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Research

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

BMJ 2022; 377 doi: https://doi.org/10.1136/bmj-2021-069116 (Published 04 May 2022) Cite this as: BMJ 2022;377:e069116

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PCSK9 inhibitors and ezetimibe for the reduction of cardiovascular events
  1. Safi U Khan, cardiologist, methodologist1,
  2. Siva H Yedlapati, general internist2,
  3. Ahmad N Lone, cardiologist, methodologist3,
  4. Qiukui Hao, methodologist, geriatrician45,
  5. Gordon Guyatt, general internist, methodologist5,
  6. Nicolas Delvaux, general practitioner, methodologist6,
  7. Geertruida E (Trudy) Bekkering, patient partnership liaison, methodologist6,
  8. Per Olav Vandvik, general internist, methodologist78,
  9. Irbaz Bin Riaz, methodologist910,
  10. Sheyu Li, endocrinologist, methodologist11,
  11. Bert Aertgeerts, general practitioner, methodologist6,
  12. Nicolas Rodondi, general internist, methodologist1213
  1. 1Department of Cardiology, Houston Methodist DeBakey Heart & Vascular Center, Houston, TX, USA
  2. 2Department of Medicine, Erie County Medical Center, Buffalo, NY, USA
  3. 3Guthrie Health System/Robert Packer Hospital, Sayre, PA, USA
  4. 4Center of Gerontology and Geriatrics/National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
  5. 5Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Canada
  6. 6Department of Public Health and Primary Care and MAGIC Primary Care, KU Leuven, Leuven, Belgium
  7. 7Clinical Effectiveness Research Group, Institute of Health Society, University of Oslo, Oslo, Norway
  8. 8MAGIC Evidence Ecosystem Foundation
  9. 9Department of Medicine, Hematology and Oncology, Mayo Clinic, Phoenix, AZ, USA
  10. 10Mass General Brigham, Harvard Medical School, Boston MA, USA
  11. 11Department of Endocrinology and Metabolism, Department of Guideline and Rapid Recommendation, Cochrane China Center, MAGIC China Center, Chinese Evidence-based Medicine Center, West China Hospital, Sichuan University, Chengdu 610041, China
  12. 12Department of General Internal Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
  13. 13Institute of Primary Health Care (BIHAM), University of Bern, Bern, Switzerland
  1. Correspondence to: S U Khan safinmc{at}gmail.com; sukhan{at}houstonmethodist.orgTwitter: @safinmc
  • Accepted 19 April 2022

Abstract

Objective To compare the impact of ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors on cardiovascular outcomes in adults taking maximally tolerated statin therapy or who are statin intolerant.

Design Network meta-analysis.

Data sources Medline, EMBASE, and Cochrane Library up to 31 December 2020.

Eligibility criteria for selecting studies Randomised controlled trials of ezetimibe and PCSK9 inhibitors with ≥500 patients and follow-up of ≥6 months.

Main outcome measures We performed frequentist fixed-effects network meta-analysis and GRADE (grading of recommendations, assessment, development, and evaluation) to assess certainty of evidence. Results included relative risks (RR) and absolute risks per 1000 patients treated for five years for non-fatal myocardial infarction (MI), non-fatal stroke, all-cause mortality, and cardiovascular mortality. We estimated absolute risk differences assuming constant RR (estimated from network meta-analysis) across different baseline therapies and cardiovascular risk thresholds; the PREDICT risk calculator estimated cardiovascular risk in primary and secondary prevention. Patients were categorised at low to very high cardiovascular risk. A guideline panel and systematic review authors established the minimal important differences (MID) of 12 per 1000 for MI and 10 per 1000 for stroke.

Results We identified 14 trials assessing ezetimibe and PCSK9 inhibitors among 83 660 adults using statins. Adding ezetimibe to statins reduced MI (RR 0.87 (95% confidence interval 0.80 to 0.94)) and stroke (RR 0.82 (0.71 to 0.96)) but not all-cause mortality (RR 0.99 (0.92 to 1.06)) or cardiovascular mortality (RR 0.97 (0.87 to 1.09)). Similarly, adding PCSK9 inhibitor to statins reduced MI (0.81 (0.76 to 0.87)) and stroke (0.74 (0.64 to 0.85)) but not all-cause (0.95 (0.87 to 1.03)) or cardiovascular mortality (0.95 (0.87 to 1.03)). Among adults with very high cardiovascular risk, adding PCSK9 inhibitor was likely to reduce MI (16 per 1000) and stroke (21 per 1000) (moderate to high certainty); whereas adding ezetimibe was likely to reduce stroke (14 per 1000), but the reduction of MI (11 per 1000) (moderate certainty) did not reach MID. Adding ezetimibe to PCSK9 inhibitor and statin may reduce stroke (11 per 1000), but the reduction of MI (9 per 1000) (low certainty) did not reach MID. Adding PCSK9 inhibitors to statins and ezetimibe may reduce MI (14 per 1000) and stroke (17 per 1000) (low certainty). Among adults with high cardiovascular risk, adding PCSK9 inhibitor probably reduced MI (12 per 1000) and stroke (16 per 1000) (moderate certainty); adding ezetimibe probably reduced stroke (11 per 1000), but the reduction in MI did not achieve MID (8 per 1000) (moderate certainty). Adding ezetimibe to PCSK9 inhibitor and statins did not reduce outcomes beyond MID, while adding PCSK9 inhibitor to ezetimibe and statins may reduce stroke (13 per 1000). These effects were consistent in statin-intolerant patients. Among moderate and low cardiovascular risk groups, adding PCSK9 inhibitor or ezetimibe to statins yielded little or no benefit for MI and stroke.

Conclusions Ezetimibe or PCSK9 inhibitors may reduce non-fatal MI and stroke in adults at very high or high cardiovascular risk who are receiving maximally tolerated statin therapy or are statin-intolerant, but not in those with moderate and low cardiovascular risk.

Footnotes

  • Contributors: SUK, QH, GG, ND, GEB, POV, IBR, SL, BA, NR conceived the study. SUK and SHY designed the search strategy. ANL performed the literature search; SUK, SHY, ANL screened studies for eligibility; SHY and ANL assessed the risk of bias; and SUK and SHY performed data extraction. UK, SHY, ANL, QH, GG, ND, GEB, POV, IBR, SL, BA, NR interpreted the data analysis; QH, GG, ND, GEB, POV, IBR, SL, BA, NR assessed the certainty of the evidence; SUK wrote the first draft of the manuscript; and all other authors revised the manuscript. SUK and NR are guarantors. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

  • Funding: This review did not receive any funding.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: SUK, SHY, ANL, QH, GG, ND, GEB, POV, IBR, SL, BA, NR had no support from any organisation for the submitted work, and no financial relationships with any organisations that might have an interest in the submitted work in the previous three years. NR’s work is partly funded by a grant from the Swiss National Scientific Foundation (33IC30_193052) about assessing the role of statins in multimorbid older adults without cardiovascular disease (www.statin-stream.ch).

  • Patient consent: Not required.

  • Transparency: The manuscript’s guarantors (SUK and NR) affirm that the manuscript is an honest, accurate and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned and registered have been explained.

  • Dissemination to participants and related patient and public communities: The paper informs the BMJ Rapid Recommendation (https://www.bmj.com/rapid-recommendations) on the use of PCSK9 inhibitors and ezetimibe, also available in MAGICapp (https://www.magicapp.org/) for organisations to reuse or adapt for their own materials and purposes.

  • Provenance and peer review: Not commissioned; externally peer reviewed.

Data availability statement

Statistical code and dataset are available from the corresponding author at safinmc@gmail.com.

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