Long-Term Impact of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors on Major Adverse Cardiovascular Events and All-Cause Mortality: A Systematic Review and Bayesian Meta-Analysis of Randomized Controlled Trials

Abstract

The introduction of proprotein convertase subtilisin/Kexin type 9 (PSCK9) inhibitors has transformed the approach to low-density lipoprotein cholesterol lowering in the prevention of atherosclerotic cardiovascular disease. This paper aims to determine the longer-term impact of these interventions on major adverse cardiovascular events (MACE) and all-cause mortality. A systematic search of major databases was conducted to identify randomised controlled trials comparing PCSK9 inhibitors with a placebo. Studies were included if they reported cardiovascular events with a follow-up duration greater than 12 months. Frequentist, Bayesian meta-analysis, and trial sequential analysis were utilised to assess the efficacy of PCSK9 inhibitors in reducing MACE. Amongst 11 studies encompassing 52,372 patients, statistically significant reductions were observed in rates of myocardial infarction (risk ratio (RR) 0.78; 95% confidence interval (CI) 0.68 to 0.89, p < 0.01, I² = 20%), coronary revascularisation (RR 0.83; 95% CI 0.75 to 0.91, p < 0.01, I² = 9.1%) and ischemic stroke (RR 0.76; 95% CI 0.66 to 0.87, p < 0.01, I² = 0%) amongst patients on PCSK9 inhibitors compared to placebo based on random-effects meta-analysis. Trial sequential analysis and Bayesian analysis supported these results, with posterior probabilities that PCSK9 inhibitors improve outcomes for myocardial infarction, coronary revascularisation, and ischemic stroke of 83.8%, 82.9%, and 69.4%, respectively. No statistically significant effect was observed for the other outcomes. This meta-analysis demonstrates significant reductions in the rate of myocardial infarction, coronary revascularisation, and ischemic stroke. Further benefits may emerge with longer-term follow-up and alternate methods of targeting PCSK9.

Keywords

PCSK9 inhibitor / Lipid-lowering therapy / LDL-C / Major adverse cardiovascular event

References

[1] Vaduganathan M, Mensah GA, Turco JV, Fuster V, Roth GA. The Global Burden of Cardiovascular Diseases and Risk. J. Am. Coll. Cardiol. 2022, 80, 2361-2371. DOI:10.1016/j.jacc.2022.11.005

[2] Tokgözoğlu L, Libby P. The dawn of a new era of targeted lipid—lowering therapies. Eur. Heart J. 2022, 43, 3198-3208. DOI:10.1093/eurheartj/ehab841

[3] 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. 2019, 41, 111-188. DOI:10.1093/eurheartj/ehz455

[4] 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. Circulation 2019, 139, 25. DOI:10.1161/CIR.0000000000000625

[5] Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, et al. Efficacy and safety of cholesterol—lowering treatment: Prospective meta—analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005, 366, 1267-1278. DOI:10.1016/S0140—6736(05)67394—1

[6] Ray KK, Molemans B, Schoonen WM, Giovas P, Bray S, Kiru G, et al. EU—Wide Cross—Sectional Observational Study of Lipid—Modifying Therapy Use in Secondary and Primary Care: The DA VINCI study. Eur. J. Prev. Cardiol. 2020, 28, 1279-1289. DOI:10.1093/eurjpc/zwaa047

[7] Alsadat N, Hyun K, Boroumand F, Juergens C, Kritharides L, Brieger DB. Achieving lipid targets within 12 months of an acute coronary syndrome: An observational analysis. Med. J. Aust. 2022, 216, 463-468. DOI:10.5694/mja2.51442

[8] Vallejo—Vaz AJ, Stevens CAT, Lyons ARM, Dharmayat KI, Freiberger T, Hovingh GK, et al. Global perspective of familial hypercholesterolaemia: A cross—sectional study from the EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC). Lancet 2021, 398, 1713-1725. DOI:10.1016/S0140—6736(21)01122—3

[9] Talic S, Marquina C, Ofori—Asenso R, Petrova M, Liew D, Owen AJ, et al. Switching, Persistence and Adherence to Statin Therapy: A Retrospective Cohort Study Using the Australian National Pharmacy Data. Cardiovasc. Drugs Ther. 2022, 36, 867-877. DOI:10.1007/s10557—021—07199—7

[10] Seidah NG, Awan Z, Chrétien M, Mbikay M. PCSK9. Circ. Res. 2014, 114, 1022-1036. DOI:10.1161/CIRCRESAHA.114.301621

[11] Sabatine MS. PCSK9 inhibitors: Clinical evidence and implementation. Nat. Rev. Cardiol. 2019, 16, 155-165. DOI:10.1038/s41569—018—0107—8

[12] Stoekenbroek RM, Lambert G, Cariou B, Hovingh GK. Inhibiting PCSK9—Biology beyond LDL control. Nat. Rev. Endocrinol. 2019, 15, 52-62. DOI:10.1038/s41574—018—0110—5

[13] Rosenson Robert S, Hegele Robert A, Fazio S, Cannon Christopher P. The Evolving Future of PCSK9 Inhibitors. J. Am. Coll. Cardiol. 2018, 72, 314-329. DOI:10.1016/j.jacc.2018.04.054

[14] Karatasakis A, Danek BA, Karacsonyi J, Rangan BV, Roesle MK, Knickelbine T, et al. Effect of PCSK9 Inhibitors on Clinical Outcomes in Patients with Hypercholesterolemia: A Meta—Analysis of 35 Randomized Controlled Trials. J. Am. Heart Assoc. 2017, 6, e006910. DOI:10.1161/JAHA.117.006910

[15] Sabatine MS, Giugliano RP, Keech AC, Narimon H, Wiviott SD, Murphy SA, et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N. Engl. J. Med. 2017, 376, 1713-1722. DOI:10.1056/NEJMoa1615664

[16] 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, 2097-2107. DOI:10.1056/NEJMoa1801174

[17] Page MJ, Moher D, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. PRISMA 2020 explanation and elaboration: Updated guidance and exemplars for reporting systematic reviews. BMJ 2021, 372, n160. DOI:10.1136/bmj.n160

[18] Barker TH, Stone JC, Sears K, Klugar M, Tufanaru C, Leonardi—Bee J, et al. The revised JBI critical appraisal tool for the assessment of risk of bias for randomized controlled trials. JBI Evid. Synth. 2023, 21, 494-506. DOI:10.11124/JBIES—22—00430

[19] Blom DJ, Hala T, Bolognese M, Lillestol MJ, Toth PD, Burgess L, et al. A 52—Week Placebo—Controlled Trial of Evolocumab in Hyperlipidemia. N. Engl. J. Med. 2014, 370, 1809-1819. DOI:10.1056/NEJMoa1316222

[20] Ginsberg HN, Rader DJ, Raal FJ, Guyton JR, Baccara—dinet MT, Lorenzato C, et al. Efficacy and Safety of Alirocumab in Patients with Heterozygous Familial Hypercholesterolemia and LDL—C of 160 mg/dl or Higher. Cardiovasc. Drugs Ther. 2016, 30, 473-483. DOI:10.1007/s10557—016—6685—y

[21] Kastelein JJP, Ginsberg HN, Langslet G, Kees Hovingh G, Ceska R, Dufour R, et al. ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia. Eur. Heart J. 2015, 36, 2996-3003. DOI:10.1093/eurheartj/ehv370

[22] Kereiakes DJ, Robinson JG, Cannon CP, Lorenzato C, Pordy R, Chaudhari U, et al. Efficacy and safety of the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab among high cardiovascular risk patients on maximally tolerated statin therapy: The ODYSSEY COMBO I study. Am. Heart J. 2015, 169, 906-915.e13. DOI:10.1016/j.ahj.2015.03.004

[23] 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, 1489-1499. DOI:10.1056/NEJMoa1501031

[24] Nicholls SJ, Puri R, Anderson TJ, Ballantyne CM, Cho L, Kastelein JJP, et al. Effect of Evolocumab on Progression of Coronary Disease in Statin—Treated Patients: The GLAGOV Randomized Clinical Trial. JAMA 2016, 316, 2373-2384. DOI:10.1001/jama.2016.16951

[25] Räber L, Ueki Y, Otsuka T, Losdat S, Häner JD, Lonborg J, et al. Effect of Alirocumab Added to High—Intensity Statin Therapy on Coronary Atherosclerosis in Patients with Acute Myocardial Infarction: The PACMAN—AMI Randomized Clinical Trial. JAMA 2022, 327, 1771-1781. DOI:10.1001/jama.2022.5218

[26] Teramoto T, Kobayashi M, Uno K, Takagi Y, Matsuoka O, Sugimoto M, et al. Efficacy and Safety of Alirocumab in Japanese Subjects (Phase 1 and 2 Studies). Am. J. Cardiol. 2016, 118, 56-63. DOI:10.1016/j.amjcard.2016.04.011

[27] Wang H—F, Mao Y—C, Xu X—Y, Zhao S—Y, Han D—D, Ge S—Y, et al. Effect of alirocumab and evolocumab on all—cause mortality and major cardiovascular events: A meta—analysis focusing on the number needed to treat. Front. Cardiovasc. Med. 2022, 9, 1016802. DOI:10.3389/fcvm.2022.1016802

[28] Wang X, Wen D, Chen Y, Ma L, You C. PCSK9 inhibitors for secondary prevention in patients with cardiovascular diseases: A bayesian network meta—analysis. Cardiovasc. Diabetol. 2022, 21, 107. DOI:10.1186/s12933—022—01542—4

[29] Bai J, Gong LL, Li QF, Wang ZH. Long—term efficacy and safety of proprotein convertase subtilisin/kexin 9 monoclonal antibodies: A meta—analysis of 11 randomized controlled trials. J. Clin. Lipidol. 2018, 12, 277-291.e3. DOI:10.1016/j.jacl.2018.01.004

[30] Schmidt AF, Carter J—PL, Pearce LS, Wilkins JT, Overington JP, Hingorani AD, et al. PCSK9 monoclonal antibodies for the primary and secondary prevention of cardiovascular disease. Cochrane Database Syst. Rev. 2020, 2020, CD011748. DOI:10.1002/14651858.CD011748.pub3

[31] Khan SU, Yedlapati SH, Lone AN, Hao Q, Guyatt G, Delvaux N, et al. PCSK9 inhibitors and ezetimibe with or without statin therapy for cardiovascular risk reduction: A systematic review and network meta—analysis. BMJ 2022, 377, e069116. DOI:10.1136/bmj—2021—069116

[32] Cohen JC, Boerwinkle E, Mosley TH, Hobbs HH.Sequence Variations in PCSK9, Low LDL, and Protection against Coronary Heart Disease. N. Engl. J. Med. 2006, 354, 1264-1272. DOI:10.1056/NEJMoa054013

[33] Kent ST, Rosenson RS, Avery CL, Chen Y—DI, Correa A, Cummings SR, et al. PCSK9 Loss—of—Function Variants, Low—Density Lipoprotein Cholesterol, and Risk of Coronary Heart Disease and Stroke. Circ. Cardiovasc. Genet. 2017, 10, e001632. DOI:10.1161/CIRCGENETICS.116.001632

[34] Huang C—C, Fornage M, Lloyd—Jones DM, Wei GS, Boerwinkle E, Liu K. Longitudinal Association of PCSK9 Sequence Variations with Low—Density Lipoprotein Cholesterol Levels. Circ. Cardiovasc. Genet. 2009, 2, 354-361. DOI:10.1161/CIRCGENETICS.108.828467

[35] Giugliano RP, Wiviott SD, Blazing MA, De Ferrari GM, Park J—G, Murphy SA, et al. Long—term Safety and Efficacy of Achieving Very Low Levels of Low—Density Lipoprotein Cholesterol: A Prespecified Analysis of the IMPROVE—IT Trial. JAMA Cardiol. 2017, 2, 547-555. DOI:10.1001/jamacardio.2017.0083

[36] Giugliano RP, Pedersen TR, Park J—G, De Ferrari GM, Gaciong ZA, Ceska R, et al. Clinical efficacy and safety of achieving very low LDL—cholesterol concentrations with the PCSK9 inhibitor evolocumab: A prespecified secondary analysis of the FOURIER trial. Lancet 2017, 390, 1962-1971. DOI:10.1016/S0140—6736(17)32290—0

[37] Schwartz GG, Gabriel Steg P, Bhatt DL, Bittner VA, Diaz R, Goodman SG, et al. Clinical Efficacy and Safety of Alirocumab After Acute Coronary Syndrome According to Achieved Level of Low—Density Lipoprotein Cholesterol: A Propensity Score—Matched Analysis of the ODYSSEY OUTCOMES Trial. Circulation 2021, 143, 1109-1122. DOI:10.1161/CIRCULATIONAHA.120.049447

[38] Gaba P, O’Donoghue ML, Park J—G, Wiviott SD, Atar D, Kuder JF, et al. Association Between Achieved Low—Density Lipoprotein Cholesterol Levels and Long—Term Cardiovascular and Safety Outcomes: An Analysis of FOURIER—OLE. Circulation 2023, 147, 1192-1203. DOI:10.1161/CIRCULATIONAHA.122.063399

[39] Giugliano RP, Mach F, Zavitz K, Kurtz C, Im K, Kanevsky E, et al. Cognitive Function in a Randomized Trial of Evolocumab. N. Engl. J. Med. 2017, 377, 633-643. DOI:10.1056/NEJMoa1701131

[40] Janik MJ, Urbach DV, van Nieuwenhuizen E, Zhao J, Yellin O, Baccara—Dinet MT, et al. Alirocumab treatment and neurocognitive function according to the CANTAB scale in patients at increased cardiovascular risk: A prospective, randomized, placebo—controlled study. Atherosclerosis 2021, 331, 20-27. DOI:10.1016/j.atherosclerosis.2021.06.913

[41] Patti G, Spinoni EG, Grisafi L, Mehran R, Mennuni M. Safety and efficacy of very low LDL—cholesterol intensive lowering: A meta—analysis and meta—regression of randomized trials. Eur. Heart J. Cardiovasc. Pharmacother. 2022, 9, 138-147. DOI:10.1093/ehjcvp/pvac049

[42] Brandts J, Ray KK. Low Density Lipoprotein Cholesterol—Lowering Strategies and Population Health. Circulation 2020, 141, 873-876. DOI:10.1161/CIRCULATIONAHA.119.043406

[43] Robinson JG. Starting Primary Prevention Earlier with Statins. Am. J. Cardiol. 2014, 114, 1437-1442. DOI:10.1016/j.amjcard.2014.07.076

[44] Bohula EA, Giugliano RP, Leiter LA, Verma S, Park J—G, Sever PS, et al. Inflammatory and Cholesterol Risk in the FOURIER Trial. Circulation 2018, 138, 131-140. DOI:10.1161/CIRCULATIONAHA.118.034032

[45] Simantiris S, Antonopoulos AS, Papastamos C, Benetos G, Koumallos N, Tsioufis K, et al. Lipoprotein(a) and inflammation— pathophysiological links and clinical implications for cardiovascular disease. J. Clin. Lipidol. 2023, 17, 55-63. DOI:10.1016/j.jacl.2022.10.004

[46] Nordestgaard BG, Langsted A. Lipoprotein(a) as a cause of cardiovascular disease: Insights from epidemiology, genetics, and biology. J. Lipid Res. 2016, 57, 1953-1975. DOI:10.1194/jlr.R071233

[47] Bittner VA, Szarek M, Aylward PE, Bhatt DL, Diaz R, Edelberg JM, et al. Effect of Alirocumab on Lipoprotein(a) and Cardiovascular Risk After Acute Coronary Syndrome. J. Am. Coll. Cardiol. 2020, 75, 133-144. DOI:10.1016/j.jacc.2019.10.057

[48] Filippatos TD, Kei A, Rizos CV, Elisaf MS. Effects of PCSK9 Inhibitors on Other Than Low—Density Lipoprotein Cholesterol Lipid Variables. J. Cardiovasc. Pharmacol. Ther. 2018, 23, 3-12. DOI:10.1177/1074248417724868

[49] Pérez de Isla L, Díaz—Díaz JL, Romero MJ, Muñiz—Grijalvo O, Mediavilla JD, Argüeso R, et al. Alirocumab and Coronary Atherosclerosis in Asymptomatic Patients with Familial Hypercholesterolemia: The ARCHITECT Study. Circulation 2023, 147, 1436-1443. DOI:10.1161/CIRCULATIONAHA.122.062557

[50] O’Donoghue ML, Giugliano RP, Wiviott SD, Atar D, Keech A, Kuder JF, et al. Long—Term Evolocumab in Patients with Established Atherosclerotic Cardiovascular Disease. Circulation 2022, 146, 1109-1119. DOI:10.1161/CIRCULATIONAHA.122.061620

[51] Ray KK, Wright RS, Kallend D, Koenig W, Leiter LA, Raal FJ, et al. Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol. N. Engl. J. Med. 2020, 382, 1507-1519. DOI:10.1056/NEJMoa1912387

[52] O’Donoghue ML, Rosenson RS, Gencer B, López JAG, Lepor NE, Baum SJ, et al. Small Interfering RNA to Reduce Lipoprotein(a) in Cardiovascular Disease. N. Engl. J. Med. 2022, 387, 1855-1864. DOI:10.1056/NEJMoa2211023

[53] Liu C, Chen J, Chen H, Zhang T, He D, Luo Q, et al. PCSK9 Inhibition: From Current Advances to Evolving Future. Cells 2022, 11, 2972. DOI:10.3390/cells11192972

[54] Kazi DS, Moran AE, Coxson PG, Penko J, Ollendorf DA, Pearson S, et al. Cost—effectiveness of PCSK9 Inhibitor Therapy in Patients with Heterozygous Familial Hypercholesterolemia or Atherosclerotic Cardiovascular Disease. JAMA 2016, 316, 743-753. DOI:10.1001/jama.2016.11004

[55] Arrieta A, Hong JC, Khera R, Virani SS, Krumholz HM, Nasir K. Updated Cost—effectiveness Assessments of PCSK9 Inhibitors from the Perspectives of the Health System and Private Payers: Insights Derived from the FOURIER Trial. JAMA Cardiol. 2017, 2, 1369-1374. DOI:10.1001/jamacardio.2017.3655

[56] Mercep I, Strikic D, Hrabac P, Pecin I, Reiner Ž. PCSK9 inhibition: From effectiveness to cost—effectiveness. Front. Cardiovasc. Med. 2024, 11, 1339487. DOI:10.3389/fcvm.2024.1339487

[57] Muntner P, Ghazi L, Jones J, Dhalwani N, Poudel B, Wen Y, et al. Persistence and Adherence to PCSK9 Inhibitor Monoclonal Antibodies Versus Ezetimibe in Real—World Settings. Adv. Ther. 2024, 41, 2399-2413. DOI:10.1007/s12325—024—02868—z

[58] Ye X, Zhang S, Zhong X, Li M, Liu M, Zhuang X, et al. Real—World Assessment of the Association Between PCSK9i Adherence and LDL Reduction and Variability in a Chinese Clinical Practice. Clin. Epidemiol. 2025, 17, 537-546. DOI:10.2147/CLEP.S507761