Proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors treatment induce large reductions in low-density lipoprotein cholesterol (LDLc) and major cardiovascular events. Clinical trials might have been underpowered to test the effect of PSCK9 inhibitors treatment on myocardial infarction and stroke, two of the most relevant cardiovascular events, since all analyzed a combined endpoint.
we performed a meta-analysis, with currently available studies involving PCSK9 inhibitors and event rate adjudication, with the aim of assessing treatment effects on myocardial infarction and stroke.
We included 81,700 patients, 41,979 treated with a PSCK9 inhibitors: 17,244 with evolocumab; 13,720 with bococizumab and 11,015 with alirocumab. A total of 1,319 cases of myocardial infarctions were registered in the treatment group vs. 1,608 in controls, resulting in 19.0% reduction associated with PCSK9 treatment (RR: 0.81, 95% CI 0.76–0.87). Similarly, PCSK9 inhibitors treatment resulted in a 25% reduction of stroke (RR: 0.75, 95% CI 0.65–0.85) when all studies were analyzed together and the statistically significant heterogeneity was not observed in the analysis restricted to end-point based clinical trials. PCSK9 inhibitors treatment had no effect on mortality (RR: 0.95, 95% CI 0.86–1.04).
PCSK9 inhibitors reduce the incidence of myocardial infarction by 19% and stroke by 25%.
This is a preview of subscription content, log in to check access.
Buy single article
Instant access to the full article PDF.
Price includes VAT for USA
Ference BA, Ginsberg HN, Graham I, Ray KK, Packard CJ, Bruckert E, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J. 2017;38(32):2459–72. https://doi.org/10.1093/eurheartj/ehx144.
Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, 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. J Am Coll Cardiol. 2019;73(24):e285–350. https://doi.org/10.1016/j.jacc.2018.11.003.
Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk: The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS). Eur Heart J. 2020;41(1):111–88. https://doi.org/10.1093/eurheartj/ehz455.
Lloyd-Jones DM, Morris PB, Ballantyne CM, Birtcher KK, Daly DD Jr, DePalma SM, et al. 2017 Focused Update of the 2016 ACC Expert Consensus Decision Pathway on the Role of Non-Statin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk: A Report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol. 2017;70(14):1785–822. https://doi.org/10.1016/j.jacc.2017.07.745.
Sabatine MS, Giugliano RP, Wiviott SD, Raal FJ, Blom DJ, Robinson J, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372(16):1500–9. https://doi.org/10.1056/NEJMoa1500858.
Robinson JG, Farnier M, Krempf M, Bergeron J, Luc G, Averna M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372(16):1489–99. https://doi.org/10.1056/NEJMoa1501031.
Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376(18):1713–22. https://doi.org/10.1056/NEJMoa1615664.
Ridker PM, Tardif JC, Amarenco P, Duggan W, Glynn RJ, Jukema JW, et al. Lipid-reduction variability and antidrug-antibody formation with bococizumab. N Engl J Med. 2017;376(16):1517–26. https://doi.org/10.1056/NEJMoa1614062.
Schwartz GG, Steg PG, Szarek M, Bhatt DL, Bittner VA, Diaz R, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med. 2018;379(22):2097–107. https://doi.org/10.1056/NEJMoa1801174.
Casula M, Olmastroni E, Boccalari MT, Tragni E, Pirillo A, Catapano AL. Cardiovascular events with PCSK9 inhibitors: an updated meta-analysis of randomised controlled trials. Pharmacol Res. 2019;143:143–50. https://doi.org/10.1016/j.phrs.2019.03.021.
Bhatt DL, Eagle KA, Ohman EM, Hirsch AT, Goto S, Mahoney EM, et al. Comparative determinants of 4-year cardiovascular event rates in stable outpatients at risk of or with atherothrombosis. JAMA. 2010;304:1350–7.
Cordero A, Lopez-Palop R, Carrillo P, Frutos A, Bertomeu-Martinez V. Addition of antiangina drugs and recurrent cardiovascular events associated with incomplete revascularization in acute coronary syndrome. Rev Esp Cardiol (Engl Ed). 2018;71(3):217–9. https://doi.org/10.1016/j.rec.2017.01.032.
Rodriguez-Manero M, Cordero A, Kreidieh O, Garcia-Acuna JM, Seijas J, Agra-Bermejo RM, et al. Proposal of a novel clinical score to predict heart failure incidence in long-term survivors of acute coronary syndromes. Int J Cardiol. 2017;243:211–5. https://doi.org/10.1016/j.ijcard.2017.07.084.
Agra Bermejo R, Cordero A, Garcia-Acuna JM, Gomez Otero I, Varela Roman A, Martinez A, et al. Determinants and prognostic impact of heart failure and left ventricular ejection fraction in acute coronary syndrome settings. Rev Esp Cardiol (Engl Ed). 2018;71(10):820–8. https://doi.org/10.1016/j.rec.2017.10.030.
Szarek M, White HD, Schwartz GG, Alings M, Bhatt DL, Bittner VA, et al. Alirocumab reduces total nonfatal cardiovascular and fatal events in the ODYSSEY OUTCOMES trial. J Am Coll Cardiol. 2019. https://doi.org/10.1016/j.jacc.2018.10.039.
Nicholls SJ, Puri R, Anderson T, Ballantyne CM, Cho L, Kastelein JJ, et al. Effect of evolocumab on progression of coronary disease in statin-treated patients: the GLAGOV randomized clinical trial. JAMA. 2016;316(22):2373–84. https://doi.org/10.1001/jama.2016.16951.
Moher D, Cook DJ, Eastwood S, Olkin I, Rennie D, Stroup DF. Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement. Quality of reporting of meta-analyses. Lancet. 1999;354(9193):1896–900.
Sterne JAC, Sutton AJ, Ioannidis JPA, Terrin N, Jones DR, Lau J, et al. Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ. 2011;343:d4002. https://doi.org/10.1136/bmj.d4002.
Kohli M, Patel K, MacMahon Z, Ramachandran R, Crook MA, Reynolds TM, et al. Pro-protein subtilisin kexin-9 (PCSK9) inhibition in practice: lipid clinic experience in 2 contrasting UK centres. Int J Clin Pract. 2017;71(11):e13032. https://doi.org/10.1111/ijcp.13032.
Knickelbine T, Jia L, White SK, Garberich RF, Oberembt SJ, Wills S, et al. A systematic approach for successful PCSK9 inhibitor prescribing in clinical practice. J Clin Lipidol. 2019;13(2):265–71. https://doi.org/10.1016/j.jacl.2019.01.005.
Cordero A, Fácila L, Rodríguez-Mañero M, Gómez-Martínez MJ, Bertomeu-Martínez V, González-Juanatey JR. Initial real-world experience with PCSK-9 inhibitors in current indications for reimbursement in Spain. Revista Española de Cardiología (English Edition). 2019. https://doi.org/10.1016/j.rec.2019.03.008.
Trankle C, Wohlford G, Buckley LF, Kadariya D, Ravindra K, Markley R, et al. Alirocumab in Acute Myocardial Infarction: Results from the Virginia Commonwealth University Alirocumab Response Trial (VCU-AlirocRT). Journal of Cardiovascular Pharmacology. 2019.
Thongtang N, Sitthananun C, Sriussadaporn S, Nitiyanant W. Efficacy of low- and moderate-intensity statins for achieving low- density lipoprotein cholesterol targets in Thai type 2 diabetic patients. J Diabetes Metab Disord. 2017;16(1):6. https://doi.org/10.1186/s40200-017-0290-x.
Galve E, Cordero A, Cequier A, Ruiz E, Gonzalez-Juanatey JR. Degree of lipid control in patients with coronary heart disease and measures adopted by physicians. REPAR Study. Rev Esp Cardiol (Engl Ed). 2016;69(10):931–8. https://doi.org/10.1016/j.rec.2016.02.012.
Reiner Z, De Backer G, Fras Z, Kotseva K, Tokgözoglu L, Wood D, et al. Lipid lowering drug therapy in patients with coronary heart disease from 24 European countries – Findings from the EUROASPIRE IV survey. Atherosclerosis. 2016;246:243–50. https://doi.org/10.1016/j.atherosclerosis.2016.01.018.
Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372(25):2387–97. https://doi.org/10.1056/NEJMoa1410489.
De Backer G, Jankowski P, Kotseva K, Mirrakhimov E, Reiner Ž, Rydén L, et al. Management of dyslipidaemia in patients with coronary heart disease: results from the ESC-EORP EUROASPIRE V survey in 27 countries. Atherosclerosis. 2019;285:135–46. https://doi.org/10.1016/j.atherosclerosis.2019.03.014.
Descamps OS, Fraass U, Dent R, März W, Gouni-Berthold I. Anti-PCSK9 antibodies for hypercholesterolaemia: overview of clinical data and implications for primary care. Int J Clin Pract. 2017;71(8):e12979. https://doi.org/10.1111/ijcp.12979.
Zamora A, Masana L, Comas-Cufi M, Plana N, Vila A, Garcia-Gil M, et al. Number of patients eligible for PCSK9 inhibitors based on real-world data from 2.5 million patients. Rev Esp Cardiol (Engl Ed). 2018;71(12):1010–7. https://doi.org/10.1016/j.rec.2018.03.003.
Cordero A, Fácila L, Galve E, González Juanatey JR. Estimated percentage of patients with stable coronary heart disease candidates for PCSK9 inhibitors. Rev Esp Cardiol. 2019;72(6):518–9. https://doi.org/10.1016/j.recesp.2018.11.017.
Cannon CP, Sanchez RJ, Klimchak AC, Khan I, Sasiela WJ, Reynolds MR, et al. Simulation of the impact of statin intolerance on the need for Ezetimibe and/or Proprotein Convertase Subtilisin/Kexin type 9 inhibitor for meeting low-density lipoprotein cholesterol goals in a population with atherosclerotic cardiovascular disease. Am J Cardiol. 2019. https://doi.org/10.1016/j.amjcard.2019.01.028.
Sabatine MS, Leiter LA, Wiviott SD, Giugliano RP, Deedwania P, De Ferrari GM, et al. Cardiovascular safety and efficacy of the PCSK9 inhibitor evolocumab in patients with and without diabetes and the effect of evolocumab on glycaemia and risk of new-onset diabetes: a prespecified analysis of the FOURIER randomised controlled trial. Lancet Diabetes Endocrinol. 2017;5(12):941–50. https://doi.org/10.1016/S2213-8587(17)30313-3.
Sabatine MS, De Ferrari GM, Giugliano RP, Huber K, Lewis BS, Ferreira J, et al. Clinical benefit of evolocumab by severity and extent of coronary artery disease. Circulation. 2018;138(8):756–66. https://doi.org/10.1161/CIRCULATIONAHA.118.034309.
Bonaca MP, Nault P, Giugliano RP, Keech AC, Pineda AL, Kanevsky E, et al. Low-density lipoprotein cholesterol lowering with evolocumab and outcomes in patients with peripheral artery disease: insights from the FOURIER trial (Further cardiovascular outcomes research with PCSK9 inhibition in subjects with elevated risk). Circulation. 2018;137(4):338–50. https://doi.org/10.1161/CIRCULATIONAHA.117.032235.
Khan SU, Riaz H, Rahman H, Khan MU, Khan MS, Alkhouli M, 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. https://doi.org/10.1016/j.jacl.2019.05.014.
Cordero A, Fácila L, Rodríguez-Mañero M, Gómez-Martínez MJ, Bertomeu-Martínez V, González-Juanatey JR. Initial real-world experience with PCSK-9 inhibitors in current indications for reimbursement in Spain. Rev Esp Cardiol (Engl Ed). 2019;72(11):968–70. https://doi.org/10.1016/j.rec.2019.03.008.
Szarek M, White HD, Schwartz GG, Alings M, Bhatt DL, Bittner VA, et al. Alirocumab reduces total nonfatal cardiovascular and fatal events: the ODYSSEY OUTCOMES trial. J Am Coll Cardiol. 2019;73(4):387–96. https://doi.org/10.1016/j.jacc.2018.10.039.
Murphy SA, Pedersen TR, Gaciong ZA, Ceska R, Ezhov MV, Connolly DL, et al. Effect of the PCSK9 inhibitor evolocumab on total cardiovascular events in patients with cardiovascular disease: a prespecified analysis from the FOURIER trial reduction in total cardiovascular events with the PCSK9 inhibitor evolocumab in patients with cardiovascular diseasereduction in total cardiovascular events with the PCSK9 inhibitor evolocumab in patients with cardiovascular disease. JAMA Cardiol. 2019;4(7):613–9. https://doi.org/10.1001/jamacardio.2019.0886.
Cordero A, Galve E, Bertomeu-Martinez V, Bueno H, Facila L, Alegria E, et al. Trends in risk factors and treatments in patients with stable ischemic heart disease seen at cardiology clinics between 2006 and 2014. Rev Esp Cardiol (Engl Ed). 2016;69(4):401–7. https://doi.org/10.1016/j.rec.2015.08.011.
Investigators received the support of the Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV) Spain, the National Network for Biomedical Research in Cardiovascular Disease.
Conflict of interest
Authors declare no conflict of interest related to the results of this study.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Cordero, A., Rodríguez-Mañero, M., Fácila, L. et al. Prevention of myocardial infarction and stroke with PCSK9 inhibitors treatment: a metanalysis of recent randomized clinical trials. J Diabetes Metab Disord (2020). https://doi.org/10.1007/s40200-020-00557-6
- Acute coronary syndrome