Extended duration dual antiplatelet therapy and mortality: a systematic review and meta-analysis

Summary

Background

Treatment with aspirin and a P2Y12 inhibitor is commonly used in patients with cardiovascular disorders. The overall effect of such treatment on all-cause mortality is unknown. In the Dual Antiplatelet Therapy (DAPT) Study, continuation of dual antiplatelet therapy beyond 12 months after coronary stenting was associated with an unexpected increase in non-cardiovascular death. In view of the potential public health importance of these findings, we aimed to assess the effect of extended duration dual antiplatelet therapy on mortality by doing a meta-analysis of all randomised, controlled trials of treatment duration in various cardiovascular disorders.

Methods

We searched Medline, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) to identify randomised controlled trials assessing the effect of extended duration versus no or short duration dual antiplatelet therapy, published before Oct 1, 2014. We did a meta-analysis to pool results with a hierarchical Bayesian random-effects model. The primary outcomes were hazard ratios comparing rates of all-cause, cardiovascular, and non-cardiovascular death.

Findings

Including the DAPT Study, we identified 14 eligible trials that randomly assigned 69 644 participants to different durations of dual antiplatelet therapy. Compared with aspirin alone or short duration dual antiplatelet therapy (≤6 months), continued treatment was not associated with a difference in all-cause mortality (hazard ratio [HR] 1·04, 95% credible interval [CrI] 0·96–1·18; p=0·17). Similarly, cardiovascular (1·01, 0·93–1·12; p=0·81) and non-cardiovascular mortality (1·04, 0·90–1·26; p=0·66) were no different with extended duration versus short duration dual antiplatelet therapy or aspirin alone.

Interpretation

Extended duration dual antiplatelet therapy was not associated with a difference in the risk of all-cause, cardiovascular, or non-cardiovascular death compared with aspirin alone or short duration dual antiplatelet therapy.

Funding

None.

Introduction

Treatment with dual antiplatelet therapy with a combination of aspirin and a P2Y12 inhibitor is widely used for the prevention of ischaemic complications associated with many cardiovascular diseases, including peripheral arterial, cerebrovascular, and coronary artery disease. In each of these diseases, the duration of treatment that best balances the benefits and risks of dual antiplatelet therapy is uncertain. In patients at high risk of ischaemic events, dual antiplatelet therapy might prevent potentially fatal thrombotic events. However, risks of adverse events with long-term dual antiplatelet therapy, mainly mediated through bleeding, also exist and could outweigh benefits, such that overall mortality is unchanged or even increased.

Findings of studies assessing the effect of extended duration dual antiplatelet therapy on mortality have varied. Results of the Clopidogrel and Aspirin versus Aspirin Alone for the Prevention of Atherothrombotic Events (CHARISMA) trial¹ showed no difference in all-cause mortality in a heterogeneous population with or at risk of cardiovascular disease treated with dual antiplatelet therapy versus aspirin alone. However, findings of the Secondary Prevention of Small Subcortical Strokes (SPS3)² trial showed a significant increase in mortality associated with dual antiplatelet therapy compared with aspirin alone in patients with recent lacunar infarcts, an unexpected finding that was not entirely attributable to bleeding. Most recently, the Dual Antiplatelet Therapy (DAPT) Study,³ an international multicentre, randomised, double-blind, placebo-controlled trial that compared 30 with 12 months of dual antiplatelet therapy after percutaneous coronary intervention with stents, showed that continuation of treatment beyond 12 months in participants given drug-eluting stents was associated with reduction in ischaemic events (stent thrombosis and myocardial infarction), but also an unexpected increase in non-cardiovascular death and nominal difference in total mortality over the primary analysis period.

If true, an increase in non-cardiovascular and all-cause mortality due to extended treatment with dual antiplatelet therapy would have an important effect on the many cardiovascular patients treated with these agents every year. Therefore, we aimed to assess the effect of extended duration dual antiplatelet therapy on all-cause, cardiovascular, and non-cardiovascular mortality by doing a comprehensive meta-analysis of randomised controlled trials of patients with cardiovascular disease.