Statins and ezetimibe are also administered orally and are widely available as generic products. In contrast, PCSK9 inhibitors have unknown long-term safety profiles, are administered as subcutaneous injections once or twice a month, are significantly more costly, and require education on proper use while achieving comparable or less relative risk reductions. In patients at higher risk (see Recommendation 12 for a definition) who are already receiving a maximally tolerated statin plus ezetimibe, addition of a PCSK9 inhibitor is suggested to reduce recurrent non-fatal events. As this is a Reviewed, New-replaced recommendation, the Work Group systematically reviewed evidence related to this recommendation [68,70,79,82-85] and considered the evidence put forth in the 2014 CPG.[88,89] The Work Group s confidence in the quality of the evidence was moderate. The benefits outweighed the harms and burden. There is likely to be high variation in patient and provider values and preferences because of various factors (e.g., long-term safety has not yet been established, CVD events are reduced but mortality is not impacted, route of administration issues, and high cost, feasibility of use for patients and healthcare systems). Because of these issues, the Work Group decided upon a Weak for recommendation centered on a patient s willingness to intensify drug therapy while already receiving a maximally tolerated statin plus ezetimibe. There is a need for continued investigation of the long-term safety of treatment with PCSK9 inhibitors combined with statins with or without ezetimibe, and the unknown safety of prolonged periods of very low LDL-C levels secondary to this treatment. More research on these topics would be useful: What is the optimal combination of lipid-lowering treatments or achieved LDL-C level that will result in the largest reduction in CV events (e.g.