Results of a Study Add to Concerns About Heightened Risk of Death for Digoxin Taken for Atrial Fibrillation
March 19, 2017—Washington, DC—Patients with atrial fibrillation who are given digoxin to control symptoms are at increased risk of death, whether they have been diagnosed with heart failure or not vs patients not taking the drug. This risk increases with higher blood levels of digoxin.
This conclusion, based on results of a subanalysis of the Apixaban for Reduction In STroke and Other ThromboemboLic Events in atrial fibrillation (ARISTOTLE) trial, was presented at the American College of Cardiology’s 66th Annual Scientific Session, from March 17 - 19.
Renato Lopes, MD, PhD, of Duke University Medical Center, Durham, North Carolina, explained that approximately 30% of patients with atrial fibrillation worldwide take digoxin, whose safety for patients with atrial fibrillation has come under scrutiny.
Dr. Lopes said, “A number of recent publications have questioned the safety of this drug, and different analyses looking at different questions have shown conflicting results. No randomized trials have assessed the efficacy and safety of digoxin in patients with atrial fibrillation.”
To get a more definitive answer about digoxin’s safety, Dr. Lopes and colleagues analyzed data collected in the ARISTOTLE trial, which compared apixaban with warfarin to prevent blood clot, stroke, and death in patients with atrial fibrillation.
In the ARISTOTLE trial, apixaban was found to be statistically significantly superior to warfarin for preventing blood clots, strokes, major bleeding events and death, whether patients were taking digoxin at study entry or not. The results showed that for stroke prevention in patients with atrial fibrillation, apixaban is a better option than warfarin, irrespective of digoxin use.
Of the 18,201 patients enrolled in ARISTOTLE, 17,897 had data available on heart failure status and digoxin use during the trial. Of those patients, 5824 were receiving digoxin at the start of the trial; 4434 of these participants had their blood levels of digoxin measured at baseline. A total of 6693 patients had heart failure at the time of trial enrollment.
To compensate for the lack of randomization, the researchers performed a propensity score analysis, which attempts to estimate the effect of a treatment by accounting for covariates that differ between treated and untreated patients.
Covariates included demographic characteristics; medical history; measurements of organ function; other medications, including antiarrhythmic agents; global region; clinical setting in which digoxin was initiated; heart failure status; and blood biomarkers predictive of mortality risk. Each patient taking digoxin was compared with three matched control patients from ARISTOTLE who were not taking the drug.
In patients already receiving digoxin and, therefore, more likely to tolerate the drug, the overall relationship between digoxin and death was nonsignificant. Even in this cohort, however, the risk of death was related to digoxin concentrations in the blood. For every 0.5 ng/mL increase in blood levels of digoxin, the risk of death rose by 19%. Among patients whose digoxin levels were > 1.2 ng/mL, the death rate increased by a highly significant 56%.
The risk of death was even higher for patients not taking digoxin before the trial but were started on the drug over the course of ARISTOTLE. These patients suffered a 78% increase in the risk of death from any cause and a fourfold increased risk of sudden death after starting digoxin.
Dr. Lopes said, “Most sudden deaths occurred within 6 months after digoxin was started.” This hinted at cause and effect, he said, though the fact that patients were not randomized to digoxin prevented a definitive determination of causality.
The lack of randomization and the potential for unmeasured confounding factors were the main limitations of the study. In addition, for patients receiving digoxin at study entry, researchers did not know how long they had taken the drug before study entry. Despite these limitations, the study was one of the most comprehensive to date, incorporating clinical variables, biomarker adjustments, and blood digoxin levels.
Dr. Lopes concluded that an increased risk of death from any cause—the primary endpoint—was found in both patients with and without heart failure who started digoxin. The study was one of the largest and most comprehensive analyses of the risk of digoxin use in patients with atrial fibrillation to date.
He continued, “Based on our results, digoxin should be avoided in patients with atrial fibrillation, particularly if symptoms can be alleviated with other treatments. 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 atrial fibrillation—irrespective of the presence of heart failure—seems to be the right approach.”
He added, “To definitively determine the efficacy and safety of digoxin in patients with atrial fibrillation would require a large and well powered randomized trial. Until then, our finding that digoxin may be causing more harm than good in patients with atrial fibrillation is important and may help guide clinical decision making.”Click on any of these tags to subscribe to Topic Alerts. Once subscribed, you can get a single, daily email any time PracticeUpdate publishes content on the topics that interest you.
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