Duel Over Digoxin: Is It Safe for HF?

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Digoxin has long been a mainstay in the treatment of systolic heart failure (HF). Recently, however, some studies have called its safety into question after finding the use of the drug in contemporary practice was associated with higher mortality rates.

One recent study found incident use of digoxin in patients with newly diagnosed systolic HF was associated with a 72 percent increased risk of death. Risk was higher even among patients who took other heart-related medications (Circ Cardiovasc Qual Outcomes 2013; 6:1-8).

“Current guidelines recommend digoxin with beta-blockers, but we found that even if people took digoxin with them, they still have a higher risk of dying,” says study co-author Alan S. Go, MD, of Kaiser Permanente Northern California.

These findings are similar to results of a follow-up analysis of data from AFFIRM (AF Follow-Up Investigation of Rhythm Management) (European Heart Journal 2013; 34:1481-1488). In this study, all-cause mortality was 41 percent higher in patients with atrial fibrillation (AF) on digoxin whether they had HF or not.

The original AFFIRM study randomized 4,060 patients with AF with a high risk for stroke to receive either rate control drugs or rhythm control drugs over a four-year period. After following patients for an average of 3.5 years, the researchers found a rhythm control strategy did not improve survival compared with a rate control strategy.

In the follow-up analysis, the authors re-analyzed the AFFIRM data to determine whether digoxin use was a predictor of all-cause, cardiovascular and arrhythmic cardiovascular mortality in all AF patients as well as patients with and without congestive HF and/or an ejection fraction of less than 40 percent.

In addition to the higher rate of all-cause mortality, they found that patients taking digoxin had a 35 percent higher rate of cardiovascular mortality and a 61 percent higher rate in cardiovascular mortality related to arrhythmia. “These findings call into question the widespread use of digoxin in patients with AF,” the authors wrote.

Samy Claude Elayi, MD, of the University of Kentucky College of Medicine and the senior author of the AFFIRM study, acknowledges that patients were not randomized to receive or not receive digoxin. “Patients in general, whether they had heart failure or not, had increased mortality on digoxin, but it’s not clear whether it was digoxin or because the patients who took the drug were sicker,” he says.

Although these trials made some experts wary about the safety of the drug, others say the final verdict is not in yet, given methodological limitations of both trials.

“Since the DIG [Digitalis Investigation Group] trial, we know that digoxin has been reserved for patients with more severe heart failure often not used until other therapies are failing. So selective use introduces a tremendous bias,” says Kirkwood Adams, MD, of the University of North Carolina in Chapel Hill. DIG is a large randomized controlled trial that compared digoxin to placebo in patients with chronic HF. “Naturally if patients treated with digoxin are sicker, they’re more likely to die than patients not given the drug.”

Go says patients taking digoxin in his trial were healthier in some ways. They tended to be older, hypertensive, diabetic and on beta-blockers, but were less likely to have had a heart attack and on other heart-related medications.

Clinical use

Elayi argues that their findings inform practice. “In heart failure patients, this study reminds us that if we use digoxin, we should be extremely careful,” he says. “We need to use a low dose and carefully monitor patients. The dose that is toxic is close to the dose that is therapeutic.”

Findings from other research, however, are quite different.

DIG researchers recently found in an additional analysis of data acquired in the 1990s that digoxin significantly reduced HF hospitalizations and 30-day all-cause hospital admissions among chronic HF patients, although there was no reduction in all-cause mortality (American Journal of Medicine, 2013; 126:701-708).

“It’s a neutral drug when it comes to mortality,” says co-author Ali Ahmed, MD, of the University of Alabama at Birmingham.

Ahmed argues that digoxin may be a fiscally desirable option for hospitals because of the association between use of the drug and a lower rate of hospitalizations. Medicare penalizes some 30-day HF readmissions. While DIG did not assess readmission rates, Ahmed presented data at the European Society