PCSK9 monoclonal antibodies for the primary and secondary prevention of cardiovascular disease

Cochrane Database Syst Rev. 2020 Oct 20;10(10):CD011748. doi: 10.1002/14651858.CD011748.pub3.


Background: Despite the availability of effective drug therapies that reduce low-density lipoprotein (LDL)-cholesterol (LDL-C), cardiovascular disease (CVD) remains an important cause of mortality and morbidity. Therefore, additional LDL-C reduction may be warranted, especially for people who are unresponsive to, or unable to take, existing LDL-C-reducing therapies. By inhibiting the proprotein convertase subtilisin/kexin type 9 (PCSK9) enzyme, monoclonal antibodies (PCSK9 inhibitors) reduce LDL-C and CVD risk.

Objectives: Primary To quantify the effects of PCSK9 inhibitors on CVD, all-cause mortality, myocardial infarction, and stroke, compared to placebo or active treatment(s) for primary and secondary prevention. Secondary To quantify the safety of PCSK9 inhibitors, with specific focus on the incidence of influenza, hypertension, type 2 diabetes, and cancer, compared to placebo or active treatment(s) for primary and secondary prevention.

Search methods: We identified studies by systematically searching CENTRAL, MEDLINE, Embase, and Web of Science in December 2019. We also searched ClinicalTrials.gov and the International Clinical Trials Registry Platform in August 2020 and screened the reference lists of included studies. This is an update of the review first published in 2017.

Selection criteria: All parallel-group and factorial randomised controlled trials (RCTs) with a follow-up of at least 24 weeks were eligible.

Data collection and analysis: Two review authors independently reviewed and extracted data. Where data were available, we calculated pooled effect estimates. We used GRADE to assess certainty of evidence and in 'Summary of findings' tables.

Main results: We included 24 studies with data on 60,997 participants. Eighteen trials randomised participants to alirocumab and six to evolocumab. All participants received background lipid-lowering treatment or lifestyle counselling. Six alirocumab studies used an active treatment comparison group (the remaining used placebo), compared to three evolocumab active comparison trials. Alirocumab compared with placebo decreased the risk of CVD events, with an absolute risk difference (RD) of -2% (odds ratio (OR) 0.87, 95% confidence interval (CI) 0.80 to 0.94; 10 studies, 23,868 participants; high-certainty evidence), decreased the risk of mortality (RD -1%; OR 0.83, 95% CI 0.72 to 0.96; 12 studies, 24,797 participants; high-certainty evidence), and MI (RD -2%; OR 0.86, 95% CI 0.79 to 0.94; 9 studies, 23,352 participants; high-certainty evidence) and for any stroke (RD 0%; OR 0.73, 95% CI 0.58 to 0.91; 8 studies, 22,835 participants; high-certainty evidence). Compared to active treatment the alirocumab effects, for CVD, the RD was 1% (OR 1.37, 95% CI 0.65 to 2.87; 3 studies, 1379 participants; low-certainty evidence); for mortality, RD was -1% (OR 0.51, 95% CI 0.18 to 1.40; 5 studies, 1333 participants; low-certainty evidence); for MI, RD was 1% (OR 1.45, 95% CI 0.64 to 3.28, 5 studies, 1734 participants; low-certainty evidence); and for any stroke, RD was less than 1% (OR 0.85, 95% CI 0.13 to 5.61; 5 studies, 1734 participants; low-certainty evidence). Compared to placebo the evolocumab, for CVD, the RD was -2% (OR 0.84, 95% CI 0.78 to 0.91; 3 studies, 29,432 participants; high-certainty evidence); for mortality, RD was less than 1% (OR 1.04, 95% CI 0.91 to 1.19; 3 studies, 29,432 participants; high-certainty evidence); for MI, RD was -1% (OR 0.72, 95% CI 0.64 to 0.82; 3 studies, 29,432 participants; high-certainty evidence); and for any stroke RD was less than -1% (OR 0.79, 95% CI 0.65 to 0.94; 2 studies, 28,531 participants; high-certainty evidence). Compared to active treatment, the evolocumab effects, for any CVD event RD was less than -1% (OR 0.66, 95% CI 0.14 to 3.04; 1 study, 218 participants; very low-certainty evidence); for all-cause mortality, the RD was less than 1% (OR 0.43, 95% CI 0.14 to 1.30; 3 studies, 5223 participants; very low-certainty evidence); and for MI, RD was less than 1% (OR 0.66, 95% CI 0.23 to 1.85; 3 studies, 5003 participants; very low-certainty evidence). There were insufficient data on any stroke. AUTHORS' CONCLUSIONS: The evidence for the clinical endpoint effects of evolocumab and alirocumab were graded as high. There is a strong evidence base to prescribe PCSK9 monoclonal antibodies to people who might not be eligible for other lipid-lowering drugs, or to people who cannot meet their lipid goals on more traditional therapies, which was the main patient population of the available trials. The evidence base of PCSK9 inhibitors compared with active treatment is much weaker (low very- to low-certainty evidence) and it is unclear whether evolocumab or alirocumab might be effectively used as replacement therapies. Related, most of the available studies preferentially enrolled people with either established CVD or at a high risk already, and evidence in low- to medium-risk settings is minimal. Finally, there is very limited evidence on any potential safety issues of both evolocumab and alirocumab. While the current evidence synthesis does not reveal any adverse signals, neither does it provide evidence against such signals. This suggests careful consideration of alternative lipid lowering treatments before prescribing PCSK9 inhibitors.

Trial registration: ClinicalTrials.gov NCT01764633 NCT01984424 NCT01813422 NCT02642159 NCT02585778 NCT02107898 NCT02289963 NCT01663402 NCT01854918 NCT02729025 NCT02207634 NCT02392559 NCT01624142 NCT02833844.

Publication types

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

MeSH terms

  • Antibodies, Monoclonal, Humanized / therapeutic use*
  • Anticholesteremic Agents / therapeutic use
  • Cardiovascular Diseases / prevention & control*
  • Cause of Death
  • Cholesterol, LDL / blood*
  • Cholinergic Antagonists / therapeutic use
  • Ezetimibe / therapeutic use
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use
  • Middle Aged
  • Myocardial Infarction / epidemiology
  • PCSK9 Inhibitors*
  • Primary Prevention / methods
  • Proprotein Convertase 9 / immunology
  • Randomized Controlled Trials as Topic
  • Secondary Prevention / methods
  • Stroke / epidemiology
  • Time Factors


  • Antibodies, Monoclonal, Humanized
  • Anticholesteremic Agents
  • Cholesterol, LDL
  • Cholinergic Antagonists
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • PCSK9 Inhibitors
  • PCSK9 protein, human
  • Proprotein Convertase 9
  • Ezetimibe
  • evolocumab
  • alirocumab

Associated data

  • ClinicalTrials.gov/NCT01764633
  • ClinicalTrials.gov/NCT01984424
  • ClinicalTrials.gov/NCT01813422
  • ClinicalTrials.gov/NCT02642159
  • ClinicalTrials.gov/NCT02585778
  • ClinicalTrials.gov/NCT02107898
  • ClinicalTrials.gov/NCT02289963
  • ClinicalTrials.gov/NCT01663402
  • ClinicalTrials.gov/NCT01854918
  • ClinicalTrials.gov/NCT02729025
  • ClinicalTrials.gov/NCT02207634
  • ClinicalTrials.gov/NCT02392559
  • ClinicalTrials.gov/NCT01624142
  • ClinicalTrials.gov/NCT02833844