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

Background

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.

Methods

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

• Ezetimibe reduced the risk of non-fatal MI (RR: 0.87; 95%CI: 0.80–0.94) and non-fatal stroke (0.82 ; 0.71–0.96) compared with control but not the risk of all-cause mortality (0.99; 0.92–1.06) or CV mortality (0.97; 0.87–1.09 ).
• Similarly, PCSK9is reduced the risk of MI (RR: 0.81; 95%CI: 0.76–0.87) and stroke (0.74; 0.64–0.85) compared with control but not the risk of all-cause mortality (0.95; 0.87–1.03) or CV mortality (0.95; 0.87–1.03).

Absolute risk reductions in very high–CVD risk patients

• Among patients with a very high CVD risk, adding a PCSK9i to maximally tolerated statin therapy was likely to reduce the incidence of MI (16 fewer patients per 1000) and stroke (21 fewer per 1000) (moderate to high certainty).
• Adding ezetimibe to statin treatment was likely to reduce the frequency of stroke (14 fewer per 1000), but the reduction in MI frequency (11 fewer per 1000) (both moderate certainty) did not reach the minimal important difference (MID).
• Adding ezetimibe to a PCSK9i and statin may reduce the incidence of stroke (11 fewer per 1000), but the MI reduction (9 fewer per 1000) (both low certainty) did not reach the MID.
• Adding a PCSK9i to statin and ezetimibe therapy may reduce the frequency of MI (14 fewer per 1000) and stroke (17 fewer per 1000) (both low certainty).
• In statin-intolerant patients, similar results were found.

Absolute risk reductions in high–CVD risk patients

• Among patients with a high CVD risk, adding a PCSK9i to maximally tolerated statin therapy probably led to reduction of MIs (12 fewer per 1000) and strokes (16 fewer per 1000) (both moderate certainty).
• Adding ezetimibe to a statin probably reduced stroke incidence (11 fewer per 1000), but the MI reduction (8 fewer per 1000) (both moderate certainty) did not reach the MID.
• Adding ezetimibe to PCSK9i and statin therapy did not reduce outcomes beyond the MID (moderate to low certainty), whereas the addition of a PCSK9i to ezetimibe plus statin may reduce stroke (13 fewer per 1000) (low certainty).
• These effects were consistent in statin-intolerant patients.

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

• In the moderate– and low–CVD risk groups, the addition of a PCSK9i or ezetimibe had little or no beneficial effect on the occurrence of MI or stroke in both patients on maximally tolerated statin therapy and statin-intolerant patients (moderate to low certainty).

Conclusion

References

Find this article online at BMJ.