Debating digoxin in AF: New analysis suggests no mortality risk

April 18, 2013

Birmingham, AB - One data set, two research groups, and two completely different conclusions concerning the safety of digoxin in the treatment of patients with atrial fibrillation (AF)[1]. In a new post hoc analysis of the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial, the use of digoxin was not associated with an increased risk of death or hospitalizations in patients with paroxysmal and persistent AF.

Published online April 16, 2013 in the European Heart Journal, the new report contrasts with a 2012 analysis of the same data that suggested digoxin was associated with an increased risk of all-cause mortality.

Senior researcher Dr Ali Ahmed (University of Alabama, Birmingham) told heartwire that the differing conclusions are the result of two different methodologies used to analyze the data. He said their research should reassure patients that there is no need to panic and stop taking digoxin without consulting their physician. This is particularly important for patients with heart failure, another indication for digoxin, because data from other studies, including the DIG trial, have shown that the discontinuation of digoxin increases the risk of hospitalizations.

"This is important, as heart failure is the leading cause for hospital admission and readmission for Medicare beneficiaries, and under the new healthcare reform law, hospitals are facing millions of dollars in penalties for having excessive readmission for their heart-failure patients," said Ahmed.

"Right in the middle of the paper"

To heart wire , Ahmed explained that in 2004 the AFFIRM investigators reported in Circulation a 42% increased risk of death with the use of digoxin. This finding was presented "right in the middle of the paper, and nobody paid any attention to it." However, in the 2012 analysis of AFFIRM by Dr Matthew Whitbeck (University of Kentucky, Lexington) and colleagues, which was published in the European Heart Journal, digoxin use was associated with a 41% increased risk of all-cause mortality, a 35% increased risk of cardiovascular mortality, and 61% increased risk of arrhythmic mortality[2].

The 2012 analysis gained attention, including plenty from the media, leading to concerns among patients and physicians. In fact, some clinical centers stopped using digoxin entirely in patients with AF and heart failure. "This was despite the fact digoxin is recommended by major national guidelines for use in these conditions," said Ahmed.

He believes the more plausible explanation of digoxin-associated mortality in the previous two studies is the use of digoxin as a time-dependent variable. In this method, the researchers account for treatment during the follow-up period under the assumption that the change in treatment occurs in a random fashion. However, in the case of digoxin, patients could receive digoxin only when they had heart failure or developed heart failure, the only other condition for which it is used. If digoxin is completely ineffective, because heart failure increases the risk of death, it is the result of heart failure and not the drug, he explained.

"Nearly three times as many in the digoxin group had heart failure, suggesting that heart-failure patients were more likely to be given digoxin," he told heart wire .

In their analysis, the researchers analyzed the risk of death with digoxin in propensity-matched cohorts. In AFFIRM, 4060 patients with AF were randomized to rate-control or rhythm-control strategies. Of these, 1377 received digoxin as the initial therapy at baseline, and 1329 received no digoxin. Propensity scores for digoxin use were used, and 878 pairs of patients receiving and not receiving digoxin were compared. During 3.4 years of follow-up, there was no significant effect of digoxin use on all-cause mortality, all-cause hospitalization, or nonfatal cardiac arrhythmias.

Lies, damned lies, and statistics

To heart wire , Dr Paul Hauptman (Saint Louis University School of Medicine, MO) quoted Mark Twain—"lies, damned lies, and statistics"—and said this latest paper by Ahmed, along with first author Dr Mihai Gheorghiade (Northwestern University Feinberg School of Medicine, Chicago, IL), makes a reasonable argument as to why their methodology is superior to Whitbeck et al. Not involved in either analysis, Hauptman said that both papers are limited by a lack of analysis based on serum digoxin levels, however.

"If we learned anything in heart failure, it's that digoxin levels are probably the answer to all of this confusion as to whether or not we should use it, how much to use, and so forth," said Hauptman. "We don't have parallel data in the atrial-fibrillation world, but I have no reason to believe it's different, partly because there is such an overlap between heart failure and atrial fibrillation. It's like a Venn diagram. Why would the levels correlate with outcomes in heart failure and not apply to the atrial-fibrillation population?"

The differing conclusions, he added, might be "much ado about nothing," because the standard today should be to measure serum digoxin levels. In elderly patients, particularly—and a lot of AF patients are elderly—digoxin has a narrow therapeutic window, and it doesn't take much to get into a toxic range, said Hauptman.

No increased risk of death observed here

Ahmed praised the European Heart Journal for allowing the group to take a second pass at the AFFIRM data, adding that their paper underwent critical analyses by many reviewers, including several statisticians. "After several revisions, they accepted the paper, and this is good for the field and the patients," said Ahmed. "However, the downside is, these discordant findings create confusion and may even erode trust. A lot of people, clinicians and patients alike, might still be wondering which one is correct, but now, at least, they will have the option of reviewing both papers to judge for themselves."

To heart wire , he said that clinicians should follow the clinical guidelines for AF that state that digoxin is recommended as one of the rate-control drugs and that it should be used in low doses in older adults. "Do I use digoxin for all of my patients? No. Probably not even in half of my patients with atrial fibrillation or those with heart failure. If I have an older patient who is pretty active I'll probably try a beta-blocker first. However, when I have an 85-year-old with atrial fibrillation who isn't very active and has low blood pressure, I want that patient to be helped with digoxin."

Hauptman said the latest paper levels the game with regard to digoxin and the drug is once again in "equipoise." He does not believe digoxin is going away, either, for better or for worse, and that there will likely be similar debates about its safety and efficacy 10 years from now.

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