Long-Term Impact of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors on Major Adverse Cardiovascular Events and All-Cause Mortality: A Systematic Review and Bayesian Meta-Analysis of Randomized Controlled Trials

ABSTRACT: The introduction of proprotein convertase subtilisin/Kexin type 9 (PSCK9) inhibitors has transformed the approach to low-density lipoprotein cholesterol lowering in the prevention of atherosclerotic cardiovascular disease. This paper aims to determine the longer-term impact of these interventions on major adverse cardiovascular events (MACE) and all-cause mortality. A systematic search of major databases was conducted to identify randomised controlled trials comparing PCSK9 inhibitors with a placebo. Studies were included if they reported cardiovascular events with a follow-up duration greater than 12 months. Frequentist, Bayesian meta-analysis, and trial sequential analysis were utilised to assess the efficacy of PCSK9 inhibitors in reducing MACE. Amongst 11 studies encompassing 52,372 patients, statistically significant reductions were observed in rates of myocardial infarction (risk ratio (RR) 0.78; 95% confidence interval (CI) 0.68 to 0.89, p < 0.01, I² = 20%), coronary revascularisation (RR 0.83; 95% CI 0.75 to 0.91, p < 0.01, I² = 9.1%) and ischemic stroke (RR 0.76; 95% CI 0.66 to 0.87, p < 0.01, I² = 0%) amongst patients on PCSK9 inhibitors compared to placebo based on random-effects meta-analysis. Trial sequential analysis and Bayesian analysis supported these results, with posterior probabilities that PCSK9 inhibitors improve outcomes for myocardial infarction, coronary revascularisation, and ischemic stroke of 83.8%, 82.9%, and 69.4%, respectively. No statistically significant effect was observed for the other outcomes. This meta-analysis demonstrates significant reductions in the rate of myocardial infarction, coronary revascularisation, and ischemic stroke. Further benefits may emerge with longer-term follow-up and alternate methods of targeting PCSK9.