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(Hypertension. 1998;32:410-416.)
© 1998 American Heart Association, Inc.

Scientific Contributions

Calcium Channel Blockade and Cardiovascular Prognosis in the European Trial on Isolated Systolic Hypertension

Jan A. Staessen; Lutgarde Thijs; Robert H. Fagard; Willem H. Birkenhäger; Guramy Arabidze; Speranta Babeanu; Blas Gil-Extremera; Christopher J. Bulpitt; Christopher Davidson; Peter W. de Leeuw; Aris D. Efstratopoulos; Astrid E. Fletcher; Roberto Fogari; Matti Jääskivi; Kalina Kawecka-Jaszcz; Choudomir Nachev; James C. Petrie; Marie-Laure Seux; Jaakko Tuomilehto; John Webster; Yair Yodfat; ; for the Systolic Hypertension in Europe (Syst-Eur) Trial Investigators¹

Correspondence to Jan A. Staessen, MD, PhD, Klinisch Laboratorium Hypertensie, Inwendige Geneeskunde-Cardiologie, UZ Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium. E-mail jan.staessen{at}med.kuleuven.ac.be

	Abstract

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Abstract—In the double-blind Systolic Hypertension in Europe (Syst-Eur) Trial, active treatment was initiated with nitrendipine (10 to 40 mg/d) with the possible addition of enalapril (5 to 20 mg/d) and/or hydrochlorothiazide (12.5 to 25 mg/d) titrated or combined to reduce sitting systolic blood pressure by at least 20 mm Hg to <150 mm Hg. In the control group, matching placebos were used similarly. In view of persistent concerns about the use of calcium channel blockers as first-line antihypertensive drugs, this report explored to what extent nitrendipine, administered alone, prevented cardiovascular complications. Age at randomization averaged 70.2 years and systolic/diastolic blood pressure 173.8/85.5 mm Hg. Of 2398 actively treated patients, 1327 took only nitrendipine (average dose, 23.4 mg/d), and 1042 progressed to other treatments including nitrendipine (n=757; 35.7 mg/d), enalapril (n=783; 13.4 mg/d), and/or hydrochlorothiazide (n=294; 21.0 mg/d). Compared with the whole placebo group (n=2297), patients receiving monotherapy with nitrendipine had 25% (P=0.05) fewer cardiovascular end points, and those progressing to other active treatments showed decreases (P0.01) in total mortality (40%), stroke (59%), and all cardiovascular end points (39%). Among the control patients, 863 used only the first-line placebo. Compared with this subgroup, patients receiving monotherapy with nitrendipine showed a nearly 50% (P0.004) reduction of all types of end points, including total and cardiovascular mortality. The full relative benefit from nitrendipine was seen as early as 6 months after randomization. To ascertain that the benefit conferred by the dihydropyridine was not due to selection bias, the 1327 patients remaining on monotherapy with nitrendipine were matched by gender, age, previous cardiovascular complications, and systolic blood pressure at entry with an equal number of placebo patients. In this analysis, nitrendipine reduced (P0.05) cardiovascular mortality by 41%, all cardiovascular end points by 33%, and fatal and nonfatal cardiac end points by 33%. Despite the limitations inherent in post hoc analyses, the present findings suggest that the calcium channel blocker nitrendipine, given as a single antihypertensive medication, prevents cardiovascular complications in older patients with isolated systolic hypertension.

Key Words: calcium channel blockers • hypertension, isolated systolic • prognosis

	Introduction

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The Systolic Hypertension in Europe (Syst-Eur) Trial¹ investigated whether active drug treatment reduced the incidence of stroke and other cardiovascular complications in older patients with isolated systolic hypertension.² After publication of the Systolic Hypertension in the Elderly Program (SHEP) results in 1991,³ the trial continued in view of the remaining uncertainty with regard to the primary research question,^{4 5 6} but in 1997 it was stopped because the monitoring boundary for a treatment benefit was crossed.¹ In the analysis by intention-to-treat, active treatment decreased the overall stroke rate from 13.7 to 7.9 end points per 1000 patient-years (42%; P=0.003) and the incidence of all cardiovascular complications from 33.9 to 23.3 end points per 1000 patient-years (31%; P<0.001).¹

In the Syst-Eur trial, active treatment was initiated with the dihydropyridine calcium channel blocker nitrendipine.⁷ The controversy about possible adverse effects of calcium channel blockers arose only in 1995⁸ and was not considered in 1991 or 1992, when the Ethics Committee of the Syst-Eur trial and the review boards of the participating centers decided to continue the trial. However, in view of persistent concerns about the use of calcium channel blockers as first-line antihypertensive drugs,^{8 9 10 11 12 13 14} the present analysis explored whether treatment with nitrendipine⁷ alone influenced prognosis.

	Methods

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The protocol of the Syst-Eur trial (described elsewhere^{1 2} ) was approved by the Ethics Committees of the University of Leuven and the participating centers and implemented according to the principles outlined in the Helsinki declaration.¹⁵ Eligible patients were at least 60 years old. They had a sitting average systolic blood pressure ranging from 160 to 219 mm Hg, with diastolic blood pressure <95 mm Hg and standing systolic blood pressure of at least 140 mm Hg.

After stratification by center, gender, and previous cardiovascular complications, the patients were randomized to double-blind treatment with active medication or placebo by means of a computerized random function. Active treatment was initiated with nitrendipine (first-line medication, 10 to 40 mg/d). If necessary, the calcium channel blocker was combined with or replaced by enalapril (second-line medication, 5 to 20 mg/d), hydrochlorothiazide (third-line medication, 12.5 to 25 mg/d), or both drugs. In the control group, placebos matching the first-line, second-line, and third-line active drugs were used similarly. The study medications were stepwise titrated and combined to reduce sitting systolic blood pressure by 20 mm Hg or more to <150 mm Hg.²

Statistical analysis was performed with SAS software (SAS Institute Inc) using 2-sided tests. Comparisons of means and proportions relied on the standard normal z test and the ² statistic, respectively. Net blood pressure differences after randomization were calculated by subtracting the mean change from baseline during active treatment from the corresponding change in the control group.¹⁶ By definition, the present analysis included only end points, which occurred during the double-blind phase of the trial (per-protocol analysis).¹⁷ Survival curves were compared using Kaplan-Meier survival function estimates and the log-rank test.

	Results

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Baseline Characteristics and Follow-Up
At randomization, the patients in the placebo (n=2297) and active treatment (n=2398) groups had similar characteristics. The study included 3138 women (66.8%). Cardiovascular complications at entry were present in 1402 patients (29.9%). Mean±SD age at randomization averaged 70.2±6.7 years, ranging from 60 to 98 years. The sitting blood pressure at entry was 173.8±10.0 mm Hg systolic (range, 160 to 218 mm Hg) and 85.5±5.9 mm Hg diastolic (range, 49 to 94 mm Hg).

The total number of patient-years in the per-protocol analysis was 5166 in the active treatment group and 4508 in the placebo group. Median follow-up was 1.7 years (range, 1 to 95 months) and 1.5 years (range, 1 to 90 months), respectively. Compared with the active treatment group, fewer placebo patients (P<0.001) remained on treatment with only the first-line placebo. The control patients proceeded earlier and more frequently to second-line or third-line medications (Figure 1). In the active treatment group, enalapril was started in 1021 patients, but at the termination of the trial only 122 actively treated patients were receiving single treatment with enalapril. For hydrochlorothiazide, these numbers were 413 and 53, respectively.

View larger version (16K): [in this window] [in a new window]   Figure 1. Percentage of patients in the active treatment group (solid lines) and placebo group (dotted lines) who remained on single first-line treatment (left), who progressed to the second-line medication (middle), or who took all 3 study medications (right). The curves represent Kaplan-Meier estimates, in which the denominator is the number of patients available for analysis at each time point.

Prognosis in All Randomized Patients
The per-protocol analysis included 4695 randomized patients. At 6 months, most patients randomized to active treatment were still receiving monotherapy with the first-line study medication (Figure 2). The net blood pressure reduction in the active treatment group was 7.7 mm Hg systolic (95% confidence interval [CI], 6.8 to 8.6 mm Hg) and 3.3 mm Hg diastolic (95% CI, 2.8 to 3.7 mm Hg). At this early moment in the trial (Table 1), active treatment reduced all cardiovascular end points by 55% (P=0.005), all cardiac end points by 62% (P=0.007), total mortality by 60% (P=0.01), and cardiovascular mortality by 62% (P=0.02). In contrast, the 37% reduction in fatal and nonfatal stroke was not significant. The reduction in all cardiovascular end points at 6 months was of the same order of magnitude as at 1, 2, or 4 years of follow-up (Figure 3).

View larger version (45K): [in this window] [in a new window]   Figure 2. Diagram of patient flow.

View this table: [in this window] [in a new window]   Table 1. Per-Protocol Analysis of All Patients Followed for Up to 6 Months

View larger version (23K): [in this window] [in a new window]   Figure 3. Cumulative rates of all cardiovascular end points in the per-protocol analysis. The between-group differences in the rates are presented for various follow-up intervals. The benefit of active treatment was already significant at 6 months, when most of the 4695 randomized patients were still on monotherapy with active nitrendipine or matching placebo.

Prognosis on Active Treatment in Comparison With the Whole Placebo Group
In the active treatment group, 1327 patients remained on single treatment with nitrendipine (median follow-up, 1.4 years), 1042 progressed to second-line or third-line medications (median follow-up, 2.0 years), and 29 were taking unspecified active study medication. The former 2 groups were compared with the whole placebo group (n=2297). These 3 groups had similar characteristics at baseline, with the exception of sitting systolic blood pressure. In the actively treated patients remaining on treatment with nitrendipine alone, it was on average 2.0 mm Hg lower than in the whole placebo group (171.9 versus 173.9 mm Hg; P<0.001).

In the patients receiving monotherapy with active nitrendipine (average daily dose, 23.4±11.5 mg) compared with the whole placebo group, the net blood pressure reductions at 2 years averaged 12.9 mm Hg systolic (95% CI, 11.3 to 14.5 mm Hg) and 5.7 mm Hg diastolic (95% CI, 4.9 to 6.5 mm Hg). The 1327 patients receiving monotherapy with nitrendipine experienced a 25% (95% CI, 0% to 44%; P=0.05) lower incidence of fatal and nonfatal cardiovascular end points (Table 2, left panel).

View this table: [in this window] [in a new window]   Table 2. Prognosis on Active Treatment in Comparison With the Whole Placebo Group

Of 1042 actively treated patients who progressed to enalapril or hydrochlorothiazide, 757 (72.6%) received nitrendipine (daily dose at 2 years, 35.7±9.1 mg), 783 (75.1%) took enalapril (daily dose, 13.4±6.2 mg), and 294 (28.2%) received hydrochlorothiazide (daily dose, 21.0±7.1 mg). In the actively treated progressors compared with the whole placebo group, the net blood pressure reductions at 2 years averaged 10.3 mm Hg systolic (95% CI, 8.5 to 12.1 mm Hg) and 4.9 mm Hg diastolic (95% CI, 4.0 to 5.8 mm Hg). Active treatment involving second-line or third-line drugs (Table 2, right panel) reduced total mortality by 40% (P=0.01), all cardiovascular end points by 39% (P<0.001), fatal and nonfatal stroke by 59% (P=0.001), and all cardiac end points by 29% (P=0.06).

Prognosis in Patients Remaining on Single First-Line Treatment
In 1327 actively treated patients and 863 placebo patients who during total follow-up (Figure 2) remained on the first-line medication, the net blood pressure decreases at 2 years averaged 6.4 mm Hg systolic (95% CI, 4.3 to 8.5 mm Hg) and 4.0 mm Hg diastolic (95% CI, 2.9 to 5.2 mm Hg). Nitrendipine given as the only active medication, compared with the corresponding placebo, significantly decreased the incidence of all types of end points with the exception of myocardial infarction and heart failure (Table 3).

View this table: [in this window] [in a new window]   Table 3. Prognosis in Patients Remaining on Single First-Line Treatment

Prognosis in Patients Progressing to Second-Line or Third-Line Study Medications
The 1042 actively treated patients who progressed to enalapril, hydrochlorothiazide, or both drugs were compared with the corresponding 1394 patients randomized to placebo (median follow-up, 1.8 years). In all progressors, active treatment reduced systolic blood pressure at 2 years on average by 12.6 mm Hg (95% CI, 10.7 to 14.6 mm Hg) and diastolic blood pressure by 5.5 mm Hg (95% CI, 4.5 to 6.4 mm Hg). Near median follow-up, active treatment reduced systolic blood pressure significantly more in the progressors than in the patients continuing with monotherapy with nitrendipine (net blood pressure reductions, 12.6 mm Hg versus 6.4 mm Hg; P<0.001). Among progressors (Table 4), active treatment conferred significant benefit only in terms of stroke prevention (-44%; P=0.05).

View this table: [in this window] [in a new window]   Table 4. Prognosis in Patients Progressing to Second-Line or Third-Line Study Medications

Matched-Pairs Analysis
The 1327 patients who continued monotherapy with active nitrendipine were matched by gender, age (60 to 69, 70 to 79, and 80 years), previous cardiovascular complications, and systolic blood pressure at entry (within 4 mm Hg) with an equal number of patients drawn from the control group, regardless of the type of the placebos taken (Table 5). At 2 years (median follow-up in the 2 groups), the net blood pressure reduction in the actively treated patients averaged 13.7 mm Hg systolic (95% CI, 11.9 to 15.5 mm Hg) and 5.4 mm Hg diastolic (95% CI, 4.5 to 6.4 mm Hg). Compared with the matched control group (Table 5), active nitrendipine reduced cardiovascular mortality (Figure 4) by 41% (95% CI, 0% to 66%; P=0.05), all cardiovascular end points by 33% (95% CI, 8% to 51%; P=0.01), fatal and nonfatal cardiac end points by 33% (95% CI, 0% to 55%; P=0.05), and fatal and nonfatal heart failure by 48% (95% CI, 0% to 73%; P=0.05).

View this table: [in this window] [in a new window]   Table 5. Prognosis in 1327 Patients on Single Treatment With Active Nitrendipine in Comparison With Matched1 Placebo Patients

View larger version (17K): [in this window] [in a new window]   Figure 4. Cumulative rates of cardiovascular mortality in the matched-pair analysis. The 1327 patients who throughout follow-up remained on monotherapy with active nitrendipine were matched by gender, age, previous cardiovascular complications, and systolic blood pressure at entry with an equal number of patients drawn from the whole placebo group.

	Discussion

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So-called "post hoc" analyses have inherent limitations because they may not follow the lines of randomization. However, in the per-protocol analysis of all randomized patients, this problem was minimized. At 6 months, when most actively treated patients were still receiving monotherapy with nitrendipine or matching first-line placebo (Figure 2), the reduction in all cardiovascular end points was of the same order of magnitude as at 2 or 4 years of follow-up (Figure 3). Because no other antihypertensive drugs were compared with placebo, any difference between the 2 treatment groups may have been due to blood pressure reduction rather than to a drug-class effect. The present findings are in contradiction with other smaller trials of calcium channel blockers.¹⁸ In the Syst-Eur trial, the benefit of active treatment was not less in diabetic than nondiabetic patients, as reported by other investigators.¹⁴

Patients randomized to placebo proceeded earlier and more frequently to second-line or third-line medications (Figure 1) because of the need to attain the target blood pressure. The issue of possible selection bias in the control group was addressed by contrasting prognosis in patients on monotherapy with nitrendipine with the incidence of end points in various control groups. In a first step, all placebo patients were used as controls. Patients taking nitrendipine alone had 25% fewer cardiovascular end points (Table 2, left panel), and those progressing to other active treatments (Table 2, right panel) showed decreases in total mortality (40%), stroke (59%), and all cardiovascular end points (39%). At baseline, the groups involved in these comparisons had similar cardiovascular risk profiles in terms of gender distribution, previous cardiovascular complications,¹⁷ smoking habits,¹⁷ and average age. However, compared with the placebo group as a whole, systolic blood pressure at entry was significantly lower in the actively treated patients who remained on monotherapy with active nitrendipine. Previous analyses of cardiovascular mortality¹⁷ showed a significant interaction between active treatment and systolic blood pressure at randomization, suggesting greater benefit in patients with higher initial systolic blood pressure.¹⁷ Moreover, throughout follow-up, the fall in systolic blood pressure was more pronounced in actively treated progressors than in patients who received only nitrendipine. The interaction with initial systolic blood pressure and the larger blood pressure reduction on multiple drug treatment may explain why, in comparison with the whole placebo group, the relative benefit of active treatment was more readily demonstrated in the progressors than in the patients remaining on nitrendipine alone.

A further step of the analysis compared prognosis in patients remaining on single nitrendipine treatment or in those progressing to multiple drug treatment with outcome in the corresponding placebo subgroups. Patients taking only nitrendipine showed a nearly 50% reduction of most types of end points, including total and cardiovascular mortality (Table 3), whereas in patients progressing to enalapril or hydrochlorothiazide, only total stroke was significantly reduced by 44% (Table 4). Because patients who experienced end points early in the trial withdrew from double-blind treatment and could not progress to second-line or third-line study medications, and because active treatment conferred immediate benefit (Figure 3), the rates of all types of end points were substantially higher in patients taking the first-line placebo than in those proceeding to second-line or third-line placebo tablets. The high rates in the patients on single first-line placebo treatment, in turn, facilitated the demonstration of benefit in the patients on monotherapy with active nitrendipine.

To ascertain that the apparent benefit conferred by nitrendipine was not due to selection bias in the control group, the 1327 patients remaining on single nitrendipine treatment were matched by gender, age, previous cardiovascular complications, and systolic blood pressure at entry with an equal number of placebo patients, regardless of the type of the placebos taken. In this analysis (Table 5), nitrendipine reduced cardiovascular mortality by 41%, all cardiovascular end points by 33%, and cardiac end points by 33%. In all randomized patients, the corresponding estimates of benefit in the per-protocol analysis¹⁷ were 26% (P=0.13), 32% (P=0.001), and 26% (P<0.05), respectively. Thus, the nearly one third reduction of all cardiovascular end points in the subgroup of patients on single treatment with nitrendipine is consistent with the benefit observed in all patients randomized to active treatment. This observation again suggests that cardiovascular prevention in the Syst-Eur trial may to a large extent be ascribed to calcium channel blockade. The small number of patients on single treatment with enalapril made any search for specific effects of this drug impossible.

In conclusion, the present findings demonstrate that the dihydropyridine calcium channel blocker nitrendipine, independent of associated antihypertensive drugs, prevents cardiovascular complications in older patients with isolated systolic hypertension. Several arguments support this contention. First, in the per-protocol analysis involving all patients, the incidence of cardiovascular end points was already significantly reduced at 6 months, when most actively treated patients were still on monotherapy with nitrendipine. Second, in comparison with the whole placebo group, single treatment with nitrendipine reduced the incidence of all cardiovascular end points by one fourth. Third, in comparisons involving only the patients remaining on the first-line study medication, nitrendipine nearly halved the rates of all major end points. Finally, nitrendipine reduced cardiovascular mortality, all cardiovascular and cardiac end points, and heart failure when actively treated patients remaining on single nitrendipine treatment were compared with control patients with a closely matching cardiovascular risk profile at randomization.

	Acknowledgments

 
The Syst-Eur trial, initiated by the late Professor A. Amery, was a concerted action of the BIOMED Research Program sponsored by the European Union. The trial was carried out in consultation with the World Health Organization, the International Society of Hypertension, the European Society of Hypertension, and the World Hypertension League. The trial was sponsored by BayerAG (Wuppertal, Germany). The National Fund for Scientific Research (Brussels, Belgium) provided additional support. Study medication was donated by BayerAG and Merck, Sharpe & Dohme Inc (West Point, Pa).

	Footnotes

 
¹ A complete list of the participants in this trial is given in Reference 1.

Received March 6, 1998; first decision March 27, 1998; accepted May 13, 1998.

	References

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