Atenolol as a comparator in outcome trials in hypertension: a correct choice in the past, but not for the future?

Objective: Twelve years after the design of the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study, which showed superiority of losartan- vs atenolol-based therapy for cardiovascular outcomes, we reviewed the literature for the effect of beta-blockers compared with initial placebo or no treatment on reduction of cardiovascular events to re-evaluate atenolol as the comparator in the LIFE study.

Methods: A literature search was conducted in September 2006 for randomized, controlled trials comparing beta-blockers with/without diuretics with placebo or no treatment in patients with hypertension and without recent cardiovascular morbidity. We calculated risk reductions for combined cardiovascular events, cardiovascular death, stroke, and coronary heart disease from groups of trials using atenolol first-line and all beta-blockers first-line.

Results: Five studies met the criteria. Significant risk reductions for cardiovascular events and stroke occurred in groups receiving treatment with atenolol or all beta-blockers, and for cardiovascular death in the all beta-blocker analysis. In meta-analysis of beta-blocker vs placebo or no treatment trials, risk reductions were 19% for combined cardiovascular events (95% CI 0.73-0.91, p<0.001), 15% for cardiovascular death (0.73-0.99, p = 0.037), 32% for stroke (0.57-0.82, p<0.001), and 10% for coronary heart disease (0.78-1.04, p = 0.146).

Conclusions: Beta-blocker-based antihypertensive therapy significantly reduces cardiovascular risk in hypertension compared with placebo or no treatment. Atenolol was an appropriate comparator in the LIFE study. As the results of the LIFE study and other recent trials demonstrate superiority of newer agents over atenolol, this agent is not an appropriate reference drug for future trials of cardiovascular risk in hypertension.