Serious adverse events and deaths in PCSK9 inhibitor trials reported on ClinicalTrials.gov: a systematic review

References

• Li C, Lin L, Zhang W, et al. Efficiency and safety of proprotein convertase subtilisin/kexin 9 monoclonal antibody on hypercholesterolemia: a meta-analysis of 20 randomized controlled trials. J Am Heart Assoc. 2015;4(6):e001937.
   PubMed Web of Science ®Google Scholar
• Lipinski MJ, Benedetto U, Escarcega RO, et al. The impact of proprotein convertase subtilisin-kexin type 9 serine protease inhibitors on lipid levels and outcomes in patients with primary hypercholesterolaemia: a network meta-analysis. Eur Heart J. 2016;37:536–545.
   PubMed Web of Science ®Google Scholar
• Zhang X-L, Zhu -Q-Q, Zhu L, et al. Safety and efficacy of anti-PCSK9 antibodies: a meta-analysis of 25 randomized, controlled trials. BMC Med. 2015 June;13:123.
   PubMed Web of Science ®Google Scholar
• Dicembrini I, Giannini S, Ragghianti B, et al. Effects of PCSK9 inhibitors on LDL cholesterol, cardiovascular morbidity and all-cause mortality: a systematic review and meta-analysis of randomized controlled trials. J Endocrinol Invest. 2019;42(9):1029–1039.
   PubMed Web of Science ®Google Scholar
• Karatasakis A, Danek BA, Karacsonyi J, 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. DOI:10.1161/JAHA.117.006910
   PubMed Web of Science ®Google Scholar
• Reiner Ž. PCSK9 inhibitors in clinical practice: expectations and reality. Atherosclerosis. 2018;270:187–188.
   PubMed Web of Science ®Google Scholar
• Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376(18):1713–1722.
   PubMed Web of Science ®Google Scholar
• Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med. 2018;379(22):2097–2107.
   PubMed Web of Science ®Google Scholar
• Kip KE, Hollabaugh K, Marroquin OC, et al. The problem with composite end points in cardiovascular studies. The story of major adverse cardiac events and percutaneous coronary intervention. J Am Coll Cardiol. 2008;51(7):701–707.
   PubMed Web of Science ®Google Scholar
• Thygesen K, Alpert JS, Jaffe AS, et al. Fourth universal definition of myocardial infarction (2018). Eur Heart J. 2019;40(3):237–269.
   PubMed Web of Science ®Google Scholar
• Turgeon RD, Tsuyuki RT, Gyenes GT, et al. Cardiovascular efficacy and safety of PCSK9 inhibitors: systematic review and meta-analysis including the ODYSSEY OUTCOMES Trial. Can J Cardiol. 2018;34(12):1600–1605.
   PubMed Web of Science ®Google Scholar
• Du H, Li X, Su N, et al. Proprotein convertase subtilisin/kexin 9 inhibitors in reducing cardiovascular outcomes: a systematic review and meta-analysis. Heart. 2019. DOI:10.1136/heartjnl-2019-314763
   Web of Science ®Google Scholar
• White HD, Gabriel Steg P, Szarek M, et al. Effects of alirocumab on types of myocardial infarction: insights from the ODYSSEY OUTCOMES trial. Eur Heart J. 2019;40(33):2801–2809.
   PubMed Web of Science ®Google Scholar
• Wiviott SD, Giugliano RP, Morrow DA, et al. Characterization of types and sizes of myocardial infarction reduced with evolocumab in FOURIER. Circulation [Internet]. 2017;136:A16714.
   Google Scholar
• Schmidt AF, Pearce LS, Wilkins JT, et al. PCSK9 monoclonal antibodies for the primary and secondary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2017 Apr 28;4(4):CD011748.
   Web of Science ®Google Scholar
• DHHS. 42 CFR part 11 - clinical trials registration and results information submission. Fed Regist; 2016.
   Google Scholar
• No Title [Internet]. 2016. [cited 2017 May 8]. Available from: https://prsinfo.clinicaltrials.gov/FinalRuleChanges-12Dec2016.pdf
   Google Scholar
• For A, Disclosure P, Redaction W. FDA endocrinologic and metabolic drugs advisory committee. Briefing Document; 2015 May:1–152.
   Google Scholar
• FDA. FDA ADVISORY COMMITTEE BRIEFING DOCUMENT PRALUENT TM (alirocumab); 2015.
   Google Scholar
• EMA. Assessment report repatha; 2015.
   Google Scholar
• Higgins J, Green S, editors. Cochrane handbook for systematic reviews of interventions. Version 5. The Cochrane Collaboration; 2011.
   Google Scholar
• Mansournia MA, Higgins JPT, Sterne JAC, et al. Trials, biases in randomized epidemiologists, a conversation between trialists. Epidemiology. 2017;28(1):54–59.
   PubMed Web of Science ®Google Scholar
• Cordoba G, Schwartz L, Woloshin S, et al. Definition, reporting, and interpretation of composite outcomes in clinical trials: systematic review. BMJ. 2010;341(7769):381.
   Google Scholar
• He J, Ogden LG, Bazzano LA, et al. Risk factors for congestive heart failure in US men and women: NHANES I epidemiologic follow-up study. Arch Intern Med. 2001;161(7):996–1002.
   PubMedGoogle Scholar
• Baldasseroni S, Opasich C, Gorini M, et al. Left bundle-branch block is associated with increased 1-year sudden and total mortality rate in 5517 outpatients with congestive heart failure: a report from the Italian network on congestive heart failure. Am Heart J. 2002;143(3):398–405.
   PubMed Web of Science ®Google Scholar
• Massie BM, Shah NB. Evolving trends in the epidemiologic factors of heart failure: rationale for preventive strategies and comprehensive disease management. Am Heart J. 1997;133(6):703–712.
   PubMed Web of Science ®Google Scholar
• Qureshi WT, Zhang Z-M, Chang PP, et al. Silent myocardial infarction and long-term risk of heart failure. J Am Coll Cardiol. 2018;71(1):1–8.
   PubMed Web of Science ®Google Scholar
• WHO. World heart federation. World Stroke Organization. Global Atlas on Cardiovascular disease prevention and control; 2011.
   Google Scholar
• EMA. EPAR praluent final; 2013.
   Google Scholar
• Cheng J, Pullenayegum E, Marshall JK, et al. Impact of including or excluding both-armed zero-event studies on using standard meta-analysis methods for rare event outcome: a simulation study. BMJ Open. 2016;6(8):e010983.
   PubMed Web of Science ®Google Scholar
• Friedrich JO, Adhikari NKJ, Beyene J. Inclusion of zero total event trials in meta-analyses maintains analytic consistency and incorporates all available data. BMC Med Res Methodol. 2007;7(1):5.
   PubMedGoogle Scholar
• Sweeting MJ, Sutton AJ, Lambert PC. What to add to nothing? Use and avoidance of continuity corrections in meta-analysis of sparse data. Stat Med. 2004;23(9):1351–1375.
   PubMed Web of Science ®Google Scholar
• Sabatine MS, Giugliano RP, Wiviott SD, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372(16):150315080057008.
   Web of Science ®Google Scholar
• Navarese EP, Kołodziejczak M, Schulze V, et al. Effects of proprotein convertase subtilisin/kexin type 9 antibodies in adults with hypercholesterolemia: a systematic review and meta-analysis. Ann Intern Med. 2015;163(1):40–51.
   PubMed Web of Science ®Google Scholar
• McKenney JM, Koren MJ, Kereiakes DJ, et al. Safety and efficacy of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease, SAR236553/REGN727, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy. J Am Coll Cardiol. 2012 June;59(25):2344–2353.
   PubMed Web of Science ®Google Scholar
• Teramoto T, Kondo A, Kiyosue A, et al. Efficacy and safety of alirocumab in patients with hypercholesterolemia not adequately controlled with non-statin lipid-lowering therapy or the lowest strength of statin: ODYSSEY NIPPON study design and rationale. Lipids Health Dis. 2017;16(1). DOI:10.1186/s12944-017-0513-7
   PubMedGoogle Scholar
• Schwartz GG, Bessac L, Berdan LG, et al. Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: rationale and design of the ODYSSEY Outcomes trial. Am Heart J. 2014;168(5):682–689.e1.
   PubMed Web of Science ®Google Scholar
• Ballantyne CM, Neutel J, Cropp A, et al. Results of bococizumab, a monoclonal antibody against proprotein convertase subtilisin/kexin type 9, from a randomized, placebo-controlled, dose-ranging study in statin-treated subjects with hypercholesterolemia. Am J Cardiol. 2015 May;115(9):1212–1221.
   PubMed Web of Science ®Google Scholar
• Ridker PM, Tardif JC, Amarenco P, et al. Lipid-reduction variability and antidrug- antibody formation with bococizumab. N Engl J Med. 2017;376:1517–1526.
   PubMed Web of Science ®Google Scholar
• Ridker PM, Revkin J, Amarenco P, et al. Cardiovascular efficacy and safety of bococizumab in high-risk patients. N Engl J Med. 2017;376(16):1527–1539.
   PubMed Web of Science ®Google Scholar
• Giugliano RP, Desai NR, Kohli P, et al. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in combination with a statin in patients with hypercholesterolaemia (LAPLACE-TIMI 57): a randomised, placebo-controlled, dose-ranging, phase 2 study. Lancet. 2012;380(9858):2007–2017.
   PubMed Web of Science ®Google Scholar
• Koren MJ, Scott R, Kim JB, et al. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 as monotherapy in patients with hypercholesterolaemia (MENDEL): a randomised, double-blind, placebo-controlled, phase 2 study. Lancet. 2012;380(9858):1995–2006.
   PubMed Web of Science ®Google Scholar
• Raal F, Scott R, Somaratne R, et al. Low-density lipoprotein cholesterol-lowering effects of AMG 145, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease in patients with heterozygous familial hypercholesterolemia: the reduction of LDL-C with PCSK9 inhibition heterozygous familial hypercholesterolemia disorder (RUTHERFORD) randomized trial. Circulation. 2012 Nov;126(20):2408–2417.
   PubMed Web of Science ®Google Scholar
• Sullivan D, Olsson AG, Scott R, et al. Effect of a monoclonal antibody to PCSK9 on Low-density lipoprotein cholesterol levels in statin-intolerant patients. JAMA. 2012;308(23):2497.
   PubMed Web of Science ®Google Scholar
• Blom DJ, Hala T, Bolognese M, et al. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N Engl J Med. 2014;370(19):1809–1819.
   PubMed Web of Science ®Google Scholar
• Roth EM, McKenney JM, Hanotin C, et al. Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia. N Engl J Med. 2012 Nov;367(20):1891–1900.
   PubMed Web of Science ®Google Scholar
• Hirayama A, Honarpour N, Yoshida M, et al. Effects of evolocumab (AMG 145), a monoclonal antibody to PCSK9, in hypercholesterolemic, statin-treated Japanese patients at high cardiovascular risk–primary results from the phase 2 YUKAWA study. Circ J. 2014;78(5):1073–1082.
   PubMed Web of Science ®Google Scholar
• Koren MJ, Lundqvist P, Bolognese M, et al. Anti-PCSK9 monotherapy for hypercholesterolemia: the MENDEL-2 randomized, controlled phase III clinical trial of evolocumab. J Am Coll Cardiol. 2014;63(23):2531–2540.
   PubMed Web of Science ®Google Scholar
• Robinson JG, Nedergaard BS, Rogers WJ, et al. Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia. Jama. 2014;311(18):1870.
   PubMed Web of Science ®Google Scholar
• Kiyosue A, Honarpour N, Xue A, et al. Effects of evolocumab (Amg 145) in hypercholesterolemic, statin-treated, japanese patients at high cardiovascular risk: results from the phase III yukawa 2 study. J Am Coll Cardiol. 2015;65(10):A1369.
   PubMed Web of Science ®Google Scholar
• Raal FJ, Stein EA, Dufour R, et al. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet. 2015;385(9965):331–340.
   PubMed Web of Science ®Google Scholar
• Amgen. FLOREY trial; 2016.
   Google Scholar
• Nicholls SJ, Puri R, Anderson T, et al. Effect of evolocumab on progression of coronary disease in statin-treated patients: the GLAGOV randomized clinical trial. JAMA. 2016;316(22):2373–2384.
   PubMed Web of Science ®Google Scholar
• Kastelein JJP, Nissen SE, Rader DJ, et al. Safety and efficacy of LY3015014, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9): a randomized, placebo-controlled Phase 2 study. Eur Heart J. 2016 May;37(17):1360–1369.
   PubMed Web of Science ®Google Scholar
• Baruch A, Mosesova S, Davis JD, et al. Effects of RG7652, a monoclonal antibody against PCSK9, on LDL-C, LDL-C subfractions, and inflammatory biomarkers in patients at high risk of or with established coronary heart disease (from the phase 2 EQUATOR study). Am J Cardiol. 2017;119(10):1576–1583.
   PubMed Web of Science ®Google Scholar
• Stein EA, Gipe D, Bergeron J, et al. Effect of a monoclonal antibody to PCSK9, REGN727/SAR236553, to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomised controlled trial. Lancet. 2012 July;380(9836):29–36.
   PubMed Web of Science ®Google Scholar
• Kastelein JJP, Ginsberg HN, Langslet G, 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 Nov;36(43):2996–3003.
   PubMed Web of Science ®Google Scholar
• Kereiakes DJ, Robinson JG, Cannon CP, 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 June;169(6):906–915.e13.
   PubMed Web of Science ®Google Scholar
• Sabatine MS, Giugliano RP, Wiviott SD, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372(16):1500–1509.
   PubMed Web of Science ®Google Scholar
• Ginsberg HN, Rader DJ, Raal FJ, 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 Oct;30(5):473–483.
   PubMed Web of Science ®Google Scholar
• Stroes E, Guyton JR, Lepor N, et al. Efficacy and safety of alirocumab 150 mg every 4 weeks in patients with hypercholesterolemia not on statin therapy: the ODYSSEY CHOICE II study. J Am Heart Assoc. 2016;5(9):e003421.
   PubMed Web of Science ®Google Scholar
• Teramoto T, Kobayashi M, Tasaki H, et al. Efficacy and safety of alirocumab in Japanese patients with heterozygous familial hypercholesterolemia or at high cardiovascular risk with hypercholesterolemia not adequately controlled with statins- ODYSSEY JAPAN randomized controlled trial. Circ J. 2016 Aug;80(9):1980–1987.
   PubMed Web of Science ®Google Scholar
• Silverman MG, Ference BA, Im K, et al. Association between lowering LDL-C and cardiovascular risk reduction among different therapeutic interventions: a systematic review and meta-analysis. Jama. 2016;316(12):1289–1297.
   PubMed Web of Science ®Google Scholar
• Schroll JB, Penninga EI, Gøtzsche PC, et al. Assessment of adverse events in protocols, clinical study reports, and published papers of trials of orlistat: a document analysis. PLOS Med. 2016;13(8):e1002101.
   PubMed Web of Science ®Google Scholar
• Schroll JB, Maund E, Gøtzsche PC. Challenges in coding adverse events in clinical trials: a systematic review. PLoS One. 2012;7(7):e41174.
   PubMed Web of Science ®Google Scholar
• Bajaj NS, Patel N, Kalra R, et al. Neurological effects of proprotein convertase subtilisin/kexin type 9 inhibitors: direct comparisons. Eur Hear J. 2018;4(2):132–141.
   Web of Science ®Google Scholar
• He XX, Zhang R, Zuo PY, et al. The efficacy advantage of evolocumab (AMG 145) dosed at 140 mg every 2 weeks versus 420 mg every 4 weeks in patients with hypercholesterolemia: evidence from a meta-analysis. Eur J Intern Med. 2017;38:52–60.
   PubMed Web of Science ®Google Scholar
• Sfera D and Sauber C. The comprehensive guide to clinical research: a practical handbook for gaining insight into the clinical research industry kindle edition. LLC DSCS Sweat Equity & Investments; 2019.
   Google Scholar
• Tse T, Williams RJ, Zarin DA. Reporting “basic results” in ClinicalTrials.gov. Chest. 2009;136:295–303.
   PubMed Web of Science ®Google Scholar
• Hartung DM, Zarin DA, Guise JM, et al. Reporting discrepancies between the ClinicalTrials.gov results database and peer-reviewed publications. Ann Intern Med. 2014;160(7):477–483.
   PubMed Web of Science ®Google Scholar
• Tang E, Ravaud P, Riveros C, et al. Comparison of serious adverse events posted at ClinicalTrials.gov and published in corresponding journal articles. BMC Med. 2015;13(1). DOI:10.1186/s12916-015-0430-4
   PubMedGoogle Scholar
• Becker JE, Krumholz HM, Ben-Josef G, et al. Reporting of results in ClinicalTrials.gov and high-impact journals. JAMA. 2014;311(10):1063–1065.
   PubMed Web of Science ®Google Scholar
• Grundy SM, Stone NJ, Bailey AL, 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.
   PubMed Web of Science ®Google Scholar
• Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020;41:111–188.
   PubMed Web of Science ®Google Scholar