The Treatment Effect of an ACE-Inhibitor Based Regimen with Perindopril in Relation to Beta-Blocker use in 29,463 Patients with Vascular Disease: a Combined Analysis of Individual Data of ADVANCE, EUROPA and PROGRESS Trials

Abstract

Introduction: In everyday practice, angiotensin converting enzyme inhibitors and beta-blockers are cornerstone treatments in patients with (cardio-)vascular disease. Clear data that evaluate the effects of the combination of these agents on morbidity and mortality are lacking.

Methods: In this retrospective pooled analysis of three large perindopril outcome trials (ADVANCE, EUROPA, PROGRESS), clinical outcomes were evaluated in 29,463 patients with vascular disease. Multivariate Cox regression analyses were performed in patients randomized to a perindopril-based regimen or placebo (treatment effect), and data were stratified according to background beta-blocker treatment. The primary endpoint was a composite of cardiovascular mortality, non-fatal myocardial infarction, and stroke.

Results: The cumulative incidence of the primary endpoint over mean follow-up of 4.0 years (Sd 1.0) was significantly lower in the beta-blocker/perindopril group (9.6%; 545/5700 patients) as compared to beta-blocker/placebo (11.8%; 676/5718 patients) (p < 0.01). Adding perindopril to existing beta-blocker treatment reduced the relative risk of the primary endpoint by 20% (hazard ratio (HR) 0.80; 95% confidence interval (CI) 0.71-0.90), non-fatal myocardial infarction by 23% (HR 0.77; 95% CI 0.65-0.91), and all-cause mortality by 22% (HR 0.78; 95% CI 0.68-0.88) as compared to placebo. Significant treatment benefit was not observed for stroke (HR 0.93; 95% CI 0.75-1.15). Significance was maintained for the primary endpoint and cardiovascular endpoints when data were further stratified by baseline hypertension. However, the mortality benefit was only observed in patients with hypertension with background beta-blocker use.

Conclusions: These data suggest that the beneficial cardioprotective effects of perindopril treatment are additive to the background beta-blockers use.

Keywords: ACE-inhibitor; Beta-blocker; Hypertension; Perindopril; Prevention; Vascular disease.

Fig. 1

Cumulative incidence survival function of the primary endpoint in 29,463 patients by Cox regression analysis. The primary endpoint was defined as the composite of cardiovascular mortality, non-fatal myocardial infarction, and stroke. Subgroups were defined as no beta-blocker/placebo (n = 9015; solid red line), beta-blocker/placebo (n = 5718; solid black line), no beta-blocker/perindopril (n = 9030; dotted red line), and beta-blocker/perindopril (n = 5700; dotted black line). Cumulative incidence in percentages (%) and follow-up duration in years are represented on the y-axis and x-axis, respectively

Fig. 2

Treatment effect of perindopril-based regimen in beta-blocker stratum: Forest plot. A Cox regression multivariate analysis was performed to calculate HRs and 95% CIs with adjustments for full model. The primary endpoint was the composite endpoint of cardiovascular mortality, non-fatal MI, and stroke. Among the 11,418 patients taking a beta-blocker, 5700 were randomized to a perindopril-based regimen and 5718 to placebo. P interaction was significant for all-cause mortality and CV mortality; all other p interactions are ns. CI, confidence interval, CV cardiovascular, HR hazard ratio, MI myocardial infarction, revasc revascularization, TIA transient ischemic attack

Fig. 3

Cumulative incidence of all-cause mortality in patients randomized to perindopril-based regimen and placebo in the beta-blocker stratum. Subgroups were defined as beta-blocker/placebo (n = 5718; solid black line) and beta-blocker/perindopril (n = 5700; dotted black line). Cumulative incidence in percentages (%) and follow-up duration in years are represented on the y-axis and x-axis, respectively

Fig. 4

Treatment effect of ACE-inhibitor-based regimen with perindopril in the stratum of beta-blocker use according to baseline hypertension: Forest plot. Subanalyses were performed according to baseline hypertension. Of the 5700 patients in the beta-blocker/perindopril group, 2876 patients had HTN (50.5%). Of the 5718 patients in the beta-blocker/placebo, 2962 patients had HTN (51.8%). A Cox regression multivariate analysis was performed to calculate HRs and 95% CIs with adjustments for full model. CI confidence interval, CV cardiovascular, HR hazard ratio, HTN hypertension, MI myocardial infarction, ns not significant. P for interaction all-cause mortality 0.01; all other p interaction terms ns