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Anti-hypertensive therapy reduced the incidence of stroke in older patients with isolated systolic hypertension
Anti-hypertensive therapy reduced the incidence of stroke in older patients with isolated systolic hypertension
Staessen JA, Fagard R, Thijs Let al for the Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. Lancet 1997; 350:757-764
Objective To examine the efficacy of nitrendipine with the possible addition of enalapril and hydrochlorothiazide in comparison to placebo in reducing the risk of stroke in older patients with isolated systolic hypertension. Design Randomized, double-blind, placebocontrolled trial with 2-year mean duration of follow-up. Setting 198 centers in 23 countries across western and eastern Europe. Patients 4695 patients over the age of 60 years (mean age 70; 67% women) with sitting OMMENTAW' The data from the SYST-EUR trial appear to replicate and extend the findings of the Systolic Hypertension in the Elderly Program (SH EP)? Treatment of patients with isolated systolic hypertension or predominant systolic hypertension reduces the subsequent rate of stroke. As was found for the diuretic-based regimen in SHEP, the nitrendipine-based regimen used in SYST-EUR showed a substantial reduction in rates of fatal and non-fatal stroke (RR 0.58; 95% CI 0.40-0.83; P = 0.003). These findings are further corroborated by the recent publication of a non-randomized trial, the Shanghai Trial of Nifedipine in the Elderly (STONE)? In STONE, patients with isolated systolic hypertension treated with long-acting nifedipine had lower rates of stroke than those who were given placebo (RR 0.43; Cl 0.24-0.77). The levels of pre-randomization 8P, age, and other demographic and risk factor characteristics were similar between the SYST-EUR and SHEP studies. Also, the amount of BP lowering was nearly equivalent between the two studies. In
22
systolic BP between 160 and 219 mm Hg and diastolic BP < 95 mm Hg on the average of six baseline measurements. Intervention Patients were randomly allocated to receive nitrendipine (10-40 mg daily) and, if necessary, enalapril (5-20 mg daily) and hydrochlorothiazide (12.5-25 mg daily), and matching placebo. A reduction in systolic BP by at least 20 mm Hg to less than 150 mm Hg was desired. Main outcome measures The primary end-point was fatal and nonfatal stroke. Other main end-points were death, retinal hemorrhage or exudates, MI, CHF, dissecting aortic aneurysm and renal insufficiency. SYST-EUR the reduction of stroke (44%) was slightly greater than that seen in 5HEP (37%) but this level of difference is unlikely to be meaningful. SHEP showed a reduction in total CHD of 25% and in total CVD of 32% while the corresponding numbers for SYSTEUR were reductions of 26% and 31%, respectively. In the SYST-EUR trial, the nitrendipine-based regimen did not have nearly the impact on heart failure (RR 0.71; CI 0.47-1.10; P= 0.12) shown in SHEP (RR 0.51; CI 0.37-0.71; P< 0.001). However, some of this difference could be explained by the fact that the duration of follow-up in SYST-EUR was substantially shorter than that in the SHEP trial. However, one troubling issue with regard to SYST-EUR is that the number of participants lost to follow-up was larger than is usually seen in carefully conducted trials (118 lost in the placebo group and 121 lost in the active drug group) so it remains possible that the SYST-EUR trial overestimated the benefit observed with treatment. Although some have used the data from these t w o trials to draw inferences with regard to the relative superiority of
EVIDENCE-BASED CARDIOVASCULAR MEDICINE
Main results The trial was terminated prematurely because of a significant benefit in the active treatment group for the primary outcome of stroke. At a median of 2 years follow-up, systolic and diastolic BPs had fallen by a mean of 13 and 2 mm Hg, respectively, in the placebo group and by a mean of 23 and 7 mm Hg, respectively, in the intervention group. Significantlyfewer patients in the active intervention group than in the placebo group experienced the primary outcome of fatal or non-fatal stroke (7.9 vs 13.7%; relative risk reduction [RRR] 42%; 95% CI 17-60%; P = 0.003). There was a trend toward active treatment being associated with fewer deaths from cardiovascular cause (9.8 vs 13.5%; RRR 27%; C1-2 to +48; P = 0.07) but no association with ail-canse mortality (20.5 vs 24%; RRR 14%; C1-9 to +33; P = 0.22). All fatal and non-fatal cardiovascular events were Jess frequent in the active treatment group (23.3 vs 33.9%; RRR 31%; CI 14-45%; P < 0.001). Conclusion Anti-hypertensivetreatment with nitrendipine, followed by enalapril and hydrochlorothiazide if necessary, was associated with fewer strokes and other adverse cardiovascular events in older patients with isolated systolic hypertension. diurettcs or dihydropyridine calciumchannel-blockers, such comparisons are tenuous at best because each study basically compared an active treatment regimen vs placebo. Therefore, the major finding of these t w o studies is that BP lowering in patients with isolated systolic hypertension does reduce stroke and other forms of CVD events as well. Any issues of comparisons between t w o active treatment regimens should be left up to the ongoing large scale multi-center trials such as the Antihypertension Lipid Lowering Heart Attack Trial (ALLHAT) 3 currently being undertaken in the USA by the National Heart, Lung and Blood Institute. W i l l i a m B. Applegate, MD University o f Tennessee Memphis, TIM, USA O t h e r sources 1. Curb JD, Pressel SL, Cutler JA et al.
JAMA 1996; 276:1886-1892 2. Gong L, Zhang W, Zhu Y et al.
J Hypertens 1996; 14:1237-1245
3. Davis BR, Cutler JA, Gordon DJ et al. Am J Hypertens 1996; 9:342-360
MARCH 1998
Staessen JA, Fagard R, Thijs Let al for the Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. Lancet 1997; 350:757-764
Objective To examine the efficacy of nitrendipine with the possible addition of enalapril and hydrochlorothiazide in comparison to placebo in reducing the risk of stroke in older patients with isolated systolic hypertension. Design Randomized, double-blind, placebocontrolled trial with 2-year mean duration of follow-up. Setting 198 centers in 23 countries across western and eastern Europe. Patients 4695 patients over the age of 60 years (mean age 70; 67% women) with sitting OMMENTAW' The data from the SYST-EUR trial appear to replicate and extend the findings of the Systolic Hypertension in the Elderly Program (SH EP)? Treatment of patients with isolated systolic hypertension or predominant systolic hypertension reduces the subsequent rate of stroke. As was found for the diuretic-based regimen in SHEP, the nitrendipine-based regimen used in SYST-EUR showed a substantial reduction in rates of fatal and non-fatal stroke (RR 0.58; 95% CI 0.40-0.83; P = 0.003). These findings are further corroborated by the recent publication of a non-randomized trial, the Shanghai Trial of Nifedipine in the Elderly (STONE)? In STONE, patients with isolated systolic hypertension treated with long-acting nifedipine had lower rates of stroke than those who were given placebo (RR 0.43; Cl 0.24-0.77). The levels of pre-randomization 8P, age, and other demographic and risk factor characteristics were similar between the SYST-EUR and SHEP studies. Also, the amount of BP lowering was nearly equivalent between the two studies. In
22
systolic BP between 160 and 219 mm Hg and diastolic BP < 95 mm Hg on the average of six baseline measurements. Intervention Patients were randomly allocated to receive nitrendipine (10-40 mg daily) and, if necessary, enalapril (5-20 mg daily) and hydrochlorothiazide (12.5-25 mg daily), and matching placebo. A reduction in systolic BP by at least 20 mm Hg to less than 150 mm Hg was desired. Main outcome measures The primary end-point was fatal and nonfatal stroke. Other main end-points were death, retinal hemorrhage or exudates, MI, CHF, dissecting aortic aneurysm and renal insufficiency. SYST-EUR the reduction of stroke (44%) was slightly greater than that seen in 5HEP (37%) but this level of difference is unlikely to be meaningful. SHEP showed a reduction in total CHD of 25% and in total CVD of 32% while the corresponding numbers for SYSTEUR were reductions of 26% and 31%, respectively. In the SYST-EUR trial, the nitrendipine-based regimen did not have nearly the impact on heart failure (RR 0.71; CI 0.47-1.10; P= 0.12) shown in SHEP (RR 0.51; CI 0.37-0.71; P< 0.001). However, some of this difference could be explained by the fact that the duration of follow-up in SYST-EUR was substantially shorter than that in the SHEP trial. However, one troubling issue with regard to SYST-EUR is that the number of participants lost to follow-up was larger than is usually seen in carefully conducted trials (118 lost in the placebo group and 121 lost in the active drug group) so it remains possible that the SYST-EUR trial overestimated the benefit observed with treatment. Although some have used the data from these t w o trials to draw inferences with regard to the relative superiority of
EVIDENCE-BASED CARDIOVASCULAR MEDICINE
Main results The trial was terminated prematurely because of a significant benefit in the active treatment group for the primary outcome of stroke. At a median of 2 years follow-up, systolic and diastolic BPs had fallen by a mean of 13 and 2 mm Hg, respectively, in the placebo group and by a mean of 23 and 7 mm Hg, respectively, in the intervention group. Significantlyfewer patients in the active intervention group than in the placebo group experienced the primary outcome of fatal or non-fatal stroke (7.9 vs 13.7%; relative risk reduction [RRR] 42%; 95% CI 17-60%; P = 0.003). There was a trend toward active treatment being associated with fewer deaths from cardiovascular cause (9.8 vs 13.5%; RRR 27%; C1-2 to +48; P = 0.07) but no association with ail-canse mortality (20.5 vs 24%; RRR 14%; C1-9 to +33; P = 0.22). All fatal and non-fatal cardiovascular events were Jess frequent in the active treatment group (23.3 vs 33.9%; RRR 31%; CI 14-45%; P < 0.001). Conclusion Anti-hypertensivetreatment with nitrendipine, followed by enalapril and hydrochlorothiazide if necessary, was associated with fewer strokes and other adverse cardiovascular events in older patients with isolated systolic hypertension. diurettcs or dihydropyridine calciumchannel-blockers, such comparisons are tenuous at best because each study basically compared an active treatment regimen vs placebo. Therefore, the major finding of these t w o studies is that BP lowering in patients with isolated systolic hypertension does reduce stroke and other forms of CVD events as well. Any issues of comparisons between t w o active treatment regimens should be left up to the ongoing large scale multi-center trials such as the Antihypertension Lipid Lowering Heart Attack Trial (ALLHAT) 3 currently being undertaken in the USA by the National Heart, Lung and Blood Institute. W i l l i a m B. Applegate, MD University o f Tennessee Memphis, TIM, USA O t h e r sources 1. Curb JD, Pressel SL, Cutler JA et al.
JAMA 1996; 276:1886-1892 2. Gong L, Zhang W, Zhu Y et al.
J Hypertens 1996; 14:1237-1245
3. Davis BR, Cutler JA, Gordon DJ et al. Am J Hypertens 1996; 9:342-360
MARCH 1998