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(1) Epidemiology and risks Pharmaceutical Journal Vol 263 No 7059 p280-283 August 21, 1999 Continuing Education

Hypertension (1) Epidemiology and risks By Charles Spencer, MBBS, MRCP and Gregory Lip, MD, FRCPE Dr Spencer is a research fellow and Dr Lip is consultant cardiologist and reader in medicine at the University department of medicine, City hospital, Birmingham This article is the first in a new series on hypertension. It provides an overview of this common condition and discusses the long-term complications that may arise as a result of not treating hypertension Hypertension is not an uncommon problem. In the 1996 Health Survey for England, the prevalence was found to be approximately 50 per cent in people aged between 65 and 74 years. It was higher still above this age.1 With the increasing age of the general population, the prevalence of hypertension and its complications is likely to increase rather than decrease. Many people will be unaware that they have the condition until they fall victim to its complications, ie, stroke, heart disease, peripheral vascular disease, renal failure and retinopathy. The detection and treatment of hypertension is, therefore, vital in the battle to reduce cardiovascular disease and strokes. These are currently major causes of death in the United Kingdom. The science of hypertension has advanced rapidly since the development of accurate, non-invasive measurement of systolic blood pressure. This resulted from the invention of the sphygmomanometer, by Scipione Riva-Rocci just over a century ago, and the discovery of the Korotkoff sounds a few years later. The pace of scientific discovery is continuing to accelerate as we approach the new millennium. Hypertension is a rapidly changing field of medicine, which provides major challenges for the physician and pharmacist alike. Definition of hypertension The definition of hypertension is necessarily arbitrary and varies between expert groups. However, it can be defined pragmatically as that level of blood pressure above which the use of antihypertensive treatment does more good than harm. This level will vary from patient to patient and balances the risks of untreated hypertension with those of long-term exposure to antihypertensive drugs and their side effects. It is important to take into account not only the pathological consequences of hypertension but also the psychological and social consequences of labelling a patient as hypertensive. These include difficulties in finding employment and life insurance. The 1993 guidelines of the British Hypertension Society (currently under revision and to be published in the Journal of Human Hypertension in September) take a fairly conservative view, suggesting treatment of patients with uncomplicated hypertension and a systolic blood pressure above 160mmHg or a diastolic blood pressure above 100mmHg, after several measurements over a period of time.2 In contrast, the more recent guidelines from the American joint national committee on prevention, detection, evaluation and treatment of high blood pressure (JNC-VI) define hypertension as a systolic blood pressure of greater than 140mmHg and/or a diastolic blood pressure of greater than 90mmHg.3 Prevalence of hypertension The prevalence of hypertension varies depending on the definition used. Using the stricter definition of systolic blood pressure greater than 140mmHg or a diastolic pressure greater than 90mmHg, or current treatment with antihypertensive medication, the prevalence of hypertension varies from 4 per cent in 18-29 year olds to 65 per cent in the over 80s in the United States population.4 Hypertension is not distributed evenly in the community and, even within the United Kingdom, blood pressure varies with geography. For example, a survey of 24 large towns found the lowest mean

blood pressure in Shrewsbury, while the highest was in Dunfermline where the blood pressure was, on average, 17/11mmHg higher than in Shrewsbury.5 On a wider scale, differences in blood pressure are even greater, to the extent that, in some primitive communities, hypertension is virtually unknown. To understand the problem of hypertension, it is important to grasp its impact on the whole population. Within a population, blood pressure is a continuous variable, distributed in a roughly normal (or Gaussian) manner. Thus, there are not two separate groups of individuals (that is, those with and those without hypertension) but a continuous range of blood pressures from the lowest to the highest. The majority of individuals fall somewhere in the middle (see Figure 1). This has important implications for public health. Although those with high blood pressures are individually at greater risk of stroke and coronary heart disease, there are very few of them. Even if they all had their hypertension perfectly treated, there would be little impact on the number of strokes and heart attacks occurring in the population as a whole. Conversely, reducing the blood pressure of the whole population by only a few mmHg would significantly cut the rate of stroke and coronary heart disease. This should not, of course, distract us from treating those at highest risk, in whom large gains in life expectancy and risk reduction can be made. Aetiology of hypertension Over 95 per cent of patients with hypertension have primary (or essential) hypertension, in which there is no immediately obvious underlying cause. This definition is somewhat misleading, in that all hypertension clearly has a cause, which probably includes complex genetic and environmental factors. In a small minority of patients (2 to 5 per cent of hypertensives), hypertension is "secondary" or due to an underlying disease, usually involving the kidneys or endocrine system (see Panel 1). Effective treatment of the underlying condition can sometimes abolish the hypertension. Identifying patients with secondary hypertension will be discussed as part of a future article. Panel 1: causes of secondary hypertension Endocrine Phaeochromocytoma Conn's syndrome Vascular Coarctation of the aorta Renal artery stenosis Renal Intrinsic renal disease (eg, glomerulonephritis) Polycystic kidney Chronic renal failure Drugs Oral contraceptives Sympathomimetics Blood pressure measurement Despite the important management decisions based upon it, blood pressure measurement in clinical practice is fraught with inaccuracy. Variation in blood pressure readings may occur due to factors within the patient (biological variation) or problems involving the observer (measurement variation). Frequent observer retraining and meticulous technique are vital. Within an individual patient, blood pressure can vary considerably. For example, it tends to be highest first thing in the morning and lowest at night. It is also higher in cold weather and after consuming caffeine, tobacco or alcohol.

The most accurate device for non-invasive blood pressure measurement is a well cared for mercury manometer; however, mercury is likely to be outlawed in the near future because of concerns about its safety. Aneroid manometers are inaccurate unless regularly calibrated. In the future, it is likely that most blood pressure readings will be made with electronic oscillometric devices, although, at the moment, only a few such machines have been carefully validated or certified for clinical use. When taking blood pressure using a sphygmomanometer, it is important that the correct size of cuff is used. The width of the air bladder should be about two-thirds of the distance from the axilla to the antecubital fossa, and it should encompass at least 80 per cent of the arm. The use of too small a cuff will result in an overestimation of the blood pressure. The patient should be seated in a quiet room with the arm supported at the same level as the heart. The cuff should be inflated to about 20mmHg above the systolic pressure, as indicated by the disappearance of the radial pulse. It should then be deflated at 2mmHg/second and the systolic pressure recorded at the first appearance of the auscultatory sounds. The diastolic pressure is indicated by the disappearance of these sounds. Decisions concerning the management of hypertension should be based on blood pressure readings taken on several occasions over a period of time. Some patients only exhibit hypertension in the presence of health professionals, especially doctors. This "white coat hypertension" should be suspected in patients who demonstrate persistently elevated blood pressures yet have little or no evidence of end organ damage, or in those who develop symptoms of hypotension even with small doses of antihypertensive drugs. Home blood pressure measurements with an automated device or 24-hour ambulatory blood pressure monitoring (ABPM) will confirm the diagnosis of "white coat hypertension" in these cases. ABPM also has a role in other special situations, such as apparent drug resistance or hypotensive symptoms while on medication. Normally, home and ambulatory blood pressures tend to be slightly lower than clinic values. It is worth remembering, therefore, that almost all the data on which recommendations about blood pressure management are made are based on clinic readings. Significance of hypertension The natural history of high blood pressure can be divided into two parts. First, hypertension can develop as a risk factor, without significant local organ damage or symptoms. Later, this can shift towards significant target organ damage, with cardiovascular symptoms. In 1990, MacMahon et al analysed nine prospective longitudinal observational studies from North America and Europe. These involved large, virtually untreated, middle-aged and predominantly male (96 per cent) populations - with a total of 4.2 million person-years of observation and a mean 10-year follow-up.6 This study confirmed the positive, continuous, independent association of stroke and coronary heart disease risk with high blood pressure (see Figure 2). The data suggested that a 5 to 6mmHg reduction in the average level of diastolic blood pressure would be associated with about a 40 per cent reduction in stroke and a 20 to 25 per cent reduction in coronary heart disease.6,7 Importantly, there was no evidence of a threshold between "normal" blood pressure and pressure associated with higher risk. Furthermore, there was little evidence in untreated populations of a so-called "J-curve", where increased risk might be seen in individuals with low blood pressures. A lower level of risk is seen in women, at least below the age of 55 years. Among Far Eastern populations, a different ratio between heart attacks and strokes is exhibited from that of Caucasion populations.8 Figure 2: Relative risks of stroke and coronary heart disease - solid

squares represent disease risks in each category relative to risk in the whole study population; sizes of squares are proportional to number of events in each diastolic blood pressure category; vertical lines show 95 per cent confidence intervals for estimates of relative risk (reproduced, with permission, from the Lancet 1990;335:765). More recent analyses have also examined systolic blood pressure. In the multiple risk factor intervention trial, a cross-tabulation of systolic and diastolic blood pressures found that the relative risk of coronary heart disease increased progressively from 1.0 with optimum levels of blood pressure (regular systolic BP <120mmHg, diastolic BP <80mmHg) to 3.23 in isolated diastolic hypertension (diastolic BP >100mmHg, systolic BP less than 120mmHg). The relative risk was 4.19 in people with isolated systolic hypertension (systolic BP >160mmHg and diastolic BP <80mmHg) and 4.57 in those with a combined increase of both systolic and diastolic BP (systolic >160mmHg, diastolic BP >100mmHg).9 Consequences of hypertension Stroke Stroke is one of the most devastating consequences of hypertension. It results not only in premature death but also in significant disability. Strokes account for about 12 per cent of all deaths, and about 25 per cent of all strokes occur in patients younger than 65 years of age. In patients with hypertension, about 80 per cent of strokes are ischaemic, caused by intra-arterial thrombosis or embolisation from the heart and large arteries. The remaining 20 per cent are from haemorrhagic causes, which may also be related to very high blood pressure. In the United Kingdom, it is estimated that 40 per cent of all strokes are attributable to systolic blood pressures of 140mmHg or more. After adjusting for age, men aged 40-59 years with systolic blood pressure of 160 to 180mmHg have about a four-fold higher risk of stroke during the next eight years than men whose systolic blood pressure is between 140 to 159mmHg. A similar but smaller relationship to diastolic blood pressure also exists.10 Data from population studies indicate that an average reduction in blood pressure of just 9/5mmHg results in a 34 per cent reduction in the incidence of stroke, and a reduction of 19/10mmHg results in a 56 per cent lower incidence of stroke.11 Elderly hypertensives are particularly prone to all forms of stroke and often sustain multiple small, asymptomatic cerebral infarcts. These lead to progressive loss of intellectual function and dementia. The recent Syst-Eur study convincingly showed that treatment of isolated systolic hypertension, which is generally more frequent in the elderly, resulted in the prevention of dementia at follow-up.12 Hypertension is also associated with an increased risk of atrial fibrillation, which is the commonest sustained cardiac rhythm disorder. In the low-risk arm of the third stroke prevention in atrial fibrillation study (SPAF-3), previous hypertension increased the risk of stroke nearly four-fold, despite aspirin therapy.13 The presence of both hypertension and atrial fibrillation are additive in terms of the risk of stroke. Coronary heart disease Fatal coronary heart disease is seven times more common among hypertensives than fatal stroke and, therefore, is the major population consequence of hypertension. Controlled trials have consistently shown that stroke and heart failure are largely preventable by the treatment of high blood pressure but the reduction of coronary thrombosis is less impressive. Nevertheless, analysis of the large treatment trials suggests that adequate treatment of hypertension reduces heart attack risk by approximately 20 per

cent. This analysis is based on blood pressure reduction with thiazides and beta-blockers, rather than the newer antihypertensive drugs.11 Left ventricular hypertrophy As a result of the increased afterload imposed on the heart by high blood pressure, the mass of the left ventricular muscle increases. While this is, initially, a compensatory response, the increased muscle mass outstrips its oxygen supply and, coupled with the reduced coronary vascular reserve seen in hypertension, can result in myocardial ischaemia even with normal coronary arteries. Thus, beyond a certain point, left ventricular hypertrophy (LVH) secondary to hypertension becomes a major risk factor for myocardial infarction, stroke, sudden death and congestive cardiac failure. This increased risk is in addition to that imposed by hypertension itself. Hypertensives with LVH are also at increased risk of cardiac arrhythmias (atrial fibrillation, ventricular arrhythmias) and atherosclerotic vascular disease (coronary and peripheral artery disease). A commonly used screening test for LVH in hypertensives is the 12-lead electrocardiogram (ECG). Nevertheless, LVH may be identified by electrocardiography in only 5-10 per cent of a hypertensive population. Echocardiography is a far more sensitive investigatio and would identify LVH in around 50 per cent of an untreated hypertensive population. Heart failure Convincing evidence from prospective epidemiological studies suggests that heart failure may be caused by high blood pressure and prevented by its control. For example, the Framingham study suggested that high blood pressure was the principal cause of heart failure.14 Those individuals with blood pressures >160/95mmHg had a six-fold higher incidence of heart failure than those with pressures less then 140/90mmHg. Although less dramatic than stroke and coronary heart disease, heart failure has a poor long term prognosis. In the Framingham study, the presence of LVH on the ECG also significantly increased the risk of heart failure.14 Furthermore, hypertension increases the risk of coronary heart disease and subsequent myocardial infarction, which can lead to damaged ventricles and heart failure. The development of atrial fibrillation, especially if hypertensive LVH and diastolic dysfunction are present, can precipitate heart failure. Finally, hypertension in association with renal artery stenosis can cause sudden pulmonary oedema, which can be corrected by treatment of the renal artery stenosis.15 It is important to remember that heart failure in association with untreated hypertension over many years can slowly be replaced by "normal" blood pressure as the left ventricle progressively fails. Large vessel arterial disease Peripheral vascular disease, as manifested by intermittent claudication, is about three times more common in patients with hypertension.16 Many patients with peripheral vascular disease also have renal artery stenosis, which may be contributing to their hypertension. Atheromatous disease in the aorta, coupled with hypertension, may progress to aortic aneurysm. High pulsatile wave stress and atheromatous disease can lead to dissection of the aorta, which carries a high short-term mortality. Extracranial carotid artery disease is also more common in hypertensives, and is one of the mechanisms by which hypertension leads to the increased risk of stroke.17 Renal Disease Malignant hypertension (see below) frequently leads to progressive renal failure. There is some controversy as to whether this is also the case in patients with mild-to-moderate essential hypertension.18 It may be that those who do develop renal failure have hypertension secondary to renal disease, rather than vice versa. Retinopathy Hypertension leads to vascular changes in the eye, referred to as hypertensive retinopathy. These changes have been classified by Keith, Wagener and Barker into four grades, which correlate with prognosis.19 The most severe

form of hypertension - malignant hypertension - is defined clinically as raised blood pressure in association with bilateral retinal flame-shaped haemorrhages, and/or cotton wool spots, and/or hard exudates, with or without papilloedema. Overall risks from hypertension Hypertension is only one of a number of major risk factors for cardiovascular disease and stroke. When considering the individual patient, it is vital to take factors, such as smoking and diabetes, into account. Treating blood pressure alone, disregarding other risk factors, is relatively ineffective at preventing stroke and myocardial infarction. The treatment of hypertension is an unusual therapeutic exercise in that large numbers of asymptomatic individuals are exposed to many years of treatment in order to prevent potential adverse events in the future. It is vital that both patients and health professionals are clear about the aims of treatment at its outset. These aims must be to prevent the complications of hypertension by reducing blood pressure to normal levels and to detect and correct other cardiovascular risk factors. The latest joint British guidelines for cardiovascular disease prevention recommend a target blood pressure of less than 140/90mmHg, or even lower in some high risk groups.20 As far as possible, achieving this should be carried out without causing the patient adverse physical effects from medication or other interventions. References 1. Prescott-Clarke P, Primatesta T. Health service for England 1996. A survey carried out on behalf of the Department of Health. London: Stationery Office, 1998 (Series HS, no 6). 2. Sever P, Beevers DG, Bulpitt C, Lever A, Ramsay L, Reid J, et al. Management guidelines in essential hypertension: report of the second working party of the British Hypertension Society. BMJ 1993;306:983. 3. Report of the joint national committee on prevention, detection, evaluation and treatment of high blood pressure (JNC VI). Arch Intern Med 1997;157:2413. 4. Working group on primary prevention of hypertension. National high blood pressure education program working group report on primary prevention of hypertension. Ibid 1993;153:186. 5. Shaper AG, Ashby D, Polock SJ. Blood pressure and hypertension in middle aged British men. J Hypertens 1988;6:367. 6. MacMahon S, Peto R, Cutler J, Collins R, Sorlie P, Neaton J, et al. Blood pressure, stroke and coronary heart disease: part I, prolonged differences in blood pressure: prospective observational studies corrected for regression dilution bias. Lancet 1990;335:765. 7. Collins R, Peto R, MacMahon S. Herbert P, Fiebach NH, Kimberley AE, et al. Blood pressure, stroke and coronary heart disease: part II, short-term reductions in blood pressure: overview of randomised drug trials in their epidemological context. Lancet 1990;335 827. 8. Eastern stroke and coronary heart disease collaborative research group. Blood pressure, cholesterol and stroke in Eastern Asia. Lancet 1998;352:1801. 9. Stamler J, Stamler R, Neaton JD. Blood pressure, systolic and diastolic, and cardiovascular risks. Arch Intern Med 1993;153:598. 10. Shaper AG, Phillips AN, Pollock SJ, Walker M, Macfarlane PW. Risk factors for stroke in middle-aged British men. BMJ 1991;302:1111. 11. MacMahon S. Blood pressure and the risks of cardiovascular disease. In: Swales JD editor. Textbook of hypertension. Oxford: Blackwell, 1994, p 46.

12. Forette F, Seux ML, Staessen JA, Thijs L, Birkenhager WH, Babarskiene MR, et al. Prevention of dementia in randomised double-blind placebo-controlled systolic hypertension in Europe (Syst-Eur) trial. Lancet 1998;352:1347. 13. Stroke prevention in atrial fibrillation study investigators. Patients at low risk of stroke during treatment with aspirin: Stroke prevention in atrial fibrillation III study. JAMA 1998;279:1273. 14. Kannel W, Castelli W, McNamara PM, McKee PA, Feinleib M. Role of blood pressure in the development of congestive heart failure: the Framingham Study. New Eng J Med 1972; 287:781. 15. Missouris CG, Buckenham T, Vallance PJT, MacGregor GA. Renal artery stenosis masquerading as congestive heart failure. Lancet 1993;342:1521. 16. Hughson WG, Mann JI, Garrod A. Intermittent claudication; prevalence and risk factors. BMJ 1978;1:1379. 17. Phillips SJ, Whisnant JP. Hypertension and the brain. The national high blood pressure education program. Arch Intern Med 1993;152:938. 18. Beevers DG, Lip GYH. Does non-malignant essential hypertension cause renal damage? A clinician's view. J Hum Hypertens 1996;10:695. 19. Keith NM, Wagener HP, Barker NW. Some different types of essential hypertension: their course and prognosis. Am J Med Sci 1939;196:332. 20. Wood D, Durrington P, Poulter N, McInnes G, Rees A, Wray R. Joint British recommendations on the prevention of coronary heart disease in clinical practice. Heart 1998;80(S2):S14.