A study published today in the European Heart Journal found no evidence that digoxin increases mortality in patients with atrial fibrillation, the opposite of results just published by another group in the same journal analyzing the same data.
Older patients with atrial fibrillation or AF also often have heart failure, the only other condition for which digoxin is approved. AF is the most common kind of cardiac arrhythmia, an electrical malfunction that throws off the heart’s rhythm and pumping rate. It may cause no symptoms or cause some patients to faint, but is seldom fatal. Heart failure, a gradual weakening of the heart’s pumping strength, contributes to 280,000 U.S. deaths each year.
Both studies were re-analyses of data first collected in 2002 as part of a randomized controlled trial called Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM). The recent study that found digoxin increases mortality used “time-varying treatment,” a statistical approach in which patients who continued to receive digoxin over the 3.4 years of the follow-up to AFFIRM were compared to those who did not.
According to current study authors, this approach is useful but can produce potentially misleading results when applied to drugs that treat serious illnesses. If patients continued digoxin treatment over the long term because they had heart failure, it may have inadvertently attributed higher mortality to digoxin when it was actually due to heart failure.
“We found that nearly three-quarters of AFFIRM patients with heart failure at the start of the trial were receiving digoxin, suggesting that heart failure was a reason for digoxin use in those patients,” said Ali Ahmed, M.D., M.P.H., professor in the divisions of Gerontology, Geriatrics, & Palliative Care and Cardiovascular Disease within the School of Medicine at the University of Alabama at Birmingham (UAB), and the new study’s senior author. “When we accounted for how many patients in the digoxin group had heart failure going in, the association between digoxin and mortality disappeared.”
Using an approach called propensity score matching, Ahmed’s team assembled a group of AFFIRM patients, some that had received digoxin and some not, but all of which were similar based on 59 characteristics, including conditions besides AF (e.g. heart failure), other medications, age, sex and race. The team found that, during the 3.4 years of follow-up, 14 percent of matched patients receiving digoxin and 13 percent of patients not getting it died.
This difference is well within the study’s margin of error and, in practical terms, represents no increase in mortality associated with digoxin (hazard ratio, 1.06; 95% confidence interval {CI}, 0.83–1.37; P=0.640). Also among matched patients, digoxin was not associated with all-cause hospitalization (hazard ratio, 0.96; 95% CI, 0.85–1.09; P=0.510) or arrhythmias (hazard ratio, 0.90; 95% CI, 0.37–2.23; P=0.827).
Larger than fibrillation
Along with its utility in the treatment of AF, digoxin was recently shown to reduce by 34 percent the chances that heart failure patients will be admitted to the hospital within 30 days of first taking it. Preventing frequent admissions became a national priority last year as the Centers for Medicare and Medicaid Services (CMS) penalized thousands of hospitals for having above average 30-day readmission rates in patients with pneumonia, heart attack or heart failure.
| Older patients with atrial fibrillation or AF also often have heart failure, the only other condition for which digoxin is approved. AF is the most common kind of cardiac arrhythmia, an electrical malfunction that throws off the heart’s rhythm and pumping rate. |
One in five Medicare recipients is readmitted within 30 days at an annual cost of $17 billion, with heart failure the most common culprit. Digoxin is known to reduce acute heart failure symptoms like shortness of breath, the kind of frightening experience that sends people racing to emergency rooms.
The current debate over the digoxin comes at the end of a long decline in its use since it failed to lower mortality in an original clinical trial. After that, its prescription rate dropped from two-thirds of patients in the 1990s to perhaps one-third today.
Research in recent years, however, has shown that digoxin at lower doses may block neurohormone systems, much like beta blockers or ACE inhibitors do. This may explain study results suggesting that low-dose digoxin not only reduces the risk of hospitalization, but may also reduce the risk of death in heart failure.
“Journal publications and related rounds of media coverage that raise concerns about a drug’s safety are often important in protecting the public’s health,” said Mihai Gheorghiade, M.D., professor of Medicine and Surgery at Northwestern University Feinberg School of Medicine, and the lead author of the new study. “However, in this case, there is no need to reassess the role of digoxin in the management of AF. Our finding that digoxin does not increase mortality should reassure the field and patients about the continued use of digoxin in AF."
In a final note, Ahmed said the scientific community has for years been urging sponsors of large clinical trials for more transparency and data sharing. The National Heart, Lung and Blood Institute (NHLBI) has been a leader in this regard, establishing the Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC), which made available the public-use copy of the AFFIRM data used in the analysis by Ahmed’s team.
About the research team
Along with Ahmed, UAB authors of the paper included Kanan Patel, MBBS, MPH, and Inmaculada Aban, Ph.D. Along with Gheorghiade, authors from other institutions were Gregg Fonarow, M.D., of the University of California, Los Angeles, John Cleland, M.D., of Hull York Medical School, Kingston-Upon-Hull in the United Kingdom, Dirk van Veldhuisen, M.D., Ph.D., of the University Medical Centre of Groningen in the Netherlands, Javed Butler, M.D., of Emory University, Andrew Epstein, M.D., of the University of Pennsylvania, Wilbert Aronow, M.D., of New York Medical College in Valhalla, N.Y., and Stefan Anker, M.D., Ph.D., of the Center for Clinical and Basic Research, IRCCS, San Raffaele, in Rome. Dr. Gheorghiade disclosed consulting relationships with industry, which are detailed in the journal article.
The original AFFIRM study was supported by the NHLBI. However, the current work was not supported by any grant funding and does not necessarily reflect the opinions or views of the AFFIRM study or the NHLBI. Dr. Ahmed was in part supported by grants from the NHLBI (R01-HL085561, R01-HL085561-S and R01-HL097047).