Patients with atrial fibrillation and at least one additional risk factor for stroke who received digoxin had higher mortality rates compared with those who did not take digoxin, according to an analysis of a randomized trial.

Among patients taking digoxin, the researchers found the risk of death was independently related to the digoxin serum concentration. The mortality risk was highest in patients whose digoxin serum concentrations were 1.2 ng/mL or higher.

Lead researcher Renato Lopes, MD, PhD, of the Duke University Medical Center, presented results of the study in a late-breaking clinical trial session at the ACC scientific session on March 19 in Washington, DC.

“Based on our study, digoxin should be avoided in patients with AFib, particularly if symptoms can be alleviated with other treatments,” Lopes said in a news release. “We showed that starting digoxin was associated with increased risk of death and sudden death, regardless of the presence of heart failure. Thus, based on our findings, avoiding digoxin in patients with AFib—irrespective of the presence of heart failure—seems to be the right approach.”

Lopes mentioned that approximately 30 percent of patients with atrial fibrillation use digoxin and that guidelines recommend the drug for rate control in atrial fibrillation patients.

The researchers analyzed data from the ARISTOTLE study, during which 18,201 patients were randomized to receive apixaban (Eliquis) or warfarin. The FDA has approved apixaban to reduce the risk of strokes and blood clots in patients with nonvalvular atrial fibrillation. Bristol-Myers Squibb and Pfizer, which manufacture and market apixaban, sponsored the study.

All of the patients had atrial fibrillation and at least one of the following risk factors: age 75 or older; prior stroke, transient ischemic attack (TIA) or systemic embolism; heart failure or left ventricular ejection fraction of 40 percent or less; diabetes; and hypertension.

The researchers had information on heart failure status and digoxin use in 17,897 patients in the ARISTOTLE trial. Of those patients, 4,434 had their blood levels of digoxin measured at baseline, while 6,693 patients had heart failure when they enrolled.

For this analysis, the researchers conducted a propensity score analysis and compared each patient taking digoxin with three matched controls from the study who did not take the medication. The mean age was 70 years old, and approximately 40 percent of patients were females. In addition, 42.9 percent of patients had heart failure or left ventricular dysfunction and approximately 23 percent had a prior stroke, TIA or systemic embolism.

Compared with patients with a baseline serum digoxin concentration of less than 0.9 ng/mL, those with a baseline serum digoxin concentration of 0.9 ng/mL to 1.2 ng/mL had a 19 percent increased adjusted mortality rate and those with a baseline concentration of 1.2 ng/mL or higher had a 56 percent increased adjusted mortality rate.

For each 0.5 ng/mL increase in baseline serum digoxin concentrations, there was a 19 percent increased risk of death, according to the researchers. In addition, the researchers found that patients who began taking digoxin during the study had a 78 percent increased risk of death compared with patients who never took digoxin. The results were similar whether or not the patients had heart failure.

In addition, patients who took digoxin had a four-fold increase in the risk of sudden death compared with patients who never took digoxin. The researchers also did not find any interaction for stroke, bleeding or death between digoxin and warfarin or apixaban

The study had a few limitations, including that it was not a randomized trial and could be subject to unmeasured confounding factors.

“To definitively determine the efficacy and safety of digoxin in atrial fibrillation patients would require a large and well-powered randomized trial,” Lopes said in a news release. “Until then, our finding that digoxin may be causing more harm than good in patients with atrial fibrillation is important and may help guide physicians in their clinical decisions when managing these patients.”