It found significant reductions in the primary composite outcome of major atherosclerotic events (e.g., non-fatal MI, coronary death, non- hemorrhagic stroke, and any arterial revascularization) in favor of the combination versus placebo (RR: 0.83, 95% CI: 0.74 0.94, NNT=48). However, the effect of ezetimibe on clinical outcomes could not be separated from that of statins. Thus, the benefit of ezetimibe alone could not be determined. The adverse effects of ezetimibe appear to be less than those associated with statins. The systematic review by Mikhailidis et al. (2011) that compared the combination of ezetimibe and a statin to increasing statin doses found that adverse effects were similar in the ezetimibe-statin combination group and the increased statin dose group.[65] However, the included trials were less than four months in length and reviewed outcomes that are neither patient centered nor within the scope of this guideline. In a separate trial evaluating ezetimibe in secondary prevention, Cannon et al. (2015), adverse events were significantly less with ezetimibe-statin combinations than high-dose statins.[67] As this is a Reviewed, New-replaced recommendation, the Work Group systematically reviewed evidence related to this recommendation.[64] The systematic evidence review did not identify evidence in primary prevention populations for reducing CV events with ezetimibe monotherapy. With the strong evidence for the efficacy of statins for improving outcomes, providers should use statins whenever feasible. The evidence for ezetimibe in primary prevention is limited to surrogate outcomes, and even these are only available in combination with statins. Based on the lack of evidence for ezetimibe s effect on CV risk in primary prevention, either alone or in combination with statins, the Work Group decided upon a Neither for nor against recommendation. This recommendation highlights the research deficits for the use of ezetimibe for primary prevention. 