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Original research article
Proprotein convertase subtilisin/kexin 9 inhibitors in reducing cardiovascular outcomes: a systematic review and meta-analysis
  1. Heyue Du1,2,
  2. Xiaodan Li3,
  3. Na Su4,
  4. Ling Li5,
  5. Xiaoting Hao6,
  6. Haihui Gao1,7,
  7. Joey Sum-Wing Kwong8,
  8. Per Olav Vandvik9,10,
  9. Xueli Yang11,
  10. Imola Nemeth12,
  11. Ify R Mordi13,
  12. Qianrui Li1,14,15,
  13. Longhao Zhang16,
  14. Li Rao16,
  15. Chim C Lang13,
  16. Jianshu Li17,
  17. Haoming Tian1,
  18. Sheyu Li1,12
  1. 1 Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, China
  2. 2 West China School of Medicine, Sichuan University, Chengdu, China
  3. 3 Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
  4. 4 Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, China
  5. 5 Chinese Evidence-based Medicine Center and CREAT group, West China Hospital, Sichuan University, Chengdu, China
  6. 6 Department of Neurology, West China Hospital, Sichuan University, Chengdu, China
  7. 7 Department of Rheumatology and Clinical Immunology, The Affiliated Hospital of Qingdao University, Qingdao, China
  8. 8 Jockey Club School of Public Health andPrimary Care, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kong, China
  9. 9 Norwegian Institute of Public Health, Oslo, Norway
  10. 10 Department of Medicine, Innlandet Hospital Trust, Gjøvik, Norway
  11. 11 Departmentof Epidemiology, Fuwai Hospital, National Center of Cardiovascular Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
  12. 12 Division of Population Health & Genomics, Ninewells Hospital, University of Dundee, Dundee, UK
  13. 13 Division of Molecular & Clinical Medicine, Ninewells Hospital, University of Dundee, Dundee, UK
  14. 14 Institute of Health Informatics, University College London, London, UK
  15. 15 Health Data Research UK London, University College London, London, UK
  16. 16 Department of Cardiology, West China Hospital, Sichuan University, Chengdu, China
  17. 17 Department of Biomedical Polymer and Artificial Organs, College of Polymer Science and Engineering, Sichuan University, Chengdu, China
  1. Correspondence to Dr Sheyu Li, Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China and Division of Population Health & Genomics, Ninewells Hospital and School of Medicine, University of Dundee, Dundee, DD1 9SY, Scotland, UK; lisheyu{at}


Background To evaluate the effects of proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors on major adverse cardiovascular events (MACE).

Methods Our systematic review included randomised controlled trials if they studied PCSK9 inhibitors in patients for primary and/or secondary prevention of cardiovascular diseases or with hypercholesterolaemia/hyperlipidaemia. Dichotomous variables from individual studies were pooled by relative risks (RR) and their 95% CIs using the random-effect model. Risk difference (RD) in the 10-year frame was also estimated using the pooled RR and the estimated baseline risk using the control group. Grading of Recommendation Assessment, Development and Evaluation was used to assess the quality of evidence.

Results We included 54 trials with 97 910 patients in the analysis. Compared with controls, PCSK9 inhibitors significantly reduced the risk of MACE by 16% (RR, 0.84; 95% CI 0.79 to 0.89; RD: 47 fewer per 1000 vs 286 as the baseline risk; 95% CI 32 to 59 fewer), non-fatal myocardial infarction (MI) by 17% (RR, 0.83; 95% CI 0.74 to 0.93; RD, 35 fewer per 1000 vs 207 as the baseline; 95% CI 13 to 53 fewer) and any stroke by 25% (RR, 0.75; 95% CI 0.65 to 0.85; RD, 16 fewer per 1000 vs 61 as the baseline; 95% CI 9 to 21 fewer) with moderate quality evidence. No significant differences were found between PCSK9 inhibitors and control groups in all-cause mortality, cardiovascular death, heart failure or unstable angina with low-quality evidence.

Conclusions This study demonstrated that PCSK9 inhibitors could significantly reduce the risk of MACE, non-fatal MI and stroke.

Trial registration PROSPERO; CRD42017073904.

  • cardiovascular disease
  • low-density lipoprotein cholesterol
  • lipid-lowering drugs
  • proprotein convertase subtilisin/kexin type 9 inhibitors
  • systematic review

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  • HD, XL and NS were the co-first authors.

  • HD, XL and NS contributed equally.

  • Contributors HT, JL and SL: planned this study. HD, XL, NS, XH and HG: performed the literature search and screening. HD, XL and NS: extracted the study data. HD and NS: performed the risk of bias assessment. HD, LL and LZ: performed the statistical analyses. JS-WK, POV and XY: provided critical comments in methodology and revised the manuscript. MRI, LR and CCL: provided critical comments in clinical cardiology. HD, XL, IN, MRI and SL: drafted the manuscript. All authors critically reviewed the manuscript and participated in the interpretation of the results. SL: is responsible for the overall content as the guarantor.

  • Funding This study was supported by grants from the National Natural Science Foundation of China (grant number 81400811 and 21534008), Cholesterol Fund by China Cardiovascular Foundation and China Heart House and the International Visiting Program for Excellent Young Scholars of Sichuan University.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; internally peer reviewed.

  • Correction notice Since this article was first published online, the author name Ify R Mordi has been corrected.