Fatal Foxglove: Digoxin in Early AF Ups Mortality Risk

Marlene Busko

August 11, 2014

PALO ALTO, CA — In a large cohort of elderly veterans newly diagnosed with atrial fibrillation [AF], those who received initial treatment with digoxin had a >20% increased risk of dying within about three years compared with their peers[1]. The risk increase was independent of age, sex, heart failure, kidney function, or concomitant use of beta-blockers, amiodarone, or warfarin.

This study, based on more than 122 000 patients who participated in The Retrospective Evaluation and Assessment of Therapies in AF (TREAT-AF), virtually all of whom were men, was published online today by the Journal of the American College of Cardiology.

"There may be perfectly valid reasons to use digoxin . . . and the drug can be useful in heart failure . . . [but this study suggests that] in the case of [AF], physicians need to ask themselves if digoxin is the right treatment of choice when there are many other safer alternatives," Dr Mintu Turakhia (Veterans Affairs Palo Alto Health Care System, CA) told heartwire . "Should we really be using digoxin as first-line therapy, given the data here?"

Guidelines explicitly recommend that digoxin can be used in the context of heart failure, but they are less explicit about patients without heart failure, he added. Moreover, last month a New York Times article[2] highlighted a recent dramatic increase in cost. "There are patients paying several hundred to several thousand dollars a year for digoxin, which is crazy because we all thought it was a good, cheap drug . . . so the incentive to use this as initial or mainstay therapy in afib is unclear.

"The use of digoxin has been declining over the past decade, and I think perhaps these and other data might influence clinicians or at least make them consider other alternatives to [this drug in AF]," Turakhia said.

Conflicting Safety Data in AF

Digoxin is one of the most widely used heart-rate control agents in the world, but the seminal Digitalis Investigation Group (DIG) trial in patients with heart failure actually excluded those with AF, Turakhia observed.

"[Clinicians have] continued using [digoxin for AF], thinking it's probably safe. At the same time, digitalis can be fatal. . . . Any emergency-room doctor, internal-medicine doctor, or cardiologist [knows] the signs and symptoms of ECG findings with digitalis [toxicity]," he noted.

More recently, a number of smaller studies based mostly on observational data have come to different conclusions about whether digoxin increases mortality risk in AF, as heartwire has reported.

In the current study, the researchers identified 122 465 US veterans who were newly diagnosed with AF from 2003 to 2008 and received digoxin within 90 days of diagnosis.

The patients had a mean age of 72 years, and only 1.6% were women. About one in four patients (23.4%) received early treatment with digoxin, and 70% were on therapy one year after the index date.

During a follow-up of roughly three years, 23.5% of the patients died.

The multivariate-adjusted mortality hazard ratio (HR) for digoxin was 1.26 (95% CI 1.23–1.29, p<0.001); the HR was similarly increased and significant in a propensity-matched analysis that included 93% of digoxin-treated patients.

A sensitivity analysis showed that it was very unlikely that unmeasured confounders—such as frailty, for example—would explain the increased risk of death. There was no difference in outcomes across different levels of kidney function.

Digoxin No Longer First Choice in AF

Digoxin should be used selectively and with care in AF patients

"It has been realized for some time that digoxin is no longer the first choice for rate control in AF patients, because other drugs are both safer and more effective," but previous studies of mortality outcomes have produced conflicting results, Dr Matthew R Reynolds (Lahey Hospital & Medical Center, Burlington, MA) writes in an accompanying editorial[3].

This "new, well-conducted study [by Turakhia et al] has several notable strengths," he adds. It is more than 20 times larger than prior observational studies and it is based on more contemporary data than the AFFIRM trial. However, unmeasured factors might mean that the "true" increased risk of mortality is lower.

"The main implication of the Turakhia et al paper and related data is that digoxin should be used selectively and with care in AF patients," according to Reynolds. "This view is reflected in the recently updated AF treatment guidelines, where beta-blockers and nondihydropyridine calcium-channel blockers were given a class I recommendation for rate control, and digoxin received no specific recommendation at all."

Based on observational studies, it is too early to recommend that the use of digoxin for rate control in AF should be abandoned altogether, Reynolds suggests. "Going forward, the role of digoxin in AF treatment may continue to diminish. For now, there are still clinical circumstances (HF, difficult rate control, low blood pressure) where this old herbal remedy remains useful," he writes.

Since "more patients are hospitalized for adverse effects from digoxin than for any cardiovascular medicine other than antiplatelet and anticoagulant drugs, . . . [when digoxin is used] it is clear that dosing should be conservative, particularly in the elderly," he cautions.

Turakhia is supported by a Veterans Health Services Research & Development Career Development Award, an American Heart Association National Scientist Development grant, a VA Health Services and Development MERIT Award, and a National Institute for Diabetes and Digestive and Kidney Diseases grant. Disclosures for the coauthors are listed in the paper. Reynolds has no relevant disclosures.

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