Overview of the outcome trials in older patients with isolated systolic hypertension

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1 Journal of Human Hypertension (1999) 13, Stockton Press. All rights reserved /99 $ Overview of the outcome trials in older patients with isolated systolic hypertension JA Staessen, JG Wang, L Thijs and R Fagard Hypertensie en Cardiovasculaire Revalidatie Eenheid, Departement voor Moleculair en Cardiovasculair Onderzoek, Katholieke Universiteit Leuven, Leuven, Belgium Aims: Isolated systolic hypertension affects over 8 to 15% of all subjects older than 60 years. In the elderly, systolic hypertension is the major modifiable cardiovascular risk factor. Three placebo-controlled outcome trials on antihypertensive drug treatment of this disorder have been published. The aim of this article was to shortly review each of these three trials and to present the pooled estimates of benefit of antihypertensive drug treatment in isolated systolic hypertension in the elderly. Methods and results: The Systolic Hypertension in the Elderly Program (SHEP) in the United States, the Systolic Hypertension in Europe (Syst-Eur) trial and the Systolic Hypertension in China (Syst-China) trial published their main findings in 1991, 1997 and 1998, respectively. The outcome results of these trials were pooled by calculating the common odds ratio for active versus placebo treatment for five major end-points. Zelen s exact test for homogeneity did not reach statistical significance for any of the end-points considered. Thus, the hypothesis of a common underlying treatment effect across the three trials was not rejected. Overall, active treatment compared with placebo, reduced allcause mortality by 17%, cardiovascular mortality by 25%, all cardiovascular end-points by 32%, total stroke by 37% and myocardial infarction including sudden death by 25%. Conclusions: The pooled results of the outcome trials in older patients with isolated systolic hypertension prove that antihypertensive drug treatment must be prescribed, if on repeated measurement systolic blood pressure is 160 mm Hg or higher. Keywords: antihypertensive drug treatment; cardiovascular complications; elderly; isolated systolic hypertension; myocardial infarction; stroke Introduction Systolic blood pressure (BP) increases with age at least until the eighth decade of life. 1,2 In contrast, diastolic BP rises only until middle-age and in older subjects either levels off or even slightly decreases. These divergent trends in systolic and diastolic BP have been observed in cross-sectional 1,2 as well as in longitudinal 1 studies and explain why pulse pressure and the prevalence of isolated systolic hypertension rise with advancing age. In Western countries the latter disorder occurs in around 15% of men and women aged 60 years or more; in octagenarians its prevalence exceeds 20% (Figure 1). Isolated systolic hypertension is largely due to a decrease in the elasticity of the large arteries and is not necessarily accompanied by a rise in mean arterial BP or peripheral resistance. 3 Systolic hypertension is the most important modifiable cardiovascular risk factor in the elderly. 3 Some studies 4 suggested that the excess cardiovascular risk of hypertensive patients, compared with age-matched normotensive controls, decreases as the age of onset of high BP is more advanced. However, this point of view is contradicted by the Correspondence: Dr Jan A. Staessen, Klinisch Laboratorium Hypertensie, Inwendige Geneeskunde-Cardiologie, U.Z. Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium evidence from numerous cross-sectional and longitudinal observational studies 3 and by the results of the outcome trials in older hypertensive patients. 5 The predominance of systolic over diastolic BP as cardiovascular risk indicator in the elderly is not an artefact due to the larger range of systolic BP, because this observation still stands, if systolic and diastolic BP are expressed on a standarised scale in units of standard deviation (s.d.). Outcome trials in isolated systolic hypertension The ultimate goal of treating elderly patients with hypertension is not to reduce their BP, but to prevent the debilitating and often lethal complications of hypertension, so that survival is prolonged and quality of life improved. Three placebo-controlled outcome trials on antihypertensive drug treatment of isolated systolic hypertension have been published. 6 8 The SHEP trial The Systolic Hypertension in the Elderly Program published its primary results in ,9 A total of 4736 (1.1%) from of those screened, aged 60 years or above, were randomised to active treatment

2 860 Treatment of isolated systolic hypertension Figure 1 Prevalence of isolated systolic hypertension by the midpoint of the age classes reported in various studies. As shown by the regression line (unweighted), the prevalence of systolic hypertension rises curvilinearly with age. The 95% CI interval for the prediction of individual points is presented for the age range from 50 to 90 years. From Staessen et al 3 with permission. (n = 2365) or placebo (n = 2371). Systolic BP ranged from 160 to 219 mm Hg and diastolic BP was less than 90 mm Hg. The average BP at entry was 170 mm Hg systolic and 77 mm Hg diastolic. Age averaged 72 years. Of the participants, 57% were female, 14% were Black and 33% had previously been treated for hypertension. Before randomisation the patients were stratified by clinical centre and by antihypertensive treatment status at initial contact. Active treatment was started with the thiazide diuretic chlorthalidone ( mg per day) with the possible addition of atenolol (25 50 mg per day). In patients with known contra-indications for atenolol, the beta-blocker could be replaced by reserpine ( mg per day). Matching placebos were used in a similar fashion in the placebo group. Follow-up averaged 4.5 years. In the placebo group the 5-year systolic-diastolic BP averaged 155/72 mm Hg and in the active treatment group 143/68 mm Hg. Active treatment reduced total stroke incidence from 16.4 to 10.4 events per 1000 patient-years ( 36%; 95% confidence interval (CI): 50% to 18%; P 0.001). Drug treatment also decreased non-fatal stroke by 37% (95% CI: 18% to 51%), non-fatal myocardial infarction by 33% (95% CI: 4% to 53%), non-fatal myocardial infarction combined with coronary death by 27% (95% CI: 6% to 43%), non-fatal left ventricular failure by 54% (95% CI: 35% to 67%) and all major cardiovascular complications by 32% (95% CI: 21% to 42%). Total mortality was not significantly influenced ( 13%; 95% CI: 27% to +5%). The 5-year absolute benefit with regard to stroke and major cardiovascular endpoints amounted to 30 and 55 events per 1000 participants, 9 respectively, and was equally observed in all stratification groups 6,9 and in diabetic as well as non-diabetic patients. 10 The Syst-Eur trial In 1989, the European Working Party on High Blood Pressure in the Elderly initiated the double-blind placebo-controlled Syst-Eur (Systolic Hypertension in Europe) trial. 7,11,12 In view of the remaining uncertainties with regard to the treatment of isolated systolic hypertension in the elderly, the Syst- Eur trial continued after the publication of the SHEP results. 9 Furthermore, the recent controversy on the role of calcium channel blockers as first-line antihy- Figure 2 Reduction in the odds of total and cardiovascular mortality in three outcome trials in older patients with isolated systolic hypertension. Solid squares represent the simple odds ratios for the individual trials and triangles are the pooled odds ratios with 95% CI. Reproduced with permission from Staessen and Wang. 26

3 Treatment of isolated systolic hypertension 861 Figure 3 Reduction in the odds of fatal and non-fatal cardiovascular end-points in three outcome trials in older patients with isolated systolic hypertension. See Figure 2 for further explanation. Reproduced with permission from Staessen and Wang. 26 pertensive agents 18,19 highlighted the lack of evidence that also this newer class of drugs could reduce cardiovascular risk. As in the SHEP study, 6,9 patients eligible for enrolment in the Syst-Eur trial 7,11 were at least 60 years old. At three run-in visits 1 month apart their sitting systolic BP on single-blind placebo treatment averaged from 160 to 219 mm Hg with diastolic BP lower than 95 mm Hg. Of the participants, 67% were female and 47% had previously been treated for hypertension. 7 After stratification for centre, sex and previous cardiovascular complications, 4695 patients were randomised. Active treatment consisted of nitrendipine (10 40 mg per day) with the possible addition of enalapril (5 20 mg per day) and/or hydrochlorothiazide ( mg per day), titrated or combined to reduce the sitting systolic BP by at least 20 mm Hg to below 150 mm Hg. Matching placebo tablets were employed similarly. Patients withdrawing from double-blind treatment were followed further to facilitate an intention-to-treat analysis. 7 At 2 years (median follow-up) the sitting BP fell by 13/2 mm Hg in the placebo group (n = 2297) and by 23/7 mm Hg in the active treatment group (n = 2398). The between-group BP differences were 10.1 mm Hg systolic (95% CI: 8.8 to 11.4 mm Hg) and 4.5 mm Hg diastolic (95% CI: 3.9 to 5.1 mm Hg). Active treatment reduced the total stroke rate from 13.7 to 7.9 events per 1000 patient-years ( 42%; 95% CI: 60% to 17%; P = 0.003). Non-fatal stroke alone decreased by 44% (95% CI: 14% to 63%; P = 0.007). In the active treatment group, all fatal and non-fatal cardiac end-points, including sudden death, declined by 26% (95% CI: 3% to 44%; P = 0.03). Non-fatal cardiac end-points decreased by 33% (95% CI: 3% to 53%; P = 0.03). A similar trend was also observed for non-fatal heart failure ( 36%; 95% CI: 60% to +2%; P = 0.06), for all cases of heart failure ( 29%; 95% CI: 53% to +10%; P = 0.12) and for fatal and non-fatal myocardial infarction ( 30%; 95% CI: 56% to +9%; P = 0.12). Active treatment reduced all fatal and non-fatal cardiovascular endpoints by 31% (95% CI: 14% to 45%; P 0.001). In the analysis by intention-to-treat 7 cardiovascular mortality tended to be less on active treatment ( 27%; 95% CI: 48% to +2%; P = 0.07), but all cause mortality was not influenced ( 14%; 95% CI: 33% to +9%; P = 0.22). Treating 1000 patients for 5 years may prevent 29 strokes or 53 major cardiovascular events. In subgroup analyses, 12 active treatment was equally beneficial in all stratification groups. Furthermore, the benefit of antihypertensive drug treatment on total (P = 0.009) and cardiovascular (P = 0.09) mortality weakened with advancing age, suggesting that in very old patients ( 80 years) only non-fatal end-points were prevented. The reduction of total mortality on active treatment also decreased (P = 0.05) with lower systolic BP at entry. For fatal and non-fatal stroke the benefit of active treatment (P = 0.01) was evident only in non-smokers (92.5% of all patients). Benefit was also noticed in patients who remained on monotherapy with active nitrendipine. 20 Nitrendipine-based treatment was particularly effective in diabetic patients, in whom active

4 862 Treatment of isolated systolic hypertension treatment was estimated to prevent 178 severe cardiovascular complications as opposed to only 22 in the non-diabetic group. 21 The per-protocol analysis 12 considered only the end-points which had occurred during double-blind treatment and confirmed the results by intention-totreat. 7 However, in the per-protocol analysis, 12 active treatment also decreased total mortality by 26% (0 to 46%; P = 0.05). The per-protocol analysis suggested that treating 1000 patients for 5 years would prevent 24 deaths, or 54 major cardiovascular endpoints, or 29 strokes, or 25 cardiac end-points. The Syst-China trial Isolated systolic hypertension occurs in around 8% of Chinese people aged 60 years or older. 22 In 1988, the Systolic Hypertension in China (Syst-China) Collaborative Group started to investigate whether active treatment could reduce the incidence of stroke and other cardiovascular complications in older patients with isolated systolic hypertension. 8,22,23 All patients were initially started on placebo. After stratification for centre, sex and previous cardiovascular complications, alternate patients (n = 1253) were assigned nitrendipine mg daily, with the possible addition of captopril mg daily, or hydrochlorothiazide mg daily, or both drugs. These study medications were titrated or combined to reduce the sitting systolic BP by at least 20 mm Hg to below 150 mm Hg. In the remaining 1141 control patients, matching placebos were employed similarly. At entry sitting BP averaged 170 mm Hg systolic and 86 mm Hg diastolic. Age averaged 66.5 years and total serum cholesterol was 5.1 mmol/l. 8 At 2 years of follow-up, the sitting systolic and diastolic blood pressures had fallen by 11 mm Hg and 2 mm Hg in the placebo group and by 20 mm Hg and 5 mm Hg in the active treatment group. The betweengroup differences were 9.1 mm Hg systolic (95% CI: 7.6 to 10.7 mm Hg) and 3.2 mm Hg diastolic (95% CI: 2.4 to 4.0 mm Hg). Active treatment reduced total stroke by 38% from 20.8 to 13.0 end-points per 1000 patient-years (95% CI: 9% to 58%; P = 0.01), allcause mortality by 39% (95% CI: 16% to 57%; P = 0.003), cardiovascular mortality by 39% (95% CI: 4% to 61%; P = 0.03), stroke mortality by 58% (95% CI: 14% to 80%; P = 0.02) and all fatal and non-fatal cardiovascular end-points by 37% (95% CI: 14% to 53%; P = 0.004). Thus, antihypertensive drug treatment prevents stroke and other cardiovascular complications in older Chinese patients with isolated systolic hypertension. Treatment of 1000 Chinese patients for 5 years could prevent 55 deaths, 39 strokes, or 59 major cardiovascular endpoints. 8 A meta-analysis The results of the three outcome trials in older patients with isolated systolic hypertension were pooled, using StatXact software version 3.0 (CYTEL Software Corporation, Cambridge, MA, USA) and methods described elsewhere. 24 Zelen s exact test for homogeneity did not reach statistical significance for any of the end-points considered. Thus, the hypothesis of a common underlying treatment effect across the three studies was not rejected. Overall, compared with placebo, active treatment reduced all-cause mortality by 17% and cardiovascular mortality by 25% (Figure 2). For the fatal and non-fatal complications combined, these reductions were 32% for all cardiovascular endpoints, 37% for stroke, and 25% for myocardial infarction including sudden death (Figure 3). Conclusions The pooled results of the three outcome trials in older patients with isolated systolic hypertension prove that antihypertensive drug treatment must be prescribed, if on repeated measurement systolic BP is 160 mm Hg or higher. The entry diastolic BP level averaged nearly 85 mm Hg in the Syst-Eur 7 and Syst- China 8 trials and was as low as 77 mm Hg in the SHEP study. 9 Thus, the present findings negate the hypothesis that vigorously lowering diastolic BP would compromise the coronary circulation and provoke rather than prevent coronary complications. 25 The evidence from the intervention trials 26 also supports the recent recommendations of the National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. This expert committee considered isolated systolic hypertension in the elderly as a compelling indication for the use of thiazide diuretics or long-acting dihydropyrides as first-line antihypertensive drugs. 27 References 1 Kannel WB, Gordon T. Evaluation of cardiovacular risk in the elderly: the Framingham study. Bull NY Acad Med 1978; 54: Staessen J et al. The increase in blood pressure with age and body mass index is overestimated by conventional sphygmomanometry. Am J Epidemiol 1992; 136: Staessen J, Amery A, Fagard R. Editorial review. Isolated systolic hypertension in the elderly. J Hypertens 1990; 8: Buck C, Baker P, Bass M, Donner A. The prognosis of hypertension according to age at onset. Hypertension 1987; 9: Thijs L et al. Why is antihypertensive drug therapy needed in elderly patients with systolodiastolic hypertension? J Hypertens 1994; 12 (Suppl 6): S25 S34. 6 The Systolic Hypertension in the Elderly Program Cooperative Research Group. 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