Guidelines for the management of arterial hypertension esc

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(Italy), Athanasios Manolis (Greece), Peter M. Nilsson (Sweden), Josep Redon (Spain), Roland E. Schmieder (Germany), Harry A.J. Struijker-Boudier (The Netherlands), Margus Viigimaa (Estonia) Document Reviewers: Gerasimos Filippatos (CPG Review Coordinator) (Greece), Stamatis Adamopoulos (Greece), Enrico Agabiti-Rosei (Italy), Ettore Ambrosioni (Italy), Vicente Bertomeu (Spain), Denis Clement (Belgium), Serap Erdine (Turkey), Csaba Farsang (Hungary), Dan Gaita (Romania), Wolfgang Kiowski (Switzerland), Gregory Lip (UK), Jean-Michel Mallion (France), Athanasios J. Manolis (Greece), Peter M. Nilsson (Sweden), Eoin O 9Brien (Ireland), Piotr Ponikowski (Poland), Josep Redon (Spain), Frank Ruschitzka (Switzerland), Juan Tamargo (Spain), Pieter van Zwieten (Netherlands), Margus Viigimaa (Estonia), Bernard Waeber (Switzerland), Bryan Williams (UK), Jose Luis Zamorano (Spain) The content of these European Society of Cardiology (ESC) Guidelines has been published for personal and educational use only. No commercial use is authorized. No part of the ESC Guidelines may be translated or reproduced in any form without written permission from the ESC. Permission c an be obtained upon submission 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 ESC Guidelines represent the views of the 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 guid elines do not, however, override the individual responsibility of health professionals to make appropriate decisions in the circumstances of the individual pati ents, in consultation with that patient, and where appropriate and necessary the patient 9s guardian or carer. It is also the health professional 9s responsibili ty to verify the rules and regulations applicable to drugs and devices at the time of prescription. The afQliations of Task Force members are listed in the Appendix. Their Disclosure forms are available on the respective societ y Web Sites. These guidelines also appear in the Journal of Hypertension , doi:10.1097/HJH.0b013e3281fc975a * Correspondence to Giuseppe Mancia, Clinica Medica, Ospedale San Gerardo, Universita Milano-Bicocca, Via Pergolesi, 33 3 20052 MONZA (Milano), Italy Tel: þ 39 039 233 3357; fax: þ 39 039 32 22 74, e-mail: giuseppe.mancia@unimib.it * Correspondence to Guy de Backer, Dept. of Public Health, University Hospital, De Pintelaan 185, 9000 Ghent, Belgium Tel: þ 32 9 240 3627; fax: þ 32 9 240 4994; e-mail: Guy.DeBacker@ugent.be European Heart Journal (2007) 28 , 1462 3 1536 doi:10.1093/eurheartj/ehm236 & 2007 The European Society of Cardiology (ESC) and European Society of Hypertension (ESH). All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org Table of Contents 1. Introduction and purposes . . . . . . . . . . . . . . . 1463 2. DeQnition and classiQcation of hypertension . . . . . 1464 2.1 Systolic versus diastolic and pulse pressure . . 1464 2.2 ClassiQcation of hypertension . . . . . . . . . . 1465 2.3 Total cardiovascular risk . . . . . . . . . . . . . 1465 2.3.1 Concept . . . . . . . . . . . . . . . . . . 1465 2.3.2 Assessment. . . . . . . . . . . . . . . . . 1466 2.3.3 Limitations . . . . . . . . . . . . . . . . . 1468 3. Diagnostic evaluation . . . . . . . . . . . . . . . . . . 1469 3.1 Blood pressure measurement . . . . . . . . . . 1469 3.1.1 OfQce or clinic blood pressure . . . . . . 1469 3.1.2 Ambulatory blood pressure. . . . . . . . 1469 3.1.3 Home blood pressure . . . . . . . . . . . 1471 3.1.4 Isolated ofQce or white coat hypertension 1471 3.1.5 Isolated ambulatory or masked hypertension . . . . . . . . . . . . . . . . 1472 3.1.6 Blood pressure during exercise and laboratory stress . . . . . . . . . . . . . 1472 3.1.7 Central blood pressure . . . . . . . . . . 1473 3.2 Family and clinical history . . . . . . . . . . . . 1473 3.3 Physical examination . . . . . . . . . . . . . . . 1473 3.4 Laboratory investigations . . . . . . . . . . . . 1473 3.5 Genetic analysis . . . . . . . . . . . . . . . . . 1474 3.6 Searching for subclinical organ damage . . . . 1475 3.6.1 Heart . . . . . . . . . . . . . . . . . . . . 1476 3.6.2 Blood vessels . . . . . . . . . . . . . . . 1476 3.6.3 Kidney . . . . . . . . . . . . . . . . . . . 1477 3.6.4 Fundoscopy . . . . . . . . . . . . . . . . 1478 3.6.5 Brain . . . . . . . . . . . . . . . . . . . . 1478 4. Evidence for therapeutic management of hypertension 1478 4.1 Introduction . . . . . . . . . . . . . . . . . . . . 1478 4.2 Event based trials comparing active treatment to placebo . . . . . . . . . . . . . . . . . . . . . 1479 4.3 Event based trials comparing more and less intense blood pressure lowering . . . . . . . . 1480 4.4 Event based trials comparing different active treatments . . . . . . . . . . . . . . . . . . . . 1480 4.4.1 Calcium antagonists versus thiazide diuretics and b -blockers . . . . . . . . . 1480 4.4.2 ACE inhibitors versus thiazide diuretics and b -blockers . . . . . . . . . . . . . . 1480 4.4.3 ACE inhibitors versus calcium antagonists . . . . . . . . . . . . . . . . 1480 4.4.4 Angiotensin receptor antagonists versus other drugs . . . . . . . . . . . . . . . . 1481 4.4.5 Trials with b -blockers. . . . . . . . . . . 1481 4.4.6 Conclusions . . . . . . . . . . . . . . . . 1482 4.5 Randomized trials based on intermediate endpoints . . . . . . . . . . . . . . . . . . . . . 1482 4.5.1 Heart . . . . . . . . . . . . . . . . . . . . 1482 4.5.2 Arterial wall and atherosclerosis . . . . 1483 4.5.3 Brain and cognitive function . . . . . . . 1484 4.5.4 Renal function and disease. . . . . . . . 1484 4.5.5 New onset diabetes . . . . . . . . . . . . 1485 5. Therapeutic approach . . . . . . . . . . . . . . . . . 1486 5.1 When to initiate antihypertensive treatment . 1486 5.2 Goals of treatment . . . . . . . . . . . . . . . . 1487 5.2.1 Blood pressure target in the general hypertensive population . . . . . . . . . 1487 5.2.2 Blood pressure targets in diabetic and very high or high risk patients . . . . . . 1488 5.2.3 Home and ambulatory blood pressure targets . . . . . . . . . . . . . . . . . . . 1489 5.2.4 Conclusions . . . . . . . . . . . . . . . . 1489 5.3 Cost-effectiveness of antihypertensive treatment . . . . . . . . . . . . . . . . . . . . . 1489 6. Treatment strategies . . . . . . . . . . . . . . . . . . 1490 6.1 Lifestyle changes . . . . . . . . . . . . . . . . . 1490 6.1.1 Smoking cessation. . . . . . . . . . . . . 1490 6.1.2 Moderation of alcohol consumption . . . 1490 6.1.3 Sodium restriction . . . . . . . . . . . . 1491 6.1.4 Other dietary changes . . . . . . . . . . 1491 6.1.5 Weight reduction . . . . . . . . . . . . . 1491 6.1.6 Physical exercise . . . . . . . . . . . . . 1491 6.2 Pharmacological therapy . . . . . . . . . . . . . 1492 6.2.1 Choice of antihypertensive drugs . . . . 1492 6.2.2 Monotherapy . . . . . . . . . . . . . . . . 1495 6.2.3 Combination treatment . . . . . . . . . 1495 7. Therapeutic approach in special conditions . . . . . 1497 7.1 Elderly . . . . . . . . . . . . . . . . . . . . . . . 1497 7.2 Diabetes mellitus . . . . . . . . . . . . . . . . . 1498 7.3 Cerebrovascular disease . . . . . . . . . . . . . 1499 7.3.1 Stroke and transient ischaemic attacks . 1499 7.3.2 Cognitive dysfunction and dementia . . 1500 7.4 Coronary heart disease and heart failure . . . 1500 7.5 Atrial Qbrillation . . . . . . . . . . . . . . . . . 1501 7.6 Non-diabetic renal disease . . . . . . . . . . . 1501 7.7 Hypertension in women . . . . . . . . . . . . . 1502 7.7.1 Oral contraceptives . . . . . . . . . . . . 1502 7.7.2 Hormone replacement therapy . . . . . 1503 7.7.3 Hypertension in pregnancy . . . . . . . . 1503 7.8 Metabolic syndrome . . . . . . . . . . . . . . . 1504 7.9 Resistant hypertension . . . . . . . . . . . . . . 1506 7.10 Hypertensive emergencies . . . . . . . . . . . . 1507 7.11 Malignant hypertension . . . . . . . . . . . . . 1507 8. Treatment of associated risk factors . . . . . . . . . 1508 8.1 Lipid lowering agents . . . . . . . . . . . . . . 1508 8.2 Antiplatelet therapy . . . . . . . . . . . . . . . 1509 8.3 Glycaemic control . . . . . . . . . . . . . . . . 1509 9. Screening and treatment of secondary forms of hypertension . . . . . . . . . . . . . . . . . . . . . . . 1510 9.1 Renal parenchymal disease . . . . . . . . . . . 1510 9.2 Renovascular hypertension . . . . . . . . . . . 1510 9.3 Phaeochromocytoma . . . . . . . . . . . . . . . 1511 9.4 Primary aldosteronism . . . . . . . . . . . . . . 1511 9.5 Cushing 9s syndrome . . . . . . . . . . . . . . . . 1512 9.6 Obstructive sleep apnoea . . . . . . . . . . . . 1512 9.7 Coarctation of the aorta . . . . . . . . . . . . . 1512 9.8 Drug-induced hypertension . . . . . . . . . . . 1512 10. Follow-up . . . . . . . . . . . . . . . . . . . . . . . . 1512 11. Implementation of guidelines . . . . . . . . . . . . . 1513 APPENDIX . . . . . . . . . . . . . . . . . . . . . . . . 1514 References . . . . . . . . . . . . . . . . . . . . . . . . 1515 1. Introduction and purposes For several years the European Society of Hypertension (ESH) and the European Society of Cardiology (ESC) decided not to produce their own guidelines on the diagnosis and treatment of hypertension but to endorse the guidelines on hypertension issued by the World Health Organization (WHO) and International Society of Hypertension (ISH) 1,2 ESC and ESH Guidelines 1463 with some adaptation to reRect the situation in Europe. However, in 2003 the decision was taken to publish ESH/ ESC speciQc guidelines 3 based on the fact that, because the WHO/ISH Guidelines address countries widely varying in the extent of their health care and availability of economic resource, they contain diagnostic and therapeutic recommendations that may be not totally appropriate for European countries. In Europe care provisions may often allow a more in-depth diagnostic assessment of cardiovascu- lar risk and organ damage of hypertensive individuals as well as a wider choice of antihypertensive treatment. The 2003 ESH/ESC Guidelines 3 were well received by the clinical world and have been the most widely quoted paper in the medical literature in the last two years. 4 However, since 2003 considerable additional evidence on important issues related to diagnostic and treatment approaches to hypertension has become available and therefore updating of the previous guidelines has been found advisable. In preparing the new guidelines the Committee estab- lished by the ESH and ESC has agreed to adhere to the prin- ciples informing the 2003 Guidelines, namely 1) to try to offer the best available and most balanced recommendation to all health care providers involved in the management of hypertension, 2) to address this aim again by an extensive and critical review of the data accompanied by a series of boxes where speciQc recommendations are given, as well as by a concise set of practice recommendations to be pub- lished soon thereafter as already done in 2003; 5 3) to pri- marily consider data from large randomized trials but also to make use, where necessary, of observational studies and other sources of data, provided they were obtained in studies meeting a high scientiQc standard; 4) to emphasize that guidelines deal with medical conditions in general and therefore their role must be educational and not prescrip- tive or coercive for the management of individual patients who may differ widely in their personal, medical and cul- tural characteristics, thus requiring decisions different from the average ones recommended by guidelines; 5) to avoid a rigid classiQcation of recommendations by the level or strength of scientiQc evidence. 6 The Committee felt that this is often difQcult to apply, that it can only apply to therapeutic aspects and that the strength of a rec- ommendation can be judged from the way it is formulated and from reference to relevant studies. Nevertheless, the contribution of randomized trials, observational studies, meta-analyses and critical reviews or expert opinions has been identiQed in the text and in the reference list. The members of the Guidelines Committee established by the ESH and ESC have participated independently in the preparation of this document, drawing on their academic and clinical experience and applying an objective and criti- cal examination of all available literature. Most have under- taken and are undertaking work in collaboration with industry and governmental or private health providers (research studies, teaching conferences, consultation), but all believe such activities have not inRuenced their judge- ment. The best guarantee of their independence is in the quality of their past and current scientiQc work. However, to ensure openness, their relations with industry, govern- ment and private health providers are reported in the ESH and ESC websites (www.eshonline.org and www.escardio. org) Expenses for the Writing Committee and preparation of these guidelines were provided entirely by ESH and ESC. 2. DeCnition and classiCcation of hypertension Historically more emphasis was placed on diastolic than on systolic blood pressure as a predictor of cardiovascular morbid and fatal events. 7 This was reRected in the early guidelines of the Joint National Committee which did not consider systolic blood pressure and isolated systolic hyper- tension in the classiQcation of hypertension. 8,9 It was reRected further in the design of early randomized clinical trials which almost invariably based patient recruitment cri- teria on diastolic blood pressure values. 10 However, a large number of observational studies has demonstrated that car- diovascular morbidity and mortality bear a continuous relationship with both systolic and diastolic blood press- ures. 7,11 The relationship has been reported to be less steep for coronary events than for stroke which has thus been labelled as the most important 8hypertension related 9 complication. 7 However, in several regions of Europe, though not in all of them, the attributable risk, that is the excess of death due to an elevated blood pressure, is greater for coronary events than for stroke because heart disease remains the most common cardiovas- cular disorder in these regions. 12 Furthermore, both systolic and diastolic blood pressures show a graded independent relationship with heart failure, peripheral artery disease and end stage renal disease. 13 3 16 Therefore, hypertension should be considered a major risk factor for an array of car- diovascular and related diseases as well as for diseases leading to a marked increase in cardiovascular risk. This, and the wide prevalence of high blood pressure in the popu- lation, 17 3 19 explain why in a WHO report high blood pressure has been listed as the Qrst cause of death worldwide. 20 2.1 Systolic versus diastolic and pulse pressure In recent years the simple direct relationship of cardiovascu- lar risk with systolic and diastolic blood pressure has been made more complicated by the Qndings of observational studies that in elderly individuals the risk is directly pro- portional to systolic blood pressure and, for any given systolic level, outcome is inversely proportional to diastolic blood pressure, 21 3 23 with a strong predictive value of pulse pressure (systolic minus diastolic). 24 3 27 The predictive value of pulse pressure may vary with the clinical characteristics of the sub- jects. In the largest meta-analysis of observational data avail- able today (61 studies in almost 1 million subjects without overt cardiovascular disease, of which 70% are from Europe) 11 both systolic and diastolic blood pressures were independently and similarly predictive of stroke and coronary mortality, and the contribution of pulse pressure was small, particularly in individuals aged less than 55 years. By con- trast, in middle aged 24,25 and elderly 26,27 hypertensive patients with cardiovascular risk factors or associated clinical conditions, pulse pressure showed a strong predictive value for cardiovascular events. 24 3 27 It should be recognized that pulse pressure is a derived measure which combines the imperfection of the original measures. Furthermore, although Qgures such as 50 or 55 mmHg have been suggested, 28 no practical cutoff values separating pulse pressure normality from abnormality at different ages have been produced. As discussed in section 3.1.7 central pulse pressure, which takes into account the 8ampliQcation phenomena 9 between the peripheral arteries ESC and ESH Guidelines 1464 and the aorta, is a more precise assessment and may improve on these limitations. In practice, classiQcation of hypertension and risk assess- ment (see sections 2.2 and 2.3) should continue to be based on systolic and diastolic blood pressures. This should be deQ- nitely the case for decisions concerning the blood pressure threshold and goal for treatment, as these have been the criteria employed in randomized controlled trials on isolated systolic and systolic-diastolic hypertension. However, pulse pressure may be used to identify elderly patients with systo- lic hypertension who are at a particularly high risk. In these patients a high pulse pressure is a marker of a pronounced increase of large artery stiffness and therefore advanced organ damage 28 (see section 3.6). 2.2 ClassiCcation of hypertension Blood pressure has a unimodal distribution in the population 29 as well as a continuous relationship with cardiovascular risk down to systolic and diastolic levels of 115 3 110 mmHg and 75 3 70 mmHg, respectively. 7,11 This fact makes the word hypertension scientiQcally questionable and its classiQcation based on cutoff values arbitrary. However, changes of a widely known and accepted terminology may generate con- fusion while use of cutoff values simpliQes diagnostic and treatment approaches in daily practice. Therefore the classi- Qcation of hypertension used in the 2003 ESH/ESC Guidelines has been retained ( Table 1 ) with the following provisos: 1. when a patient 9s systolic and diastolic blood pressures fall into different categories the higher category should apply for the quantiQcation of total cardiovascular risk, decision about drug treatment and estimation of treat- ment efQcacy; 2. isolated systolic hypertension should be graded (grades 1, 2 and 3) according to the same systolic blood pressure values indicated for systolic-diastolic hypertension. However, as mentioned above, the association with a low diastolic blood pressure (e.g. 60 3 70 mmHg) should be regarded as an additional risk; 3. the threshold for hypertension (and the need for drug treatment) should be considered as Rexible based on the level and proQle of total cardiovascular risk. For example, a blood pressure value may be considered as unacceptably high and in need of treatment in high risk states, but still acceptable in low risk patients. Support- ing evidence for this statement will be presented in the section on therapeutic approach (Section 5). The USA Joint National Committee Guidelines (JNC 7) on hypertension published in 2003 30 uniQed the normal and high normal blood pressure categories into a single entity termed 8prehypertension 9. This was based on the evidence from the Framingham study 31,32 that in such individuals the chance of developing hypertension is higher than in those with a blood pressure , 120/80 mmHg (termed 8normal 9 blood pressure) at all ages. The ESH/ESC Committee has decided not to use this terminology for the following reasons: 1) even in the Framingham study the risk of develop- ing hypertension was deQnitely higher in subjects with high normal (130 3 139/85 3 89 mmHg) than in those with normal blood pressure (120 3 129/80 3 84 mmHg) 32,33 and therefore there is little reason to join the two groups together; 2) given the ominous signiQcance of the word hypertension for the layman, the term 8prehypertension 9 may create anxiety and request for unnecessary medical visits and examinations in many subjects; 34 3) most importantly, although lifestyle changes recommended by the 2003 JNC 7 Guidelines for all prehypertensive individuals may be a valuable population strategy, 30 in practice this category is a highly differentiated one, with the extremes consisting of subjects in no need of any intervention (e.g. an elderly individual with a blood pressure of 120/80 mmHg) as well as of those with a very high or high risk proQle (e.g. after stroke or with diabetes) in whom drug treatment is required. In conclusion, it might be appropriate to use a classiQcation of blood pressure without the term 8hypertension 9. However, this has been retained in Table 1 for practical reasons and with the reservation that the real threshold for hypertension must be considered as Rexible, being higher or lower based on the total cardiovascular risk of each individual. This is further illustrated in section 2.3 and in Figure 1 . 2.3 Total cardiovascular risk (Box 1) 2.3.1 Concept For a long time, hypertension guidelines focused on blood pressure values as the only or main variables determining the need and the type of treatment. Although this approach was maintained in the 2003 JNC 7 Guidelines, 30 the 2003 ESH-ESC Guidelines 3 emphasized that diagnosis and manage- ment of hypertension should be related to quantiQcation of total (or global) cardiovascular risk. This concept is based on the fact that only a small fraction of the hypertensive population has an elevation of blood pressure alone, with the great majority exhibiting additional cardiovascular risk factors, 35 3 39 with a relationship between the severity of the blood pressure elevation and that of alterations in glucose and lipid metabolism. 40 Furthermore, when concomitantly present, blood pressure and metabolic risk factors potentiate each other, leading to a total cardiovascular risk which is greater than the sum of its individual components. 35,41,42 Finally, evidence is available that in high risk individuals thresholds and goals for antihypertensive treatment, as well as other treatment strategies, should be different from those to be implemented in lower risk individuals. 3 In order Table 1 DeQnitions and classiQcation of blood pressure (BP) levels (mmHg) Category Systolic Diastolic Optimal , 120 and , 80 Normal 120 3 129 and/or 80 3 84 High normal 130 3 139 and/or 85 3 89 Grade 1 hypertension 140 3 159 and/or 90 3 99 Grade 2 hypertension 160 3 179 and/or 100 3 109 Grade 3 hypertension 180 and/or 110 Isolated systolic hypertension 140 and , 90 Isolated systolic hypertension should be graded (1, 2,3) according to systolic blood pressure values in the ranges indicated, provided that dias- tolic values are , 90 mmHg. Grades 1, 2 and 3 correspond to classiQcation in mild, moderate and severe hypertension, respectively. These terms have been now omitted to avoid confusion with quantiQcation of total cardiovascular risk. ESC and ESH Guidelines 1465 to maximize cost-efQcacy of the management of hyperten- sion the intensity of the therapeutic approach should be graded as a function of total cardiovascular risk. 43,44 2.3.2 Assessment Estimation of total cardiovascular risk is simple in particular subgroups of patients such as those with 1) a previous diag- nosis of cardiovascular disease, 2) type 2 diabetes, 3) type 1 diabetes, and 4) individuals with severely elevated single risk factors. In all these conditions the total cardiovascular risk is high, calling for the intense cardiovascular risk redu- cing measures that will be outlined in the following sections. However, a large number of hypertensive patients does not belong to one of the above categories and identiQcation of those at high risk requires the use of models to estimate total cardiovascular risk so as to be able to adjust the inten- sity of the therapeutic approach accordingly. Several computerized methods have been developed for estimating total cardiovascular risk, i.e. the absolute chance of having a cardiovascular event usually over 10 years. However, some of them are based on Framingham data 45 which are only applicable to some European popu- lations due to important differences in the incidence of cor- onary and stroke events. 12 More recently, a European model has become available based on the large data-base provided by the SCORE project. 46 SCORE charts are available for high and low risk countries in Europe. They estimate the risk of dying from cardiovascular (not just coronary) disease over 10 years and allow calibration of the charts for individual countries provided that national mortality statistics and esti- mates of the prevalence of major cardiovascular risk factors are known. The SCORE model has also been used in the Heart- Score, the ofQcial ESC management tool for implementation of cardiovascular disease prevention in clinical practice. This is available on the ESC Web Site (www.escardio.org). The 2003 ESH/ESC Guidelines 3 classiQed the total cardio- vascular risk based on the scheme proposed by the 1999 WHO/ISH Guidelines on hypertension 2 with the extension to subjects with 8normal 9 or 8high normal 9 blood pressure. This classiQcation is retained in the present Guidelines ( Figure 1 ). The terms 8low 9, 8moderate 9, 8high 9 and 8very high 9 risk are used to indicate an approximate risk of cardi- ovascular morbidity and mortality in the coming 10 years, which is somewhat analogous to the increasing level of total cardiovascular risk estimated by the Framingham 45 or the SCORE 46 models. The term 8added 9 is used to emphasize that in all categories relative risk is greater than average risk. Although use of a categorical classiQcation provides data that are in principle less precise than those obtained Figure 1 StratiQcation of CV Risk in four categories. SBP: systolic blood pressure; DBP: diastolic blood pressure; CV: cardiovascular; HT: hypertension. Low, moderate, high and very high risk refer to 10 year risk of a CV fatal or non-fatal event. The term 8added 9 indicates that in al l categories risk is greater than average. OD: subclinical organ damage; MS: metabolic syndrome. The dashed line indicates how deQnition of hypertension may be v ariable, depending on the level of total CV risk. Box 1 Position statement: Total cardiovascular risk Dysmetabolic risk factors and subclinical organ damage are common in hypertensive patients. All patients should be classiQed not only in relation to the grades of hypertension but also in terms of the total cardiovascular risk resulting from the coexistence of different risk factors, organ damage and disease. Decisions on treatment strategies (initiation of drug treatment, BP threshold and target for treatment, use of combination treatment, need of a statin and other non-antihypertensive drugs) all importantly depend on the initial level of risk. There are severalmethods bywhich total cardiovascular riskcanbeassessed,allwithadvantagesandlimitations. Categorization of total risk as low, moderate, high, and very high added risk has the merit of simplicity and can therefore be recommended. The term 8added risk 9 refers to the risk additional to the average one. Total risk is usually expressed as the absolute risk of having a cardiovascular event within 10 years. Because of its heavy dependence on age, in young patients absolute total cardiovascular risk can be low even in the presence of high BP with additional risk factors. If insufQciently treated, however, this con- dition may lead to a partly irreversible high risk con- dition years later. In younger subjects treatment decisions should better be guided by quantiQcation of relative risk, i.e. the increase in risk in relation to average risk in the population. ESC and ESH Guidelines 1466 from equations based on continuous variables, this approach has the merit of simplicity. The 2003 WHO/ISH Guidelines 47 have further simpliQed the approach by merging the high and very high risk categories which were regarded as similar when it came to making treatment decisions. The distinction between high and very high risk categories has been maintained in the present guidelines, thereby preser- ving a separate place for secondary prevention, i.e. preven- tion in patients with established cardiovascular disease. In these patients, compared with the high risk category, not only can total risk be much higher, but multidrug treatment may be necessary throughout the blood pressure range from normal to high. The dashed line drawn in Figure 1 illustrates how total cardiovascular risk evaluation inRuences the deQ- nition of hypertension when this is correctly considered as the blood pressure value above which treatment does more good than harm. 48 Table 2 indicates the most common clinical variables that should be used to stratify the risk. They are based on risk factors (demographics, anthropometrics, family history of premature cardiovascular disease, blood pressure, smoking habits, glucose and lipid variables), measures of target organ damage, and diagnosis of diabetes and associated clinical conditions as outlined in the 2003 Guidelines. 3 The following new points should be highlighted: 1. The metabolic syndrome 49 has been mentioned because it represents a cluster of risk factors often associated with high blood pressure which markedly increases car- diovascular risk. No implication is made that it rep- resents a pathogenetic entity. 2. Further emphasis has been given to identiQcation of target organ damage, since hypertension-related subcli- nical alterations in several organs indicate progression in the cardiovascular disease continuum 50 which mark- edly increases the risk beyond that caused by the simple presence of risk factors. A separate Section (3.6) is devoted to searching for subclinical organ damage where evidence for the additional risk of each subclinical alteration is discussed and the proposed cutoff values are justiQed. Table 2 Factors inRuencing prognosis Risk factors Subclinical organ damage Systolic and diastolic BP levels Electrocardiographic LVH (Sokolow-Lyon . 38 mm; Cornell . 2440 mm*ms) or: Levels of pulse pressure (in the elderly) Echocardiographic LVH 8 (LVMI M 125 g/m 2 , W 110 g/m 2 ) Age (M . 55 years; W . 65 years) Carotid wall thickening (IMT . 0.9 mm) or plaque Smoking Carotid-femoral pulse wave velocity . 12 m/s Dyslipidaemia Ankle/brachial BP index , 0.9 - TC . 5.0 mmol/l (190 mg/dl) or: Slight increase in plasma creatinine: - LDL-C . 3.0 mmol/l (115 mg/dl) or: M: 115 3 133 m mol/l (1.3 3 1.5 mg/dl); - HDL-C: M , 1.0 mmol/l (40 mg/dl), W , 1.2 mmol/l (46 mg/dl) or: W: 107 3 124 m mol/l (1.2 3 1.4 mg/dl) - TG . 1.7 mmol/l (150 mg/dl) Low estimated glomerular Qltration rate ( , 60 ml/min/1.73 m 2 ) or creatinine clearance S ( , 60 ml/min) Fasting plasma glucose 5.6 3 6.9 mmol/L (102 3 125 mg/dl) Microalbuminuria 30 3 300 mg/24 h or albumin-creatinine ratio: 22 (M); or 31 (W) mg/g creatinine Abnormal glucose tolerance test Abdominal obesity (Waist circumference . 102 cm (M), . 88 cm (W)) Family history of premature CV disease (M at age , 55 years; W at age , 65 years) Diabetes mellitus Established CV or renal disease Fasting plasma glucose 7.0 mmol/l (126 mg/dl) on repeated measurements, or Cerebrovascular disease: ischaemic stroke; cerebral haemorrhage; transient ischaemic attack Postload plasma glucose . 11.0 mmol/l (198 mg/dl) Heart disease: myocardial infarction; angina; coronary revascularization; heart failure Renal disease: diabetic nephropathy; renal impairment (serum creatinine M . 133, W . 1 24 mmol/l); proteinuria ( . 300 mg/ 24 h) Peripheral artery disease Advanced retinopathy: haemorrhages or exudates, papilloedema Note: the cluster of three out of 5 risk factors among abdominal obesity,alteredfastingplasmaglucose,BP . 130/85 mmHg,low HDL-cholesterol and high TG (as deQned above) indicates the presence of metabolic syndrome M: men; W: women; CV: cardiovascular disease; IMT: intima-media thickness; BP: blood pressure; TG: triglycerides; C: cholestero l; S Cockroft Gault formula; MDRD formula; 8 Risk maximal for concentric LVH (left ventricular hypertrophy): increased LVMI (left ventricular mass index) with a wall thick- ness/radius ratio . 0.42. ESC and ESH Guidelines 1467 3. The list of renal markers of organ damage has been expanded, to include estimates of creatinine clearance by the Cockroft-Gault formula 51 or of glomerular Ql- tration rate by the MDRD formula, 52 because of the evi- dence that these estimated values are a more precise index of the cardiovascular risk accompanying renal dysfunction. 4. Microalbuminuria has now been considered as an essen- tial component in the assessment of organ damage because its detection is easy and relatively inexpensive. 5. Concentric left ventricular hypertrophy has been ident- iQed as the cardiac structural parameter that more markedly increases cardiovascular risk. 6. Whenever possible the recommendation is made to measure organ damage in different tissues (e.g. heart, blood vessels, kidney and brain) because multiorgan damage is associated with a worse prognosis. 53 7. Increased pulse wave velocity is added to the list of factors inRuencing prognosis as an early index of large artery stiffening, 54,55 although with the caveat that it has a limited availability in the clinical practice. 8. A low ankle to brachial blood pressure ratio ( , 0.9) is listed as a relatively easy to obtain marker of athero- sclerotic disease and increased total cardiovascular risk. 56 9. Not only is assessment of organ damage recommended pre-treatment (in order to stratify risk) but also during therapy because of the evidence that regression of left ventricular hypertrophy and reduction of protei- nuria indicate treatment-induced cardiovascular pro- tection. 57 3 61 10. There may be reasons to include an elevated heart rate as a risk factor because of a growing body of evidence that elevated heart rate values relate to the risk of car- diovascular morbidity and mortality as well as to all cause mortality. 62 3 65 Also, there is evidence that an elev- ated heart rate increases the risk of new onset hyperten- sion 66,67 and is frequently associated with metabolic disturbances and the metabolic syndrome. 67 3 69 However, because of the wide range of accepted resting heart rate normality values (60 to 90 beats/ min), no cutoff heart rate can be offered presently to increase the accuracy of total cardiovascular risk stratiQcation. 11. The major diagnostic elements for classifying subjects in the high or very high risk categories are summarized in Table 3 . It is worth noticing that multiple risk factors, diabetes or organ damage invariably place a subject with hypertension, and even with high normal blood pressure, in the high risk category. 2.3.3 Limitations All currently available models for cardiovascular risk assess- ment have limitations which must be appreciated. Total car- diovascular risk models do not consider the duration of exposure to a risk factor or disease and their quantiQcation is usually based on some risk factors only, while paying limited attention to other variables linked to cardiovascular outcome (e.g. physical activity and stress). 70 Furthermore, the signiQcance of target organ damage in determining cal- culation of overall risk is dependent on how carefully the damage is assessed, based on available facilities. Also, there are several additional markers of target organ damage that have not been listed in Table 2 because of a dif- Qculty in measurement, less well established prognostic importance or practical problems (low availability, high dependence on operator 9s skill, lack of standardization, time requirement, invasiveness, cost, etc.). However, because these measurements are currently the object of extensive research, which may make them more useful in the near future they have been discussed in section 3.6 and listed in Table 4 together with an assessment of their clinical value and limitations. The issue is further discussed in Section 3.6. Conceptual limitations should also be mentioned. One should never forget that the rationale of estimating total cardiovascular risk is to govern the best use of limited resources to prevent cardiovascular disease, that is to grade preventive measures in relation to the increased risk. Yet, stratiQcation of absolute risk is often used by private or public healthcare providers to establish a barrier below which treatment is discouraged. The threshold of 20% risk of cardiovascular disease in 10 years is arbitrary and simplistic, and use of a cutoff value leading to intense interventions above this threshold and no action at all below cannot be supported. One should be aware of the strong effect of age on total cardiovascular risk models. It is so strong that younger adults (particularly women) are unlikely to reach high risk levels even when they have more than one major risk factor and a clear increase in rela- tive risk (i.e. the existing risk compared to their peers). By contrast, most elderly men (e.g. . 70 years) will often 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 on older subjects, whose potential lifespan is relatively short despite interven- tion, and little attention is given to young subjects at high relative risk despite the fact that, in the absence of inter- vention, their long term 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. As already suggested in the 2003 ESH-ESC Guidelines, 3 these shortcomings may be avoided by Table 3 High/Very high risk subjects BP 180 mmHg systolic and/or 110 mmHg diastolic Systolic BP . 160 mmHg with low diastolic BP ( , 70 mmHg) Diabetes mellitus Metabolic syndrome 3 cardiovascular risk factors One or more of the following subclinical organ damages: 3 Electrocardiographic (particularly with strain) or echocardiographic (particularly concentric) left ventricular hypertrophy 3 Ultrasound evidence of carotid artery wall thickening or plaque 3 Increased arterial stiffness 3 Moderate increase in serum creatinine 3 Reduced estimated glomerular Qltration rate or creatinine clearance 3 Microalbuminuria or proteinuria Established cardiovascular or renal disease ESC and ESH Guidelines 1468 using the relative risk as a guide to the need and the intensity of therapeutic interventions in young subjects. This is poss- ible with the HeartScore management tool (www.escardio. org), with the update provided by the guidelines on cardio- vascular disease prevention in clinical practice issued by the Fourth Joint European Task Force. 71 It is important to remember that in young individuals who are at low absolute risk just because of their age but who carry important risk factors, non-pharmacological and, if necessary, pharmaco- logical interventions should be implemented to improve their risk proQle and prevent the development of a high risk condition later in life. In the absence of treatment, this can occur even earlier than indicated in risk charts because risk factors tend to become more pronounced with ageing and a life time blood pressure elevation is frequently accompanied by development of organ damage. 3. Diagnostic evaluation Diagnostic procedures aim at: 1) establishing blood pressure levels; 2) identifying secondary causes of hypertension; 3) evaluating the overall cardiovascular risk by searching for other risk factors, target organ damage and concomitant diseases or accompanying clinical conditions. The diagnostic procedures comprise: 3 repeated blood pressure measurements 3 medical history 3 physical examination 3 laboratory and instrumental investigations. Some of these should be considered part of the routine approach in all subjects with high blood pressure; some are rec- ommended and may be used extensively in the developed health systems of Europe; some are indicated only when suggested by the basic examination or the clinical course of the patient. 3.1 Blood pressure measurement Blood pressure is characterized by large spontaneous vari- ations both during the day and between days, months and seasons. 72 3 74 Therefore the diagnosis of hypertension should be based on multiple blood pressure measurements, taken on separate occasions over a period of time. If blood pressure is only slightly elevated, repeated measurements should be obtained over a period of several months to deQne the patients 8usual 9 blood pressure as accurately as possible. On the other hand, if the patient has a more marked blood pressure elevation, evidence of hypertension- related organ damage or a high or very high cardiovascular risk proQle, repeated measurements should be obtained over shorter periods of time (weeks or days). In general, the diagnosis of hypertension should be based on at least 2 blood pressure measurements per visit and at least 2 to 3 visits, although in particularly severe cases the diagnosis can be based on measurements taken at a single visit. Blood pressures can be measured by the doctor or the nurse in the ofQce or in the clinic (ofQce or clinic blood pressure), by the patient or a relative at home, or automati- cally over 24 h. Based on speciQc recommendations of the European Society of Hypertension, 75 these procedures can be summarized as follows: 3.1.1 OfCce or clinic blood pressure Blood pressure can be measured by a mercury sphygmoman- ometer the various parts of which (rubber tubes, valves, quantity of mercury, etc.) should be kept in proper working order. Other non-invasive devices (auscultatory or oscillometric semiautomatic devices) can also be used and will indeed become increasingly important because of the progressive banning of the medical use of mercury. How- ever, these devices should be validated according to standard- ized protocols ( 76 and website: www.dableducational.org), and their accuracy should be checked periodically by com- parison with mercury sphygmomanometric values. Instruc- tions for correct ofQce blood pressure measurements are summarized in Box 2. 3.1.2 Ambulatory blood pressure (Box 3) Several devices (mostly oscillometric) are available for auto- matic blood pressure measurements in patients allowed to conduct a near normal life. They provide information on 24-hour average blood pressure as well as on mean values over more restricted periods such as the day, night or morning. This information should not be regarded as a sub- stitute for information derived from conventional blood pressure measurements. However, it may be considered of important additional clinical value because cross-sectional and longitudinal studies have shown that ofQce blood pressure has a limited relationship with 24-h blood pressure and thus with that occurring in daily life. 77 3 79 These studies have also shown that ambulatory blood pressure 1) corre- lates with hypertension-related organ damage and its changes by treatment more closely than does ofQce blood pressure, 80 3 85 2) has a relationship with cardiovascular events that is steeper than that observed for clinic blood pressure, with a prediction of cardiovascular risk greater than, and additional to the prediction provided by ofQce blood pressure values in populations as well as in untreated and treated hypertensives, 86 3 96 and 3) measures more Table 4 Availability, prognostic value and cost of some markers of organ damage (scored from 0 to 4 pluses) Markers CV predictive value Availability Cost Electrocardiography þþ þþþþ þ Echocardiography þþþ þþþ þþ Carotid Intima-Media Thickness þþþ þþþ þþ Arterial stiffness (Pulse wave velocity) þþþ þ þþ Ankle-Brachial index þþ þþ þ Coronary calcium content þ þ þþþþ Cardiac/Vascular tissue composition ? þ þþ Circulatory collagen markers ? þ þþ Endothelial dysfunction þþ þ þþþ Cerebral lacunae/White matter lesions ? þþ þþþþ Est. Glomerular Filtration Rate or Creatinine Clearance þþþ þþþþ þ Microalbuminuria þþþ þþþþ þ ESC and ESH Guidelines 1469 accurately than clinic blood pressure the extent of blood pressure reduction induced by treatment, because of a higher reproducibility over time 97,98 and an absent or negli- gible 8white coat 9 99 and placebo effect. 100,101 Although some of the above advantages can be obtained by increasing the number of ofQce blood pressure measurements, 82,98 24-hour ambulatory blood pressure monitoring may be useful at the time of diagnosis and at varying intervals during treatment. Effort should be made to extend ambulat- ory blood pressure monitoring to 24 hours in order to obtain information on both daytime and nighttime blood pressure proQles, day-night blood pressure difference, morning blood pressure rise and blood pressure variability. Daytime and nighttime blood pressure values and changes by treat- ment are related to each other, 78,79 but the prognostic value of nighttime blood pressure has been found to be superior to that of daytime blood pressure. 87,89 3 92,94 In addition, subjects in whom nocturnal decrease in blood pressure is blunted (non-dippers) 102 have been reported to have a greater prevalence of organ damage and a less favourable outcome, although in some studies the prog- nostic value of this phenomenon was lost when multi- variate analysis included 24-h average blood pressure. 87,88,90,92,93,103 3 106 Evidence is also available that cardiac and cerebrovascular events have a peak prevalence in the morning, 107 3 110 possibly in relation to the sharp blood pressure rise occurring at awaking from sleep, 72,111 3 113 as well as to an increased platelet aggregability, a reduced Qbrinolytic activity and a sympathetic activation. 114 3 118 Worsening of organ damage and the incidence of events have also been related to blood pressure variability as quan- tiQed by the standard deviation around mean values. 119 3 121 Although in these studies the role of confounding factors was not always excluded, an independent role of blood pressure variability has recently been conQrmed by a long- term observational study. 122 When measuring 24-hour blood pressure 75 care should be taken to: Use only devices validated by international standardized protocols. Use cuffs of appropriate size and compare the initial values with those from a sphygmomanometer to check that the differences are not greater than + 5 mmHg. Set the automatic readings at no more than 30 min inter- vals to obtain an adequate number of values and have most hours represented if some readings are rejected because of artefact. Automatic deRation of the equipment should be at a rate of no more than 2 mmHg/s. Instruct the patients to engage in normal activities but to refrain from strenuous exercise, and to keep the arm extended and still at the time of cuff inRations. Box 2 Blood pressure (BP) measurement When measuring BP, care should be taken to: Allow the patients to sit for several minutes in a quiet room before beginning BP measurements Take at least two measurements spaced by 1 3 2 minutes, and additional measurements if the Qrst two are quite different Use a standard bladder (12 3 13 cm long and 35 cm wide) but have a larger and a smaller bladder available for fat and thin arms, respectively. Use the smaller bladder in children Have the cuff at the heart level, whatever the position of the patient Use phase I and V (disappearance) Korotkoff sounds to identify systolic and diastolic BP, respectively Measure BP in both arms at Qrst visit to detect possible differences due to peripheral vascular disease. In this instance, take the higher value as the reference one Measure BP 1 and 5 min after assumption of the stand- ing position in elderly subjects, diabetic patients, and in other conditions in which postural hypotension may be frequent or suspected Measure heart rate by pulse palpation (at least 30 sec) after the second measurement in the sitting position Box 3 Position statement: Ambulatory and home BP measurements Ambulatory BP Although ofQce BP should be used as reference, ambu- latory BP may improve prediction of cardiovascular risk in untreated and treated patients Normal values are different for ofQce and ambulatory BP ( Table 5 ) 24-h ambulatory BP monitoring should be considered, in particular, when - considerable variability of ofQce BP is found over the same or different visits - high ofQce BP is measured in subjects otherwise at low total cardiovascular risk - there is a marked discrepancy between BP values measured in the ofQce and at home - resistance to drug treatment is suspected - hypotensive episodes are suspected, particu larly in elderly and diabetic patients - ofQce BP is elevated in pregnant women and pre- eclampsia is suspected Home BP Self-measurement of BP at home is of clinical value and its prognostic signiQcance is now demonstrated. These measurements should be encouraged in order to: - provide more information on the BP lowering effect of treatment at trough, and thus on therapeutic coverage throughout the dose-to-dose time interval - improve patient 9s adherence to treatment regimens - there are doubts on technical reliability/ environmental conditions of ambulatory BP data Self-measurement of BP at home should be discouraged whenever: - it causes anxiety to the patient - it induces self-modiQcation of the treatment regimen Normal values are different for ofQce and home BP ( Table 5 ) ESC and ESH Guidelines 1470 Ask the patient to provide information in a diary on unusual events and on duration and quality of night sleep. Obtain another ambulatory blood pressure if the Qrst examination has less than 70% of the expected number of valid values because of frequent artefacts. Ensure that the proportion of valid values is similar for the day and night periods. Remember that ambulatory blood pressure is usually several mmHg lower than ofQce blood pressure. 123 3 125 As shown in Table 5 , different population studies indicate that ofQce values of 140/90 mmHg correspond to average 24-h values of either 125 3 130 mmHg systolic and 80 mmHg diastolic, the corresponding average daytime and nighttime values being 130 3 135/85 and 120/70 mmHg. These values may be regarded as approxi- mate threshold values for diagnosing hypertension by ambulatory blood pressure. Clinical judgement should be mainly based on average 24-hour, day and/or night values. Other information derived from ambulatory blood pressure (e.g. morning blood pressure surge and blood pressure standard devi- ations) is clinically promising, but the Qeld should still be regarded as in the research phase. 3.1.3 Home blood pressure (Box 3) Self-measurement of blood pressure at home cannot provide the extensive information on daily life blood pressure values provided by ambulatory blood pressure monitoring. However, it can provide values on different days in a setting close to daily life. When averaged over a period of a few days these values share some of the advantages of ambulatory blood pressure, that is they are free of a signiQ- cant white coat effect, are more reproducible and predict the presence and progression of organ damage as well as the risk of cardiovascular events better than ofQce values. 81,89,90,92,126,127 Therefore, home blood pressure measurements for suitable periods can be recommended before and during treatment also because this relatively cheap procedure may improve patient adherence to treatment. 128 When advising self-measurement of blood pressure at home: 75 Suggest the use of validated devices. Few of the presently available wrist devices for measurement of blood pressure have been validated satisfactorily; 76 should any of these wrist devices be used, the subject should be rec- ommended to keep the arm at heart level during the measurement. Prefer semiautomatic devices rather than a mercury sphygmomanometer to avoid the difQculty posed by having to educate the patient on its use and the error derived from hearing problems in elderly individuals. Instruct the patient to make measurements in the sitting position after several minutes rest, preferably in the morning and in the evening. Inform him or her that values may differ between measurements because of spontaneous blood pressure variability. Avoid requesting that an excessive number of values are measured and ensure that those measurements include the period prior to drug intake so as to have information on the duration of treatment effects. Remember that, as for ambulatory blood pressure, normal values are lower for home than for ofQce blood pressure. Take 130 3 135/85 mmHg as the values that approximately correspond to 140/90 mmHg measured in the ofQce or clinic ( Table 5 ). Give the patient clear instructions on the need to provide the doctor with proper documentation of the measured values and to avoid self-alterations of the treatment regimens. 3.1.4 Isolated ofCce or white coat hypertension In some patients ofQce blood pressure is persistently elev- ated while daytime or 24-hour blood pressure, or home blood pressure, are within their normal range. This con- dition is widely known as 8 white coat hypertension 9, 129 although the more descriptive and less mechanistic term 8isolated of?ce (or clinic) hypertension 9 is preferable because the ofQce ambulatory blood pressure difference does not correlate with the ofQce blood pressure elevation induced by the alerting response to a doctor or a nurse, 130 that is the true 8white coat effect 9 . 131,132 Regardless of the terminology, evidence is now available that isolated ofQce hypertension may be present in about 15% of the general population and that it may account for a noticeable fraction (one third or more) of individuals in whom hyper- tension is diagnosed. 106,133,134 There is evidence that in individuals with isolated ofQce hypertension cardiovascular risk is less than in individuals with both raised ofQce and ambulatory blood pressure. 90,92,106,133 3 138 However, several, although not all studies, have reported this con- dition to be associated with a prevalence of organ damage and metabolic abnormalities greater than that of normoten- sive subjects, which suggests that it may not be a clinically innocent phenomenon. 133 Evidence of its adverse prognostic relevance is less consistent in outcome studies when data are properly adjusted for age and gender 92,106,133,138 but there is one report of its association with a rate of cardiovas- cular events that is intermediate between that of subjects in whom normal blood pressure and hypertension are found both in and out of ofQce. 133 It is difQcult to predict which patients found to be hyper- tensive in the ofQce will have isolated ofQce hypertension, but this condition is more common when there is a grade 1 (mild) hypertension in females, at older ages, in non- smokers, in hypertension of recent onset and when there is a limited number of ofQce blood pressure measurements. 75 Isolated ofQce hypertension should be diagnosed whenever ofQce blood pressure is 140/90 mmHg on at least 3 Table 5 Blood pressure thresholds (mmHg) for deQnition of hypertension with different types of measurement SBP DBP OfQce or clinic 140 90 24-hour 125 3 130 80 Day 130 3 135 85 Night 120 70 Home 130 3 135 85 ESC and ESH Guidelines 1471 occasions, while 24-hour mean and daytime blood pressures are within their normal range. Its diagnosis can also be based on home blood pressure values (when the average of several home readings is , 135/85 mmHg and ofQce values 140/90 mmHg), bearing in mind that subjects with isolated ofQce hypertension diagnosed by ambulatory blood pressure monitoring may not be entirely the same group identiQed by home blood pressure measurements. 133,139 Some individuals may have a high home and a normal ambulatory blood pressure and vice versa. IdentiQcation of isolated ofQce hypertension should be followed by a search for metabolic risk factors and organ damage. Drug treatment should be instituted when there is evidence of organ damage or a high cardiovascular risk proQle. However, lifestyle changes and a closefollow-uparerecommendedinallpatientswithisolated ofQce hypertension even when it is decided not to start pharmacological treatment. 3.1.5 Isolated ambulatory or masked hypertension The reverse phenomenon of 8 white coat hypertension 9 has also been described: individuals with normal ofQce blood pressure ( , 140/90 mmHg) may have elevated ambulatory or home blood pressure values, a condition termed 8 isolated ambulatory hypertension 9 or 8 masked hyperten- sion 9. 92,95,106,132 3 134,137,139 3 41 The prevalence in the popu- lation is about the same as that of isolated ofQce hypertension 106,133,134,141 and it has been calculated that about 1 in 7 or 8 subjects with a normal ofQce blood pressure may fall into this category. 133 Although limited information exists on the persistence of this condition over time, 142 such individuals have been shown to have greater than normal prevalence of organ damage, 139 with an increased prevalence of metabolic risk factors 133 compared with sub- jects with a truly normal blood pressure. Outcome studies have suggested that masked hypertension increases cardio- vascular risk, which appears to be close to that of in- and out-of-ofQce hypertension. 92,106,133,134,137,141 In conclusion, studies made in the last few years have pro- vided a growing body of evidence on the clinical importance of out-of-ofQce blood pressure measurements as these characterize more precisely the severity of hypertension and identify a higher risk proQle in some apparently normo- tensive individuals. In a recent long-term observational study the 12-year risk of death progressively increased from the condition of being normotensive on ofQce, home, and 24-hour deQnitions to the condition of being found hypertensive by one, two and all three blood pressure measurement modalities. 133 Ambulatory and home blood pressures may provide useful information even when there is no apparent elevation in clinic blood pressure, particularly in subjects in whom multiple risk factors and organ damage are present. 3.1.6 Blood pressure during exercise and laboratory stress Both physical and mental stressors have been applied in the laboratory to assess the blood pressure response to challen- ging stimuli and its potential clinical utility. Physical stress involves active physical activity (dynamic or static exercise) or passive physical stress, such as the cold pressor test. Mental stress is evoked via a problem of mathematical, tech- nical or decisional nature. 143 All stressors increase blood pressure and the variable indi- vidual blood pressure response has been evaluated with regard to the prediction of new onset hypertension, target organ damage and incident cardiovascular disease or death. Data on the prediction of future hypertension are conRict- ing. 144 Some studies reported a signiQcant and independent risk for incident hypertension in subjects who showed dis- proportionate exercise blood pressure responses, 145 and in male civil servants blood pressure reactions to mental stress predicted future blood pressure values and hyperten- sion at a 10 year follow-up. 146 However, only a small fraction of the variance of future blood pressure values was explained by the different response to mental stress, and other studies 147 have led to negative results. As to organ damage, most studies on normotensive and hypertensive subjects did not observe a signiQcant relation- ship between the pressor effect of dynamic exercise and left ventricular hypertrophy after proper adjustment for resting blood pressure, 148 3 154 but in a recent report the change of systolic blood pressure from rest to submaximal exercise was found to be a strong predictor of left ventricular hyper- trophy in prehypertensive individuals. 155 The signiQcance of blood pressure reactivity to static exercise has been rarely addressed but no signiQcant association between the blood pressure response to handgrip and left ventricular mass has been reported in one study, 156 while the blood pressure increase induced by the cold pressor test predicted left ven- tricular mass 153 in one but not another report. 157 The blood pressure effect of an arithmetic task was signiQcantly related to left ventricular concentric remodelling but not to left ventricular mass in one study, 158 while other studies failed to Qnd positive associations between left ventricular structure and this type of blood pressure reactivity. 153,157 There is conRicting evidence as to whether an exagger- ated blood pressure response to bicycle exercise can predict cardiovascular morbidity and mortality independent of resting values, 149,159 although the results of a 21-year follow up have recently shown that both supine and 6-min exercise systolic blood pressures provide predictive infor- mation on cardiovascular death, particularly in subjects with mild blood pressure elevation. 160 However, the matter may be different in more severe hypertension. Whether an excessive blood pressure rise during exercise adds prognostic information to blood pressure at rest may depend on the effect of exercise on cardiac output. If the exercise-induced rise in cardiac output is impaired, as it can be seen in severe hypertension, exercise blood pressure can no longer carry an independent prognostic signiQcance. There is some evidence that an impaired reduction of sys- temic vascular resistance during exercise carries a worse prognosis. 159,161 In conclusion, the results on the independent relationships of the blood pressure response to physical and mental stres- sors, future hypertension and target organ damage are not consistent and, if signiQcant, the additional explained variance is small. As to the prediction of cardiovascular events, the 21-year follow-up study mentioned above 160 suggests that an exercise test may provide some additional prognostic information at least in subjects with mild blood pressure elevation, because in the absence of other risk factors or organ damage a decision on the need for thera- peutic intervention may be difQcult. Finally, it should not be forgotten that non-invasive blood pressure ESC and ESH Guidelines 1472 measurements during exercise are limited to systolic values, and that their accuracy is much less than that of resting values. 3.1.7 Central blood pressure Due to the variable superimposition of incoming and reRected pressure waves along the arterial tree, aortic sys- tolic and pulse pressure (i.e. the pressure exerted at the level of the heart, brain and kidney) may be different from the conventionally measured brachial pressure. 162 Fur- thermore, the claim has long been made that peripheral and central systolic and pulse pressures may be diffe

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