Statins and risk of thromboembolism: A meta-regression to disentangle the efficacy-to-effectiveness gap using observational and trial evidence

Abstract

Background and aims: Meta-analyses of randomised controlled trials (RCTs) and observational studies indicate a lower risk of venous thromboembolism (VTE) associated with statin treatment. We aimed to compare the effect of statin therapy in these two settings and to identify and quantify potential factors to explain statin efficacy and effectiveness.

Methods and results: We electronically searched on December 11th, 2018, articles reporting on first VTE events in RCTs (statin vs placebo) and in observational studies (participants exposed vs non-exposed to statin). We performed Knapp-Hartung random-effect meta-analyses to calculate pooled relative risks (RRs) of VTE events associated with statin treatment, separately for RCTs and observational studies; and estimated the ratio of the relative risk (RRR) comparing RCTs and observational studies using meta-regressions, progressively adjusted for study-level characteristics. Twenty-one RCTs (115,107 participants; 959 events) and 8 observational studies (2,898,096 participants; 19,671 events) were included. Pooled RRs for RCTs and observational studies were 0.82 (95% confidence interval (CI): 0.67-1.00; I² 19.2%) and 0.60 (95% CI: 0.42-0.86; I² 86.3%), respectively. In meta-regressions, the unadjusted RRR indicated a nonsignificant 23% smaller benefit in RCTs (RRR 0.77; 95% CI: 0.52-1.13); accounting for age, sex, geographical region, and duration of follow-up, there was a sensible change of the RRR which resulted 0.30 (95% CI: 0.13-0.68).

Conclusion: Differences in the characteristics between patients included in RCTs and those in observational studies may account for the differential effect of statins in preventing VTE in the two settings.

Keywords: Clinical trials; Meta-analysis; Meta-regression; Observational study; Real-world evidence; Statin; Venous thromboembolism.