Meta-analysis of randomized clinical trials comparing PCSK9 monoclonal antibody versus ezetimibe/placebo in patients at high cardiovascular risk

Atherosclerosis. 2021 Jun:326:25-34. doi: 10.1016/j.atherosclerosis.2021.04.008. Epub 2021 May 7.


Background and aims: Proprotein convertase subtilisin/kexin type 9 monoclonal antibodies (PCSK9 mAbs) reduce circulating low-density lipoprotein cholesterol (LDL-C) by controlling the expression of LDL-receptor on the surface of hepatocytes. This meta-analysis aimed at evaluating the efficacy of PCSK9 mAbs on clinical and lipid-lowering outcomes.

Methods: PubMed, Embase, and were searched from inception until November 2020 for randomized controlled trials (RCTs) that compared PCSK9 mAbs with ezetimibe or placebo in patients at high cardiovascular risk.

Results: Twenty eight RCTs with a total of 89,115 participants were included. Compared with placebo, PCSK9 mAbs significantly reduced the risk of major adverse cardiac events (MACEs) (RR 0.83, 95% CI 0.79 to 0.88, p < 0.00001). However, no difference was observed in occurring MACEs between PCSK9 mAbs and ezetimibe (RR 0.70, 95% CI 0.40 to 1.20, p = 0.20). Secondary analyses show that PCSK9 mAbs were not superior to ezetimibe in preventing stroke (RR 0.38, 95% CI 0.09 to 1.69, p = 0.20), myocardial infarction (RR 0.95, 95% CI 0.47 to 1.90, p = 0.88), and cardiovascular death (RR 0.44, 95% CI 0.14 to 1.43, p = 0.17). Compared with placebo, PCSK9 mAbs significantly reduced the incidence of stroke (RR 0.75, 95% CI 0.66 to 0.86, p < 0.0001) and myocardial infarction (RR 0.81, 95% CI 0.76 to 0.87, p < 0.00001), but not the risk of cardiovascular death (RR 0.96, 95% CI 0.86 to 1.07, p = 0.45). As for lipid-lowering efficacy, PCSK9 mAbs markedly reduced percent change of LDL-C from baseline to week 12 and 24 compared to ezetimibe or placebo.

Conclusions: In patients at high cardiovascular risk, PCSK9 mAbs could effectively reduce MACEs, stroke, and myocardial infarction compared with placebo. However, PCSK9 mAbs were not superior to ezetimibe in preventing adverse cardiovascular events in our study; RCTs with long-term follow-up and cardiovascular events as the research endpoint are still needed.

Keywords: Adverse cardiovascular events; Ezetimibe; High cardiovascular risk; Low-density lipoprotein cholesterol; PCSK9 monoclonal antibody; Placebo.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal*
  • Anticholesteremic Agents*
  • Cardiovascular Diseases*
  • Ezetimibe*
  • Heart Disease Risk Factors
  • Humans
  • Proprotein Convertase 9
  • Randomized Controlled Trials as Topic
  • Treatment Outcome


  • Antibodies, Monoclonal
  • Anticholesteremic Agents
  • PCSK9 protein, human
  • Proprotein Convertase 9
  • Ezetimibe