PMID- 36881395 OWN - NLM STAT- MEDLINE DCOM- 20230410 LR - 20230607 IS - 2213-1787 (Electronic) IS - 2213-1779 (Print) IS - 2213-1779 (Linking) VI - 11 IP - 4 DP - 2023 Apr TI - Medication-Attributable Adverse Events in Heart Failure Trials. PG - 425-436 LID - S2213-1779(22)00721-1 [pii] LID - 10.1016/j.jchf.2022.11.026 [doi] AB - BACKGROUND: Initiation and up-titration of guideline-directed medical therapies (GDMTs) for heart failure with reduced ejection fraction (HFrEF) remains suboptimal, in part because of concerns regarding tolerability and adverse events (AEs). OBJECTIVES: The authors sought to compare rates of AE in patients randomized to GDMT medication vs placebo in a meta-analysis of landmark cardiovascular outcomes trials. METHODS: The authors assessed rates of reported AE in 17 landmark HFrEF clinical trials across each class of GDMT in the placebo and intervention arms. The overall rates of AE for each drug class, the absolute difference in frequency in AEs between the placebo and intervention arms, and the odds of each AE according based on randomization strata were calculated. RESULTS: AE were reported commonly in trials across each class of GDMT, with 75% to 85% of participants reporting at least 1 AE. There was no significant difference in the frequency of AE between the intervention and placebo arms, except for angiotensin-converting enzyme inhibitors (87.0% [95% CI: 85.0%-88.8%] vs 82.0% [95% CI: 79.8%-84.0%], absolute difference: +5% with intervention; P < 0.001). There was no significant difference in drug discontinuation because of AE between placebo and intervention arms in angiotensin-converting enzyme inhibitors, mineralocorticoid receptor antagonists, sodium glucose cotransporter 2 inhibitors, or angiotensin receptor neprilysin inhibitor/angiotensin II receptor blocker trials. Patients randomized to beta-blocker were significantly less likely to stop study drug because of AE than placebo (11.3% [95% CI: 10.3%-12.3%] vs 13.7% [95% CI: 12.5%-14.9%], absolute difference: -1.1%; P = 0.015). When individual types of AE were assessed, the initiation of an intervention vs placebo resulted in small differences in absolute frequency of AE that were largely not statistically significant. CONCLUSIONS: In clinical trials of GDMT for HFrEF, AEs are observed frequently. However, rates of AE are similar between active medication and control, suggesting these may reflect the high risk nature of the heart failure disease state rather than be attributive to a specific therapy. CI - Copyright (c) 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved. FAU - Harrington, Josephine AU - Harrington J AD - Duke Clinical Research Institute, Durham, North Carolina, USA; Department of Medicine, Division of Cardiology, Duke University Hospital, Durham North Carolina, USA. FAU - Fonarow, Gregg C AU - Fonarow GC AD - Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles Medical Center, Los Angeles, California, USA. FAU - Khan, Muhammad Shahzeb AU - Khan MS AD - Department of Medicine, Division of Cardiology, Duke University Hospital, Durham North Carolina, USA. FAU - Hernandez, Adrian AU - Hernandez A AD - Duke Clinical Research Institute, Durham, North Carolina, USA; Department of Medicine, Division of Cardiology, Duke University Hospital, Durham North Carolina, USA. FAU - Anker, Stefan AU - Anker S AD - Department of Cardiology (CVK) and Berlin Institute of Health Center for Regenerative Therapies (BCRT), German Centre for Cardiovascular Research (DZHK) partner site Berlin, Charite Universitatsmedizin Berlin, Berlin, Germany; Institute of Heart Disease, Wroclaw Medical University, Wroclaw, Poland. FAU - Bohm, Michael AU - Bohm M AD - Department of Medicine, Saarland University Hospital, Homburg/Saar, Germany. FAU - Greene, Stephen J AU - Greene SJ AD - Duke Clinical Research Institute, Durham, North Carolina, USA; Department of Medicine, Division of Cardiology, Duke University Hospital, Durham North Carolina, USA. FAU - Felker, G Michael AU - Felker GM AD - Duke Clinical Research Institute, Durham, North Carolina, USA; Department of Medicine, Division of Cardiology, Duke University Hospital, Durham North Carolina, USA. FAU - Vaduganathan, Muthiah AU - Vaduganathan M AD - Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. FAU - Butler, Javed AU - Butler J AD - Baylor Scott and White Research Institute, Dallas Texas, USA; Department of Medicine, University of Mississippi, Jackson, Mississippi, USA. Electronic address: Javed.butler@bwshealth.org. LA - eng GR - T32 HL069749/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Meta-Analysis DEP - 20230201 PL - United States TA - JACC Heart Fail JT - JACC. Heart failure JID - 101598241 RN - 0 (Angiotensin Receptor Antagonists) RN - 0 (Angiotensin-Converting Enzyme Inhibitors) RN - 0 (Sodium-Glucose Transporter 2 Inhibitors) SB - IM CIN - JACC Heart Fail. 2023 Apr;11(4):437-439. PMID: 36892490 EIN - JACC Heart Fail. 2023 Jun;11(6):733. PMID: 37286264 MH - Humans MH - *Angiotensin Receptor Antagonists/adverse effects MH - *Angiotensin-Converting Enzyme Inhibitors/adverse effects MH - *Heart Failure/therapy MH - Randomized Controlled Trials as Topic MH - *Sodium-Glucose Transporter 2 Inhibitors/adverse effects MH - Stroke Volume PMC - PMC10084875 MID - NIHMS1884942 OTO - NOTNLM OT - adverse events OT - guideline-directed medical therapy OT - heart failure COIS- Funding Support and Author Disclosures Dr Harrington has received salary support from T32 training grant T32HL069749. Dr Fonarow has done consulting for Abbott, Amgen, AstraZeneca, Bayer, Cytokinetics, Janssen, Medtronic, Merck, and Novartis. Dr Felker has received research grants from the National Heart, Lung, and Blood Institute, American Heart Association, Amgen, Bayer, BMS, Merck, Cytokinetics, and CSL-Behring; has acted as a consultant to Novartis, Amgen, BMS, Cytokinetics, Medtronic, Cardionomic, Boehringer-Ingelheim, American Regent, Abbott, AstraZeneca, Reprieve, Myovant, Sequana, Windtree Therapuetics, and Whiteswell; and has served on clinical endpoint committees/data safety monitoring boards for Amgen, Merck, Medtronic, EBR Systems, V-Wave, LivaNova, Siemens, and Rocket Pharma. Dr Bohm is supported by the Deutsche Forschungsgemeinschaft (German Research Foundation; TTR 219, project number 322900939); and has received personal fees from Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Medtronic, Novartis, Servier, and Vifor during the conduct of the study. Dr Hernandez has received research grants from American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squib, Merck, Novartis, and Verily; and has done consulting for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squib, Myokardia, and Novo Nordisk. Dr Anker has received fees from Abbott, Bayer, Boehringer Ingelheim, Cardiac Dimension, Impulse Dynamics, Novartis, Occlutech, Servier, and Vifor Pharma; and has received grant support from Abbott and Vifor Pharma. Dr Greene has received research support from the Duke University Department of Medicine Chair's Research Award, American Heart Association, National Heart Lung and Blood Institute, Amgen, AstraZeneca, Bristol Myers Squibb, Cytokinetics, Merck and Co Inc, Novartis, Pfizer, and Sanofi; has served on advisory boards for Amgen, AstraZeneca, Boehringer Ingelheim/Lilly, Bristol Myers Squibb, Cytokinetics, Roche Diagnostics, and Sanofi; has served as a consultant for Amgen, Bayer, Bristol Myers Squibb, Merck and Co Inc, PhamaIN, Roche Diagnostics, Sanofi, Tricog Health, Urovant Pharmaceuticals, and Vifor; and has received speaker fees from Boehringer Ingelheim. Dr Vaduganathan has received research grant support or served on advisory boards for American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, Boehringer Ingelheim, Cytokinetics, Lexicon Pharmaceuticals, Novartis, Pharmacosmos, Relypsa, Roche Diagnostics, Sanofi, and Tricog Health; has had speaker engagements with Novartis, AstraZeneca, and Roche Diagnostics; and has participated on clinical trial committees for studies sponsored by Galmed, Novartis, Bayer AG, Occlutech, and Impulse Dynamics. Dr Butler has served as a consultant to Abbott, Adrenomed, Amgen, Array, AstraZeneca, Bayer, Berlin Cures, Boehringer Ingelheim, Bristol-Myers Squib, CVRx, G3 Pharmaceutical, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Occlutech, Relypsa, Roche, Sanofi, SC Pharma, V-Wave Limited, and Vifor. Dr Khan has reported that he has no relationships relevant to the contents of this paper to disclose. EDAT- 2023/03/08 06:00 MHDA- 2023/04/07 10:19 PMCR- 2023/04/10 CRDT- 2023/03/07 11:27 PHST- 2022/09/30 00:00 [received] PHST- 2022/11/21 00:00 [revised] PHST- 2022/11/29 00:00 [accepted] PHST- 2023/04/07 10:19 [medline] PHST- 2023/03/08 06:00 [pubmed] PHST- 2023/03/07 11:27 [entrez] PHST- 2023/04/10 00:00 [pmc-release] AID - S2213-1779(22)00721-1 [pii] AID - 10.1016/j.jchf.2022.11.026 [doi] PST - ppublish SO - JACC Heart Fail. 2023 Apr;11(4):425-436. doi: 10.1016/j.jchf.2022.11.026. Epub 2023 Feb 1.