AFFIRM analysis questions digoxin’s safety

An analysis of AFFIRM data cast doubt on the widespread use of digoxin to manage patients with atrial fibrillation (AF). The drug was associated with a significant increase in all-cause mortality, according to results published online Nov. 26 in the European Heart Journal.

“Digoxin has survived as a mainstay of therapy for AF and CHF [congestive heart failure] for decades despite controversies about its safety and continues to be utilized in the U.S. and worldwide,” wrote Matthew G. Whitbeck, MD, of the Gill Heart Institute at the University of Kentucky in Lexington, and colleagues. “Digoxin use has ranged from 35 to 70 percent in recent AF studies despite limited data addressing its safety for this indication.”

Whitbeck and colleagues obtained archived data from AFFIRM (AF Follow-Up Investigation of Rhythm Management), a clinical trial that randomized 4,060 AF patients at high risk for stroke to either rhythm control or rate control over four years with a mean follow-up of 3.5 years. AFFIRM found that rhythm control failed to improve survival compared with rate control, a strategy that frequently used calcium channel blockers, beta-blockers and digoxin. The authors noted that because of the AFFIRM findings, many physicians began to favor rate control strategies for treating AF patients.

For their post-hoc analysis, they used multivariate Cox proportional hazards models to determine whether digoxin use predicted all-cause, cardiovascular and arrhythmic mortality in AF patients, including subsets of patients with or without CHF. They defined CHF as a history of CHF or left ventricular ejection fraction of less than 40 percent. They also explored gender and digoxin use, based on previous studies that suggested increased mortality in women given digoxin.

Whitbeck and colleagues found that all-cause mortality was 41 percent higher in patients who received digoxin. In analyses controlling for comorbidities and propensity scores, digoxin was associated with a 37 percent increase in mortality for patients with and without HF. Its use also was associated with a 35 percent increase in mortality from cardiovascular causes and a 61 percent increase in mortality from arrhythmic causes. Gender did not influence the outcomes.

“These findings mean that physicians should try to control a patient’s heart rate by using alternatives as a first line, such as beta-blockers and calcium blockers; if digoxin is used, use a low dose with careful clinical follow-up, evaluate potential drug interactions when starting new medications and monitor digoxin levels,” said senior author Claude S. Elayi, MD, also of the Gill Heart Institute, in a release. “Patients should be aware of potential toxicity and see their physician immediately in specific clinical situations, for instance, if they experience palpitations or syncope, as those may precede arrhythmic death.”

The authors pointed out that AFFIRM did not randomize patients to either digoxin use or a control. They wrote that the associations found in their analyses may be overestimates due to confounders. They also lacked data on digoxin dosing, adherence and duration of treatment.

“While our results strongly suggest that mortality was increased by digoxin in the AFFIRM study, the pathophysiological mechanism remains to be elucidated,” they wrote. Based on their results, they suggested digoxin’s role in the treatment of AF patients with or without HF should be reassessed.