Impact of statin dose on major cardiovascular events: A mixed treatment comparison meta-analysis involving more than 175,000 patients

BACKGROUND: The benefit of statins in the reduction of cardiovascular events was demonstrated in several placebo-controlled trials. More intensive therapy seems to be associated with greater benefit. Our objective was to compare different statin doses in the reduction of cardiovascular events and deaths, combining direct and indirect evidence, through mixed treatment comparisons (MTC). METHODS: We conducted a systematic review in MEDLINE and Cochrane CENTRAL. A random-effects Bayesian MTC model was used to combine placebo-controlled and direct statin comparison trials. Intensity of statin doses was classified according to expected LDL-cholesterol reduction effect: ≤30% as low; 30-40%, intermediate, and ≥40%, high. Outcomes evaluated were non-fatal myocardial infarction (MI), stroke, coronary revascularization and coronary, cardiovascular and all-cause death. Inconsistency was assessed with split-node methodology. RESULTS: 47 trials (11 with direct statin comparisons) were included. High doses reduced non-fatal MI by 28% (95% CI: 18%-36%) and by 14% (7%-21%) when compared to low and intermediate doses, respectively. High doses also diminished revascularization [RR versus low and intermediate doses of 0.81 (0.69-0.95) and 0.88 (0.77-0.99), respectively] and stroke [RR of 0.83 (0.68-0.99) against low doses]. Regimen intensity did not change death rates (e.g., for all-cause mortality, RRs of 0.93 (0.80-1.06) and 0.98 (0.87-1.08) for high vs. low and intermediate doses, respectively). No statistical inconsistencies were found in the analyses. CONCLUSIONS: In this study, in which all available evidence from statin trials was simultaneously analyzed, the benefit of more intensive therapy was restricted to non-fatal events.