ent from those to be implemented in lower-risk individuals.There is evidence that,in high-risk individuals,BP control is more dif?cult and more frequently requires the combination of antihypertensive drugs with other therapies,such as aggressive lipid-lowering treatments. The therapeutic approach should consider total CV risk in addition to BP levels in order to maximize cost-effectiveness of the manage-ment of hypertension.

2.4.1Assessment 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 risk-reducing measures.However,a large number of patients with hypertension do not belong to any of the above cat-egories and the identi?cation 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 risk.41–48Their values and limitations have been reviewed recently.49The 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 over10years based on age,gender,smoking habits,total cholesterol and SBP.43The 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 high-risk and one for low-risk coun-tries.The electronic,interactive version of SCORE,known as Heart-Score(available through https://www.wendangku.net/doc/1614079067.html,),is adapted to also

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allow adjustment for the impact of high-density 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.Furthermore,the implication that total CV risk estimation 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 and/or an abnormal glucose tolerance test,who do not meet the diagnostic criteria for dia-betes.

?Individuals with increased triglycerides,?brinogen,apolipoprotein B,lipoprotein(a)levels and high-sensitivity C-reactive protein.?Individuals with a family history of premature CVD (before the age of 55years in men and 65years in women).In SCORE,total CV risk is expressed as the absolute risk of dying from CVD within 10years.Because of its heavy dependence on age,in young patients,absolute total CV risk can be loweven in the presence of high BP with additional risk factors.If insuf?ciently treated,however,this condition may lead to a partly irreversible high-risk condition years later.In younger subjects,treatment decisions should better be guided by quanti?cation of relative risk or by esti-mating heart and vascular age.A relative-risk chart is available in the Joint European Societies’Guidelines on CVD Prevention in Clinical Practice,50which is helpful when advising young persons.

Further emphasis has been given to identi?cation of asymptomatic OD,since hypertension-related 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 3.7)is devoted to searching for asymptomatic OD,51–53where 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 1999and 2003WHO/International Society of Hypertension Guidelines and the 2003and 2007ESH/ESC Guidelines)1,2,54,55have strati?ed 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 2012ESC prevention guidelines.50The classi?cation in low,moderate,high and very high risk is retained in the current guidelines and refers to the 10-year risk of CV mortality as de?ned by the 2012ESC prevention guidelines (Figure 1).50The factors on which the strati?cation is based are summarized in Table 4.

2.4.2Limitations

All currently available models for CV risk assessment have limitations that must be appreciated.The signi?cance 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,strati?cation 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 130–139or DBP 85–89

Grade 1 HT SBP 140–159or DBP 90–99Grade 2 HT SBP 160–179or DBP 100–109Grade 3 HT SBP ≥180or DBP ≥110No 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 OD/RFs

Very high risk Very high risk

Very high risk

Very high risk

Figure 1Strati?cation of total CV risk in categories of low,moderate,high and very high risk according to SBP and DBP and prevalence of asymptomatic OD,diabetes,CKD stage or symptomatic CVD.Subjects with a high normal of?ce but a raised out-of-of?ce BP (masked hypertension)a CV risk in the hypertension range.Subjects with a high of?ce BP but normal out-of-of?ce BP (white-coat hypertension),particularly if there diabetes,OD,CVD or CKD,have lower risk than sustained hypertension for the same of?ce BP.

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3.1.2Out-of-of?ce blood pressure

The major advantage of out-of-of?ce BP monitoring is that it provides a large number of BP measurements away from the medical environ-ment,which represents a more reliable assessment of actual BP than of?ce BP.Out-of-of?ce BP is commonly assessed by ABPM or HBPM, usually by self-measurement.A few general principles and remarks hold for the two types of monitoring,in addition to recommenda-tions for of?ce BP measurement:64–67

?The procedure should be adequately explained to the patient,with verbal and written instructions;in addition,self-measurement of BP requires appropriate training under medical supervision.

?Interpretation of the results should take into account that the re-producibility of out-of-of?ce BP measurements is reasonably good for24-h,day and night BP averages but less for shorter periods within the24hs and for more complex and derived indices.68

?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.

?Of?ce BP is usually higher than ambulatory and home BP and the difference increases as of?ce BP increases.Cut-off values for the de?nition of hypertension for home and ambulatory BP,according

Table6.64–67

?Devices should have been evaluated and validated according to international standardized protocols and should be properly maintained and regularly calibrated;at least every6months.The validation status can be obtained on dedicated websites.

3.1.2.1Ambulatory blood pressure monitoring

3.1.2.1.1Methodological aspects A number of methodological aspects have been addressed by the ESH Working Group on Blood Pressure Monitoring.64,65ABPM is performed with the patient wearing a portable BP measuring device,usually on the non-dominant arm,for a24–25h period,so that it gives information on BP during daily activities and at night during sleep.At the time of?tting of the portable device,the difference between the initial values and those from BP measurement by the operator should not be greater than 5mmHg.In the event of a larger difference,the ABPM cuff should be removed and?tted again.The patient is instructed to engage in normal activities but to refrain from strenuous exercise and,at the time of cuff in?ation,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 in?uence BP,in addition to the times of drug ingestion,meals and going to-and rising from bed.In clinical practice,measurements are often made at15min intervals during the day and every30min overnight;exces-sive intervals between BP readings should be avoided because they reduce the accuracy of24-h BP estimates.69It may be recommended that measurements be made at the same frequency during the dayand night—for example every20min throughout.The measurements are downloaded to a computer and a range of analyses can be performed.At least70%of BPs during daytime and night-time 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-?cient 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 irregular.70

3.1.2.1.2Daytime,night-time and24-hour blood pressure In addition to the visual plot,average daytime,night-time and24-h BP are the most commonly used variables in clinical practice.Average daytime and night-time 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,?xed 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 from10am to8pm and from midnight to6am correspond well with the actual waking and sleeping BPs,71but other short,?xed time periods have been pro-posed,such as from9am to9pm and from1am to6am.In the event of different measurement intervals during the day and the night,and to account for missing values,it is recommended that average24-h BP be weighted for the intervals between successive readings or to cal-culate the mean of the24hourly averages to avoid overestimation of average24-h BP.72

The night-to-day BP ratio represents the ratio between average night-time and daytime BP.BP normally decreases during the night—de?ned as‘dipping’.Although the degree of night-time dipping has a normal distribution in a population setting,it is generally agreed that the?nding of a nocturnal BP fall of.10%of daytime values(night–day BP ratio,0.9)will be accepted as an arbitrary cut-off to de?ne subjects as‘dippers’.Recently,more dipping categories have been proposed:absence of dipping,i.e.nocturnal BP increase(ratio.1.0);mild dipping(0.9,ratio≤1.0);dipping (0.8,ratio≤0.9);and extreme dipping(ratio≤0.8).One should bear in mind that the reproducibility of the dipping pattern is limited.73,74Possible 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. 3.1.2.1.3Additional analyses A number of additional indices may be derived from ABPM recordings.75–81They include:BP variability,75 morning BP surge,76,77,81blood pressure load,78and the ambulatory arterial stiffness index.79,80However,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 guidelines,64,65including informa-tion on facilities recommended for ABPM software in clinical prac-tice,which include the need for a standardized clinical report,an interpretative report,a trend report to compare recordings obtained over time and a research report,offering a series of additional para-meters such as those listed above.

3.1.2.1.4Prognostic signi?cance of ambulatory blood pressure Several studies have shown that hypertensive patients’left ventricular hyper-trophy(LVH),increased carotid intima-media thickness(IMT)and other markers of OD correlate with ambulatory BP more closely than with of?ce BP.82,83Furthermore,24-h average BP has been con-sistently shown to have a stronger relationship with morbid or fatal events than of?ce BP.84–87There are studies in which accurately measured of?ce BP had a predictive value similar to ambulatory BP.87Evidence from meta-analyses of published observational studies and pooled individual data,88–90however,has shown that am-bulatory BP in general is a more sensitive risk predictor of clinical CV outcomes,such as coronary morbid or fatal events and stroke,than of?ce 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 disease.89–93Studies that accounted for daytime and night-time BP in the same statistical model found that night-time BP is a stronger predictor than daytime BP.90,94The night–day ratio is a signi?cant predictor of clinical CV outcomes but adds little prognostic information over and above24-h BP.94,95 With regard to the dipping pattern,the most consistent?nding is that the incidence of CV events is higher in patients with a lesser drop in nocturnal BP than in those with greater drop,89,91,92,95,96 although the limited reproducibility of this phenomenon limits the reliability of the results for small between-group differences in nocturnal hypotension.89,91,92,95Extreme dippers may have an increased risk for stroke.97However,data on the increased CV risk in extreme dippers are inconsistent and thus the clinical signi?cance of this phenomenon is uncertain.89,95

3.1.2.2Home blood pressure monitoring

3.1.2.2.1Methodological aspects The ESH Working Group on Blood Pressure Monitoring has proposed a number of recommendations for HBPM.66,67The technique usually involves self-measurement 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-rently not recommended but their use might be justi?ed in obese sub-jects with extremely large arm circumference.For diagnostic evaluation,BP should be measured daily on at least3–4days and pref-erably on7consecutive 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,after5min of rest and with two measurements per occasion taken1–2min apart:the results are reported in a standardized logbook immediately after

each measurement.However,BP values reported by the patient may not always be reliable,which can be overcome by storage in a memory-equipped device.Home BP is the average of these readings, with exclusion of the?rst monitoring https://www.wendangku.net/doc/1614079067.html,e of telemonitoring and smartphone applications for HBPM may be of further advantage.98,99 Interpretation of the results should always be under the close guid-ance of the physician.

When compared with of?ce BP,HBPM yields multiple measure-ments over several days,or even longer periods,taken in the indivi-dual’s usual https://www.wendangku.net/doc/1614079067.html,pared with ambulatory BP,it provides measurements over extended periods and day-to-day BP variability,is cheaper,100more widely available and more easily re-peatable.However,unlike ABPM,it does not provide BP data during routine,day-to-day activities and during sleep,or the quanti?-cation of short-term BP variability.101

3.1.2.2.2Prognostic signi?cance of home BP Home BP is more closely related to hypertension-induced OD than of?ce BP,particularly LVH,82,83and recent meta-analyses 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 signi?cantly better with home BP than with of?ce BP.102,103 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 BP,82,83and that the prognostic signi?cance of home BP is similar to that of ambulatory BP after adjustment for age and gender.104,105

3.1.3White-coat(or isolated of?ce)hypertension

and masked(or isolated ambulatory)hypertension

Of?ce BP is usually higher than BP measured out of the of?ce,which has been ascribed to the alerting response,anxiety and/or a condi-tional response to the unusual situation,106and in which regression to the mean may play a role.Although several factors involved in of?ce or out-of-of?ce BP modulation may be involved,107the differ-ence between the two is usually referred to—although somewhat improperly—as the‘white-coat effect’,107,108whereas‘white-coat-’or‘isolated of?ce-’or‘isolated clinic hypertension’refers to the con-dition in which BP is elevated in the of?ce at repeated visits and normal out of the of?ce,either on ABPM or HBPM.Conversely,BP may be normal in the of?ce 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 cut-off value for of?ce BP is the conventional140/90mmHg,most studies in white-coat or masked hypertension have used a cut-off value of 135/85mmHg for out-of-of?ce daytime or home BP and130/ 80mmHg for24-h BP.Notably,there is only moderate agreement between the de?nition of white-coat or masked hypertension diag-nosed by ABPM or HBPM.101It is recommended that the terms ‘white-coat hypertension’and‘masked hypertension’be reserved to de?ne untreated individuals.

3.1.3.1White-coat hypertension

Based on four population studies,the overall prevalence of white-coat hypertension averaged13%(range9–16%)and it amounted to about32%(range25–46%)among hypertensive subjects in these surveys.109Factors related to increased prevalence of white-coat hypertension are:age,female sex and non-smoking.Prevalence is lower in the case of target OD or when of?ce BP is based on repeated measurements or when measured by a nurse or another healthcare provider.110,111The prevalence is also related to the level of of?ce BP:for example,the percentage of white-coat hyper-tension amounts to about55%in grade1hypertension and to only about10%in grade3hypertension.110OD 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 events.105,109,112,113Whether subjects with white-coat hypertension can be equalled to true normotensive individuals is an issue still under debate because,in some studies,the long-term CV risk of this condi-tion was found to be intermediate between sustained hypertension and true normotension,105whereas in meta-analyses it was not sig-ni?cantly different from true normotension when adjusted for age,gender and other covariates.109,112,113The possibility exists that,because white-coat hypertensive patients are frequently treated,the reduction of clinic BP leads to a reduced incidence of CV events.112Other factors to consider are that,compared with true normotensive subjects,in white-coat hypertensive patients,(i)out-of-of?ce BP is higher,105,109(ii)asymptomatic OD such as LVH may be more frequent,114and(iii)this is the case also for metabolic risk factors and long-term risk of new-onset diabetes and progression to sustained hypertension.115,116It is recommended that the diagnosis of white-coat hypertension be con?rmed within 3–6months and these patients be investigated and followed-up closely,including repeated out-of-of?ce BP measurements(see Section6.1).

3.1.3.2Masked hypertension

The prevalence of masked hypertension averages about13% (range10–17%)in population-based studies109Several factors may raise out-of-of?ce BP relative to of?ce BP,such as younger age,male gender,smoking,alcohol consumption,physical activity, exercise-induced hypertension,anxiety,job stress,obesity,diabetes, CKD and family history of hypertension and the prevalence is higher when of?ce BP is in the high normal range.117Masked hypertension is frequently associated with other risk factors,asymptomatic OD and increased risk of diabetes and sustained hypertension.114–119 Meta-analyses 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 hypertension.109,112,117 The fact that masked hypertension is largely undetected and untreated may have contributed to this?nding.In diabetic patients masked hypertension is associated with an increased risk of nephro-pathy,especially when the BP elevation occurs mainly during the night.120,121

3.1.4Clinical indications for out-of-of?ce blood pressure

It is now generally accepted that out-of-of?ce BP is an important adjunct to conventional of?ce BP measurement,but the latter cur-rently remains the‘gold standard’for screening,diagnosis and man-agement of hypertension.The time-honoured value of of?ce BP, however,has to be balanced against its important limitations,which have led to the increasingly frequent suggestion that out-of-of?ce BP measurements play an important role in hypertension manage-ment.Although there are important differences between ABPM

and HBPM,the choice between the two methods will in the?rst place depend on 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 con?rm borderline or abnormal?ndings on HBPM with ABPM,122which is currently considered the reference for out-of-of?ce BP,with the additional advantage of providing night-time BP values.Furthermore,most—if not all—patients should be familiarized with self-measurement of BP in order to optimize follow-up,for which HBPM is more suitable than ABPM.However, (self-measured)HBPM may not be feasible because of cognitive im-pairment or physical limitations,or may be contra-indicated because of anxiety or obsessive patient behaviour,in which case ABPM may be more suitable.Conditions considered as clinical indi-cations for out-of-of?ce BP measurement for diagnostic purposes are listed in Table7.

3.1.5Blood 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 BP.123Exer-cise testing usually involves dynamic exercise,either on a bicycle ergometer or a treadmill.Notably,only SBP can be measured reliably with non-invasive methods.There is currently no consensus on normal BP response during dynamic exercise testing.A SBP of ≥210mmHg for men and≥190mmHg for women has been termed‘exercise hypertension’in a number of studies,but other de?-nitions of an exaggerated BP response to exercise have also been used.124,125Furthermore,the increase of SBP at?xed submaximal exercise is related to pre-exercise BP,age,arterial stiffness and ab-dominal obesity and is somewhat greater in women than in men and less in?t than in un?t individuals.123–127Most—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 rest.123,124,128However,exercise testing to predict future hypertension is not recommended because of a number of limitations,such as lack of standardization of methodology and de?nitions.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 patients.123,124Also the results on the prognostic signi?cance of exercise BP are not consistent,125which 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 arterioles.123,129Whether 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 outcome.125,130In the case of normal resting BP,exercise-induced hypertension can be considered an indication for ABPM because of its association with masked hypertension.131On the other hand,when hypertension is associated with cardiac dysfunction and blunted exercise-induced increase of cardiac output,the prog-nostic signi?cance of exercise BP may be lost.129Finally,a higher BP during exercise may even carry a better prognosis,such as in 75-year-old individuals,132in patients with suspected cardiac disease,133or with heart failure,134in whom a higher exercise BP implies relatively preserved systolic cardiac function.125In 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 nature.123However,these laboratory stress tests in general do not re?ect real-life 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 signi?cant,the additional explained variance is usually small.123,135A recent meta-analysis sug-gested that greater responsiveness to acute mental stress has an adverse effect on future CV risk status—a composite of elevated BP,hypertension,left ventricular mass(LVM),subclinical atheroscler-osis and clinical cardiac events.136The overall results suggest that BP measurements during mental stress tests are currently not clinically useful.

3.1.6Central 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 re?ected wave.137It should be analysed at the central level,i.e.in the ascending aorta,since it represents the true load imposed on heart,brain,kidney and large arteries.The phenomenon of wave re-?ection can be quanti?ed through the augmentation index—de?ned as the difference between the second and?rst systolic peaks, expressed as a percentage of the pulse pressure,preferably adjusted for heart rate.Owing to the variable superimposition of incoming and re?ected 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 document.138

Early epidemiological studies in the2000s showed that central aug-mentation index and pulse pressure,directly measured by carotid tonometry,were independent predictors of all-cause and CV mortal-ity in patients with ESRD.139A recent meta-analysis con?rmed these ?ndings in several populations.140However,the additive predictive value of central BP beyond brachial BP was either marginal or not stat-istically signi?cant in most studies.140

Thus the current guidelines,like previous ones,2,141consider 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 ampli?cation of the central pressure wave, while central BP is normal.142

3.2Medical history

The medical history should address the time of the?rst 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 pregnancy-related 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 and/or premature CVD is an important?rst 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 Table8.

3.3Physical examination

Physical examination aims to establish or verify the diagnosis of hypertension,establish current BP,screen for secondary causes of hypertension and re?ne global CV risk estimation.BP should be measured as summarized in Section3.1.1and should be repeated to con?rm 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.20mmHg and/or in DBP.10mmHg—if con?rmed—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?brillation,including silent atrial?brillation.Details on physical examination are summar-ized in Table9.3.4Summary of recommendations on blood pressure measurement,history,and physical examination

3.5Laboratory investigations

Laboratory investigations are directed at providing evidence for the presence of additional risk factors,searching for 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 Table10.

3.6Genetics

A positive family history is a frequent feature in hypertensive patients,143,144with the heritability estimated to vary between35% and50%in the majority of studies,145and heritability has been con-?rmed for ambulatory BP.146Several rare,monogenic forms of hyper-tension have been described,such as glucocorticoid-remediable

aldosteronism,Liddle’s syndrome and others,where a single gene mu-tation fully explains the pathogenesis of hypertension and dictates the best treatment modality.147Essential hypertension is a highly hetero-geneous disorder with a multifactorial aetiology.Several genome-wide association studies and their meta-analyses point to a total of 29single nucleotide polymorphisms,which are associated with systolic and/or diastolic BP.148These ?ndings might become useful contributors to risk scores for OD.

3.7Searching 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

therapy.158Proper evaluation of the LV in hypertensive patients includes linear measurements of interventricular septal and poster-ior wall thickness and internal end-diastolic diameter.While left ventricular mass (LVM)measurements indexed for body size iden-tify LVH,relative wall thickness or the wall-to-radius ratio (2×pos-terior wall thickness/end-diastolic diameter)categorizes geometry (concentric or eccentric).Calculation of LVM is currently per-formed according to the American Society of Echocardiography formula.159Although the relation between LVM and CV risk is con-tinuous,thresholds of 95g/m 2for women and 115g/m 2(BSA)for men are widely used for estimates of clear-cut LVH.159Indexation of LVM for height,in which height to the allometric power of 1.7or 2.7has been used,160,161can be considered in overweight and obese patients in order to scale LVM to body size and avoid under-diagnosis of LVH.159It has recently been shown that the optimal method is to scale allometrically by body height to the exponent 1.7(g/m 1.7)and that different cut-offs for men and women should

itional information and is a prerequisite for the diagnosis of diastolic dysfunction.Left atrial size is best assessed by its indexed volume or LAVi.159LAVi≥34mL/m2has been shown to be an independent predictor of death,heart failure,atrial?brillation and ischaemic stroke.172

Normal ranges and cut-off values for hypertensive heart disease for key echocardiographic parameters are summarized in Table11. The most used scaling for evaluating LVH in hypertension is to divide LVM by body surface area(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 parameters recommended by the American Society of Echocardiography and the European Association of Echocardiog-raphy 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 LVH.173,174However,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.the initial evaluation.However,a wider or more restricted use will depend on availability and cost.

3.7.1.3Cardiac 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 consequences.175,176

3.7.1.4Myocardial ischaemia

Speci?c procedures are reserved for diagnosis of myocardial is-chaemia in hypertensive patients with LVH.177This is particular-ly challenging because hypertension lowers the speci?city of exercise electrocardiography and perfusion scintigraphy.178An exercise test,demonstrating a normal aerobic capacity and without signi?cant 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-terpretable/ambiguous,an imaging test of inducible ischaemia, such as stress cardiac MRI,perfusion scintigraphy,or stress echocardiography is warranted for a reliable identi?cation of myocardial ischaemia.178–180Stress-induced wall motion abnor-malities are highly speci?c for angiographically assessed

epicardial coronary artery stenosis,whereas myocardial perfu-sion abnormalities are frequently found with angiographically normal coronary arteries associated with LVH and/or coronary microvascular disease.177The use of dual echocardiographic imaging of regional wall motion and transthoracic,Doppler-derived coronary?ow 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).180A coronary?ow reserve≤1.91has been shown to have an independent prognostic value in hypertension.181,182

3.7.2Blood vessels

3.7.2.1Carotid arteries

Ultrasound examination of the carotid arteries with measurement of intima media thickness(IMT)and/or the presence of plaques has been shown to predict the occurrence of both stroke and myocardial infarction,independently of traditional CV risk factors.51,183–186This holds true,both for the IMT value at the carotid bifurcations(re?ect-ing primarily atherosclerosis)and for the IMT value at the level of the common carotid artery(re?ecting 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.0.9mm has been taken as a conservative estimate of existingabnormalities in the2007Guidelines,2the thresh-old value for high CV risk was higher in the elderly patients of the Car-diovascular Health Study and in the middle-aged patients of the European Lacidipine Study on Atherosclerosis(ELSA)study(1.06 and1.16mm,respectively).184,186Presence of a plaque can be iden-ti?ed by an IMT≥1.5mm or by a focal increase in thickness of0.5mm or50%of the surrounding carotid IMT value.187Although plaque has a strong independent predictive value for CV events,51,183–185,188 presence of a plaque and increased carotid IMT added little to each other for predicting CV events and re-classifying patients into another risk category in the Atherosclerosis Risk In Commu-nities(ARIC)study.185A recent systematic review concluded that the added predictive value of additional carotid screening may be primarily found in asymptomatic individuals at intermediate CV risk.189

3.7.2.2Pulse wave velocity

Large artery stiffening and the wave-re?ection phenomenon have been identi?ed as being the most important pathophysiological determinants of ISH and pulse pressure increase with ageing.190 Carotid-femoral PWV is the‘gold standard’for measuring aortic stiff-ness.138Although the relationship between aortic stiffness and events is continuous,a threshold of.12m/s has been suggested by the2007ESH/ESC Guidelines as a conservative estimate of signi?-cant alterations of aortic function in middle-aged hypertensive patients.2A recent expert consensus statement adjusted this thresh-old value to10m/s,191by using the direct carotid-to-femoral distance and taking into account the20%shorter true anatomical distance travelled by the pressure wave(i.e.0.8×12m/s or10m/s).Aortic stiffness has independent predictive value for fatal and non-fatal CV events in hypertensive patients.192,193The additive value of PWV above and beyond traditional risk factors,including SCORE and Fra-mingham risk score,has been quanti?ed in a number of studies.51,52,194,195In addition,a substantial proportion of patients at intermediate risk could be reclassi?ed into a higher or lower CV risk,when arterial stiffness is measured.51,195,196

3.7.2.3Ankle–brachial index

Ankle–brachial index(ABI)can be measured either with automated devices,or with a continuous-wave Doppler unit and a BP sphygmo-manometer.A low ABI(i.e.,0.9)signals PAD and,in general, advanced atherosclerosis,197has predictive value for CV events,198and was associated with approximately twice the 10-year CV mortality and major coronary event rate,compared with the overall rate in each Framingham category.198Furthermore, 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 approaching20%in10years.198,199 However,ABI is more useful for detecting PAD in individuals with

a high likelihood of PAD.

3.7.2.4Other 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,199–202but the invasiveness of the method makes this ap-proach unsuitable for general use.Increase in coronary calcium,as quanti?ed by high-resolution cardiac computed tomography,has also been prospectively validated as a predictor of CVD and is highly effective in re-stratifying asymptomatic adults into either a moderate or a high CVD risk group,203,204but the limited availability and high cost of the necessary instrumentations present serious problems. Endothelial dysfunction predicts outcome in patients with a variety of CVDs,205although data on hypertension are still rather scant.206 Furthermore,the techniques available for investigating endothelial re-sponsiveness to various stimuli are laborious,time consuming and often invasive.

3.7.3Kidney

The diagnosis of hypertension-induced renal damage is based on the?nding of a reduced renal function and/or the detection of elevated urinary excretion of albumin.207Once detected,CKD is classi?ed according to eGFR,calculated by the abbreviated ‘modi?cation of diet in renal disease’(MDRD)formula,208the Cockcroft-Gault formula or,more recently,through the Chronic Kidney Disease EPIdemiology Collaboration (CKD-EPI)formula,209which require age,gender,ethnicity and serum creatinine.When eGFR is below60mL/min/1.73m2, three different stages of CKD are recognized:stage3with values between30–60mL/min/1.73m2;and stages4and5 with values below30and15mL/min/1.73m2,respectively.210 These formulae help to detect mild impairment of renal

function when serum creatinine values are still within the normal range.211A reduction in renal function and an increase in CV risk can be inferred from the?nding of increased serum levels of cystatin C.212A slight increase(up to20%)in serum creatinine may sometimes occur when antihypertensive therapy—particularly by renin-angiotensin system(RAS)block-ers—is instituted or intensi?ed but this should not be taken as a sign of progressive renal deterioration.Hyperuricaemia is frequently seen in untreated hypertensive patients(particularly in pre-eclampsia)and has been shown to correlate with a reduced renal blood?ow and nephrosclerosis.213

While an elevated serum creatinine concentration or a low eGFR point to diminished renal function,the?nding of an increased rate of urinary albumin or protein excretion points,in general,to a de-rangement in glomerular?ltration barrier.Microalbuminuria has been shown to predict the development of overt diabetic nephro-pathy in both type1and type2diabetic patients,214while the pres-ence of overt proteinuria generally indicates the existence of established renal parenchymatous disease.215In both diabetic and non-diabetic hypertensive patients,microalbuminuria,even below the threshold values usually considered,216has been shown to predict CV events,217–225and continuous relationships between CV,as well as non-CV mortality and urinary albumin/creatinine ratios.3.9mg/g in men and.7.5mg/g in women,have been reported in several studies.224,226Both 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 cumulative.227,228An arbitrary thresh-old for the de?nition of microalbuminuria has been established as 30mg/g of creatinine.228

In conclusion,the?nding 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 death.218,229–233Therefore 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.

3.7.4Fundoscopy

The traditional classi?cation system of hypertensive retinopathy by fundoscopy is based on the pioneering work by Keith, Wagener and Barker in1939and its prognostic signi?cance has been documented in hypertensive patients.234Grade III (retinal haemorrhages,microaneurysms,hard exudates,cotton wool spots)and grade IV retinopathy(grade III signs and papil-loedema and/or macular oedema)are indicative of severe hypertensive retinopathy,with a high predictive value for mor-tality.234,235Grade 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 stringent.236,237Most of these analyses have been done by retinal photography with interpretation by ophthalmologists, which is more sensitive than direct ophthalmoscopy/fundoscopy by general physicians.238Criticism with respect to the reprodu-cibility of grade I and grade II retinopathy has been raised,since even experienced investigators displayed high inter-observer and intra-observer variability(in contrast to advanced hypertensive retinopathy).239,240

The relationship of retinal vessel calibre to future stroke events has been analysed in a systematic review and individual participant meta-analysis:wider retinal venular calibre predicted stroke,whereas the calibre of retinal arterioles was not asso-ciated with stroke.241Retinal arteriolar and venular narrowing, similarly to capillary rarefaction in other vascular beds,242,243 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 de?ned.243–244The 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 use.245–248New 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 investigated.249

3.7.5Brain

Hypertension,beyond its well-known 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 individuals.250,251The most common types of brain lesions are white matter hyperintensities,which can be seen in almost all elderly individuals with hypertension250–although with variable severity–and silent infarcts,the large majority of which are small and deep(lacunar infarctions)and the frequency of which varies between10%and30%.252Another type of lesion, more recently identi?ed,are microbleeds,seen in about5%of individuals.White matter hyperintensities and silent infarcts are associated with an increased risk of stroke,cognitive decline and dementia.250,252–254In 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 damage.255Availability 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 loss.255–257As cognitive dis-turbances in the elderly are,at least in part,hypertension related,258,259suitable cognitive evaluation tests may be used in the clinical assessment of the elderly hypertensive patient.

3.7.6Clinical value and limitations

Table12summarizes the CV predictive value,availability,reproduci-bility and cost-effectiveness of procedures for detection of OD.The recommended strategies for the search for OD are summarized in the Table.

3.7.7Summary 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 page21.

3.8Searching for secondary forms

of hypertension

A speci?c,potentiallyreversiblecauseofBPelevationcanbeidenti?edin 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(Tables9,10,13).Furthermore,a sec-ondaryformofhypertensioncanbeindicatedbyasevereelevationinBP, sudden onset or worsening of hypertension,poor BP response to drug therapyand OD disproportionate to the duration of hypertension.If the basal work-up leads to the suspicion that the patient is suffering from a secondary form of hypertension,speci?c diagnostic procedures may become necessary,as outlined in Table13.Diagnostics of secondary forms of hypertension,especially in cases with a suspicion of endocrine hypertension,should preferably be performed in referral centres.

4Treatment approach

4.1Evidence favouring therapeutic reduction of high blood pressure

Evidence favouring the administration of BP-lowering drugs to reduce the risk of major clinical CV outcomes(fatal and non-fatal stroke,myocardial infarction,heart failure and other CV deaths)in hypertensive individuals results from a number of RCTs—mostly placebo-controlled—carried out between1965and1995.Their meta-analysis260was referred to in the2003edition of ESH/ESC Guidelines.1Supportive evidence also comes from?nding that a BP-induced regression of OD,such as LVH and urinary protein excre-tion,may be accompanied by a reduction of fatal and non-fatal out-comes,261,262although this evidence is obviously indirect,being derived from post-hoc correlative analyses of randomized data. Randomizedtrials based onhard clinicalCVoutcomes do,however, alsohave limitations,which have beenconsidered inprevious ESH/ESC Guidelines:2(i)to limit thenumberofpatients needed,trials commonly enrol high-risk patients(old age,concomitant or previous disease)and (ii)for practical reasons,the duration of controlled trials is necessarily short(in best cases between3and6years,with an average time to an endpoint of only half of this)—so that recommendations for life-long 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 bene?ts measured during the?rst 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.

4.2When to initiate antihypertensive drug treatment

4.2.1Recommendations of previous Guidelines

The2007ESH/ESC Guidelines,2like many other scienti?c guide-lines,54,55,264recommended the use of antihypertensive drugs in