Physicians' Academy for Cardiovascular Education

Absolute effects of PCSK9i and ezetimibe across different CVD risk groups

PCSK9 inhibitors and ezetimibe with or without statin therapy for cardiovascular risk reduction: a systematic review and network meta-analysis

Literature - Khan SU, Yedlapati SH, Lone SN, et al. - BMJ. 2022 May 4;377:e069116. doi: 10.1136/bmj-2021-069116

Introduction and methods


Statins are regarded as first-line drugs for CVD risk reduction, while ezetimibe and PCSK9i are recommended as add-on therapies for patients who are statin intolerant or who are unable to achieve the LDL-c target value despite maximally tolerated statin therapy [1-3]. The absolute CV benefits of ezetimibe and PCSK9i depend on the individual’s baseline CVD risk [4,5]. However, the absolute effects of these agents, separately or in combination, on CV outcomes across CVD risk groups are uncertain.

Aim of the study

The researchers set out to estimate the extent of absolute CVD risk reduction with ezetimibe and PCSK9i in adults who were taking maximally tolerated statin therapy or who were statin intolerant, across 4 CVD risk groups.


This was a systematic review and network meta-analysis of data from 14 RCTs, in which adults (83,660 in total) who were receiving maximally tolerated statin therapy and had a baseline LDL-c value ≥70 mg/dL (≥1.8 mmol/L) or who were statin intolerant and were considering further CVD risk reduction, were randomized to receive PCSK9i versus control, ezetimibe versus control, or PCSK9i versus ezetimibe. To generate reliable estimates, only studies with a sample size ≥500 patients and a follow-up duration ≥6 months were included.

Relative risks (RRs) and absolute risks per 1000 patients treated over 5 years were calculated for the following outcomes: non-fatal MI, non-fatal stroke, all-cause mortality, and CV mortality. Absolute risk differences were estimated assuming constant RRs. The CVD risk groups were: (a ) low risk (1–2 CVD risk factors); (b) moderate risk (3–4 CVD risk factors); (c) high risk (≥5 CVD risk factors, or hereditary/familial lipid disorder without any CVD risk factor); and (d) very high risk (established CVD or hereditary/familial lipid disorder).

To assess the certainty of the evidence in the studies, the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) method was used.

Main results

Relative risk reductions

Absolute risk reductions in very high–CVD risk patients

Absolute risk reductions in high–CVD risk patients

Absolute risk reductions in moderate– or low–CVD risk patients


Both PCSK9is and ezetimibe may reduce the incidence of non-fatal MI or stroke in adults at very high or high CVD risk who are receiving maximally tolerated statin therapy or who are statin intolerant but not in those with a moderate or low CVD risk. In addition, these medications did not seem to lower all-cause or CVD mortality. The authors believe that prescribing these lipid-lowering drugs should be considered for appropriate candidates with a very high or high CVD risk, to achieve desired CV benefits.


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