The clinical benefits of immediate versus delayed use of PCSK9 inhibitors for patients with established atherosclerotic cardiovascular disease in the UK

Background Many patients with established atherosclerotic cardiovascular disease (ASCVD) do not reach LDL-C goals. Despite their established clinical benefits, access to PCSK9i in the UK remains limited, with a stepwise approach requiring clinicians to use ezetimibe before PCSK9i can be prescribed to patients who need lipid-lowering therapy intensification. While the clinical and economic benefits of adding PCSK9i to standard of care was previously demonstrated (1.14 life years (LYs) gained and a number needed to treat (NNT) of 4.5 to prevent a cardiovascular (CV) death), the clinical benefits of immediate PCSK9i use versus this stepwise approach for patients with established ASCVD in the UK have not been quantified. Purpose To assess the clinical benefits of immediate PCSK9i use versus delayed use (ezetimibe first, with PCSK9i added 3 years later) in patients with established ASCVD in the UK whose LDL-C goal is not reached with maximally tolerated statin therapy. Methods A cohort state-transition Markov model was used to estimate cardiovascular outcomes for immediate versus delayed PCSK9i use in patients with established ASCVD whose LDL-C goal is not reached with maximally tolerated statin therapy in the UK over a lifetime horizon. The model includes the following states/events: ischemic stroke, myocardial infarction, acute limb ischemia or amputation, unstable angina, revascularization, CV and non-CV death. The model tracks first versus subsequent events and time since last event. Transition probabilities were derived from UK real-world ASCVD risks using CPRD-HES-ONS. LDL-C efficacy data for PCSK9i, ezetimibe, and PCSK9i plus ezetimibe were obtained from the literature. The association between LDL-C reduction and CV event risk was based on Cholesterol Treatment Trialists' studies, with time-dependent risk reduction incorporated. LYs and CV events were not discounted. Results Among patients with ASCVD, immediate versus delayed PCSK9i use led to an increase of 0.31 LYs per patient over a lifetime. The estimated non-fatal, fatal, and total CV events avoided per 1,000 patients were 16, 7, and 23, respectively. NNT to prevent one non-fatal, fatal, or any CV event were 61, 147, and 43, respectively, over a lifetime (35 years; mean starting age 65). For the 1.3 million eligible UK patients, total estimated non-fatal, fatal, and all CV events avoided over a lifetime were 21,408, 8,848, and 30,256, respectively. Conclusions Providing clinicians the option for immediate PCSK9i use increases LYs and prevents tens of thousands of CV events among ASCVD patients not at LDL-C goal with maximally tolerated statin therapy in the UK. These findings suggest that a stepwise approach through ezetimibe delays effective care and increases CV events. Guidelines and policymakers should consider earlier, more intensive LDL-C lowering strategies to maximize cardiovascular health outcomes.