Published: Aug 11, 2014 | Updated: Aug 11, 2014
Digoxin was associated with increased risk of death in patients with newly diagnosed atrial fibrillation (Afib), independent of drug adherence, kidney function, cardiovascular comorbidities, and concomitant therapies, researchers reported.
In an observational study cumulative mortality rates were higher for digoxin-treated new Afib patients than for untreated patients, and digoxin use was independently associated with mortality after multivariate adjustment and propensity matching, the retrospective cohort study showed.
These findings, gathered from 122,465 patients from 2003-2008, cause us to look more closely at what is to understand about digoxin use in new Afib, wrote Mintu Turakhia, MD, cardiologist and Director of the Cardiac Electrophysiology program at the Palo Alto (Calif.) VA Health Care System, and colleagues in the Journal of the American College of Cardiology on Aug. 11.
The American Heart Association and American College of Cardiology Foundation recommendations from March of this year point out that digoxin "is not usually first-line therapy. It may be combined with a beta blocker and/or a nondihydropyridine calcium channel blocker when ventricular rate control is insufficient and may be useful in patients with HF."
"We attempted to address a major evidence gap in the management of atrial fibrillation," study author Turakhia told MedPage Today. "There's not one randomized trial using digoxin in Afib."
The DIG (Digitalis Investigation Group) trial, which found that digoxin reduced the rate of hospitalization of patients with chronic heart failure, excluded patients with Afib, said Turakhia.
"I'm not saying we should stop digoxin in all patients or that physicians should never use it,"added Turakhia. "We have to make sure we're using digoxin in the right patients."
These findings may be more representative of current U.S. practice than that of previous analyses, wroteMatthew Reynolds, MD, a cardiologist at Lahey Hospital in Burlington, Mass., and Director of Economics and Quality of Life Assessment at the Harvard Clinical Research Institute, in an accompanying editorial. The sample size is at least 20 times larger than in any prior study on the topic and is drawn from many clinical centers around the U.S. The time frame of observation is also more recent than in other studies.
Data on digoxin and mortality in Afib have been conflicting, wrote Reynolds.
Two studies from Sweden reached differing conclusions regarding a possible link between digoxin and mortality in Afib patients after adjustment for confounding factors: one reported an association and the other did not.
Similarly, two post-hoc analyses of the AFFIRM (Atrial fibrillation Follow-Up Investigation of Rhythm Management) trial reported opposite conclusions as to whether or not digoxin increases mortality.
The results, if taken on face value, suggest that we should not be using digoxin for the treatment of atrial fibrillation, Niteesh Choudhry, MD, PhD, an internist at Brigham and Women's Hospital and health services researcher, told MedPage Today.
But, even with the adjustments the authors did, there are important limitations with an observational study, he said.
There were population differences between patients who received digoxin and those who did not."There are several reasons to think that the digoxin group was sicker," said Choudhry. Patients who were prescribed digoxin had higher rates of heart failure, lower rates of hypertension, and higher rates of taking rate-controlling medications.
"Digoxin is used in practice for specific types of patients and by specific types of providers," said Choudhry.
"It's hard to reliably conclude that it's the digoxin that was killing patients. It may well be their disease that is killing them."
Methods and Findings
Researchers identified patients with newly diagnosed, nonvalvular Afib who were seen and received treatment within 90 days in an outpatient setting. They used data from the U.S. Department of Veterans Affairs (VA) healthcare system between VA fiscal years 2004 and 2008.
Exclusion criteria included a prior Afib diagnosis, history of valve disease, repair or replacement, thyroid disease, kidney transplant, or cardiac surgery within the past 30 days.
The study cohort included 122,465 patients with a mean age of 72.1 years (plus or minus 10.3 years). Only 1.6% were women. Over one third (36.8%) had an eGFR <60 ml/min/1.73m2 or were on dialysis.
Of these patients, 23.4% received digoxin during the initial 90 days after Afib diagnosis.
Compared with nonrecipients, digoxin recipients were of similar age but had a higher prevalence of congestive heart failure (21.3% vs 14.1%), lower prevalence of hypertension (55.8% vs 65.6%), and higher prevalence of receipt of beta-blockers, angiotensin receptor blockers, antiplatelet therapy, diuretics, and warfarin.
Total follow-up time was 353,168 patient-years. Nearly one quarter (23.5%) of patients died during the observation period.
Digoxin recipients had significantly higher unadjusted mortality compared with nonrecipients (HR 1.37, 95% CI 1.33-1.40).
In a propensity-matched subset that included 93% of the digoxin-treated patients, the association between digoxin and mortality was significant but attenuated (HR 1.21, 95% CI 1.17-1.25).
Subgroup analysis revealed that the association was consistent regardless of gender, age, previous diagnosis of heart failure, and concomitant medications including warfarin, beta-blockers, and amiodarone.
Digoxin was also associated with a significant increase in risk of death regardless of eGFR, except in dialysis patients. This was surprising to Turakhia, who thought there would be a gradient effect across kidney disease.
To determine whether an unmeasured confounder or set of confounders could explain the propensity-matched HR of digoxin for death, the authors provided a sensitivity analysis revealing the prevalence of a potential confounder that would obviate their results. Examples of unmeasured confounders could be frailty, ejection fraction, NYHA Class, or disease severity of individual comorbidities, Turakhia toldMedPage Today.
Limitations
Study generalizability may be limited by nearly-all male (98.4%) population, particularly since a post-hoc analysis of the DIG trial showed an interaction between sex and outcomes in patients with heart failure, wrote Reynolds. However, in that study, the risk was higher in women than in men.
"Findings from observational studies always suffer from the reality that treatment decisions in medicine are nonrandom and frequently made on the basis of factors that cannot be measured," he added.
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