Application Value of PCSK9 Inhibitor in Cardiovascular High Risk Patients: A Meta-Analysis
-
Liming Zhao
,
Ying Liu
,
Ziting Cao
,
Jun Wang
,
Xin Huo
Abstract
Background: Proprotein convertase subtilisin / Kexin type 9 (PCSK9) inhibitors are efficacious lipid-lowering agents. This drug is related to improving the prognosis of patients with cardiovascular disease (CVD). The purpose of this meta-analysis was to systematically analyze the safety and efficacy of PCSK9 inhibitors in all published randomized controlled trials (RCTs).
Methods: As of October 25, 2021, we searched PubMed, EMBASE, MEDLINE, Cochrane Library and web of science.
Results: From 684 articles, we included 11 trials for meta-analysis, including 52511 participants (26938 in the PCSK9 inhibitor group and 25573 in the control group). In terms of effectiveness, PCSK9 inhibitors reduced the risk of major adverse cardiovascular events(MACE) (OR=0.89, 95% Cl: 0.83-0.95, P=0.0009), but did not significantly reduce the risk of cardiovascular death (OR=0.95, 95% Cl: 0.84-1.07, P=0.38) or all-cause death (OR=0.93, 95% Cl: 0.85-1.03, P=0.18); In terms of safety, PCSK9 did not increase the risk of treatment-emergent adverse events (TEAE)(OR=0.98, 95% Cl: 0.94-1.02, P=0.28).
Conclusion: PCSK9 inhibitors can significantly reduce the risk of MACE in patients with high cardiovascular risk, which is well tolerated, but the impact on the risk of death is unclear.
1. Barale C, Melchionda E, Morotti A, Russo I (2021). PCSK9 Biology and Its Role in Atherothrombosis. Int J Mol Sci, 22(11):5880.
2. Sabatine MS (2019). PCSK9 inhibitors: clini-cal evidence and implementation. Nat Rev Cardiol, 16(3):155-165.
3. Borén J, Chapman MJ, Krauss RM, et al (2020). Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, genetic, and therapeu-tic insights: a consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J, 41(24):2313-2330.
4. O'Donoghue ML, Fazio S, Giugliano RP, et al (2019). Lipoprotein(a), PCSK9 Inhibi-tion, and Cardiovascular Risk. Circulation, 139(12):1483-1492.
5. Jang AY, Lim S, Jo SH, Han SH, Koh KK (2021). New Trends in Dyslipidemia Treatment. Circ J, 85(6):759-768.
6. Muraki I (2021). Role of Proprotein Con-vertase Subtilisin/Kexin Type 9 (PCSK9) on Lipid Metabolism and Insulin Re-sistance in Human. J Atheroscler Thromb, 28(4):317-318
7. Hamamura H, Adachi H, Enomoto M, et al (2021). Serum Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) is In-dependently Associated with Insulin Re-sistance, Triglycerides, Lipoprotein (a) Levels but not Low-Density Lipoprotein Cholesterol Levels in a General Popula-tion. J Atheroscler Thromb, 28(4):329-337.
8. Shahreyar M, Salem SA, Nayyar M, George LK, Garg N, Koshy SKG (2018). Hyper-lipidemia: Management with Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors. J Am Board Fam Med, 31(4):628-634.
9. Spolitu S, Dai W, Zadroga JA, Ozcan L (2019). Proprotein convertase subtil-isin/kexin type 9 and lipid metabolism. Curr Opin Lipidol, 30(3):186-191.
10. Turgeon RD, Tsuyuki RT, Gyenes GT, Pearson GJ (2018). Cardiovascular Effi-cacy and Safety of PCSK9 Inhibitors: Systematic Review and Meta-analysis In-cluding the ODYSSEY OUTCOMES Trial. Can J Cardiol, 34(12):1600-1605.
11. Casula M, Olmastroni E, Boccalari MT, Tragni E, Pirillo A, Catapano AL (2019). Cardiovascular events with PCSK9 in-hibitors: an updated meta-analysis of randomised controlled trials. Pharmacol Res, 143:143-150.
12. Cumpston M, Li T, Page MJ, Chandler J, Welch VA, Higgins JP, Thomas J (2019). Updated guidance for trusted systematic reviews: a new edition of the Cochrane Handbook for Systematic Reviews of In-terventions. Cochrane Database Syst Rev, 10:ED000142.
13. Koskinas KC, Windecker S, Pedrazzini G, et al (2019). Evolocumab for Early Reduc-tion of LDL Cholesterol Levels in Pa-tients with Acute Coronary Syndromes (EVOPACS). J Am Coll Cardiol, 74(20):2452-2462.
14. Sabatine MS, Giugliano RP, Keech AC, et al (2017). Evolocumab and Clinical Out-comes in Patients with Cardiovascular Disease. N Engl J Med, 376(18):1713-1722.
15. Nicholls SJ, Puri R, Anderson T, et al (2016). Effect of Evolocumab on Progression of Coronary Disease in Statin-Treated Pa-tients: The GLAGOV Randomized Clin-ical Trial. JAMA, 316(22):2373-2384.
16. Kereiakes DJ, Robinson JG, Cannon CP, Lorenzato C, Pordy R, Chaudhari U, Colhoun HM (2015). Efficacy and safety of the proprotein convertase subtil-isin/kexin type 9 inhibitor alirocumab among high cardiovascular risk patients on maximally tolerated statin therapy: The ODYSSEY COMBO I study. Am Heart J, 169(6):906-915.e13.
17. Cannon CP, Cariou B, Blom D, et al (2015). Efficacy and safety of alirocumab in high cardiovascular risk patients with inade-quately controlled hypercholesterolaemia on maximally tolerated doses of statins: the ODYSSEY COMBO II randomized controlled trial. Eur Heart J, 36(19):1186-94.
18. Han YL, Ma YY, Su GH, et al (2020). [Effi-cacy and safety of alirocumab versus ezetimibe in high cardiovascular risk Chi-nese patients with hyperlipidemia: OD-YSSEY EAST Study-Chinese sub-population analysis]. Zhonghua Xin Xue Guan Bing Za Zhi, 48(7):593-599.
19. Ako J, Hibi K, Tsujita K, et al (2019). Effect of Alirocumab on Coronary Atheroma Volume in Japanese Patients with Acute Coronary Syndrome - The ODYSSEY J-IVUS Trial. Circ J, 83(10):2025-2033.
20. Robinson JG, Farnier M, Krempf M, et al (2015). Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med, 372(16):1489-99.
21. Schwartz GG, Steg PG, Szarek M, et al (2018). Alirocumab and Cardiovascular Outcomes after Acute Coronary Syn-drome. N Engl J Med, 379(22):2097-2107.
22. Hirayama A, Honarpour N, Yoshida M, Yamashita S, Huang F, Wasserman SM, Teramoto T (2014). Effects of evo-locumab (AMG 145), a monoclonal anti-body to PCSK9, in hypercholesterolemic, statin-treated Japanese patients at high cardiovascular risk--primary results from the phase 2 YUKAWA study. Circ J, 78(5):1073-82.
23. Kiyosue A, Honarpour N, Kurtz C, Xue A, Wasserman SM, Hirayama A (2016). A Phase 3 Study of Evolocumab (AMG 145) in Statin-Treated Japanese Patients at High Cardiovascular Risk. Am J Cardiol, 117(1):40-7.
24. Ballantyne CM, Neutel J, Cropp A, et al (2015). Results of bococizumab, a mono-clonal antibody against proprotein con-vertase subtilisin/kexin type 9, from a randomized, placebo-controlled, dose-ranging study in statin-treated subjects with hypercholesterolemia. Am J Cardiol, 115(9):1212-21.
25. Nicholls SJ, Puri R, Anderson T, et al (2018). Effect of Evolocumab on Coronary Plaque Composition. J Am Coll Cardiol, 72(17):2012-2021.
26. Fonarow GC, van Hout B, Villa G, Arellano J, Lindgren P (2019). Updated Cost-effectiveness Analysis of Evolocumab in Patients With Very High-risk Atheroscle-rotic Cardiovascular Disease. JAMA Car-diol, 4(7):691-695.
27. Bhatt DL, Briggs AH, Reed SD, et al (2020). Cost-Effectiveness of Alirocumab in Pa-tients With Acute Coronary Syndromes: The ODYSSEY OUTCOMES Trial. J Am Coll Cardiol, 75(18):2297-2308.
2. Sabatine MS (2019). PCSK9 inhibitors: clini-cal evidence and implementation. Nat Rev Cardiol, 16(3):155-165.
3. Borén J, Chapman MJ, Krauss RM, et al (2020). Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, genetic, and therapeu-tic insights: a consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J, 41(24):2313-2330.
4. O'Donoghue ML, Fazio S, Giugliano RP, et al (2019). Lipoprotein(a), PCSK9 Inhibi-tion, and Cardiovascular Risk. Circulation, 139(12):1483-1492.
5. Jang AY, Lim S, Jo SH, Han SH, Koh KK (2021). New Trends in Dyslipidemia Treatment. Circ J, 85(6):759-768.
6. Muraki I (2021). Role of Proprotein Con-vertase Subtilisin/Kexin Type 9 (PCSK9) on Lipid Metabolism and Insulin Re-sistance in Human. J Atheroscler Thromb, 28(4):317-318
7. Hamamura H, Adachi H, Enomoto M, et al (2021). Serum Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) is In-dependently Associated with Insulin Re-sistance, Triglycerides, Lipoprotein (a) Levels but not Low-Density Lipoprotein Cholesterol Levels in a General Popula-tion. J Atheroscler Thromb, 28(4):329-337.
8. Shahreyar M, Salem SA, Nayyar M, George LK, Garg N, Koshy SKG (2018). Hyper-lipidemia: Management with Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors. J Am Board Fam Med, 31(4):628-634.
9. Spolitu S, Dai W, Zadroga JA, Ozcan L (2019). Proprotein convertase subtil-isin/kexin type 9 and lipid metabolism. Curr Opin Lipidol, 30(3):186-191.
10. Turgeon RD, Tsuyuki RT, Gyenes GT, Pearson GJ (2018). Cardiovascular Effi-cacy and Safety of PCSK9 Inhibitors: Systematic Review and Meta-analysis In-cluding the ODYSSEY OUTCOMES Trial. Can J Cardiol, 34(12):1600-1605.
11. Casula M, Olmastroni E, Boccalari MT, Tragni E, Pirillo A, Catapano AL (2019). Cardiovascular events with PCSK9 in-hibitors: an updated meta-analysis of randomised controlled trials. Pharmacol Res, 143:143-150.
12. Cumpston M, Li T, Page MJ, Chandler J, Welch VA, Higgins JP, Thomas J (2019). Updated guidance for trusted systematic reviews: a new edition of the Cochrane Handbook for Systematic Reviews of In-terventions. Cochrane Database Syst Rev, 10:ED000142.
13. Koskinas KC, Windecker S, Pedrazzini G, et al (2019). Evolocumab for Early Reduc-tion of LDL Cholesterol Levels in Pa-tients with Acute Coronary Syndromes (EVOPACS). J Am Coll Cardiol, 74(20):2452-2462.
14. Sabatine MS, Giugliano RP, Keech AC, et al (2017). Evolocumab and Clinical Out-comes in Patients with Cardiovascular Disease. N Engl J Med, 376(18):1713-1722.
15. Nicholls SJ, Puri R, Anderson T, et al (2016). Effect of Evolocumab on Progression of Coronary Disease in Statin-Treated Pa-tients: The GLAGOV Randomized Clin-ical Trial. JAMA, 316(22):2373-2384.
16. Kereiakes DJ, Robinson JG, Cannon CP, Lorenzato C, Pordy R, Chaudhari U, Colhoun HM (2015). Efficacy and safety of the proprotein convertase subtil-isin/kexin type 9 inhibitor alirocumab among high cardiovascular risk patients on maximally tolerated statin therapy: The ODYSSEY COMBO I study. Am Heart J, 169(6):906-915.e13.
17. Cannon CP, Cariou B, Blom D, et al (2015). Efficacy and safety of alirocumab in high cardiovascular risk patients with inade-quately controlled hypercholesterolaemia on maximally tolerated doses of statins: the ODYSSEY COMBO II randomized controlled trial. Eur Heart J, 36(19):1186-94.
18. Han YL, Ma YY, Su GH, et al (2020). [Effi-cacy and safety of alirocumab versus ezetimibe in high cardiovascular risk Chi-nese patients with hyperlipidemia: OD-YSSEY EAST Study-Chinese sub-population analysis]. Zhonghua Xin Xue Guan Bing Za Zhi, 48(7):593-599.
19. Ako J, Hibi K, Tsujita K, et al (2019). Effect of Alirocumab on Coronary Atheroma Volume in Japanese Patients with Acute Coronary Syndrome - The ODYSSEY J-IVUS Trial. Circ J, 83(10):2025-2033.
20. Robinson JG, Farnier M, Krempf M, et al (2015). Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med, 372(16):1489-99.
21. Schwartz GG, Steg PG, Szarek M, et al (2018). Alirocumab and Cardiovascular Outcomes after Acute Coronary Syn-drome. N Engl J Med, 379(22):2097-2107.
22. Hirayama A, Honarpour N, Yoshida M, Yamashita S, Huang F, Wasserman SM, Teramoto T (2014). Effects of evo-locumab (AMG 145), a monoclonal anti-body to PCSK9, in hypercholesterolemic, statin-treated Japanese patients at high cardiovascular risk--primary results from the phase 2 YUKAWA study. Circ J, 78(5):1073-82.
23. Kiyosue A, Honarpour N, Kurtz C, Xue A, Wasserman SM, Hirayama A (2016). A Phase 3 Study of Evolocumab (AMG 145) in Statin-Treated Japanese Patients at High Cardiovascular Risk. Am J Cardiol, 117(1):40-7.
24. Ballantyne CM, Neutel J, Cropp A, et al (2015). Results of bococizumab, a mono-clonal antibody against proprotein con-vertase subtilisin/kexin type 9, from a randomized, placebo-controlled, dose-ranging study in statin-treated subjects with hypercholesterolemia. Am J Cardiol, 115(9):1212-21.
25. Nicholls SJ, Puri R, Anderson T, et al (2018). Effect of Evolocumab on Coronary Plaque Composition. J Am Coll Cardiol, 72(17):2012-2021.
26. Fonarow GC, van Hout B, Villa G, Arellano J, Lindgren P (2019). Updated Cost-effectiveness Analysis of Evolocumab in Patients With Very High-risk Atheroscle-rotic Cardiovascular Disease. JAMA Car-diol, 4(7):691-695.
27. Bhatt DL, Briggs AH, Reed SD, et al (2020). Cost-Effectiveness of Alirocumab in Pa-tients With Acute Coronary Syndromes: The ODYSSEY OUTCOMES Trial. J Am Coll Cardiol, 75(18):2297-2308.
| Files | ||
| Issue | Vol 52 No 5 (2023) | |
| Section | Review Article(s) | |
| DOI | https://doi.org/10.18502/ijph.v52i5.12707 | |
| Keywords | ||
| Cardiovascular risk Adverse events Proprotein convertase 9 Alirocumab Evolocumab | ||
| Rights and permissions | |
|
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Zhao L, Liu Y, Cao Z, Wang J, Huo X. Application Value of PCSK9 Inhibitor in Cardiovascular High Risk Patients: A Meta-Analysis. Iran J Public Health. 2023;52(5):903-912.
