The EUROPA trial (EUropean trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease, Lancet 2003;362(9386):782-8) showed that perindopril significantly reduced the primary composite end point of cardiovascular (CV) death, myocardial infarction (MI), and cardiac arrest, in patients with stable coronary artery disease (CAD) in comparison with placebo and on top of other therapies. In the ASCOT-BPLA trial in hypertensive patients at risk of CV events, amlodipine ± perindopril therapy reduced risk of death and CV events in comparison with beta-blocker ± thiazide.

The goal of this study was to study the effect of the ACE inhibitor perindopril compared with placebo in patients with stable CAD receiving calcium channel blockers (CCB) on the risk reduction in major cardiac events and death and to assess the synergistic effects between perindopril and CCB. Among 12,218 EUROPA patients, 2,122 patients received CCB throughout the study: 1,022 patients in the perindopril group (Per/CCB+) and 1100 patients in the placebo group (Pl/CCB+).

Baseline characteristics were similar in all groups. Looking at the trial's primary endpoint, the percentage of patients experiencing cardiovascular death, MI, or resuscitated cardiac arrest was lowest in those who were given perindopril plus CCBs (4.89% vs. 6.58% for perindopril with no CCBs; 7.45% for placebo plus CCBs; 7.98% for placebo with no CCBs; p<0.05 for all comparisons). Perindopril plus CCBs also reduced the risk for all-cause mortality by 46% (p<0.01), cardiovascular mortality by 41% (p=0.09), fatal and nonfatal MI by 28% (p=0.10), and hospitalization for HF by 54% (p=0.25).

Synergy was considered when Hazard ratio (HR) of perindopril+CCB was inferior to HR (Perindopril alone) x HR (CCB alone). The calculation showed that the effect between perindopril and CCB was synergistic for all end points studied.

In patients with stable CAD already receiving a CCB, addition of perindopril provides significant reduction in all-cause mortality and major cardiac events. The synergistic action between perindopril and CCB, which underlies the clinical benefit, deserves further investigation.