Absolute effects of PCSK9i and ezetimibe across different CVD risk groups

17/07/2022

A network meta-analysis shows both PCSK9i and ezetimibe may reduce non-fatal MI and stroke in adults on maximum statin therapy or with statin intolerance who are at very high or high CVD risk but not in those at moderate or low risk.

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

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.

References

1. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation 2019;139: e1046-81.

2. Mach F, Baigent C, Catapano AL, et al, ESC Scientific Document Group. 2019 ESC/EAS Guidelines for 2.the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J 2020;41:111-88. doi:10.1093/eurheartj/ehz455

3. Visseren FLJ, Mach F, Smulders YM, et al, ESC National Cardiac Societies, ESC Scientific Document Group. 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J 2021;42:3227-337. doi:10.1093/eurheartj/ehab484

4. Navarese EP, Robinson JG, Kowalewski M, et al. Association between baseline LDL-C level and total and cardiovascular mortality after LDL-C lowering: a systematic review and meta-analysis. JAMA 2018;319:1566-79. doi:10.1001/jama.2018.2525

5. Khan SU, Riaz H, Rahman H, et al. Association of baseline LDL-C with total and cardiovascular mortality in patients using proprotein convertase subtilisin-kexin type 9 inhibitors: A systematic review and meta-analysis. J Clin Lipidol 2019;13:538-49. doi:10.1016/j.jacl.2019.05.014

Find this article online at BMJ.

Register

We're glad to see you're enjoying PACE-CME…
but how about a more personalized experience?

Register for free