Atrial fibrillation is present in around 3.7–4.2% of those aged 60–70 years, and in 10–17% of those aged 80 years or older.1 It occurs more frequently in men, with a male to female ratio of 1.2:1.1 One of the oldest drugs in cardiology, digoxin, is used by around 30% or more of patients with this condition.2 Amid concerns raised for the safety profile of this drug, a new trial reported at the American College of Cardiology 2017 Annual Scientific Session that patients with atrial fibrillation who are taking digoxin are at an increased risk of death, whether or not they have heart failure, compared with patients not taking the drug.3 In patients already receiving digoxin, who may therefore be more likely to tolerate the drug, the overall relationship between digoxin use and death was non-significant. However, even in this group, the risk of death was correlated to digoxin blood levels: for every 0.5 ng/ml increase in concentration, the risk of death increased by 19%. Among patients who had digoxin blood levels in excess of 1.2 ng/ml, the death rate rose by 56%.
Patients who were not taking digoxin prior to the trial who began to take it during the study’s course had a 78% higher risk of death from any cause. Further, the risk of sudden death after receiving digoxin increased four-fold. Most sudden deaths in the Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation (ARISTOTLE) trial happened within six months of starting digoxin.
The ARISTOTLE trial, in which 18,201 patients were enrolled, was presented by lead investigator, Renato Lopes, professor of medicine in the division of cardiology at the Duke University Medical Center. A total of 17,897 patients had data available on digoxin use and heart failure status during the trial and, of these, 5,824 were receiving digoxin at the start of the trial and 4,434 had their blood levels of digoxin measured. To try to address the lack of random assignment to digoxin use, a propensity score analysis was used to account for covariates. These included demographic characteristics, medical history, organ function measurements, other medications, geographic location, clinical setting where digoxin treatment was initiated, heart failure status and blood biomarkers that may predict the risk of death. Every patient receiving digoxin was compared with three matched controlled patients who were not receiving the drug.
ARISTOTLE comprehensively included clinical variables, biomarker adjustments and blood levels of digoxin. Major limitations are the lack of randomisation and the potential for unmeasured confounders. Further, the investigators did not know how long patients may have been taking digoxin before study entry. However, the findings are significant, particularly as there are, as yet, no randomised data assessing the efficacy and safety of digoxin in patients with atrial fibrillation.
‘To definitively determine the efficacy and safety of digoxin in atrial fibrillation patients 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 physicians in their clinical decisions when managing these patients,’ said Lopes.
Funding Study funding was received by the Bristol-Myers Squibb and Pfizer Alliance in conjunction with the Duke Clinical Research Institute.
1. Zoni-Berisso M, Lercari F, Carazza T, Domenicucci S, Epidemiology of atrial fibrillation: European perspective, Clin Epidemiol, 2014;6:213–20.
2. Ziff OJ, Kotecha D, Digoxin: The good and the bad, Trends Cardiovasc Med, 2016;26:585–95.
3. Lopes R, Digoxin and Mortality in Patients with Atrial Fibrillation with and without Heart Failure: Does Serum Digoxin Concentration Matte. Available at: www.acc.org/about-acc/press-releases/2017/03/18/08/47/sun-1045am-new-study-adds-to-concerns-about-heightened-risk-of-death-for-afib-patients-taking-digoxin?w_nav=S#sthash.c7LMhTht.dpuf (accessed 2 May 2017).