The ODYSSEY LONG TERM trial did perform a post hoc analysis of a combination of secondary prevention and FH patients that showed benefit but did not separate the primary and secondary prevention populations.[69] Because the systematic review of primary prevention patients showed no benefit in any outcome, the Work Group has no basis to recommend PCSK9 inhibitors in any primary prevention population. The high cost of these therapies and unknown long-term safety led the Work Group to recommend against this therapy until a patient-oriented outcome benefit is demonstrated. Although primary and secondary prevention studies show the short-term adverse effects of PCSK9 inhibitors are limited, the side effects beyond three years are unknown. The most common adverse event is injection site reactions, which occur at a higher rate compared to placebo. However, Schmidt et al. (2017) demonstrated a significant increase in the risk of adverse events, mainly myalgia and influenza, with PCSK9 inhibitors compared to placebo.[70] The primary limitation of studies exploring the safety of PCSK9 inhibitors for primary prevention is their limited follow-up. Unlike the evidence evaluating the effects of statins, which include trials with longer term safety outcomes in secondary prevention, the PCSK9 literature is limited to safety outcomes of up to three years. The possibility of long-term reactions, adverse events, or consequences of prolonged levels of very low LDL-C with these agents are unknown. PCSK9 inhibitors are extremely expensive and of questionable cost-effectiveness, even in populations where there is evidence of efficacy such as secondary prevention. A systematic review by Korman et al. (2018) included two cost-effectiveness analyses and even in secondary prevention found that PCSK9 inhibitors did not meet a willingness to pay (WTP) threshold of $100,000 per additional quality-adjusted life year (QALY).