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Synergistic effect of perindopril and calcium channel blockers in prevention of cardiac events and death in coronary artery disease patients - analysis from the EUROPA study.

Clinical Trial Update II

Presenter report:

Bertrand, Michel


The EUROPA trial conducted in stable coronary artery disease (CAD) showed that perindopril significantly reduced the primary composite end point of cardiovascular (CV) death, myocardial infarction (MI), and cardiac arrest, 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 presentation is (1) 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 (2) to assess the synergistic effects between perindopril and CCB. Among 12,218 EUROPA patients, 2122 patients received CCB throughout the study: 1022 patients in the perindopril group (Per/CCB+) and 1100 patients in the placebo group (Pl/CCB+).

Results: Baseline characteristics were similar in the Per/CCB+ and Pl/CCB+ groups. Event rate for the primary end point was 4.9% in the Per/CCB+ group versus 7.45% in the Pl/CCB+ group (relative risk reduction 35.5%, P<0.05). Per/CCB+ also reduced the risk for all-cause mortality by 46% (P<0.01), CV 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.

Conclusion: 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.


Discussant report:

Sever, Peter (United KingdomWatch webcast)

Synergism is a widely misused term to describe the effects of two separate drug treatments on a common endpoint .  Its true meaning is that of a positive interaction between two treatments such that the benefit of combining  two drugs is greater than the sum of the benefits obtained when the two treatments are used alone. It is often a term incorrectly assigned to the additive benefits of two treatments.

To detect true synergism in clinical studies is difficult, and most studies are  underpowered to detect synergism. Studies may be designed as parallel group comparisons or cross-over design, but in either case, require an assessment of the effects of the individual drugs compared with placebo and an effect of the combined drugs compared with placebo on the same outcome. In an outcome trial, this will involve an evaluation of endpoint rates in four “cells” :- drug A alone, drug B alone, drug A and drug B, placebo A and placebo B.

Bertrand and colleagues report an assessment of synergy between the angiotensin converting enzyme inhibitor perindopril, and calcium channel blockers (CCBs) in a post hoc analysis of data from the EUROPA  trial, where outcome data were available for those assigned perindopril or placebo, in subjects who were either on treatment with CCBs or not.

Although not apparent from initial subgroup analyses of the total EUROPA database (Lancet 2003), when comparisons were restricted to those who were recorded as taking CCBs at all visits during the follow up period (thereby reducing the number “on CCBs”  from almost 4000 to just over 2000 ), the risk reductions in cardiovascular (CV) death, non-fatal myocardial infarction (MI) and resuscitated cardiac arrest (the primary endpoint) and all cause mortality, associated with assignment to perindopril compared with placebo, were greater in those receiving CCBs compared with those who were not.

All comparisons were, however, between non randomised groups and subject to confounding by indication bias e.g those receiving CCBs would be more likely to be hypertensive (which was indeed the case) and by differences in demographics between groups at baseline e.g in those receiving CCBs there were fewer giving a history of prior MI and fewer taking beta blockers.

Nevertheless the results are of interest and hypothesis generating. There are, however,  problems with regard to the methodology for the assessment of synergy.

Synergy is present when the effect of the combined treatment [perindopril and CCB] versus placebo is greater than that predicted from the sum of the effects of either drug compared with placebo, when used alone (in the case of the latter obtained by multiplying the hazard ratios obtained for the individual drugs). This does not seem to have been the analysis presented by the authors.

Nevertheless, the data presented for the primary endpoints for the 4 cells proposed above allows one to calculate predicted versus observed risk reductions (HRs),  but without any correction for differences in baseline variables. These were HR = 0.61, observed and 0.77, predicted. Attempts to correct for difference in baseline characteristics between groups would be likely to alter these differences.


Thus, in summary, these data suggest the possibility of a positive interaction between perindopril and CCBs in preventing CV endpoints in patients with stable CHD. There are no prior reports of such an interaction and no obvious underlying explanation. An alternative explanation is that these observations could have arisen by chance.


Fox KM; EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease Investigators.
Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study).
Lancet 2003;362(9386):782-8.




Clinical Trial Update II

Notes to editor

This congress report accompanies a presentation given at the ESC Congress 2008. Written by the author himself/herself, this report does not necessarily reflect the opinion of the European Society of Cardiology.

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.