Longer-term impact of PCSK9 inhibitors on major adverse cardiovascular events and all-cause mortality: a systematic review and meta-analysis of randomised controlled trials

Abstract

Abstract Background The development of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors offers a novel treatment option for lowering cardiovascular risk profiles through significant reductions in low-density lipoprotein cholesterol. Whilst their effect on improving patients' lipid profiles has been well-established in clinical trials, their impact on major adverse cardiovascular events (MACE) and all-cause mortality in the longer-term is of interest since PCSK9 inhibitors are becoming an important addition to the current armament of lipid-lowering therapies. Purpose This systematic review and meta-analysis seeks to evaluate the longer-term effect (≥ 12 months) of PCSK9 inhibitors on MACE and all-cause mortality, compared to placebo, in patients with dyslipidaemia or atherosclerotic cardiovascular disease. Methods A systematic search of databases including PubMed, Ovid, and Cochrane Central Register of Controlled Trials was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines in January 2023. Two reviewers screened for phase 3 randomised-controlled trials (RCTs) comparing the anti-PCSK9 monoclonal antibodies currently in use (alirocumab and evolocumab) to placebo in adult patients. Trials were included if they had a follow-up of at least 12 months from initiation of treatment and reported on MACE or all-cause mortality. Demographic data, clinical characteristics, MACE outcomes such as rates of myocardial infarction, coronary revascularisation, cardiovascular death, hospitalisation for heart failure, hospitalisation for unstable angina, stroke and all-cause mortality outcomes were extracted. A random effects model was used for meta-analysis with dichotomous outcomes reported as odds ratio (OR), 95% confidence intervals (CI) and I² metric to assess heterogeneity. Results The incidence of myocardial infarction and coronary revascularisation was reported in ten studies (encompassing 57,890 participants) out of the eleven RCTs that met our inclusion criteria. Meta-analysis demonstrated statistically significant reduction in myocardial infarction (OR -0.27, 95% CI -0.40 to -0.15, p <0.01, I² = 25.5%) and coronary revascularisation (OR -0.20, 95% CI -0.28 to -0.11, p <0.01, I² =12.4%) for patients on PCSK9 inhibitors compared to placebo. Heterogeneity was considered moderate and low respectively for these outcomes. No statistically significant effect was observed for other MACE or all-cause mortality. Conclusions The results of this study suggest that PCSK9 inhibitors can significantly reduce rates of myocardial infarction and coronary revascularisation in patients over the long-term (≥ 12 months). Further studies with longer-term follow-up are needed to fully evaluate the impact of PCSK9 inhibitors across MACE outcomes, and to inform clinical decision-making.Myocardial Infarction Forest PlotCoronary Revascularisation Forest Plot