Abstract and Introduction
Abstract
Background The purposes of the study were to determine the effects of addition of perindopril to long-term continuous treatment with calcium-channel blocker (CCB) on cardiac outcomes in the stable coronary artery disease (CAD) population of EUROPA and to explore the presence of synergy between perindopril and CCB in secondary prevention.
Methods We identified participants receiving CCB at every visit during the 4.2-year follow-up and analyzed the effect of addition of perindopril (n = 1,022 perindopril/CCB vs n = 1,100 placebo/CCB).
Results Addition of perindopril to CCB significantly reduced total mortality by 46% (P < .01 vs placebo) and primary end point (a composite of cardiovascular mortality, nonfatal myocardial infarction, and resuscitated cardiac arrest) by 35% (P < .05 vs placebo). There were 41%, 54%, and 28% reductions in cardiovascular mortality, hospitalization for heart failure, and myocardial infarction, respectively. Comparison of hazard ratios suggests the presence of a clinical synergy between perindopril and CCB, with a greater effect than addition of individual effects.
Conclusion Addition of perindopril to CCB in stable CAD patients had a significant supplementary impact on cardiac outcomes and mortality.
Introduction
Secondary prevention with an angiotensin-converting enzyme (ACE) inhibitor in coronary artery disease (CAD) is often combined with symptomatic treatment with a calcium-channel blocker (CCB). Such a regimen has the added benefit of better control of blood pressure (BP) in the case of hypertension, in line with the more intensive targets required in high-risk patients (<130/80 mm Hg). The rationale for the treatment of hypertension with a combination of perindopril and the CCB amlodipine is based on the results of the Anglo-Scandinavian Cardiac Outcomes Trial—Blood Pressure-Lowering Arm (ASCOT-BPLA) trial, which included hypertensive individuals with ≥3 other cardiovascular risk factors. ASCOT compared a more "modern" regimen of amlodipine ± perindopril versus an "older" regimen, namely, β-blocker ± thiazide diuretic, and found that amlodipine/perindopril significantly reduced total and cardiovascular mortality by 11% and 24%, respectively (both P < .05). Similar reductions were observed for the rates of fatal and nonfatal stroke and cardiovascular events and procedures. The weight of the results from ASCOT contributed to early modification of guidelines regarding the treatment of hypertension in Europe. Angiotensin-converting enzyme inhibitors and CCBs are considered to act in synergy in hypertension, in increased BP lowering, improved fibrinolytic balance, and reduction of secondary effects.
The European Trial on Reduction of Cardiac Events with Perindopril in patients with stable Coronary Artery Disease (EUROPA) showed that ACE inhibition with perindopril significantly reduced a composite primary end point of cardiovascular death, nonfatal myocardial infarction (MI), and resuscitated cardiac arrest by 20% for 4.2 years (event rates 8.0% for perindopril vs 9.9% for placebo, P < .0005). At baseline, 32% (n = 3,955) of the EUROPA population were receiving CCB, and subgroup analysis showed a difference in primary end point in favor of perindopril in those patients (event rates 9.9% for perindopril vs 11.7% for placebo). However, that subgroup analysis was independent of the continuity of CCB use throughout the rest of the 4.2 years of the trial because it depended only on CCB use at baseline.
In this report, we describe clinical evidence suggesting a clinical synergy between the ACE inhibitor perindopril and CCB in secondary prevention for patients with stable CAD. In this post hoc analysis, we used the EUROPA database to explore the effect of long-term continuous treatment with perindopril and CCB on outcomes in patients with stable CAD. We identified 2 EUROPA subpopulations in each of the randomization groups: one of participants who received CCB at every visit from baseline to the study end and another subpopulation of participants who never received CCB at any point in the study. We analyzed the effect of allocation to perindopril versus placebo in each of these subpopulations on the composite primary end point, total and cardiovascular mortality, the occurrence of MI, and hospitalization for heart failure.