VA Study Latest in Debate about Old Drug’s Safety
By Brenda L. Mooney
PALO ALTO, CA – A new study is calling into question the practice of treating atrial fibrillation with digoxin, finding that patients on the digitalis derivative were 1.2 times more likely to die than comparable patients prescribed other therapies.
“The take-home point is to question whether people should really be on this drug,” said lead author Mintu Turakhia, MD, director of cardiac electrophysiology at the VA Palo Alto Health Care System and assistant professor at Stanford University School of Medicine. “These data challenge the current guidelines.”
Turakhia’s study was only the latest salvo in a heated international debate about the safety of digoxin in treating atrial fibrillation (AF) patients.
For the latest study, published recently in the Journal of the American College of Cardiology, researchers analyzed records from 122,465 VA patients who received a new diagnosis of atrial fibrillation between 2003 and 2008.
During that time period, digoxin was prescribed to 23% of patients, and 70% remained on the drug a year later.
Study results indicated that the increased risk of death from digoxin persisted, regardless of age, use of other drugs such as beta-blockers, amiodarone or warfarin or co-morbidities such as history of kidney disease, heart attack or heart failure.
“This is going to be as close to proof positive as we get because we may never have a randomized trial of this drug,” Turakhia pointed out. Pharmaceutical companies lack the incentive to finance studies on a long-accepted, generic drug, he suggested.
The ongoing controversy over prescribing digoxin for AF already has reduced use at the VA and elsewhere.
Another recent study, which included data as recent as 2011, found that the proportion of patients with new AF episodes who were prescribed oral rate or rhythm control medications at the VA decreased modestly from 2002 through 2011. The use of digoxin decreased by more than 50%, with amiodarone therapy decreasing by 17% from 2002 through 2011, according to research from the Iowa City, IA, VAMC.2
That study, published recently in the American Heart Journal, noted, “Prescribing rate control medications with or without antiarrhythmic drugs is often the first course treatment for atrial fibrillation (AF). Clinical trial data suggest that antiarrhythmic drugs are only marginally effective and have multiple drawbacks, whereas rate control alone is sufficient for most patients with minimally symptomatic AF.”
Overall, the percentage of patients receiving an oral rate-controlling medication decreased from 74.9% in 2002 through 2003 to 70.9% in 2010 through 2011, according to the Iowa City study. While the use of digoxin decreased dramatically, the use of beta blockers metoprolol and carvedilol increased. Amiodarone remained the most frequently prescribed drug despite a decrease in use.
“Rate control remains the dominant strategy for treating new AF,” those authors concluded. “The decrease in the use of oral antiarrhythmics may be due to lack of concrete data suggesting mortality and morbidity benefit as well as increasing use of the ablation approach.”
Turakhia suggested that digoxin has remained in the mix because physicians and patients trust the drug due to its longtime use. Digitalis derivatives have been employed at least since the 18th century.
“There’s an evidence gap,” he said, explaining that he decided to do a review because digoxin hasn’t undergone the rigorous testing of most other atrial fibrillation treatment options.
The subsequent study overwhelmingly included male veterans—only 1.6% were female—and Turakhia suggested that additional research should try to determine if the drug has the same effect in women.
He argued that many other therapies with better safety results are available to treat atrial fibrillation compared with digoxin, which slows the heart rate but does not correct it to a normal rhythm.
“We are not asserting this drug should never be used,” Turakhia said. “However, in light of the many other drugs that can be used to slow down the heart rate in atrial fibrillation, patients and providers need to ask whether digoxin should be the treatment of choice when there are other, safer drugs.”
Turakhia also was the lead author in another study, published two years ago in the Journal of the American College of Cardiology, which found higher increased mortality with use of digoxin in veterans with chronic kidney disease, especially in those on dialysis.3
Those studies are just one of many in the continuing debate about the safety of digoxin for AF.
For example, two studies published last year in the European Heart Journal came to opposite conclusions, even though they were analyzing the same data, first collected in 2002 as part of the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) trial.
While one study found safety concerns with the drug’s use for AF, authors of the other vehemently defended the old standby.4
“Journal publications and related rounds of media coverage that raise concerns about a drug’s safety are often important in protecting the public’s health,” said Mihai Gheorghiade, MD, professor of Medicine and Surgery at Northwestern University Feinberg School of Medicine, who was the lead author of the study finding no increased mortality. “However, in this case, there is no need to reassess the role of digoxin in the management of AF. Our finding that digoxin does not increase mortality should reassure the field and patients about the continued use of digoxin in AF.”
1Turakhia, MP, Santangeli P, Winkelmayer WC, Xu, X, et al. Increased Mortality Associated With Digoxin in Contemporary Patients With Atrial Fibrillation: Findings From the TREAT-AF Study. Veterans Affairs Palo Alto Health Care System, Palo Alto, California † Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, California
§ Division of Nephrology, Department of Medicine, Stanford University School of Medicine, Stanford, California
‖ Stanford Center for Sleep Sciences & Medicine, Division of Sleep Medicine, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California
∗∗ Maimonides Heart & Vascular Center, New York, New York
†† Veterans Affairs Eastern Colorado Health Care System, Denver, Colorado, J Am Coll Cardiol. 2014;64(7):660-668. doi:10.1016/j.jacc.2014.03.060
2Vaughan-Sarrazin MS, Mazur A, Chrischilles E, Cram P. Trends in the pharmacologic management of atrial fibrillation: Data from the Veterans Affairs health system. Am Heart J. 2014 Jul;168(1):53-9.e1. doi: 10.1016/j.ahj.2014.03.024. Epub 2014 May 2. PubMed PMID: 24952860.
3Turakhia M, Yang F, Xu X, Winkelmayer W, Hoang D, Heidenreich P. Interaction Among Digoxin Use, Kidney Function and Mortality in Patients with Atrial Fibrillation: The TREAT-AF Study. ACC Moderated Poster ContributionsMcCormick Place South, Hall AMonday, March 26, 2012, 11:00 a.m.-NoonSession Title: Arrhythmias: AF/SVT: Continuing Role of Pharmacologic Therapy for Atrial ArrhythmiasAbstract Category: 16. Arrhythmias: AF/SVTPresentation Number: 1238-261. J Am Coll Cardiol. 2012;59(13s1):E685-E685. doi:10.1016/S0735-1097(12)60686-X
4Gheorghiade M, Fonarow GC, van Veldhuisen DJ, Cleland JG, Butler J, Epstein AE, Patel K, Aban IB, Aronow WS, Anker SD, Ahmed A. Lack of evidence of increased mortality among patients with atrial fibrillation taking digoxin: findings from post hoc propensity-matched analysis of the AFFIRM trial. Eur Heart J. 2013 May;34(20):1489-97. doi: 10.1093/eurheartj/eht120. Epub 2013 Apr 16. PubMed PMID: 23592708; PubMed Central PMCID: PMC3659306.Published online