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No evidence that Digoxin increases mortality in patients with atrial fibrillation

A study published in the European Heart Journal found no evidence that Digoxin increases mortality in patients with atrial fibrillation ( AF ), the opposite of results just published by another group in the same journal analyzing the same data.

Older patients with atrial fibrillation also often have heart failure, and Digoxin is approved to treat both conditions. Atrial fibrillation 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 the earlier study that found Digoxin increases mortality in atrial fibrillation and the study published now were re-analyses of data first collected as part of a clinical trial called Atrial Fibrillation Follow-up Investigation of Rhythm Management ( AFFIRM ) in 2002. The recent study that found Digoxin increases mortality used an approach called time-varying treatment, where patients who continued to receive Digoxin over 3.4 years as part of the follow-up to AFFIRM were compared to those who did not.

According to current study, this time-varying treatment technique produced misleading results. By analyzing data from sicker patients who required continued Digoxin treatment over the long term, it inadvertently introduced bias in its analysis of Digoxin-related mortality.

Digoxin is recommended by major national guidelines for use in heart failure and atrial fibrillation. It is an inexpensive drug that is generally well tolerated at low doses, and there is no reason to question its usefulness or reassess its safety. Although Digoxin has been used for over two centuries, it was approved by the FDA in the late 1999s under its strict guidelines for new drug approval based on its safety and efficacy data from multiple randomized clinical trials.

To test the safety of Digoxin, the Northwestern University’s researchers used AFFIRM patient data to assemble a group found to be similar based on 59 characteristics, including age, sex, race, other conditions beside atrial fibrillation ( including heart failure ) and other medications. Researchers then divided this pool of similar patients into two groups, one that had received Digoxin therapy and a second that had not.

The researchers found that during the 3.4 years of follow-up, 14% of patients receiving Digoxin and 13% 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, HR=1.06; P=0.640 ). Among matched patients, Digoxin was also not associated with all-cause hospitalization ( HR=0.96; P=0.510 ) or arrhythmias ( HR=0.90; P=0.827 ).

The researchers conducted the study out of concern that older patients might be deprived of Digoxin, which can be helpful in treating atrial fibrillation. They worried that the perception that Digoxin increases mortality in atrial fibrillation might gain traction and extend to the treatment of heart failure.

It has been recently demonstrated that Digoxin could reduce by 34% the chances that heart failure patients will be admitted to the hospital within 30 days of first taking it. Preventing frequent admissions is national priority, as the Centers for Medicare and Medicaid Services ( CMS ) penalized thousands of hospitals in 2012 for above average 30-day readmission rates in patients with pneumonia, heart attack or heart failure.

The current debate over the Digoxin comes at the end of a decline in use since it failed to lower mortality in an original clinical trial. Research in recent years, however, has shown that Digoxin is the only drug in its class ( positive inotropes ) that does not increase mortality at the traditional dose, and that it may block neurohormone systems like beta blockers or ACE inhibitors. 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. ( Xagena )

Source: Northwestern University, 2013