(2010) analyzed five trials comparing a high- to moderate-dose statin and demonstrated a statistically significant reduction in any major vascular event (non-fatal MI, coronary heart disease [CHD] death, coronary revascularization, stroke) in favor of the higher dose (unweighted RR: 0.85, 95% CI: 0.82 0.89, NNT=125) versus the moderate statin dose.[56] In these meta-analyses, there was no statistically significant difference in CV or all-cause mortality when comparing high-dose statins to lower dose statins.[56,77,78] The incremental benefit was only statistically significant for a reduction in non-fatal events (e.g., MI, stroke, and revascularization). High-dose Statin Safety Studies of both primary and secondary prevention suggest that higher statin doses increase the risk for statin-related adverse events. The most commonly reported adverse events of statins in RCTs are elevated liver enzymes without reports of liver failure and muscle symptoms with rare cases of rhabdomyolysis. A meta-analysis by Silva et al. (2007), which was not identified in the 2014 or 2019 systematic evidence review, showed that high-dose simvastatin and atorvastatin were associated with more adverse events (OR: 1.44, 95% CI: 1.33 1.55) and more discontinuation due to adverse events (OR: 1.28, 95% CI: 1.18 1.39) than lower dose statins.[54] These interventions were also associated with statistically more LFT and CK abnormalities. A meta-analysis of 17 RCTs limited to high-dose atorvastatin, Li et al. (2016), showed a higher risk for liver transaminase elevation (RR: 4.59, 95% CI: 3.26 6.48) and discontinuation due to adverse events (RR: 1.29, 95% CI: 1.17 1.42) versus placebo or lower dose atorvastatin but no significant increase in CK, myalgia, or rhabdomyolysis.