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The heart rate control drug digoxin may independently raise risk of death in atrial fibrillation, a clinical trial subanalysis suggested.
After adjustment for clinical characteristics and comorbidities, the drug was associated with 41% elevated all-cause mortality (P<0.001), reported Claude Elayi, MD, of the Gill Heart Institute at the University of Kentucky in Lexington, and colleagues.
Cardiovascular mortality and arrhythmic mortality were similarly elevated with digoxin in the post-hoc AF Follow-Up Investigation of Rhythm Management (AFFIRM) trial analysis, they wrote in the European Heart Journal online.
"These findings call into question the widespread use of digoxin in patients with atrial fibrillation," Elayi's group stated, recommending that the drug's role be reassessed.
Guidelines already recommend digoxin be used as a second-line agent for rate control in atrial fibrillation and as monotherapy only for sedentary patients, commented Anne Gillis, MD, of the University of Calgary in Alberta.
The study just adds to the impetus for caution, said Gillis, president of the Heart Rhythm Society.
"We emphasize to primary care physicians, cardiologists, and our electrophysiology colleagues that first-line rate control therapy for atrial fibrillation should be either beta-blockers, diltiazem, or verapamil," she told MedPage Today.
"Digoxin, if required for combination therapy, obviously needs to be used with caution and digoxin levels need to be monitored in such cases."
The drug, which comes from the foxglove plant, has been used for centuries in heart failure but is controversial today "due to its narrow therapeutic index and a potential to contribute to life-threatening ventricular tachyarrhythmias and severe bradyarrhythmias," the researchers explained.
Randomized trials with strict monitoring of serum levels of digoxin have shown no negative effect of the drug on mortality in heart failure without atrial fibrillation, whereas large observational studies have shown an impact on all-cause and cardiovascular mortality.
To help sort out the role of residual potential confounding versus inherent drug toxicity, Elayi's group examined nonrandomized use of digoxin among the 4,060 patients in the AF Follow-Up Investigation of Rhythm AFFIRM trial.
That trial was designed to compare rate- versus rhythm-control in an atrial fibrillation population considered at high risk for stroke.
Fully 69% of patients took digoxin within 6 months of randomization, during the study, or both, which Gillis noted was a reflection of practice patterns a decade ago.
Those who did take digoxin were more likely to die during the mean 3.5 years of follow-up.
The 69% of patients who took digoxin within 6 months of randomization, during the study, or both were more likely to die during the mean 3.5 years of follow-up.
Along with the overall survival difference, cardiovascular mortality remained 35% elevated after controlling for clinical and demographic variables and propensity scores (P=0.016).
Arrhythmic deaths were 61% more common among digoxin-treated patients in the adjusted analysis as well (P=0.009).
The effect didn't appear to differ by sex, and was elevated both among patients without heart failure and those with it (estimated hazard ratios 1.37 and 1.41, P=0.019 and P=0.010, respectively).
"Patients without congestive heart failure or low ejection fraction lack the neurohormonal and inotropic derangements that may improve with digoxin, while remaining exposed to its potential deleterious effects such as pro-arrhythmia and bradycardia," Elayi's group noted.
Even for those with heart failure, "it may be hypothesized that potential benefits are offset by deleterious effects," they added.
A step-wise regression analysis looking for explanatory variables showed the biggest attenuation in the all-cause survival link was adjustment for NYHA functional class, which dropped the mortality excess from 66% to 49%, though still statistically significant.
The lowest estimate for the excess risk was 36%.
The researchers cautioned that their findings may still have overestimated the association due to unknown or unmeasured potential confounders.
"However, given the large observed magnitude of effect and directionally consistent main and sensitivity analyses, invalidation of these results by residual confounding appears implausible," they argued.
Cardiac causes of death without evidence of ischemia were more common among the 56% of deaths with digoxin in use as of the last follow-up visit (37% versus 27% of deaths without digoxin, P=0.007).
Cancer, pulmonary, and noncardiovascular causes of death didn't differ by digoxin status.
The exact mechanism for a mortality effect of digoxin wasn't clear from the study, which didn't record digoxin levels routinely monitored as part of standard clinical care or the exact duration of or adherence to digoxin treatment.
"However, it is important to note that real-world patients, including those in AFFIRM, are not routinely subject to the close follow-up and frequent monitoring of serum digoxin concentrations mandated in the DIG study [N Engl J Med 1997; 336: 525–533]," which showed a neutral effect of the drug in heart failure without atrial fibrillation, Elayi's group wrote.
"It is possible that such strict monitoring is required to ensure safety," they added.
From the American Heart Association:
- AHA Atrial Fibrillation Summit: A Conference Report from the American Heart Association
- Focused Update on the Management of Patients With Atrial Fibrillation
The researchers reported no conflicts of interest. Gillis also reported having no conflicts of interest to disclose.
- Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner