Synopsis of a Cochrane systematic review on PCSK9 monoclonal antibodies for the primary and secondary prevention of cardiovascular disease

This study provided convincing evidence to add PCSK9 inhibitors to traditional lipid-lowering therapies (LLTs) to reduce the risk of cardiovascular disease (CVD), including myocardial infarction (MI) and stroke, as well as all-cause mortality.

Key Takeaway

  • This abridged version of a previously published Cochrane review highlighted the convincing level of evidence to add PCSK9 inhibitors to traditional LLTs to reduce the risk of CVD, including MI and stroke, as well as all-cause mortality.
  • High certainty evidence was noted for studies assessing the effect of PCSK9 inhibitors vs placebo when added to background statin or ezetimibe therapy.
    • However, in the case of PCSK9 inhibitors directly compared with active treatment (either statins, ezetimibe or combination therapy), the evidence base was weaker, and it was unclear if there was a protective or harmful effect in these patients.
  • This review further noted the lack of sufficient data to exclude possible (long-term) safety signals on influenza, hypertension, cancer diagnosis or T2DM.

Why This Matters

  • In patients with insufficient response to, or who are unable to tolerate traditional low-density lipoprotein-cholesterol (LDL-C)-lowering therapies (statins or ezetimibe), PCSK9 inhibitors may provide an alternative treatment.
  • Present synopsis summarized the findings from a recent update of a Cochrane systematic review with focus on outcomes, safety, and the quality of evidence from the randomized clinical trials (RCTs) evaluating PCSK9 inhibitors.

Study Design

  • Systematic review of 24 RCTs evaluating PCSK9 monoclonal antibodies for the primary and secondary prevention of CVDs:
    • Databases: Cochrane Central Register of Controlled Trials, MEDLINE, Embase, Web of Science, ClinicalTrials.gov and the International Clinical Trials Registry Platform
    • Eligibility criteria: Parallel-group and factorial RCTs with at least 24 weeks of follow-up were eligible
    • Exclusion criteria: Studies evaluating bococizumab and RG7652 (as these were discontinued)
    • Primary outcomes: (1) Composite endpoint of CVD (defined as urgent coronary revascularization, unstable angina pectoris, non-fatal and fatal MI, non-fatal and fatal stroke, and coronary heart disease death); (2) all-cause mortality; (3) MI; and (4) stroke
    • Secondary outcomes: (1) Influenza; (2) T2DM; (3) cancer; and (4) hypertension

Key Results

Predominantly high-risk patients were included in the RCTs evaluated in the Cochrane review (patients with non-optimal LDL-C concentration despite treatment with statins or ezetimibe, or with a history of CVD):
Patient characteristics

  • Overall participants: N = 60,997 ([for whom this was reported: men = 71%; women = 29%; race/ethnicity = 83% Caucasian]; age = 61.57 vs 57.93 years)
  • The study sample included:
    • A total of 1,879 participants who had familial hypercholesterolemia (FH)
    • 18,908 (31%) with a diagnosis of T2DM at baseline
    • No prior history of CVD (n = 4,590)

Trial characteristics

  • Alirocumab was evaluated in 18 trials, while evolocumab in 6 trials
    • Comparator: Placebo in 18 trials, while ezetimibe and/or statins in 6 trials; study period: 2011–2018; setting: outpatient and home settings; countries: international
  • PCSK9 inhibitors studied (randomization): Alirocumab = 43.5% participants; evolocumab = 56.5% participants

Key outcomes*

  • PCSK9 inhibitors vs placebo (+background LLT [either statin, ezetimibe or a combination of these]): High certainty of evidence
    • Composite endpoint of CVD (relative effect — odds ratio [OR {95% confidence interval; CI}]): Alirocumab vs placebo = 0.87 (0.80–0.94); evolocumab vs placebo = 0.84 (0.78–0.91)
    • All-cause mortality (relative effect — OR [CI]): Alirocumab vs placebo = 0.83 (0.72–0.96); evolocumab vs placebo = 1.04 (0.91–1.19)
    • MI (relative effect — OR [CI]): Alirocumab vs placebo = 0.86 (0.79–0.94); evolocumab vs placebo = 0.72 (0.64–0.82)
    • Any stroke (relative effect — OR [CI]): Alirocumab vs placebo = 0.73 (0.58–0.91); evolocumab vs placebo = 0.79 (0.65–0.94)

Limitations

  • Low/very low quality of evidence for studies directly comparing PCSK9 inhibitor efficacy with statins and/or ezetimibe (alirocumab: low; evolocumab: very low)
  • Limited information was available regarding potential safety issues of either evolocumab or alirocumab

*Please refer the source publication (Carter et al.) for details of reported outcomes (including risk difference and certainty of evidence [Tables 1 and 2]).

    1. Carter JP, Hingorani AD, Wilkins J, Schmidt AF. Cochrane corner: PCSK9 monoclonal antibodies for the primary and secondary prevention of cardiovascular disease. Heart. 2022;108(1):14–15. doi: 10.1136/heartjnl-2021-319629. PMID: 34815331.

MAT-KW-2200323/V1/NOV2022