Because of the low cost of generic ezetimibe, studies of ezetimibe monotherapy for primary prevention would offer the highest potential benefit. C. Safety of Newer Therapies The long-term risks of PCSK9 inhibitors and bempedoic acid have not been established, warranting continued surveillance of post-marketing adverse event reports and the persistence of effect on CVD risk reduction in longer term follow-up. No negative health outcomes have been reported from very low LDL-C levels, including levels <50 mg/dL, caused by lipid-lowering drugs in observational studies or post hoc analyses of clinical trials to date. However, if future evidence supports that a minimum threshold LDL-C level is necessary, based upon safety risks, more frequent monitoring may be needed when high intensity treatments are employed. D. Stratifying Primary Prevention Benefits by Patient Risk Estimates Primary prevention studies include primarily patients with 10-year CV risk estimates of >12% with smaller numbers between 6 12% risk and very few <6%. No primary prevention study has used estimated CV risk as inclusion criteria or provided individual patient predicted cardiac risk data. Future primary prevention studies should include lower risk populations, measure predicted risk, and stratify the randomization procedure (using block randomization) by pretreatment CV risk estimate. We recognize that such a study may be impractical given the extremely large sample size and costs.[148] E. Prospective Studies to Improve Statin Adherence The high quality evidence for the benefit of statins for primary and secondary prevention makes adherence a key goal. The limited studies to date suggest that repeated trials of statins increase adherence, but the evidence base is sparse. Both clinic intervention strategies and alterations to prescribing patterns should be evaluated. The efficacy of proposed adjusted statin dosing schedules, such as intermittent dosing, should be studied with respect to both adherence and patient-oriented outcomes. 