Legacy effects of statins on cardiovascular and all-cause mortality: a meta-analysis

Objectives: To assess evidence for 'legacy' (post-trial) effects on cardiovascular disease (CVD) mortality and all-cause mortality among adult participants of placebo-controlled randomised controlled trials (RCTs) of statins.

Design: Meta-analysis of aggregate data.

Setting/participants: Placebo-controlled statin RCTS for primary and secondary CVD prevention.

Methods: Data sources: PubMed, Embase from inception and forward citations of Cholesterol Treatment Trialists' Collaborators RCTs to 16 June 2016.

Study selection: Two independent reviewers identified all statin RCT follow-up reports including ≥1000 participants, and cardiovascular and all-cause mortality.

Data extraction and synthesis: Two independent reviewers extracted data in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.

Main outcomes: Post-trial CVD and all-cause mortality.

Results: We included eight trials, with mean post-trial follow-up ranging from 1.6 to 15.1 years, and including 13 781 post-trial deaths (6685 CVD). Direct effects of statins within trials were greater than legacy effects post-trials. The pooled data from all eight studies showed no evidence overall of legacy effects on CVD mortality, but some evidence of legacy effects on all-cause mortality (p=0.01). Exploratory subgroup analysis found possible differences in legacy effect for primary prevention trials compared with secondary prevention trials for both CVD mortality (p=0.15) and all-cause mortality (p=0.02). Pooled post-trial HR for the three primary prevention studies demonstrated possible post-trial legacy effects on CVD mortality (HR=0.87; 95% CI 0.79 to 0.95) and on all-cause mortality (HR=0.90; 95% CI 0.85 to 0.96).

Conclusions: Possible post-trial statin legacy effects on all-cause mortality appear to be driven by the primary prevention studies. Although these relative benefits were smaller than those observed within the trial, the absolute benefits may be similar for the two time periods. Analysis of individual patient data from follow-up studies after placebo-controlled statin RCTs in lower-risk populations may provide more definitive evidence on whether early treatment of subclinical atherosclerosis is likely to be beneficial.