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Pharmacological treatment of hypertension
Pharmacological treatment of hypertension
Management of hypertension theoretically provides one of the best models for the definition of optimum treatment. Precise clinical assessment is straightforward, risk welldocumented in large observational studies, and benefits confirmed in extensive intervention trials. This plethora of information, whilst making the task of treatment easy at one level, has generated several unresolved questions and controversy. A partial solution to such problems is to obtain more information, largely from clinical trials. However, some of the debate centres on the need to create arbitrary dividing lines in gradients of risk and benefit, distinctions that can be based only on relative judgments of value and cost. Thus it is not surprising that, despite access to a common pool of data, published national and international guidelines differ considerably.1 Beneftts of treatment Reversal of risk produced by lowering blood
pressure has
been shown only for drug treatment. An initial metaanalysis of trials in 1986 concluded that the risk of fatal and non-fatal stroke attributable to raised blood pressure was completely reversed by antihypertensive therapy,2 whereas the impact on coronary heart disease (a reduction of 8%) was not significant. A later meta-analysis in 1990 confirmed the reversal of stroke risk but also recorded a significant reduction in coronary heart disease (— 14%), although this figure fell somewhat short of the impact that would have been predicted if the attributable risk had been completely reversed (20-25%). The evolution of non-significant trends to significant effects is commonly seen in cumulative meta-analyses as additional trials are published.4 However, the 1990 meta-analysis included only one additional trial that had been reported in the interim, together with three older small trials, none of which contributed significantly to the change in benefit reported. The greater reduction in coronary events was due to the omission of one multifactorial trial (MRFIT) in which treated patients had a marginally increased overall infarction rate5 and the inclusion of more data from one large trial, the Hypertension Detection and Follow-up Program In the 1986 meta-analysis, (HDFP).6 only documented myocardial electrocardiographically infarctions were included; in 1990, the broader criterion of clinical history was used. A more recent meta-analysis7 included data from three subsequently reported trials in elderly patients-the STOP-Hypertension trial,8 the MRC trial in the elderly,9 and the Systolic Hypertension in the Elderly Program (SHEP).lO Again, the risk of stroke attributable to hypertension was reversed (—38%). The reduction in coronary events was larger and more significant than in the previous meta-analysis ( - 16%). The confidence limits for Department of Medicine, Clinical Sciences Building, Leicester Royal Infirmary, PO Box 65, Leicester LE2 7LX, (ProfJ D Swales FRCP)
380
UK
this
latter figure (8-23%) overlap with the excess epidemiological risk (20-25%), so it is possible that both coronary risk and stroke risk are completely reversed by treatment of hypertension-ie, a treated patient assumes the epidemiological risk associated with the blood pressure level attained as a result of treatment. It would be premature to reach this conclusion for two reasons. First, although there is remarkable agreement among published trials on the impact of treatment on stroke, this is not the case with coronary heart disease. The largest randomised trial, carried out by the UK Medical Research Council" in patients aged 35-64 years, showed merely a 5 % difference between the treated and control groups. By contrast, trials in the elderly showed reductions of 8-27%. The only trial not carried out in the elderly to show a significant reduction was the HDFP z20%)." In that study there was a very high frequency of coronary heart disease when the clinical history criterion was used, and the trial design was unique in that the "control" group consisted of patients referred back after randomisation for usual care. Consequently, treatment probably differed in several respects in the two groups and this discrepancy may have had a more favourable impact on ischaemic heart disease. Since this trial contributed 43% of the coronary events in the 1990 meta-analysis and 31% in the 1993 meta-analysis, there may have been a systematic bias as a result of flawed design. A statistical test for heterogeneity was negative, but this measure is not very sensitive and important differences in design and outcome measures could have been overlooked. Despite such misgivings, the consistent trend in all the major trials for a reduction in coronary events, and the impressive significant impact in some trials, particularly in the elderly, allow us to conclude that treatment reduces the frequency of ischaemic heart disease. Nevertheless, the extent of that impact is uncertain and is likely to remain so for some years, and the observed effect may well be
heterogeneous, depending on patient groups studied (particularly in relation to age) and classes of drugs used (see below). Meta-analyses that pool disparate studies cannot help us to make such fine distinctions, but where findings are reasonably consistent, as for stroke, they provide robust overall conclusions. There are other reasons to be cautious before we apply the results of end-point trials to clinical practice. 3-5 years’ in
clinical trial may
lifetime’s cerebral experience. Although are it is more haemorrhage probably pressure related, difficult to envisage complete sustained reversibility of the risks attributed to atheroma as a result of lowering pressure, especially when atheromatous lesions may be established at the time of starting treatment. Impairment of prognosis which only becomes apparent after prolonged observation can be seen in patients with malignant hypertension, among whom a low-risk group can be defined with normal renal function on presentation. Treatment for the first 5 years restored life expectancy to normal in these patients but there was a decline subsequently (figure 1).’z treatment
a
some
reflect endpoints such not
a
as
Treatment of severe hypertension The graded nature of the risk associated with hypertension indicates that there is no natural dividing line between those who should be treated and those who should not. At one extreme lie patients with severe hypertension associated with advanced retinopathy (accelerated or malignant hypertension). Medical treatment has transformed the prognosis of such patients (figure 1), most of whom die within a year if left untreated. The presence of hypertensive haemorrhages, cotton wool spots, or papilloedema is therefore an indication for immediate treatment. However, this does not mean acute blood pressure lowering, for example with intravenous diazoxide, which has caused cerebral infarction in some patients.13 Cerebral infarction has been observed even when blood pressure is reduced only to normal levels, and seems to be caused by upregulation in hypertensive patients of the autoregulatory range of pressures over which cerebral blood flow is held constant despite changes in systemic pressure. Such upregulation is protective when systemic pressure is high, but there is an increased risk of cerebral ischaemia when pressure is lowered. Even buccal absorption of nifedipine from a broken capsule, which is often recommended for urgent reduction of blood pressure in malignant hypertension, has caused cerebral infarction.14 In the absence of complications such as hypertensive left ventricular failure or encephalopathy, there is no justification for rapid blood pressure lowering. Oral regimens should be used that are not qualitatively different from those recommended for non-malignant hypertension, although treatment should be initiated during a few days of rest to avoid the acute spikes of blood pressure associated with everyday activity.
Mild to moderate
hypertension
has been castigated, the grounds that even modest increases in blood pressure produce a several-fold increase in relative risk and make a major contribution to population morbidity and mortality.15 This is a powerful argument in discussions of population preventive measures but it is not persuasive in the treatment of individual patients in whom absolute risk is the primary consideration. Thus, in the MRC trial of treatment in mild hypertension, although there was a highly significant reduction in the incidence of stroke, this benefit amounted to one stroke in 850 patient-years of treatment." There are important socioeconomic implications in these findings, Endpoint trials have shown significant benefit in patients whose recruitment diastolic blood pressure exceeds 90 mm Hg. Because blood pressures are distributed in a unimodal fashion, there is an exponential increase in patients eligible for treatment as the threshold is lowered. In the screening programme for the HDFP, for example, although 8-4% of the population had a diastolic blood pressure 100 mm Hg, 25-3% had a diastolic blood pressure 90 mm Hg. More than 20% of adults in some populations are already receiving antihypertensive drugs, and in some elderly groups this figure exceeds 50%.16 The individual benefits associated with lowering the threshold for drug treatment are again illustrated in the MRC study." Whilst 333 patients with an entry blood pressure in the 105-109 range require treatment for 1 year to prevent one stroke, the figure rises to 666 patients with a blood pressure of 100 mm Hg or more, and to 2000 for those with a diastolic blood pressure
The
"mild"
hypertension particularly by epidemiologists, on term
Time (yr)
Figure 1: Survival curve for 100 patients with accelerated (malignant) hypertension Patients were divided into those who had impaired renal function on presentation (IRF) and those who had normal renal function (NRF) as determined by serum creatinine. Normal life-expectancy is shown for comparison (EXP). (From reference 12, with permission.)
of 95 or more. In older patients the returns are much higher. In the European Working Party on Hypertension in the Elderly (EWPHE trial), recruitment age was 60 or more.17 Only 142 patients required 1 year of treatment to prevent a stroke. The different weighting attached to such considerations is reflected in different threshold levels of blood pressure recommended for drug treatment by various specialist bodies. Thus the British Hypertension Society18 guidelines recommend a diastolic threshold of 100 mm Hg whereas the US Joint-National Committee19 recommends a diastolic blood pressure of 90 mm Hg, with the proviso that "some physicians may electively withhold antihypertensive therapy from patients with a diastolic blood pressure in the 90-94 mm Hg range". The WHO/International Society of Hypertension 20 guidelines adopt an intermediate diastolic blood pressure of 95 mm Hg.
Defining the high-risk patient absolute standards for identification of high-risk patients, other than to define the point below which treatment would produce net harm as a result of adverse drug effects outweighing benefit. Moreover, there are no trial data to indicate where this point occurs, but it is clearly influenced by age, sex, and the presence of other cardiovascular risk-factors. The most rational approach was adopted in the New Zealand guidelines, which use as a starting point a value judgment about absolute risk.21 The decision was that an absolute risk of cardiovascular disease of 20% over 10 years was significant and justified treatment. Even so, use of this criterion led to a rather high blood pressure threshold for younger hypertensive patients. Accordingly, a threshold value of 170/100 mm Hg was recommended for individuals aged 40-60 years, although the 10-year cardiovascular risk in this group was below 20%. There
are
no
381
In terms of cost-effectiveness, the New Zealand approach has much to commend it. The disadvantage is the complexity of the risk stratification on which it is based and the consequent need to consult a table of relevant risks before the indications for drug treatment can be determined for an individual. No other guidelines attempt the rigorous definition of risk essayed by the New Zealand group. All guidelines implicitly if not explicitly recognise the need to focus treatment on individuals at higher absolute risk to avoid the necessity of treating large populations for small benefit.’ The precise definition of "higher risk" is left open, although it clearly reflects the putative benefits set against the social costs of treating large populations, which in turn reflect differences in health care systems and divergent expectations. However, high risk is identified in all guidelines by the sustained height of blood pressure and the presence of other risk factors such as diabetes, hyperlipidaemia, smoking, left ventricular hypertrophy, and established target-organ damage.
Value of repeated
measures
There is a broad consensus that blood pressure should be measured repeatedly in patients with mild hypertension before drug treatment is initiated. Repeated measures should give a better indication of the "usual" pressure, which correlates more strongly with risk than do "casual" values.22 Most guidelines recommend 3-6 months of observations in patients with the mildest degrees of hypertension; the period of observation is curtailed in patients with higher pressures. Regression to the mean and habituation to pressure measurement usually produce a fall in recorded pressures, thereby reducing the number of patients meeting any arbitrary criterion for drug treatment. Although this advice is widely accepted it is not entirely rational. The evidence of benefit is derived from endpoint trials with considerably shorter run-in periods than those recommended. In the MRC trial," for example, the two screening blood pressures (measured by nurses) were 1-4 weeks apart. Blood pressure at entry was slightly higher (measured by a doctor), but fell over the next 10 weeks, even in the placebo group. Thus steady-state blood pressures after 3-6 months of observation may reflect a more severe degree of hypertension than the same entry blood pressures in clinical trials. The conditions of measurement and even who measures the blood pressure may likewise be
important. Ambulatory and home blood pressure monitoring theoretically offer more precise targeting of patients with sustained hypertension. However, there are no trial data to guide us on the key question-ie, which blood pressure measured by these techniques should be the threshhold for drug treatment? The main role of these methods is in the detection of "white-coat hypertension"-ie, artificially raised blood pressures, measured usually by a doctor. Ambulatory blood pressures probably correlate better with cardiovascular risk 23 and with surrogate measures of target-organ damage such as left ventricular hypertrophy ;24 when they are not significantly increased there is little justification for drug treatment. The presence of other cardiovascular risk factors defines patients who are at especially high risk as a result of multiplicative interaction with blood pressure. It is reasonable to anticipate greater absolute benefit in such patients, even when the threshold for drug treatment is 382
reduced by 5-10 mm Hg. Most guidelines suggest this. Alderman25 has gone further by pointing to the potential value of blood pressure lowering in normotensive subjects at high cardiovascular risk, but there are no endpoint trials to confirm this view. Although most efforts should be directed towards reversal of risk factors (eg, smoking and hyperlipidaemia), blood pressure control assumes greater importance in mild and borderline hypertensives at high cardiovascular risk. Elderly individuals especially are at increased risk, even in the absence of hypertension.
Systolic hypertension Most of the endpoint trials have used the diastolic criterion for recruitment, but systolic blood pressure, especially in the elderly, is closely associated with cardiovascular risk.26 There are several reasons for this paradox. Historically, diastolic blood pressure attracted the greatest attention before full epidemiological data were available. Second, since raised systolic blood pressure was perceived to be due to loss of elastic compliance in the aorta and large arteries, increases in this measure might simply be serving as a marker of established damage. Third, and perhaps most persuasively, systolic hypertension is more difficult to treat since substantial lowering of systolic pressure in a patient with isolated systolic hypertension may produce diastolic hypotension. However, the SHEP triall° produced striking evidence in favour of treating isolated systolic hypertension (systolic > 160 mm Hg, diastolic < 90 mm Hg). Despite mean systolic pressures that were only 111 1 mm Hg lower, there were 36% fewer strokes and 27% fewer myocardial infarctions in the treated group. Although the SHEP trial was confined to elderly patients, the epidemiological risks are shared by younger individuals. As a result, there is now a consensus that systolic blood pressures over 160 mm Hg should be treated, and most guidelines suggest treatment at lower levels, especially in younger patients.
Target blood pressure Observational studies indicate that the relation between blood pressure and cardiovascular risk is linear-ie, the lowest blood pressures carry the lowest risk. Logically, therefore, the lower the blood pressure attained with treatment the better. This view is further supported by reports from blood pressure clinics, which have shown less than anticipated reductions in cardiovascular mortality associated with suboptimal blood pressure control .27,11 Nevertheless, a retrospective clinic study of 902 treated hypertensive patients described a J-shaped relation between myocardial infarction and attained diastolic blood pressure in patients with pre-existing ischaemic heart disease.29 Infarctions were at their lowest in patients whose treated blood pressure was 85-90 mm Hg and were significantly higher when the blood pressure was below this range. Whilst a similar phenomenon has been observed in prospective clinical trials,3° it has also been reported in the placebo group;this observation suggests that a low diastolic pressure may be a marker for more severe disease in patients with pre-existing ischaemic heart disease. This notion is further supported by an association between low attained blood pressures and greater loss in weight and lower haemoglobin concentrations in the EWPHE trial .31 Treatment with one particular antihypertensive class of drug-ie, beta-blockade in normotensive subjects after myocardial infarction-is likewise associated with a highly significant reduction in mortality.33 Retrospective
Figure 2: British Hypertension Society guidelines for drug treatment of hypertension Taken from reference 18, with permission.
* = repeated
measurements.
subgroup analysis is very prone to error. The Hypertension Optimal Treatment Trial, which randomises patients to different target blood pressures, may provide more guidance when the results become available in 1995/1996. Meanwhile, for patients with ischaemic heart disease, target pressures of 80-90 mm Hg are a reasonable compromise. Systolic blood pressure control is likely to be limited by constraints on efficacy and by diastolic hypotension, although pressures of 140 mm Hg or below are ideal. In the SHEP trials the mean attained pressure was 144 mm Hg compared with a pressure of 155-1mm Hg in the placebo group at the end of the trial.
Selection of therapy The most widely adopted approach is to begin treatment with a single drug. If control is inadequate, the dose is increased (unless there is a flat blood pressure doseresponse curve, as with diuretics) and other classes of drug are added (combination therapy). Some combinations have well-documented additive effects-ie, diuretic and angiotensin converting enzyme (ACE) inhibitor, diuretic and beta-blocker, calcium antagonist and beta-blocker, ACE inhibitor and calcium antagonist. The endpoint trials that have unequivocally shown benefit necessarily used the established therapy at the time they were designed. Newer classes of agent (calcium antagonists, ACE inhibitors, and alpha-antagonists) have not therefore been tested and relevant data are not likely to be available for several years. Since (at least over the trial period), hypertension-attributable stroke risk was totally reversed, one could argue that newer agents have no benefits in this context. How far coronary risk is reduced by the older agents is debatable, and depends on the trials included in the meta-analysis. Some researchers have argued that diuretics and beta-blockers have specific disadvantages in the form of adverse metabolic effects and that the newer classes of drugs have advantages in their
impact on atheroma. I tend to find these arguments simplistic in the absence of endpoint trial evidence.35 Atheroma
a multifactorial condition in which influences are as important as metabolic effects. The fact that population-based epidemiological risk factor analysis cannot include haemodynamic variables does not mean that these are unimportant. Prediction of the impact of a drug on cardiovascular events on the basis of an observational association between lipids and events in untreated populations is not especially convincing. The metabolic argument has also lost some of its strength with the finding that low-dose thiazide diuretics (eg, bendrofluazide 2-5 mg/day) have very few metabolic effects, although blood pressure lowering efficacy is
is
haemodynamic
preserved.36 Various groups of patients may respond differently to drugs. Thus diuretics produced a more favourable coronary outcome in the MRC trial of treatment in the elderly,9 and the SHEP trial,lO which used chlorthalidone as first-line treatment, showed a substantial reduction in non-fatal myocardial infarction in elderly patients with systolic hypertension. Attempts to show primary cardioprotection from beta-blockade in younger hypertensives have not been successful. Direct prospective comparisons of betablockers with other treatments have proved "negative" on three occasions-the MRC trial in mild hypertension" and the HAPPHY37 and IPPPSH trials.38 A possible difficulty is that many patients require combination treatment, which may dilute the effect of single drugs and consequently reduce the power of a trial. Duration may also be too short to reveal differential effects. When the metoprolol arm of the HAPPHY trial was continued as the MAPHY study,39 there was a significantly lower mortality from myocardial infarction in the metroprolol group. In addition, later subgroup analysis of the MRC trial in mild hypertension" showed significantly greater reduction in total myocardial infarctions (ie, including silent infarction diagnosed 383
electrocardiographically) in the propranolol-treated group. Neither of these pieces of evidence is as conclusive as an adequately designed prospective study but, in the absence of other data, beta-blockade seems to be preferable as first-line therapy in younger patients and low-dose diuretics in older patients. Beta-blockers should of course be regarded as the first choice in patients who have sustained a myocardial infarction and have no evidence of cardiac failure. On these grounds, the newer classes of drug would be reserved for patients in whom first-line therapy with diuretics or beta-blockers is either contraindicated or ineffective. Thus, beta-blockers and ACE inhibitors are less effective in Afro-Caribbean blacks. Additionally, there are more specific indications for the newer agents. ACE inhibitors extend life and decrease the myocardial infarction rate in patients with left ventricular dysfunction.4° These drugs have also been shown to reduce proteinuria and slow the rate of decline in glomerular filtration rate in diabetic hypertensives, although the specificity of this observation is uncertain.41 The role of the newer classes of antihypertensive drug is one of the most controversial topics in the whole area of hypertension. Two national expert groups have changed their advice in successive reports, despite the absence of substantial further relevant evidence.’ The economic consequences of therapeutic recommendations are considerable. There is at least a 50-fold difference in price between low-dose diuretics and the newer drugs. For therapy that may be given lifelong to more than one fifth of the adult population, the potential burden on health care systems is immense. Several cost-benefit analyses have been carried out,42-44 but these depend critically on assumptions about specific impact of drugs on coronary heart disease, for which there are no convincing data either way. Another approach is to take the most optimistic assumption-ie, that the newer drugs completely reverse hypertension-attributable coronary heart disease whereas older agents reduce the risk only by the proportion shown in meta-analyses. The difference (about 10% of myocardial infarction) would then represent the incremental benefit obtained by using the newer agents. At best, this is an order-of-magnitude calculation. However, on the basis of the MRC trial experience," the reduction would represent one coronary event (fatal and non-fatal) per 2000 patientyears. This result would be achieved at a cost of about ,240 000 ($360 000) per event. This calculation, of course, is based on the assumption that a longer period of treatment does not widen the differential between different classes of agents and that the newer agents have no specific action on non-hypertension-related ischaemic heart disease. However, the effects would have to be substantial to reduce this figure to more manageable levels.
Overview Most unselected patients seen by clinicians will have mild to moderate hypertension on first presentation-ie, diastolic pressure 90-109 mm Hg and systolic pressure 140-179 mm Hg, classified by the Joint National Committee as stage 1 and stage 2.19 Drug treatment should not be initiated until after a period of observation, extending to 3-6 months (figure 2). The higher the average pressure the shorter the period of observation, which should be terminated if there is advanced retinopathy. The interval should be used to encourage non-pharmacological
384
therapy and to assess other cardiovascular risk factors such as the presence of smoking, serum lipids, blood glucose, left ventricular hypertrophy, and established cardiovascular disease. The only sensitive and widely available measure of left ventricular hypertrophy is echocardiography, and cost currently limits its use. Where access is restricted, a reasonable compromise is to do echocardiography when there is suspicion, on clinical or electrocardiographic grounds, of left ventricular hypertrophy, or when clinic blood pressures are thought to be artificially high and ambulatory blood pressure monitoring is unavailable. If there is doubt about the use of drug treatment the presence of left ventricular hypertrophy is a strong indication to proceed. It is important to assess other risk factors for two reasons: (a) they may require treatment in their own right, and (b) the presence of additional risk factors lowers the threshold blood pressures for which drug treatment has to be initiated. Sustained blood pressures above the agreed threshold at the end of the period of observation require drug therapy. Diuretics or beta-blockers should remain first-line agents unless they are contraindicated on pharmacological grounds or unless there is an indication for the use of a specific class of drug-eg, ACE inhibitors in patients with left ventricular dysfunction.
References 1 2
3
4
5
6
7
8
Swales JD. Guidelines on guidelines. J Hypertens 1993; 11: 899-903. MacMahon SW, Cutler JA, Furberg CD, Payne GH. The effects of drug treatment for hypertension on morbidity and mortality and cardiovascular disease: a review of randomised control trials. Prog Cardiovasc Dis 1986; 39 (suppl 1): 99-118. Collins R, Peto R, MacMahon S, et al. Blood pressure, stroke, and coronary heart disease. Part 2, short-term reductions in blood pressure: overview of randomised drug trials in their epidemiological context. Lancet 1990; 335: 827-38. Antman EM, Lau J, Kupelnick B, Mosteller F, Chalmers TC. A comparison of results of meta-analyses of randomized control trials and recommendations of clinical experts. JAMA 1992; 268: 240-48. Multiple Risk Factor Intervention Trial Research Group. Multiple Risk Factor Intervention Trial: risk factor changes and mortality results. JAMA 1982; 248: 1465-77. Hypertension Detection and Follow-up Program Cooperative Group. Five year findings of the Hypertension Detection and Follow-up Program, 5: effects of stepped care treatment on the incidence of myocardial infarction and angina pectoris. Hypertension 1984; 6 (suppl I): I198-206. Collins R, Peto R. Anti-hypertensive therapy: effects on stroke and coronary heart disease. In: Swales JD, ed. Textbook of hypertension. Oxford: Blackwell Scientific, 1994: 1156-64. Dahlof B, Lindholm LH, Hansson L, Schersten B, Ekbom T, Wester PO. Morbidity and mortality in the Swedish Trial in Old Patients with Hypertension (STOP-Hypertension). Lancet 1991; 338:
1281-85. Medical Research Council Working Party. MRC trial of treatment of hypertension in older adults: principal results. BMJ 1992; 304: 405-12. 10 SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. JAMA 1991; 265: 255-64. 11 Miall WE, Greenberg G. Mild hypertension: is there a pressure to treat? Cambridge: Cambridge University Press, 1987. 12 Bing RF, Heagerty AM, Russell GI, Swales JD, Thurston H. Prognosis in malignant hypertension. J Hypertens 1986; 4 (suppl 6): s42-44. 13 Ledingham JGG, Rajagopalan B. Cerebral complications in the treatment of accelerated hypertension. Q J Med 1979; 48: 25-41. 14 Kennedy M. Risk versus benefits in cardiovascular therapy. Adverse Drug Reaction Bull 1992; 156: 587-90. 15 Stamler J, Keaton JD, Wentworth DN. Blood pressure (systolic and diastolic) and risk of fatal coronary heart disease. Hypertension 1989; 13 (suppl I): I2-12. 16 Coroni-Huntley J, La Croix AZ, Havlik KJ. Race and sex differentials in the impact of hypertension in the United States: the National Health and Nutrition Examination I. Epidemiologic follow-up study. Arch Intern Med 1989; 149: 780-88.
9
Amery A, Birkenhäger W, Brixko P, et al. Mortality and morbidity results from the European Working Party on High Blood Pressure in the Elderly Trial. Lancet 1985; i: 1349-54. 18 Sever P, Beevers G, Bulpitt C, et al. Management guidelines in essential hypertension: report of the Second Working Party of the British Hypertension Society. BMJ 1993; 306: 983-87. 19 Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure. The fifth report of the Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure (JNC-V). Arch Intern Med 1993; 153: 154-83. 20 Guidelines Sub-Committee of the WHO/ISH Mild Hypertension
point beyond which pressure reduction is dangerous? JAMA 1991;
17
Liaison Committee. 1993 Guidelines for the management of mild
hypertension: memorandum from a World Health Organisation/ International Society of Hypertension meeting. J Hypertens 1993;
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905-18. 21
Jackson R, Barham P, Bills J, et al. Management of raised blood pressure in New Zealand: a discussion document. BMJ 1993; 307:
107-10. 22 MacMahon S, Peto R, Cutler J, et al. Blood pressure, stroke, and coronary heart disease. Part 1, prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet 1990; 335: 765-74. 23 White WB, Schulman P, McCabe EJ, Dey HM. Average daily blood pressure, not office blood pressure, determines cardiac function in patients with hypertension. JAMA 1989; 261: 873-77. 24 Manciá G. Ambulatory blood pressure monitoring: research and clinical applications. J Hypertens 1990; 8 (suppl 7): s1-13. 25 Alderman MH. Blood pressure management: individualised treatment based on absolute risk and the potential for benefit. Ann Intern Med 1993; 119: 329-35. 26 Sagie A, Martin G, Larson SD, Levy D. The natural history of borderline isolated systolic hypertension. N Engl J Med 1993; 329: 1912-17.
27 Isles CG, Walker LM, Beevers DG, et al. Mortality in patients of the Glasgow Blood Pressure Clinic. J Hypertens 1986; 4: 141-56. 28 Lindholm L, Ejlertsson G, Schersten B. High risk of cerebrovascular morbidity in well-treated male hypertensives: a retrospective study of 40-59 year olds hypertensives in Swedish Primary Care District. Acta Med Scand 1984; 216: 251-59. 29 Cruickshank JM, Thorp JM, Zacharias FJ. Benefits and potential harm of lowering high blood pressure. Lancet 1987; i: 581-85. 30 Farnett K, Mulrow CD, Linn WD, Lucey CR, Tuley MR. The J-curve phenomenon and the treatment of hypertension. Is there a
265: 489-95. 31
Coope J, Warrender TS. Lowering blood pressure.
Lancet 1987; i:
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32 Staessen J, Bulpitt C, Clement D, et al. Relationship between mortality and treated blood pressure in elderly patients with hypertension: report of the European Working Party on High Blood Pressure in the Elderly. BMJ 1989; 298: 1552-56. 33 Yusuf S, Peto R, Lewis J. Beta blockade during and after myocardial infarction: an overview of randomised trials. Prog Cardiovasc Dis 1985; 27: 335-71. 34 The HOT Study Group. The Hypertension Optimal Treatment (HOT) Study: a prospective study of the optimal therapeutic goal and of the value of a low dose aspirin in anti-hypertensive treatment. Blood Pressure 1993; 2: 62-68. 35 Swales JD. Antihypertensive drugs and plasma lipids. Br Heart J 1991; 66: 409-10. 36 Carlsen JE, Kober L, Trop-Pedersen C, Johansen P. Relation between dose of bendrofluazide, antihypertensive effect and adverse biochemical effects. BMJ 1990; 300: 975-78. 37 Wilhemsen L, Berglund G, Elmfeldt D, et al. Beta-blockers versus diuretics in hypertensive men: main results from the HAPPHY trial.
J Hypertens 1987; 300: 975-78. 38 The IPPPSH Collaborative Group. Cardiovascular risk and risk factors in a randomized trial of treatment based on the beta-blocker oxprenolol: the International Prospective Primary Prevention Study in Hypertension (IPPPSH). J Hypertens 1985; 3: 379-92. 39 Wikstrand J, Warnold I, Olsson G, Tuomilheto J, Elmfeldt D, Berglund G. Primary prevention with metoprolol in patients with hypertension. JAMA 1988; 259: 1976-82. 40 Yusuf S, Pepine C, Garces C, et al. Effect of enalapril on myocardial infarction and unstable angina in patients with low ejection fractions. Lancet 1992; 340: 1173-78. 41 Mogensen CE. Angiotensin converting enzyme inhibitors and diabetic nephropathy. BMJ 1992; 304: 327-28. 42 Weinstein MC, Stason WB. Allocation of resources to manage hypertension. N Engl J Med 1977; 296: 732-39. 43 Kawachi I, Malcolm LA. Cost effectiveness of treating mild-to-moderate hypertension: a re-appraisal. J Hypertens 1991; 9: 199-208. 44 Johannesson M, Fagerberg B. A health economic comparison of diet and drug treatment in obese men with mild hypertension. J Hypertens 1992; 10: 1063-70.
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Management of hypertension theoretically provides one of the best models for the definition of optimum treatment. Precise clinical assessment is straightforward, risk welldocumented in large observational studies, and benefits confirmed in extensive intervention trials. This plethora of information, whilst making the task of treatment easy at one level, has generated several unresolved questions and controversy. A partial solution to such problems is to obtain more information, largely from clinical trials. However, some of the debate centres on the need to create arbitrary dividing lines in gradients of risk and benefit, distinctions that can be based only on relative judgments of value and cost. Thus it is not surprising that, despite access to a common pool of data, published national and international guidelines differ considerably.1 Beneftts of treatment Reversal of risk produced by lowering blood
pressure has
been shown only for drug treatment. An initial metaanalysis of trials in 1986 concluded that the risk of fatal and non-fatal stroke attributable to raised blood pressure was completely reversed by antihypertensive therapy,2 whereas the impact on coronary heart disease (a reduction of 8%) was not significant. A later meta-analysis in 1990 confirmed the reversal of stroke risk but also recorded a significant reduction in coronary heart disease (— 14%), although this figure fell somewhat short of the impact that would have been predicted if the attributable risk had been completely reversed (20-25%). The evolution of non-significant trends to significant effects is commonly seen in cumulative meta-analyses as additional trials are published.4 However, the 1990 meta-analysis included only one additional trial that had been reported in the interim, together with three older small trials, none of which contributed significantly to the change in benefit reported. The greater reduction in coronary events was due to the omission of one multifactorial trial (MRFIT) in which treated patients had a marginally increased overall infarction rate5 and the inclusion of more data from one large trial, the Hypertension Detection and Follow-up Program In the 1986 meta-analysis, (HDFP).6 only documented myocardial electrocardiographically infarctions were included; in 1990, the broader criterion of clinical history was used. A more recent meta-analysis7 included data from three subsequently reported trials in elderly patients-the STOP-Hypertension trial,8 the MRC trial in the elderly,9 and the Systolic Hypertension in the Elderly Program (SHEP).lO Again, the risk of stroke attributable to hypertension was reversed (—38%). The reduction in coronary events was larger and more significant than in the previous meta-analysis ( - 16%). The confidence limits for Department of Medicine, Clinical Sciences Building, Leicester Royal Infirmary, PO Box 65, Leicester LE2 7LX, (ProfJ D Swales FRCP)
380
UK
this
latter figure (8-23%) overlap with the excess epidemiological risk (20-25%), so it is possible that both coronary risk and stroke risk are completely reversed by treatment of hypertension-ie, a treated patient assumes the epidemiological risk associated with the blood pressure level attained as a result of treatment. It would be premature to reach this conclusion for two reasons. First, although there is remarkable agreement among published trials on the impact of treatment on stroke, this is not the case with coronary heart disease. The largest randomised trial, carried out by the UK Medical Research Council" in patients aged 35-64 years, showed merely a 5 % difference between the treated and control groups. By contrast, trials in the elderly showed reductions of 8-27%. The only trial not carried out in the elderly to show a significant reduction was the HDFP z20%)." In that study there was a very high frequency of coronary heart disease when the clinical history criterion was used, and the trial design was unique in that the "control" group consisted of patients referred back after randomisation for usual care. Consequently, treatment probably differed in several respects in the two groups and this discrepancy may have had a more favourable impact on ischaemic heart disease. Since this trial contributed 43% of the coronary events in the 1990 meta-analysis and 31% in the 1993 meta-analysis, there may have been a systematic bias as a result of flawed design. A statistical test for heterogeneity was negative, but this measure is not very sensitive and important differences in design and outcome measures could have been overlooked. Despite such misgivings, the consistent trend in all the major trials for a reduction in coronary events, and the impressive significant impact in some trials, particularly in the elderly, allow us to conclude that treatment reduces the frequency of ischaemic heart disease. Nevertheless, the extent of that impact is uncertain and is likely to remain so for some years, and the observed effect may well be
heterogeneous, depending on patient groups studied (particularly in relation to age) and classes of drugs used (see below). Meta-analyses that pool disparate studies cannot help us to make such fine distinctions, but where findings are reasonably consistent, as for stroke, they provide robust overall conclusions. There are other reasons to be cautious before we apply the results of end-point trials to clinical practice. 3-5 years’ in
clinical trial may
lifetime’s cerebral experience. Although are it is more haemorrhage probably pressure related, difficult to envisage complete sustained reversibility of the risks attributed to atheroma as a result of lowering pressure, especially when atheromatous lesions may be established at the time of starting treatment. Impairment of prognosis which only becomes apparent after prolonged observation can be seen in patients with malignant hypertension, among whom a low-risk group can be defined with normal renal function on presentation. Treatment for the first 5 years restored life expectancy to normal in these patients but there was a decline subsequently (figure 1).’z treatment
a
some
reflect endpoints such not
a
as
Treatment of severe hypertension The graded nature of the risk associated with hypertension indicates that there is no natural dividing line between those who should be treated and those who should not. At one extreme lie patients with severe hypertension associated with advanced retinopathy (accelerated or malignant hypertension). Medical treatment has transformed the prognosis of such patients (figure 1), most of whom die within a year if left untreated. The presence of hypertensive haemorrhages, cotton wool spots, or papilloedema is therefore an indication for immediate treatment. However, this does not mean acute blood pressure lowering, for example with intravenous diazoxide, which has caused cerebral infarction in some patients.13 Cerebral infarction has been observed even when blood pressure is reduced only to normal levels, and seems to be caused by upregulation in hypertensive patients of the autoregulatory range of pressures over which cerebral blood flow is held constant despite changes in systemic pressure. Such upregulation is protective when systemic pressure is high, but there is an increased risk of cerebral ischaemia when pressure is lowered. Even buccal absorption of nifedipine from a broken capsule, which is often recommended for urgent reduction of blood pressure in malignant hypertension, has caused cerebral infarction.14 In the absence of complications such as hypertensive left ventricular failure or encephalopathy, there is no justification for rapid blood pressure lowering. Oral regimens should be used that are not qualitatively different from those recommended for non-malignant hypertension, although treatment should be initiated during a few days of rest to avoid the acute spikes of blood pressure associated with everyday activity.
Mild to moderate
hypertension
has been castigated, the grounds that even modest increases in blood pressure produce a several-fold increase in relative risk and make a major contribution to population morbidity and mortality.15 This is a powerful argument in discussions of population preventive measures but it is not persuasive in the treatment of individual patients in whom absolute risk is the primary consideration. Thus, in the MRC trial of treatment in mild hypertension, although there was a highly significant reduction in the incidence of stroke, this benefit amounted to one stroke in 850 patient-years of treatment." There are important socioeconomic implications in these findings, Endpoint trials have shown significant benefit in patients whose recruitment diastolic blood pressure exceeds 90 mm Hg. Because blood pressures are distributed in a unimodal fashion, there is an exponential increase in patients eligible for treatment as the threshold is lowered. In the screening programme for the HDFP, for example, although 8-4% of the population had a diastolic blood pressure 100 mm Hg, 25-3% had a diastolic blood pressure 90 mm Hg. More than 20% of adults in some populations are already receiving antihypertensive drugs, and in some elderly groups this figure exceeds 50%.16 The individual benefits associated with lowering the threshold for drug treatment are again illustrated in the MRC study." Whilst 333 patients with an entry blood pressure in the 105-109 range require treatment for 1 year to prevent one stroke, the figure rises to 666 patients with a blood pressure of 100 mm Hg or more, and to 2000 for those with a diastolic blood pressure
The
"mild"
hypertension particularly by epidemiologists, on term
Time (yr)
Figure 1: Survival curve for 100 patients with accelerated (malignant) hypertension Patients were divided into those who had impaired renal function on presentation (IRF) and those who had normal renal function (NRF) as determined by serum creatinine. Normal life-expectancy is shown for comparison (EXP). (From reference 12, with permission.)
of 95 or more. In older patients the returns are much higher. In the European Working Party on Hypertension in the Elderly (EWPHE trial), recruitment age was 60 or more.17 Only 142 patients required 1 year of treatment to prevent a stroke. The different weighting attached to such considerations is reflected in different threshold levels of blood pressure recommended for drug treatment by various specialist bodies. Thus the British Hypertension Society18 guidelines recommend a diastolic threshold of 100 mm Hg whereas the US Joint-National Committee19 recommends a diastolic blood pressure of 90 mm Hg, with the proviso that "some physicians may electively withhold antihypertensive therapy from patients with a diastolic blood pressure in the 90-94 mm Hg range". The WHO/International Society of Hypertension 20 guidelines adopt an intermediate diastolic blood pressure of 95 mm Hg.
Defining the high-risk patient absolute standards for identification of high-risk patients, other than to define the point below which treatment would produce net harm as a result of adverse drug effects outweighing benefit. Moreover, there are no trial data to indicate where this point occurs, but it is clearly influenced by age, sex, and the presence of other cardiovascular risk-factors. The most rational approach was adopted in the New Zealand guidelines, which use as a starting point a value judgment about absolute risk.21 The decision was that an absolute risk of cardiovascular disease of 20% over 10 years was significant and justified treatment. Even so, use of this criterion led to a rather high blood pressure threshold for younger hypertensive patients. Accordingly, a threshold value of 170/100 mm Hg was recommended for individuals aged 40-60 years, although the 10-year cardiovascular risk in this group was below 20%. There
are
no
381
In terms of cost-effectiveness, the New Zealand approach has much to commend it. The disadvantage is the complexity of the risk stratification on which it is based and the consequent need to consult a table of relevant risks before the indications for drug treatment can be determined for an individual. No other guidelines attempt the rigorous definition of risk essayed by the New Zealand group. All guidelines implicitly if not explicitly recognise the need to focus treatment on individuals at higher absolute risk to avoid the necessity of treating large populations for small benefit.’ The precise definition of "higher risk" is left open, although it clearly reflects the putative benefits set against the social costs of treating large populations, which in turn reflect differences in health care systems and divergent expectations. However, high risk is identified in all guidelines by the sustained height of blood pressure and the presence of other risk factors such as diabetes, hyperlipidaemia, smoking, left ventricular hypertrophy, and established target-organ damage.
Value of repeated
measures
There is a broad consensus that blood pressure should be measured repeatedly in patients with mild hypertension before drug treatment is initiated. Repeated measures should give a better indication of the "usual" pressure, which correlates more strongly with risk than do "casual" values.22 Most guidelines recommend 3-6 months of observations in patients with the mildest degrees of hypertension; the period of observation is curtailed in patients with higher pressures. Regression to the mean and habituation to pressure measurement usually produce a fall in recorded pressures, thereby reducing the number of patients meeting any arbitrary criterion for drug treatment. Although this advice is widely accepted it is not entirely rational. The evidence of benefit is derived from endpoint trials with considerably shorter run-in periods than those recommended. In the MRC trial," for example, the two screening blood pressures (measured by nurses) were 1-4 weeks apart. Blood pressure at entry was slightly higher (measured by a doctor), but fell over the next 10 weeks, even in the placebo group. Thus steady-state blood pressures after 3-6 months of observation may reflect a more severe degree of hypertension than the same entry blood pressures in clinical trials. The conditions of measurement and even who measures the blood pressure may likewise be
important. Ambulatory and home blood pressure monitoring theoretically offer more precise targeting of patients with sustained hypertension. However, there are no trial data to guide us on the key question-ie, which blood pressure measured by these techniques should be the threshhold for drug treatment? The main role of these methods is in the detection of "white-coat hypertension"-ie, artificially raised blood pressures, measured usually by a doctor. Ambulatory blood pressures probably correlate better with cardiovascular risk 23 and with surrogate measures of target-organ damage such as left ventricular hypertrophy ;24 when they are not significantly increased there is little justification for drug treatment. The presence of other cardiovascular risk factors defines patients who are at especially high risk as a result of multiplicative interaction with blood pressure. It is reasonable to anticipate greater absolute benefit in such patients, even when the threshold for drug treatment is 382
reduced by 5-10 mm Hg. Most guidelines suggest this. Alderman25 has gone further by pointing to the potential value of blood pressure lowering in normotensive subjects at high cardiovascular risk, but there are no endpoint trials to confirm this view. Although most efforts should be directed towards reversal of risk factors (eg, smoking and hyperlipidaemia), blood pressure control assumes greater importance in mild and borderline hypertensives at high cardiovascular risk. Elderly individuals especially are at increased risk, even in the absence of hypertension.
Systolic hypertension Most of the endpoint trials have used the diastolic criterion for recruitment, but systolic blood pressure, especially in the elderly, is closely associated with cardiovascular risk.26 There are several reasons for this paradox. Historically, diastolic blood pressure attracted the greatest attention before full epidemiological data were available. Second, since raised systolic blood pressure was perceived to be due to loss of elastic compliance in the aorta and large arteries, increases in this measure might simply be serving as a marker of established damage. Third, and perhaps most persuasively, systolic hypertension is more difficult to treat since substantial lowering of systolic pressure in a patient with isolated systolic hypertension may produce diastolic hypotension. However, the SHEP triall° produced striking evidence in favour of treating isolated systolic hypertension (systolic > 160 mm Hg, diastolic < 90 mm Hg). Despite mean systolic pressures that were only 111 1 mm Hg lower, there were 36% fewer strokes and 27% fewer myocardial infarctions in the treated group. Although the SHEP trial was confined to elderly patients, the epidemiological risks are shared by younger individuals. As a result, there is now a consensus that systolic blood pressures over 160 mm Hg should be treated, and most guidelines suggest treatment at lower levels, especially in younger patients.
Target blood pressure Observational studies indicate that the relation between blood pressure and cardiovascular risk is linear-ie, the lowest blood pressures carry the lowest risk. Logically, therefore, the lower the blood pressure attained with treatment the better. This view is further supported by reports from blood pressure clinics, which have shown less than anticipated reductions in cardiovascular mortality associated with suboptimal blood pressure control .27,11 Nevertheless, a retrospective clinic study of 902 treated hypertensive patients described a J-shaped relation between myocardial infarction and attained diastolic blood pressure in patients with pre-existing ischaemic heart disease.29 Infarctions were at their lowest in patients whose treated blood pressure was 85-90 mm Hg and were significantly higher when the blood pressure was below this range. Whilst a similar phenomenon has been observed in prospective clinical trials,3° it has also been reported in the placebo group;this observation suggests that a low diastolic pressure may be a marker for more severe disease in patients with pre-existing ischaemic heart disease. This notion is further supported by an association between low attained blood pressures and greater loss in weight and lower haemoglobin concentrations in the EWPHE trial .31 Treatment with one particular antihypertensive class of drug-ie, beta-blockade in normotensive subjects after myocardial infarction-is likewise associated with a highly significant reduction in mortality.33 Retrospective
Figure 2: British Hypertension Society guidelines for drug treatment of hypertension Taken from reference 18, with permission.
* = repeated
measurements.
subgroup analysis is very prone to error. The Hypertension Optimal Treatment Trial, which randomises patients to different target blood pressures, may provide more guidance when the results become available in 1995/1996. Meanwhile, for patients with ischaemic heart disease, target pressures of 80-90 mm Hg are a reasonable compromise. Systolic blood pressure control is likely to be limited by constraints on efficacy and by diastolic hypotension, although pressures of 140 mm Hg or below are ideal. In the SHEP trials the mean attained pressure was 144 mm Hg compared with a pressure of 155-1mm Hg in the placebo group at the end of the trial.
Selection of therapy The most widely adopted approach is to begin treatment with a single drug. If control is inadequate, the dose is increased (unless there is a flat blood pressure doseresponse curve, as with diuretics) and other classes of drug are added (combination therapy). Some combinations have well-documented additive effects-ie, diuretic and angiotensin converting enzyme (ACE) inhibitor, diuretic and beta-blocker, calcium antagonist and beta-blocker, ACE inhibitor and calcium antagonist. The endpoint trials that have unequivocally shown benefit necessarily used the established therapy at the time they were designed. Newer classes of agent (calcium antagonists, ACE inhibitors, and alpha-antagonists) have not therefore been tested and relevant data are not likely to be available for several years. Since (at least over the trial period), hypertension-attributable stroke risk was totally reversed, one could argue that newer agents have no benefits in this context. How far coronary risk is reduced by the older agents is debatable, and depends on the trials included in the meta-analysis. Some researchers have argued that diuretics and beta-blockers have specific disadvantages in the form of adverse metabolic effects and that the newer classes of drugs have advantages in their
impact on atheroma. I tend to find these arguments simplistic in the absence of endpoint trial evidence.35 Atheroma
a multifactorial condition in which influences are as important as metabolic effects. The fact that population-based epidemiological risk factor analysis cannot include haemodynamic variables does not mean that these are unimportant. Prediction of the impact of a drug on cardiovascular events on the basis of an observational association between lipids and events in untreated populations is not especially convincing. The metabolic argument has also lost some of its strength with the finding that low-dose thiazide diuretics (eg, bendrofluazide 2-5 mg/day) have very few metabolic effects, although blood pressure lowering efficacy is
is
haemodynamic
preserved.36 Various groups of patients may respond differently to drugs. Thus diuretics produced a more favourable coronary outcome in the MRC trial of treatment in the elderly,9 and the SHEP trial,lO which used chlorthalidone as first-line treatment, showed a substantial reduction in non-fatal myocardial infarction in elderly patients with systolic hypertension. Attempts to show primary cardioprotection from beta-blockade in younger hypertensives have not been successful. Direct prospective comparisons of betablockers with other treatments have proved "negative" on three occasions-the MRC trial in mild hypertension" and the HAPPHY37 and IPPPSH trials.38 A possible difficulty is that many patients require combination treatment, which may dilute the effect of single drugs and consequently reduce the power of a trial. Duration may also be too short to reveal differential effects. When the metoprolol arm of the HAPPHY trial was continued as the MAPHY study,39 there was a significantly lower mortality from myocardial infarction in the metroprolol group. In addition, later subgroup analysis of the MRC trial in mild hypertension" showed significantly greater reduction in total myocardial infarctions (ie, including silent infarction diagnosed 383
electrocardiographically) in the propranolol-treated group. Neither of these pieces of evidence is as conclusive as an adequately designed prospective study but, in the absence of other data, beta-blockade seems to be preferable as first-line therapy in younger patients and low-dose diuretics in older patients. Beta-blockers should of course be regarded as the first choice in patients who have sustained a myocardial infarction and have no evidence of cardiac failure. On these grounds, the newer classes of drug would be reserved for patients in whom first-line therapy with diuretics or beta-blockers is either contraindicated or ineffective. Thus, beta-blockers and ACE inhibitors are less effective in Afro-Caribbean blacks. Additionally, there are more specific indications for the newer agents. ACE inhibitors extend life and decrease the myocardial infarction rate in patients with left ventricular dysfunction.4° These drugs have also been shown to reduce proteinuria and slow the rate of decline in glomerular filtration rate in diabetic hypertensives, although the specificity of this observation is uncertain.41 The role of the newer classes of antihypertensive drug is one of the most controversial topics in the whole area of hypertension. Two national expert groups have changed their advice in successive reports, despite the absence of substantial further relevant evidence.’ The economic consequences of therapeutic recommendations are considerable. There is at least a 50-fold difference in price between low-dose diuretics and the newer drugs. For therapy that may be given lifelong to more than one fifth of the adult population, the potential burden on health care systems is immense. Several cost-benefit analyses have been carried out,42-44 but these depend critically on assumptions about specific impact of drugs on coronary heart disease, for which there are no convincing data either way. Another approach is to take the most optimistic assumption-ie, that the newer drugs completely reverse hypertension-attributable coronary heart disease whereas older agents reduce the risk only by the proportion shown in meta-analyses. The difference (about 10% of myocardial infarction) would then represent the incremental benefit obtained by using the newer agents. At best, this is an order-of-magnitude calculation. However, on the basis of the MRC trial experience," the reduction would represent one coronary event (fatal and non-fatal) per 2000 patientyears. This result would be achieved at a cost of about ,240 000 ($360 000) per event. This calculation, of course, is based on the assumption that a longer period of treatment does not widen the differential between different classes of agents and that the newer agents have no specific action on non-hypertension-related ischaemic heart disease. However, the effects would have to be substantial to reduce this figure to more manageable levels.
Overview Most unselected patients seen by clinicians will have mild to moderate hypertension on first presentation-ie, diastolic pressure 90-109 mm Hg and systolic pressure 140-179 mm Hg, classified by the Joint National Committee as stage 1 and stage 2.19 Drug treatment should not be initiated until after a period of observation, extending to 3-6 months (figure 2). The higher the average pressure the shorter the period of observation, which should be terminated if there is advanced retinopathy. The interval should be used to encourage non-pharmacological
384
therapy and to assess other cardiovascular risk factors such as the presence of smoking, serum lipids, blood glucose, left ventricular hypertrophy, and established cardiovascular disease. The only sensitive and widely available measure of left ventricular hypertrophy is echocardiography, and cost currently limits its use. Where access is restricted, a reasonable compromise is to do echocardiography when there is suspicion, on clinical or electrocardiographic grounds, of left ventricular hypertrophy, or when clinic blood pressures are thought to be artificially high and ambulatory blood pressure monitoring is unavailable. If there is doubt about the use of drug treatment the presence of left ventricular hypertrophy is a strong indication to proceed. It is important to assess other risk factors for two reasons: (a) they may require treatment in their own right, and (b) the presence of additional risk factors lowers the threshold blood pressures for which drug treatment has to be initiated. Sustained blood pressures above the agreed threshold at the end of the period of observation require drug therapy. Diuretics or beta-blockers should remain first-line agents unless they are contraindicated on pharmacological grounds or unless there is an indication for the use of a specific class of drug-eg, ACE inhibitors in patients with left ventricular dysfunction.
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3
4
5
6
7
8
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