- Email: [email protected]
Treatment of isolated systolic hypertension in the elderly: evidence from three clinical trials
European Journal of Internal Medicine 10 Ž1999. 82–87 www.elsevier.comrlocaterejim
Review article
Treatment of isolated systolic hypertension in the elderly: evidence from three clinical trials Jan A. Staessen ) , Jerzy Ga¸sowski, Ji G. Wang Hypertensie en CardioÕasculaire ReÕalidatie Eenheid, Departement Moleculair en CardioÕascular Onderzoek, Katholieke UniÕersiteit LeuÕen, LeuÕen, Belgium Received 6 April 1999; received in revised form 12 April 1999; accepted 13 April 1999
Abstract Isolated systolic hypertension affects over 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 for this disorder have been published. The aim of this article was to briefly review the main findings of each of these three trials and to present pooled estimates of the benefit of antihypertensive drug treatment in isolated systolic hypertension in the elderly. A total of 11 825 patients were enrolled in the Systolic Hypertension in the Elderly Program ŽSHEP; N s 4736. in the United States, and in the Systolic Hypertension in Europe ŽSyst-Eur; N s 4695. and the Systolic Hypertension in China ŽSyst-China; N s 2394. trials. The outcome results of these trials were pooled by calculating the common odds ratio for active vs. placebo treatment. Overall, compared to placebo, active treatment reduced all-cause mortality by 17%, cardiovascular mortality by 25%, all cardiovascular endpoints by 32%, total stroke by 37%, and myocardial infarction including sudden death by 25%. Thus, 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 mmHg or higher. q 1999 Elsevier Science B.V. All rights reserved. Keywords: Antihypertensive drug treatment; Cardiovascular complications; Elderly; Isolated systolic hypertension; Myocardial infarction; Stroke
1. Introduction Systolic blood pressure increases with age, at least until the eighth decade of life w1,2x. In contrast, diastolic blood pressure rises only until middle age; in older subjects, it either levels off or may even decrease slightly. These divergent trends in systolic and diastolic blood pressure have been observed in cross-sectional w1,2x as well as in longitudinal w1x studies and explain why pulse pressure and the prevalence of isolated systolic hypertension rise with advancing age. In Western countries, the latter disorder
)
Corresponding author. Studiecoordinatiecentrum, Laboratorium Hy¨ pertensie, Campus Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium. Tel.: q32-16-34-7104 Žoffice., q32-15-41-1747 Žhome.; fax: q32-1634-7106 Žoffice., q32-15-41-4542 Žhome.; E-mail: jan.staessen@ med.kuleuven.ac.be
occurs in around 15% of men and women aged 60 years or more; in octogenarians, its prevalence even exceeds 20% ŽFig. 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 blood pressure or peripheral resistance w3x. Systolic hypertension is the most important modifiable cardiovascular risk factor in the elderly w3x. Some studies w4x suggest that the excess cardiovascular risk of hypertensive patients compared with age-matched normotensive controls decreases as the age of onset of high blood pressure increases. However, this theory is contradicted by evidence from numerous cross-sectional and longitudinal, observational studies w3x and by the results of the outcome trials in older hypertensive patients w5x. The predominance of systolic over diastolic blood pressure as a cardiovascular risk indicator in the elderly is not an artifact due to the larger range of systolic blood pressure because this is observed when systolic and diastolic blood are ex-
0953-6205r99r$ - see front matter q 1999 Elsevier Science B.V. All rights reserved. PII: S 0 9 5 3 - 6 2 0 5 Ž 9 9 . 0 0 0 2 7 - 8
J.A. Staessen et al.r European Journal of Internal Medicine 10 (1999) 82–87
Fig. 1. Prevalence of isolated systolic hypertension by the midpoint of the age classes reported in various studies. As shown by the regression line Žunweighted., the prevalence of systolic hypertension rises curvilinearly with age. The 95% confidence interval ŽCI. for the prediction of individual points is presented for the age range from 50 to 90 years. I, white men; B, black men; `, white women, v, black women. From Staessen et al. w3x with permission.
pressed on a standardized scale in units of standard deviation.
2. Outcome trials in isolated systolic hypertension The ultimate goal of treating elderly patients with hypertension is not to reduce their blood pressure, but to prevent the cardiovascular complications of hypertension so that longevity increases and quality of life improves. Three placebo-controlled outcome trials on antihypertensive drug treatment of isolated systolic hypertension have been published w6–8x. 2.1. The Systolic Hypertension in the Elderly Program (SHEP) trial The SHEP published its primary results in 1991 w6,9x. A total of 4736 subjects Ž1.1%. of 447 921 aged 60 years or above who were screened were randomized to active treatment Ž N s 2365. or placebo Ž N s 2371.. Systolic blood pressure ranged from 160 to 219 mmHg and diastolic blood pressure was less than 90 mmHg. The average blood pressure at entry was 170 mmHg systolic and 77 mmHg diastolic. Age averaged 72 years. Of the participants, 57% were female, 14% were black, and 33% had previously
83
been treated for hypertension. Before randomization the patients were stratified by clinical center and by antihypertensive treatment status at initial contact. Active treatment was started with the thiazide diuretic chlorthalidone Ž12.5– 25 mgrday. with the possible addition of atenolol Ž25–50 mgrday.. In patients with known contra-indications for atenolol, the beta-blocker could be replaced by reserpine Ž0.05–0.1 mgrday.. 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 systolicrdiastolic blood pressure averaged 155r72 mmHg and in the active treatment group 143r68 mmHg. Active treatment reduced total stroke incidence from 16.4 to 10.4 events per 1000 patient-years Žy36%; 95% CI: y50% to y18%; P - 0.001.. Drug treatment also decreased nonfatal stroke by 37% ŽCI: 18% to 51%., nonfatal myocardial infarction by 33% ŽCI: 4% to 53%., nonfatal myocardial infarction combined with coronary death by 27% ŽCI: 6% to 43%., nonfatal left ventricular failure by 54% ŽCI: 35% to 67%., and all major cardiovascular complications by 32% ŽCI: 21% to 42%.. Total mortality was not significantly influenced Žy13%; CI: y27% to q5%.. The 5-year absolute benefit with regard to stroke and major cardiovascular endpoints amounted to 30 and 55 events per 1000 participants, respectively, w9x and was equally observed in all stratification groups w6,9x. At baseline, 583 SHEP patients Ž12.3%. had non-insulin-dependent diabetes mellitus, 4149 patients did not have diabetes, and 4 patients could not be classified w10x in the SHEP control group, the rate of all cardiovascular complications was 63.0 events per 1000 patient-years in the diabetic patients Ž N s 300. and 36.8 events per 1000 patient-years in the group without diabetes Ž N s 2069.. In the diabetic Ž N s 283. and nondiabetic Ž N s 2080. patients randomized to active treatment, these rates were reduced to 42.8 and 26.6 events per 1000 patient-years, respectively w10x. Thus, in the SHEP trial ŽFig. 2., active treatment decreased the incidence of all cardiovascular complications to the same extent Žy34%. in diabetics ŽCI: y54% to y6%. and nondiabetics ŽCI: y45% to y21%. w10x. 2.2. The Syst-Eur trial In 1989, the European Working Party on High Blood Pressure in the Elderly initiated the double-blind, placebocontrolled Syst-Eur trial w7,11,12x. In view of the remaining uncertainties with regard to the treatment of isolated systolic hypertension in the elderly w13–17x, the Syst-Eur trial continued after the publication of the SHEP results w9x. Furthermore, the recent controversy surrounding the role of calcium channel blockers as first-line antihypertensive agents w18,19x highlighted the lack of evidence that also this newer class of drugs could reduce cardiovascular risk.
84
J.A. Staessen et al.r European Journal of Internal Medicine 10 (1999) 82–87
Fig. 2. Outcome results in the SHEP w10x and in the Systolic Hypertension in Europe ŽSyst-Eur. w21x trial. For these comparisons, the endpoints were standardized to the definitions used in the SHEP trial. From Tuomilehto et al. w21x with permission.
As in the SHEP study w6,9x, patients eligible for enrollment in the Syst-Eur trial w7,11x were at least 60 years old. At three run-in visits 1 month apart, their sitting systolic blood pressure on single-blind placebo treatment ranged from 160 to 219 mmHg with diastolic blood pressure lower than 95 mmHg. Of the participants, 67% were female and 47% had previously been treated for hypertension w7x. After stratification for center, sex, and previous cardiovascular complications, 4695 patients were randomized. Active treatment consisted of nitrendipine Ž10–40 mgrday. with the possible addition of enalapril Ž5–20
mgrday. andror hydrochlorothiazide Ž12.5–25 mgrday., titrated or combined to reduce the sitting systolic blood pressure by at least 20 mmHg to below 150 mmHg. Matching placebo tablets were employed similarly. Patients withdrawing from double-blind treatment were followed further to facilitate an intention-to-treat analysis w7x. At 2 years Žmedian follow-up., the sitting blood pressure fell by 13r2 mmHg in the placebo group Ž N s 2297. and by 23r7 mmHg in the active treatment group Ž N s 2398.. The between-group blood pressure differences were 10.1 mmHg systolic ŽCI: 8.8 to 11.4 mmHg. and
J.A. Staessen et al.r European Journal of Internal Medicine 10 (1999) 82–87
4.5 mmHg diastolic ŽCI: 3.9 to 5.1 mmHg.. Active treatment reduced the total stroke rate from 13.7 to 7.9 events per 1000 patient-years Žy42%; CI: y60% to y17%; P s 0.003.. Nonfatal stroke alone decreased by 44% ŽCI: 14% to 63%; P s 0.007.. In the active treatment group, all fatal and nonfatal cardiac endpoints, including sudden death, declined by 26% ŽCI: 3% to 44%; P s 0.03.. Nonfatal cardiac endpoints decreased by 33% ŽCI: 3% to 53%; P s 0.03.. A similar trend was observed for nonfatal heart failure Žy36%; CI: y60% to q2%; P s 0.06., for all cases of heart failure Žy29%; CI: y53% to q10%; P s 0.12., and for fatal and nonfatal myocardial infarction Žy30%; CI: y56% to q9%; P s 0.12.. Active treatment reduced all fatal and nonfatal cardiovascular endpoints by 31% ŽCI: 14% to 45%; P - 0.001.. In the intention-to-treat analysis w7x cardiovascular mortality tended to be less with active treatment Žy27%; CI: y48% to q2%; P s 0.07., but all-cause mortality was not influenced Žy14%; CI: y33% to q9%; P s 0.22.. Treating 1000 patients for 5 years could prevent 29 strokes or 53 major cardiovascular events. In subgroup analyses w12x, active treatment was equally beneficial in all stratification groups. Furthermore, the benefit of antihypertensive drug treatment on total Ž P s 0.009. and cardiovascular Ž P s 0.09. mortality weakened with advancing age, suggesting that in very old patients ŽG 80 years. only nonfatal endpoints were prevented. The reduction in total mortality with active treatment also decreased Ž P s 0.05. with lower systolic blood pressure at entry. For fatal and nonfatal stroke, the benefit of active treatment Ž P s 0.01. was evident only in nonsmokers Ž92.5% of all patients.. Benefit was also noticed in patients who remained on monotherapy with active nitrendipine w20x. Of the 4695 randomized Syst-Eur patients, 492 Ž10.5%. had diabetes mellitus at entry. Compared with the 4203 nondiabetic patients, the diabetics had higher systolic blood pressure Ž175.3 vs. 173.7 mmHg., lower diastolic blood pressure Ž84.5 vs. 85.6 mmHg., higher mean blood glucose concentrations Ž8.2 vs. 5.1 mmolrl., higher body mass index Ž28.3 vs. 27 kgrm2 ., and lower HDL cholesterol concentrations Ž1.3 vs. 1.4 mmolrl. w21x. A significantly greater proportion of the diabetic patients had experienced cardiovascular complications before enrollment, and the rate of cardiovascular complications during the trial was about twice the rate observed in the nondiabetics. Active treatment significantly reduced cardiovascular complications in diabetics ŽFig. 2.. After controlling for possible confounders, total mortality was reduced by 55% ŽCI: 15% to 76%., cardiovascular mortality by 76% ŽCI: 33% to 91%., all cardiovascular endpoints by 69% ŽCI: 41% to 84%., fatal and nonfatal stroke by 73% ŽCI: 26% to 90%., and all cardiac endpoints by 63% ŽCI: 10% to 85%.. In the nondiabetic patients, active treatment decreased all cardiovascular endpoints by 26% ŽCI: 6% to 41%. and fatal and nonfatal stroke by 38% ŽCI: 8% to 58%.. Active treatment
85
reduced total mortality, cardiovascular mortality, and all cardiovascular endpoints significantly more in the diabetic than in the nondiabetic patients Ž P-values: 0.04, 0.02, and 0.01, respectively.. Thus, the dihydropyridine-based treatment was particularly effective in diabetic patients, in whom active treatment was estimated to prevent 178 severe cardiovascular complications as opposed to only 22 in the nondiabetic group w21x. The per-protocol analysis w12x considered only the endpoints that had occurred during double-blind treatment and confirmed the results by intention-to-treat w7x. However, in the per-protocol analysis w12x, active treatment also decreased total mortality by 26% ŽCI: 0% to 46%; P s 0.05.. The per-protocol analysis suggested that treating 1000 patients for 5 years would prevent 24 deaths, 54 major cardiovascular endpoints, 29 strokes, or 25 cardiac endpoints. The Vascular Dementia Project w22–24x investigated whether antihypertensive drug treatment could reduce the incidence of dementia. At baseline and follow-up, cognitive function was assessed with the Mini Mental State Examination w25x; if the score was 23 or less, the diagnosis of dementia was established based on the DSM-III-R criteria w26x. In total, 2418 patients were enrolled in the dementia study. Median follow-up by intention to treat was 2.0 years. Among the 32 incident cases of dementia, 23 were Alzheimer’s disease, 7 had a mixed etiology, and only 2 were vascular. Compared with placebo Ž N s 1180., active treatment Ž N s 1238. reduced the incidence of dementia by 50% Ž0% to 76%; P s 0.05. from 7.7 to 3.8 cases per 1000 patient-years. At the risk observed in the placebo group, treating 1000 hypertensive patients for 5 years could prevent 19 cases. In the per-protocol analysis, active treatment decreased the rate by 60% Ž2% to 83%; P s 0.03.. Thus, active treatment prevented mainly degenerative dementia. 2.3. The Systolic Hypertension in China (Syst-China) trial Isolated systolic hypertension occurs in around 8% of Chinese people aged 60 years or older w27x. In 1988, the 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 w8,27,28x. All patients were initially started on placebo. After stratification for center, sex, and previous cardiovascular complications, alternate patients Ž N s 1253. were assigned nitrendipine 10–40 mg daily, with the possible addition of captopril 12.5–50.0 mg daily, or hydrochlorothiazide 12.5–50.0 mg daily, or both drugs. These study medications were titrated or combined to reduce the sitting systolic blood pressure by at least 20 mmHg to below 150 mmHg. In the remaining 1141 control patients, matching placebos were employed similarly.
86
J.A. Staessen et al.r European Journal of Internal Medicine 10 (1999) 82–87
At entry, sitting blood pressure averaged 170 mmHg systolic and 86 mmHg diastolic. Age averaged 66.5 years and total serum cholesterol was 5.1 mmolrl w8x. At 2 years of follow-up, the sitting systolic and diastolic blood pressures had fallen by 11 mmHg and 2 mmHg in the placebo group and by 20 mmHg and 5 mmHg in the active treatment group. The between-group differences were 9.1 mmHg systolic ŽCI: 7.6 to 10.7 mmHg. and 3.2 mmHg diastolic ŽCI: 2.4 to 4.0 mmHg.. Active treatment reduced total stroke by 38% from 20.8 to 13.0 endpoints per 1000 patient-years ŽCI: 9% to 58%; P s 0.01., all-cause mortality by 39% ŽCI: 16% to 57%; P s 0.003., cardiovascular mortality by 39% ŽCI: 4% to 61%; P s 0.03., stroke mortality by 58% ŽCI: 14% to 80%; P s 0.02., and all fatal and nonfatal cardiovascular endpoints by 37% ŽCI: 14% to 53%; P s 0.004.. Treatment of 1000 Chinese patients for 5 years could prevent 55 deaths, 39 strokes, or 59 major cardiovascular endpoints w8x. A subsequent subgroup analysis demonstrated that the benefit of antihypertensive treatment was particularly evident in diabetic patients and that for cardiac endpoints it tended to be slightly larger in nonsmokers w29x. Otherwise, the benefit of active treatment was not significantly influenced by the characteristics of the patients at entry into the Syst-China trial w29x. 3. A meta-analysis The results of the three outcome trials in older patients with isolated systolic hypertension were pooled, using methods described elsewhere w30,31x. Zelen’s exact test for homogeneity did not reach statistical significance for any of the endpoints considered. Thus, the hypothesis of a common underlying treatment effect across the three studies was not rejected. Overall, compared to placebo, active treatment reduced all-cause mortality by 17% ŽCI: 5% to 18%; P s 0.008. and cardiovascular mortality by 25% ŽCI: 8% to 39%; P s 0.005.; for fatal and nonfatal complications combined, these reductions were 32% for all cardiovascular endpoints ŽCI: 13% to 41%; P - 0.001., 37% for stroke ŽCI: 24% to 38%; P - 0.001., and 25% for myocardial infarction including sudden death ŽCI: 9% to 39% P - 0.001. w31x. 4. 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 blood pressure is 160 mmHg or higher. The entry diastolic blood pressure level averaged nearly 85 mmHg in the Syst-Eur w7x and SystChina w8x trials and was as low as 77 mmHg in the SHEP study w9x. These findings negate the hypothesis that vigorously lowering diastolic blood pressure compromises the
coronary circulation and provokes rather than prevents coronary complications w32x. Furthermore, long-acting dihydropyridines constitute a valid alternative to diuretics and beta-blockers in the primary prevention of cardiovascular disorders in elderly hypertensives. In isolated systolic hypertension, calcium channel blockade may be particularly indicated in diabetic patients w21x and in those at risk of dementia w24x.
References w1x Kannel WB, Gordon T. Evaluation of cardiovascular risk in the elderly: the Framingham study. Bull NY Acad Med 1978;54:573–91. w2x Staessen J, O’Brien E, Atkins N, Bulpitt CJ, Cox J, Fagard R et al. Amery A: the increase in blood pressure with age and body mass index is overestimated by conventional sphygmomanometry. Am J Epidemiol 1992;136:450–9. w3x Staessen J, Amery A, Fagard R. Editorial review. Isolated systolic hypertension in the elderly. J Hypertens 1990;8:393–405. w4x Buck C, Baker P, Bass M, Donner A. The prognosis of hypertension according to age at onset. Hypertension 1987;9:204–8. w5x Thijs L, Fagard R, Lijnen P, Staessen J, Van Hoof R, Amery A. Why is antihypertensive drug therapy needed in elderly patients with systolodiastolic hypertension? J Hypertens 1994;12 suppl 6:S25–S34. w6x The Systolic Hypertension in the Elderly Program Cooperative Research Group. Implications of the systolic hypertension in the elderly program. Hypertension 1993;21:335–43. w7x Staessen JA, Fagard R, Thijs L, Celis H, Arabidze GG, Birkenhager ¨ WH et al. For the Systolic Hypertension in Europe ŽSyst-Eur. Trial Investigators: randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. Lancet 1997;350:757–64. w8x Liu L, Wang JG, Gong L, Liu G, Staessen JA. For the Systolic Hypertension in China ŽSyst-China. Collaborative Group: comparison of active treatment and placebo for older patients with isolated systolic hypertension. J Hypertens 1998;16:1823–9. w9x SHEP Cooperative Research Group, Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program ŽSHEP.. JAMA 1991;265:3255–64. w10x Curb JD, Pressel SL, Cutler JA, Savage PJ, Applegate WB, Black H et al. For the Systolic Hypertension in the Elderly Cooperative Research Group: effect of diuretic-based antihypertensive treatment on cardiovascular disease risk in older diabetic patients with isolated systolic hypertension. JAMA 1996;276:1886–92. w11x Amery A, Birkenhager W, Bulpitt CJ, Clement D, de Leeuw P, ¨ Dollery CT et al. Syst-Eur. A multicentre trial on the treatment of isolated systolic hypertension in the elderly: objectives, protocol and organization. Aging Clin Exp Res 1991;3:287–302. w12x Staessen JA, Fagard R, Thijs L, Celis H, Birkenhager ¨ WH, Bulpitt CJ et al. For the Systolic Hypertension in Europe ŽSyst-Eur. Trial Investigators: subgroup and per-protocol analysis of the randomized European trial on isolated systolic hypertension in the elderly. Arch Intern Med 1998;158:1681–91. w13x Fletcher A, Spiegelhalter D, Staessen J, Thijs L, Bulpitt C. Implications for trials in progress of publication of positive results. Lancet 1993;342:653–7. w14x Kaplan NM. Systolic Hypertension in the Elderly Program ŽSHEP. and Swedish Trial in Old Patients With Hypertension ŽSTOP.. The promises and the potential problems. Am J Hypertens 1992;5:331–4. w15x Menard J, Day M, Chatellier G, Laragh JH. Some lessons from ´ Systolic Hypertension in the Elderly Program ŽSHEP.. Am J Hypertens 1992;5:325–30.
J.A. Staessen et al.r European Journal of Internal Medicine 10 (1999) 82–87 w16x Staessen J, Fagard R, Amery A, Isolated systolic hypertension in the elderly: implications of SHEP for clinical practice and for the ongoing trials. J Hum Hypertens 1991;5:469–74. w17x Staessen JA, Amery A, Birkenhager ¨ W. Inverse association between baseline pressure and benefit from treatment in isolated systolic hypertension. Hypertension 1994;23:269–70. w18x Furberg CD, Psaty BM, Meyer JV, Nifedipine. Dose-related increase in mortality in patients with coronary heart disease. Circulation 1995;92:1326–31. w19x Psaty BM, Heckbert SR, Koepsell TD, Siscovick DS, Raghunathan TE, Weiss NS et al. The risk of myocardial infarction associated with antihypertensive drug therapies, JAMA 1995;274:620–25. w20x Staessen JA, Thijs L, Fagard RH, Birkenhager WS, Arabidze G, ¨ Babeanu S et al. For the Systolic Hypertension in Europe ŽSyst-Eur. Trial Investigators: calcium channel blockade and cardiovascular prognosis in the European trial on isolated systolic hypertension. Hypertension 1998;32:404–09. w21x Tuomilehto J, Rastenyte D, Birkenhager ¨ WH, Thijs L, Antikainen R, Bulpitt CJ et al. For the Systolic Hypertension in Europe ŽSyst-Eur. Trial Investigators. Staessen JA: effects of calcium-channel blockage in older patients with diabetes and systolic hypertension. N Engl J Med 1999;340:677–84. w22x Forette F, Amery A, Staessen J, Strasser T, Thijs L, Beevers DG et al. Is prevention of vascular dementia possible? The Syst-Eur Vascular Dementia Project. Aging Clin Exp Res 1991;3:373–82. w23x Seux ML, Thijs L, Forette F, Staessen JA, Birkenhager ¨ WH, Bulpitt CJ et al. Correlates of cognitive status of old patients with isolated systolic hypertension: the Syst-Eur Vascular Dementia Project, J Hypertens 1998;16:963–69.
87
w24x Forette F, Seux ML, Staessen JA, Thijs L, Birkenhager WH, ¨ Babarskiene MR et al. On behalf of the Syst-Eur Investigators: prevention of dementia in randomised double-blind placebo-controlled Systolic Hypertension in Europe ŽSyst-Eur. trial. Lancet 1998;352:1347–51. w25x Folstein MF, Folstein SE, McHugh PR. ‘Mini-mental state’. A practical method for grading the cognitive state of patients for the clinician. J Psychiat Res 1975;12:189–98. w26x American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders. Washington DC, USA, 1987. w27x Collaborative Group Coordinating Center. Systolic hypertension in the elderly: Chinese trial ŽSyst-China. — interim report. Chin J Cardiol 1992;20:270–75. w28x Wang J, Liu G, Wang X, Zhang S, Sun M, Pan X et al. On behalf of the Syst-China Investigators: Long-term blood pressure control in older Chinese patients with isolated systolic hypertension: a progress report on the Syst-China trial. J Hum Hypertens 1996;10:735–42. w29x Wang JG, Staessen JA, Gong L, Liu L. For the Systolic Hypertension in China Investigator: subgroup analysis of the placebo-controlled Chinese trial on isolated systolic hypertension in the elderly. Arch Intern Med 1999, in press. w30x Thijs L, Fagard R, Lijnen P, Staessen J, Van Hoof R, Amery A. A meta-analysis of outcome trials in elderly hypertensives. J Hypertens 1992;10:1103–09. w31x Staessen JA, Wang JG. Benefit of antihypertensive drug treatment in older patients with isolated systolic hypertension. Eur Heart J 1999, in press. w32x Cruickshank JM, Thorp JM, Zacharias FJ. Benefits and potential harm of lowering high blood pressure. Lancet i 1987;581–83.
Review article
Treatment of isolated systolic hypertension in the elderly: evidence from three clinical trials Jan A. Staessen ) , Jerzy Ga¸sowski, Ji G. Wang Hypertensie en CardioÕasculaire ReÕalidatie Eenheid, Departement Moleculair en CardioÕascular Onderzoek, Katholieke UniÕersiteit LeuÕen, LeuÕen, Belgium Received 6 April 1999; received in revised form 12 April 1999; accepted 13 April 1999
Abstract Isolated systolic hypertension affects over 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 for this disorder have been published. The aim of this article was to briefly review the main findings of each of these three trials and to present pooled estimates of the benefit of antihypertensive drug treatment in isolated systolic hypertension in the elderly. A total of 11 825 patients were enrolled in the Systolic Hypertension in the Elderly Program ŽSHEP; N s 4736. in the United States, and in the Systolic Hypertension in Europe ŽSyst-Eur; N s 4695. and the Systolic Hypertension in China ŽSyst-China; N s 2394. trials. The outcome results of these trials were pooled by calculating the common odds ratio for active vs. placebo treatment. Overall, compared to placebo, active treatment reduced all-cause mortality by 17%, cardiovascular mortality by 25%, all cardiovascular endpoints by 32%, total stroke by 37%, and myocardial infarction including sudden death by 25%. Thus, 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 mmHg or higher. q 1999 Elsevier Science B.V. All rights reserved. Keywords: Antihypertensive drug treatment; Cardiovascular complications; Elderly; Isolated systolic hypertension; Myocardial infarction; Stroke
1. Introduction Systolic blood pressure increases with age, at least until the eighth decade of life w1,2x. In contrast, diastolic blood pressure rises only until middle age; in older subjects, it either levels off or may even decrease slightly. These divergent trends in systolic and diastolic blood pressure have been observed in cross-sectional w1,2x as well as in longitudinal w1x studies and explain why pulse pressure and the prevalence of isolated systolic hypertension rise with advancing age. In Western countries, the latter disorder
)
Corresponding author. Studiecoordinatiecentrum, Laboratorium Hy¨ pertensie, Campus Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium. Tel.: q32-16-34-7104 Žoffice., q32-15-41-1747 Žhome.; fax: q32-1634-7106 Žoffice., q32-15-41-4542 Žhome.; E-mail: jan.staessen@ med.kuleuven.ac.be
occurs in around 15% of men and women aged 60 years or more; in octogenarians, its prevalence even exceeds 20% ŽFig. 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 blood pressure or peripheral resistance w3x. Systolic hypertension is the most important modifiable cardiovascular risk factor in the elderly w3x. Some studies w4x suggest that the excess cardiovascular risk of hypertensive patients compared with age-matched normotensive controls decreases as the age of onset of high blood pressure increases. However, this theory is contradicted by evidence from numerous cross-sectional and longitudinal, observational studies w3x and by the results of the outcome trials in older hypertensive patients w5x. The predominance of systolic over diastolic blood pressure as a cardiovascular risk indicator in the elderly is not an artifact due to the larger range of systolic blood pressure because this is observed when systolic and diastolic blood are ex-
0953-6205r99r$ - see front matter q 1999 Elsevier Science B.V. All rights reserved. PII: S 0 9 5 3 - 6 2 0 5 Ž 9 9 . 0 0 0 2 7 - 8
J.A. Staessen et al.r European Journal of Internal Medicine 10 (1999) 82–87
Fig. 1. Prevalence of isolated systolic hypertension by the midpoint of the age classes reported in various studies. As shown by the regression line Žunweighted., the prevalence of systolic hypertension rises curvilinearly with age. The 95% confidence interval ŽCI. for the prediction of individual points is presented for the age range from 50 to 90 years. I, white men; B, black men; `, white women, v, black women. From Staessen et al. w3x with permission.
pressed on a standardized scale in units of standard deviation.
2. Outcome trials in isolated systolic hypertension The ultimate goal of treating elderly patients with hypertension is not to reduce their blood pressure, but to prevent the cardiovascular complications of hypertension so that longevity increases and quality of life improves. Three placebo-controlled outcome trials on antihypertensive drug treatment of isolated systolic hypertension have been published w6–8x. 2.1. The Systolic Hypertension in the Elderly Program (SHEP) trial The SHEP published its primary results in 1991 w6,9x. A total of 4736 subjects Ž1.1%. of 447 921 aged 60 years or above who were screened were randomized to active treatment Ž N s 2365. or placebo Ž N s 2371.. Systolic blood pressure ranged from 160 to 219 mmHg and diastolic blood pressure was less than 90 mmHg. The average blood pressure at entry was 170 mmHg systolic and 77 mmHg diastolic. Age averaged 72 years. Of the participants, 57% were female, 14% were black, and 33% had previously
83
been treated for hypertension. Before randomization the patients were stratified by clinical center and by antihypertensive treatment status at initial contact. Active treatment was started with the thiazide diuretic chlorthalidone Ž12.5– 25 mgrday. with the possible addition of atenolol Ž25–50 mgrday.. In patients with known contra-indications for atenolol, the beta-blocker could be replaced by reserpine Ž0.05–0.1 mgrday.. 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 systolicrdiastolic blood pressure averaged 155r72 mmHg and in the active treatment group 143r68 mmHg. Active treatment reduced total stroke incidence from 16.4 to 10.4 events per 1000 patient-years Žy36%; 95% CI: y50% to y18%; P - 0.001.. Drug treatment also decreased nonfatal stroke by 37% ŽCI: 18% to 51%., nonfatal myocardial infarction by 33% ŽCI: 4% to 53%., nonfatal myocardial infarction combined with coronary death by 27% ŽCI: 6% to 43%., nonfatal left ventricular failure by 54% ŽCI: 35% to 67%., and all major cardiovascular complications by 32% ŽCI: 21% to 42%.. Total mortality was not significantly influenced Žy13%; CI: y27% to q5%.. The 5-year absolute benefit with regard to stroke and major cardiovascular endpoints amounted to 30 and 55 events per 1000 participants, respectively, w9x and was equally observed in all stratification groups w6,9x. At baseline, 583 SHEP patients Ž12.3%. had non-insulin-dependent diabetes mellitus, 4149 patients did not have diabetes, and 4 patients could not be classified w10x in the SHEP control group, the rate of all cardiovascular complications was 63.0 events per 1000 patient-years in the diabetic patients Ž N s 300. and 36.8 events per 1000 patient-years in the group without diabetes Ž N s 2069.. In the diabetic Ž N s 283. and nondiabetic Ž N s 2080. patients randomized to active treatment, these rates were reduced to 42.8 and 26.6 events per 1000 patient-years, respectively w10x. Thus, in the SHEP trial ŽFig. 2., active treatment decreased the incidence of all cardiovascular complications to the same extent Žy34%. in diabetics ŽCI: y54% to y6%. and nondiabetics ŽCI: y45% to y21%. w10x. 2.2. The Syst-Eur trial In 1989, the European Working Party on High Blood Pressure in the Elderly initiated the double-blind, placebocontrolled Syst-Eur trial w7,11,12x. In view of the remaining uncertainties with regard to the treatment of isolated systolic hypertension in the elderly w13–17x, the Syst-Eur trial continued after the publication of the SHEP results w9x. Furthermore, the recent controversy surrounding the role of calcium channel blockers as first-line antihypertensive agents w18,19x highlighted the lack of evidence that also this newer class of drugs could reduce cardiovascular risk.
84
J.A. Staessen et al.r European Journal of Internal Medicine 10 (1999) 82–87
Fig. 2. Outcome results in the SHEP w10x and in the Systolic Hypertension in Europe ŽSyst-Eur. w21x trial. For these comparisons, the endpoints were standardized to the definitions used in the SHEP trial. From Tuomilehto et al. w21x with permission.
As in the SHEP study w6,9x, patients eligible for enrollment in the Syst-Eur trial w7,11x were at least 60 years old. At three run-in visits 1 month apart, their sitting systolic blood pressure on single-blind placebo treatment ranged from 160 to 219 mmHg with diastolic blood pressure lower than 95 mmHg. Of the participants, 67% were female and 47% had previously been treated for hypertension w7x. After stratification for center, sex, and previous cardiovascular complications, 4695 patients were randomized. Active treatment consisted of nitrendipine Ž10–40 mgrday. with the possible addition of enalapril Ž5–20
mgrday. andror hydrochlorothiazide Ž12.5–25 mgrday., titrated or combined to reduce the sitting systolic blood pressure by at least 20 mmHg to below 150 mmHg. Matching placebo tablets were employed similarly. Patients withdrawing from double-blind treatment were followed further to facilitate an intention-to-treat analysis w7x. At 2 years Žmedian follow-up., the sitting blood pressure fell by 13r2 mmHg in the placebo group Ž N s 2297. and by 23r7 mmHg in the active treatment group Ž N s 2398.. The between-group blood pressure differences were 10.1 mmHg systolic ŽCI: 8.8 to 11.4 mmHg. and
J.A. Staessen et al.r European Journal of Internal Medicine 10 (1999) 82–87
4.5 mmHg diastolic ŽCI: 3.9 to 5.1 mmHg.. Active treatment reduced the total stroke rate from 13.7 to 7.9 events per 1000 patient-years Žy42%; CI: y60% to y17%; P s 0.003.. Nonfatal stroke alone decreased by 44% ŽCI: 14% to 63%; P s 0.007.. In the active treatment group, all fatal and nonfatal cardiac endpoints, including sudden death, declined by 26% ŽCI: 3% to 44%; P s 0.03.. Nonfatal cardiac endpoints decreased by 33% ŽCI: 3% to 53%; P s 0.03.. A similar trend was observed for nonfatal heart failure Žy36%; CI: y60% to q2%; P s 0.06., for all cases of heart failure Žy29%; CI: y53% to q10%; P s 0.12., and for fatal and nonfatal myocardial infarction Žy30%; CI: y56% to q9%; P s 0.12.. Active treatment reduced all fatal and nonfatal cardiovascular endpoints by 31% ŽCI: 14% to 45%; P - 0.001.. In the intention-to-treat analysis w7x cardiovascular mortality tended to be less with active treatment Žy27%; CI: y48% to q2%; P s 0.07., but all-cause mortality was not influenced Žy14%; CI: y33% to q9%; P s 0.22.. Treating 1000 patients for 5 years could prevent 29 strokes or 53 major cardiovascular events. In subgroup analyses w12x, active treatment was equally beneficial in all stratification groups. Furthermore, the benefit of antihypertensive drug treatment on total Ž P s 0.009. and cardiovascular Ž P s 0.09. mortality weakened with advancing age, suggesting that in very old patients ŽG 80 years. only nonfatal endpoints were prevented. The reduction in total mortality with active treatment also decreased Ž P s 0.05. with lower systolic blood pressure at entry. For fatal and nonfatal stroke, the benefit of active treatment Ž P s 0.01. was evident only in nonsmokers Ž92.5% of all patients.. Benefit was also noticed in patients who remained on monotherapy with active nitrendipine w20x. Of the 4695 randomized Syst-Eur patients, 492 Ž10.5%. had diabetes mellitus at entry. Compared with the 4203 nondiabetic patients, the diabetics had higher systolic blood pressure Ž175.3 vs. 173.7 mmHg., lower diastolic blood pressure Ž84.5 vs. 85.6 mmHg., higher mean blood glucose concentrations Ž8.2 vs. 5.1 mmolrl., higher body mass index Ž28.3 vs. 27 kgrm2 ., and lower HDL cholesterol concentrations Ž1.3 vs. 1.4 mmolrl. w21x. A significantly greater proportion of the diabetic patients had experienced cardiovascular complications before enrollment, and the rate of cardiovascular complications during the trial was about twice the rate observed in the nondiabetics. Active treatment significantly reduced cardiovascular complications in diabetics ŽFig. 2.. After controlling for possible confounders, total mortality was reduced by 55% ŽCI: 15% to 76%., cardiovascular mortality by 76% ŽCI: 33% to 91%., all cardiovascular endpoints by 69% ŽCI: 41% to 84%., fatal and nonfatal stroke by 73% ŽCI: 26% to 90%., and all cardiac endpoints by 63% ŽCI: 10% to 85%.. In the nondiabetic patients, active treatment decreased all cardiovascular endpoints by 26% ŽCI: 6% to 41%. and fatal and nonfatal stroke by 38% ŽCI: 8% to 58%.. Active treatment
85
reduced total mortality, cardiovascular mortality, and all cardiovascular endpoints significantly more in the diabetic than in the nondiabetic patients Ž P-values: 0.04, 0.02, and 0.01, respectively.. Thus, the dihydropyridine-based treatment was particularly effective in diabetic patients, in whom active treatment was estimated to prevent 178 severe cardiovascular complications as opposed to only 22 in the nondiabetic group w21x. The per-protocol analysis w12x considered only the endpoints that had occurred during double-blind treatment and confirmed the results by intention-to-treat w7x. However, in the per-protocol analysis w12x, active treatment also decreased total mortality by 26% ŽCI: 0% to 46%; P s 0.05.. The per-protocol analysis suggested that treating 1000 patients for 5 years would prevent 24 deaths, 54 major cardiovascular endpoints, 29 strokes, or 25 cardiac endpoints. The Vascular Dementia Project w22–24x investigated whether antihypertensive drug treatment could reduce the incidence of dementia. At baseline and follow-up, cognitive function was assessed with the Mini Mental State Examination w25x; if the score was 23 or less, the diagnosis of dementia was established based on the DSM-III-R criteria w26x. In total, 2418 patients were enrolled in the dementia study. Median follow-up by intention to treat was 2.0 years. Among the 32 incident cases of dementia, 23 were Alzheimer’s disease, 7 had a mixed etiology, and only 2 were vascular. Compared with placebo Ž N s 1180., active treatment Ž N s 1238. reduced the incidence of dementia by 50% Ž0% to 76%; P s 0.05. from 7.7 to 3.8 cases per 1000 patient-years. At the risk observed in the placebo group, treating 1000 hypertensive patients for 5 years could prevent 19 cases. In the per-protocol analysis, active treatment decreased the rate by 60% Ž2% to 83%; P s 0.03.. Thus, active treatment prevented mainly degenerative dementia. 2.3. The Systolic Hypertension in China (Syst-China) trial Isolated systolic hypertension occurs in around 8% of Chinese people aged 60 years or older w27x. In 1988, the 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 w8,27,28x. All patients were initially started on placebo. After stratification for center, sex, and previous cardiovascular complications, alternate patients Ž N s 1253. were assigned nitrendipine 10–40 mg daily, with the possible addition of captopril 12.5–50.0 mg daily, or hydrochlorothiazide 12.5–50.0 mg daily, or both drugs. These study medications were titrated or combined to reduce the sitting systolic blood pressure by at least 20 mmHg to below 150 mmHg. In the remaining 1141 control patients, matching placebos were employed similarly.
86
J.A. Staessen et al.r European Journal of Internal Medicine 10 (1999) 82–87
At entry, sitting blood pressure averaged 170 mmHg systolic and 86 mmHg diastolic. Age averaged 66.5 years and total serum cholesterol was 5.1 mmolrl w8x. At 2 years of follow-up, the sitting systolic and diastolic blood pressures had fallen by 11 mmHg and 2 mmHg in the placebo group and by 20 mmHg and 5 mmHg in the active treatment group. The between-group differences were 9.1 mmHg systolic ŽCI: 7.6 to 10.7 mmHg. and 3.2 mmHg diastolic ŽCI: 2.4 to 4.0 mmHg.. Active treatment reduced total stroke by 38% from 20.8 to 13.0 endpoints per 1000 patient-years ŽCI: 9% to 58%; P s 0.01., all-cause mortality by 39% ŽCI: 16% to 57%; P s 0.003., cardiovascular mortality by 39% ŽCI: 4% to 61%; P s 0.03., stroke mortality by 58% ŽCI: 14% to 80%; P s 0.02., and all fatal and nonfatal cardiovascular endpoints by 37% ŽCI: 14% to 53%; P s 0.004.. Treatment of 1000 Chinese patients for 5 years could prevent 55 deaths, 39 strokes, or 59 major cardiovascular endpoints w8x. A subsequent subgroup analysis demonstrated that the benefit of antihypertensive treatment was particularly evident in diabetic patients and that for cardiac endpoints it tended to be slightly larger in nonsmokers w29x. Otherwise, the benefit of active treatment was not significantly influenced by the characteristics of the patients at entry into the Syst-China trial w29x. 3. A meta-analysis The results of the three outcome trials in older patients with isolated systolic hypertension were pooled, using methods described elsewhere w30,31x. Zelen’s exact test for homogeneity did not reach statistical significance for any of the endpoints considered. Thus, the hypothesis of a common underlying treatment effect across the three studies was not rejected. Overall, compared to placebo, active treatment reduced all-cause mortality by 17% ŽCI: 5% to 18%; P s 0.008. and cardiovascular mortality by 25% ŽCI: 8% to 39%; P s 0.005.; for fatal and nonfatal complications combined, these reductions were 32% for all cardiovascular endpoints ŽCI: 13% to 41%; P - 0.001., 37% for stroke ŽCI: 24% to 38%; P - 0.001., and 25% for myocardial infarction including sudden death ŽCI: 9% to 39% P - 0.001. w31x. 4. 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 blood pressure is 160 mmHg or higher. The entry diastolic blood pressure level averaged nearly 85 mmHg in the Syst-Eur w7x and SystChina w8x trials and was as low as 77 mmHg in the SHEP study w9x. These findings negate the hypothesis that vigorously lowering diastolic blood pressure compromises the
coronary circulation and provokes rather than prevents coronary complications w32x. Furthermore, long-acting dihydropyridines constitute a valid alternative to diuretics and beta-blockers in the primary prevention of cardiovascular disorders in elderly hypertensives. In isolated systolic hypertension, calcium channel blockade may be particularly indicated in diabetic patients w21x and in those at risk of dementia w24x.
References w1x Kannel WB, Gordon T. Evaluation of cardiovascular risk in the elderly: the Framingham study. Bull NY Acad Med 1978;54:573–91. w2x Staessen J, O’Brien E, Atkins N, Bulpitt CJ, Cox J, Fagard R et al. Amery A: the increase in blood pressure with age and body mass index is overestimated by conventional sphygmomanometry. Am J Epidemiol 1992;136:450–9. w3x Staessen J, Amery A, Fagard R. Editorial review. Isolated systolic hypertension in the elderly. J Hypertens 1990;8:393–405. w4x Buck C, Baker P, Bass M, Donner A. The prognosis of hypertension according to age at onset. Hypertension 1987;9:204–8. w5x Thijs L, Fagard R, Lijnen P, Staessen J, Van Hoof R, Amery A. Why is antihypertensive drug therapy needed in elderly patients with systolodiastolic hypertension? J Hypertens 1994;12 suppl 6:S25–S34. w6x The Systolic Hypertension in the Elderly Program Cooperative Research Group. Implications of the systolic hypertension in the elderly program. Hypertension 1993;21:335–43. w7x Staessen JA, Fagard R, Thijs L, Celis H, Arabidze GG, Birkenhager ¨ WH et al. For the Systolic Hypertension in Europe ŽSyst-Eur. Trial Investigators: randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. Lancet 1997;350:757–64. w8x Liu L, Wang JG, Gong L, Liu G, Staessen JA. For the Systolic Hypertension in China ŽSyst-China. Collaborative Group: comparison of active treatment and placebo for older patients with isolated systolic hypertension. J Hypertens 1998;16:1823–9. w9x SHEP Cooperative Research Group, Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program ŽSHEP.. JAMA 1991;265:3255–64. w10x Curb JD, Pressel SL, Cutler JA, Savage PJ, Applegate WB, Black H et al. For the Systolic Hypertension in the Elderly Cooperative Research Group: effect of diuretic-based antihypertensive treatment on cardiovascular disease risk in older diabetic patients with isolated systolic hypertension. JAMA 1996;276:1886–92. w11x Amery A, Birkenhager W, Bulpitt CJ, Clement D, de Leeuw P, ¨ Dollery CT et al. Syst-Eur. A multicentre trial on the treatment of isolated systolic hypertension in the elderly: objectives, protocol and organization. Aging Clin Exp Res 1991;3:287–302. w12x Staessen JA, Fagard R, Thijs L, Celis H, Birkenhager ¨ WH, Bulpitt CJ et al. For the Systolic Hypertension in Europe ŽSyst-Eur. Trial Investigators: subgroup and per-protocol analysis of the randomized European trial on isolated systolic hypertension in the elderly. Arch Intern Med 1998;158:1681–91. w13x Fletcher A, Spiegelhalter D, Staessen J, Thijs L, Bulpitt C. Implications for trials in progress of publication of positive results. Lancet 1993;342:653–7. w14x Kaplan NM. Systolic Hypertension in the Elderly Program ŽSHEP. and Swedish Trial in Old Patients With Hypertension ŽSTOP.. The promises and the potential problems. Am J Hypertens 1992;5:331–4. w15x Menard J, Day M, Chatellier G, Laragh JH. Some lessons from ´ Systolic Hypertension in the Elderly Program ŽSHEP.. Am J Hypertens 1992;5:325–30.
J.A. Staessen et al.r European Journal of Internal Medicine 10 (1999) 82–87 w16x Staessen J, Fagard R, Amery A, Isolated systolic hypertension in the elderly: implications of SHEP for clinical practice and for the ongoing trials. J Hum Hypertens 1991;5:469–74. w17x Staessen JA, Amery A, Birkenhager ¨ W. Inverse association between baseline pressure and benefit from treatment in isolated systolic hypertension. Hypertension 1994;23:269–70. w18x Furberg CD, Psaty BM, Meyer JV, Nifedipine. Dose-related increase in mortality in patients with coronary heart disease. Circulation 1995;92:1326–31. w19x Psaty BM, Heckbert SR, Koepsell TD, Siscovick DS, Raghunathan TE, Weiss NS et al. The risk of myocardial infarction associated with antihypertensive drug therapies, JAMA 1995;274:620–25. w20x Staessen JA, Thijs L, Fagard RH, Birkenhager WS, Arabidze G, ¨ Babeanu S et al. For the Systolic Hypertension in Europe ŽSyst-Eur. Trial Investigators: calcium channel blockade and cardiovascular prognosis in the European trial on isolated systolic hypertension. Hypertension 1998;32:404–09. w21x Tuomilehto J, Rastenyte D, Birkenhager ¨ WH, Thijs L, Antikainen R, Bulpitt CJ et al. For the Systolic Hypertension in Europe ŽSyst-Eur. Trial Investigators. Staessen JA: effects of calcium-channel blockage in older patients with diabetes and systolic hypertension. N Engl J Med 1999;340:677–84. w22x Forette F, Amery A, Staessen J, Strasser T, Thijs L, Beevers DG et al. Is prevention of vascular dementia possible? The Syst-Eur Vascular Dementia Project. Aging Clin Exp Res 1991;3:373–82. w23x Seux ML, Thijs L, Forette F, Staessen JA, Birkenhager ¨ WH, Bulpitt CJ et al. Correlates of cognitive status of old patients with isolated systolic hypertension: the Syst-Eur Vascular Dementia Project, J Hypertens 1998;16:963–69.
87
w24x Forette F, Seux ML, Staessen JA, Thijs L, Birkenhager WH, ¨ Babarskiene MR et al. On behalf of the Syst-Eur Investigators: prevention of dementia in randomised double-blind placebo-controlled Systolic Hypertension in Europe ŽSyst-Eur. trial. Lancet 1998;352:1347–51. w25x Folstein MF, Folstein SE, McHugh PR. ‘Mini-mental state’. A practical method for grading the cognitive state of patients for the clinician. J Psychiat Res 1975;12:189–98. w26x American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders. Washington DC, USA, 1987. w27x Collaborative Group Coordinating Center. Systolic hypertension in the elderly: Chinese trial ŽSyst-China. — interim report. Chin J Cardiol 1992;20:270–75. w28x Wang J, Liu G, Wang X, Zhang S, Sun M, Pan X et al. On behalf of the Syst-China Investigators: Long-term blood pressure control in older Chinese patients with isolated systolic hypertension: a progress report on the Syst-China trial. J Hum Hypertens 1996;10:735–42. w29x Wang JG, Staessen JA, Gong L, Liu L. For the Systolic Hypertension in China Investigator: subgroup analysis of the placebo-controlled Chinese trial on isolated systolic hypertension in the elderly. Arch Intern Med 1999, in press. w30x Thijs L, Fagard R, Lijnen P, Staessen J, Van Hoof R, Amery A. A meta-analysis of outcome trials in elderly hypertensives. J Hypertens 1992;10:1103–09. w31x Staessen JA, Wang JG. Benefit of antihypertensive drug treatment in older patients with isolated systolic hypertension. Eur Heart J 1999, in press. w32x Cruickshank JM, Thorp JM, Zacharias FJ. Benefits and potential harm of lowering high blood pressure. Lancet i 1987;581–83.