Medication-Attributable Adverse Events in Heart Failure Trials

ACE = angiotensin-converting enzyme; ARB = angiotensin II receptor blocker; ARNI = angiotensin receptor neprilysin inhibitor; MRA = mineralocorticoid receptor antagonist; SGLT2 = sodium-glucose cotransporter 2.

Values are n (%) or frequency (95% CI).
AE = adverse event; AIRE = Acute Infarction Ramipril Efficacy; CONSENSUS = Cooperative North Scandinavian Enalapril Survival; SE = side effect; SOLVD = The Studies of Left Ventricular Dysfunction; TRACE = Trandolapril Cardiac Evaluation; other abbreviation as in Table 1.

Values are n (%) or median (IQR), unless otherwise indicated.
CAPRICORN = Carvedilol Post-infarct Survival Controlled Evaluation; COPERNICUS = Carvedilol Prospective Randomized Cumulative Survival; MERIT-HF = Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure; SAE = serious adverse event; other abbreviation as in Table 2.

Values are n (%) or frequency (95% CI), unless otherwise indicated. ^aIn RALES gynecomastia only recorded in men, n = 603 for spironolactone; n = 614 placebo.
EMPHASIS-HF = Eplerenone in Mild Patients Hospitalization Survival Study in Heart Failure; EPHESUS = Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study; MSK = musculoskeletal; RALES = Randomized Aldactone Evaluation Study; other abbreviations as in Tables 1 and 2.

Values are n (%) or median (IQR), unless otherwise indicated.
AKI = acute kidney injury; CKD = chronic kidney disease; DAPA-HF = Dapagliflozin and Prevention of Averse-Outcomes in Heart Failure; EMPEROR-Reduced = Empagliflozin Outcomes Trial in Patients with Chronic Heart Failure and a Reduced Ejection Fraction); SOLOIST-WHF = Effect of Sotagliflozin on Cardiovascular Events in Patients with Type 2 Diabetes Post Worsening Heart Failure; UTI = urinary tract infection; other abbreviations as in Tables 1, 2, and 3.

Authors and Disclosures

Josephine Harrington, MD^a,b, Gregg C. Fonarow, MD^c, Muhammad Shahzeb Khan, MD, MSC^b, Adrian Hernandez, MD, MHS^a,b, Stefan Anker, MD, PHD^d,e, Michael Böhm, MD^f, Stephen J. Greene, MD^a,b, G. Michael Felker, MD, MHS^a,b, Muthiah Vaduganathan, MD, MPH^g and Javed Butler, MD, MPH, MBA<sup>h,i

a</sup>Duke Clinical Research Institute, Durham, North Carolina, USA; ^bDepartment of Medicine, Division of Cardiology, Duke University Hospital, Durham North Carolina, USA; ^cDivision of Cardiology, David Geffen School of Medicine, University of California, Los Angeles Medical Center, Los Angeles, California, USA; ^dDepartment of Cardiology (CVK) and Berlin Institute of Health Center for Regenerative Therapies (BCRT), German Centre for Cardiovascular Research (DZHK) partner site Berlin, Charité Universitätsmedizin Berlin, Berlin, Germany; ^eInstitute of Heart Disease, Wroclaw Medical University, Wroclaw, Poland; ^fDepartment of Medicine, Saarland University Hospital, Homburg/Saar, Germany; ^gCardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; ^hBaylor Scott and White Research Institute, Dallas Texas, USA; and the ⁱDepartment of Medicine, University of Mississippi, Jackson, Mississippi, USA.

Address For Correspondence
Dr Javed Butler, Baylor Scott and White Research Institute, 3434 Live Oak Street, Suite 501, Dallas, Texas 75204, USA. E-mail: Javed.butler@bwshealth.org.

Barry Greenberg, MD, served as the Guest Editor-in-Chief for this paper. Michelle Kittleson, MD, served as the Guest Associate Editor for this paper.

The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors' institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.

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 Böhm 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.

Sidebar

Perspectives

COMPETENCY IN MEDICAL KNOWLEDGE: The use of GDMT for HFrEF remains suboptimal, likely in part because of concerns that these drugs will be poorly tolerated by patients. Although AEs occurred commonly in clinical trials of GDMT medications, it was at similar rates in the placebo and intervention arms, suggesting the initiation of GDMT was uncommon as the driver of patient symptoms and that GDMT is generally very well-tolerated in patients with HFrEF. Providers should consider whether their patient's symptoms may not be related to GDMT therapies, and, if medications are stopped for symptoms, consider retrialing them in the future.

TRANSLATIONAL OUTLOOK: More research is needed to understand the frequency with which side effects are truly attributable to GDMT. However, by examining rates of reported AE in landmark clinical trials of GDMT, we see that these events tend to occur at very similar rates between the placebo and intervention arms. This finding suggests that, although AE are common in patients with HFrEF, they may be more related to the condition of heart failure itself rather than GDMT use.

Appendix

For supplemental tables and a figure, please see the online version of this paper.