Increased Mortality With Digoxin in AF

November 30, 2012

LEXINGTON, Kentucky — The use of digoxin in patients with atrial fibrillation (AF) is being called into question, with the publication of a new study suggesting it is associated with a significant increase in all-cause mortality [1].

The study, a propensity-adjusted analysis of the AFFIRM trial that controlled for multiple comorbidities, was published online on November 27, 2012 in the European Heart Journal. It found an overall 41% increase in all-cause mortality in patients taking digoxin vs those not taking digoxin. The increase in all-cause mortality was consistently observed in men and women and in patients with and without underlying heart failure.

Senior author Dr Claude Elayi (University of Kentucky, Lexington) explained to heartwire that the use of digoxin has previously been associated with an increased risk of death in AF patients, but it has not been known whether this is because it tends to be used in sicker patients.

A major randomized trial of digoxin in heart failure (the DIG trial) showed an overall neutral effect on mortality, although death was increased in patients taking high-dose digoxin. However, hospitalizations for heart failure were reduced, and the consensus is that digoxin is beneficial in heart failure, Elayi noted.

"We would really like to see a similar randomized trial of digoxin in AF patients, but it is unlikely to ever be done, so we have tried to get the information from a large existing study, correcting the data for biases with complex statistical models.

"And the magnitude of the effect seen is so high--an increase in mortality of 41% in patients on digoxin--that even if we haven't corrected for some of the biases, I don't think it would account for the results we saw."

Elayi believes these results should make doctors think hard about whether to prescribe digoxin for AF patients, especially if they don't also have heart failure. "I'm not saying we should never use digoxin again in AF patients, more that we have to think carefully about it."

Different Advice Dependent on Heart Failure

He suggests that if patents have AF and heart failure, it is still reasonable to use digoxin. "Theoretically, digoxin should be the perfect drug for patients with both conditions, as it slows the heart rate, which is needed in AF, and we know from the DIG trial that it has benefits in heart failure. But I would caution that low doses should be used and blood levels should be carefully monitored, as digoxin can interact with many different drugs."

Digoxin's time as a first-line agent in AF patients without heart failure is over.

But Elayi now advises against use of digoxin in AF patients without heart failure. "In this group, the only benefit of digoxin is to slow the heart rate, which many other drugs can do better and more safely. So I would advise against using digoxin in such patients, unless beta blockers or calcium antagonists are not appropriate, maybe because of low blood pressure. And again, if it is used, stick to low doses with careful monitoring."

Elayi estimates that 30% to 50% of AF patients are currently taking digoxin, more in some developing countries. "It is extensively used across the planet, perhaps a bit less in the US and Europe. I hope this study will bring some warnings that digoxin's time as a first-line agent in AF patients without heart failure is over."

Nissen: Findings Raise Safety Concerns

A press release issued by the University of Kentucky quotes Dr Steve Nissen (Cleveland Clinic, OH), who was not involved in the study, as saying: "These findings raise important concerns about the safety of digoxin, one of the oldest and most controversial heart drugs. Although considered obsolete by some authorities, digoxin is still widely used. A thorough review by the FDA is warranted to determine whether regulatory action is needed, including stronger warnings about the use of digoxin in patients with atrial fibrillation" [2].

A thorough review by the FDA is warranted.

The AFFIRM trial randomized 4060 patients (39% women) to rhythm control or rate control. Overall, 2816 patients (69.4%) received digoxin within six months of randomization and/or during the study. Heart failure was present in 26% of patients.

After propensity scoring and multivariable Cox proportional models were applied, digoxin was associated with an increase in all-cause mortality, cardiovascular mortality, and arrhythmic mortality.

Hazard Ratio (95% CI) for Death on Digoxin in AF Patients

Outcome HR (95% CI) p
All-cause mortality 1.41 (1.19–1.67) 0.001
CV mortality 1.35 (1.06–1.71) 0.016
Arrhythmic mortality 1.61 (1.12–2.30) 0.009

Because in a post hoc analysis of the DIG trial there appeared to be a gender difference in the effect of digoxin, with a greater increase in mortality among women taking the drug compared with men, the effect of gender was closely observed in the current study. However, no gender interaction was seen in the AFFIRM data, with both men and women showing significantly increased overall mortality with digoxin use.