Conference Coverage

Can digoxin get another chance for heart failure?


One of the late-breaker reports at the American College of Cardiology’s annual meeting in March had results from a post hoc analysis of 16-year-old data from the DIG trial, by far the largest study to ever assess digoxin for heart failure, a treatment that precipitously dropped out of favor during the decade following the initial DIG report in 1997. Not your typical back story for a late breaker.

The researchers who ran the new analysis of the old DIG data also took what seem like two sizable leaps by framing their new look as a way to get a sense whether digoxin treatment could cut the large number of Medicare patients with heart failure who need rehospitalization within a month after a hospital discharge.

Courtesy of Wikimedia Commons

Digitalis lanata is the source of digoxin, a heart failure drug that was revisited in the American College of Cardiology’s annual meeting.

Dr. Ali Ahmed, a cardiologist from the University of Alabama, Birmingham, who presented this ACC late breaker, noted how clinicians and hospital officials are eager to find safe and effective treatments for cutting heart failure readmissions, especially since last Oct. 1 when the Centers for Medicare and Medicaid Services began penalizing hospitals that accumulate high heart failure readmission numbers.

One leap was that the patients in the 1990s enrolled in the Digitalis Investigation Group (DIG) trial all had chronic, stable heart failure, without recent hospitalization. Although the post hoc analysis that Dr. Ahmed presented showed that the half of the DIG patients who were aged 65 or older had their heart failure hospitalization rate cut by a third while on digoxin, compared with patients on placebo, a statistically significant difference for the analysis’ primary endpoint, Dr. Ahmed admitted in his talk that the relevance of his findings to the new Medicare penalties was doubly limited. First, because the DIG population comprised ambulatory patients rather than ones just out of the hospital, and second because the endpoint examined in DIG was index hospital admission rather than readmission. Two pretty important differences.

On top of that, many heart failure experts who heard the results were quick to question the meaning in 2013 of data collected from heart failure patients back in the mid-1990s whose background regimens completely lacked beta-blockers, aldosterone receptor antagonists (spironolactone and eplerenone), and implanted cardiac devices, treatments that have since become cornerstones of heart failure management.

Digoxin "is not a therapy we should embrace wholeheartedly until there is a new trial with contemporary management," commented Dr. Mariell L. Jessup, a heart failure specialist at the University of Pennsylvania, Philadelphia, who cochaired the late-breaker session in which Dr. Ahmed spoke.

But if it was so questionable to use 16-year old, clearly outdated data to address in a post hoc way an issue – 30-day hospital readmissions for heart failure – with at best tangential relevance to what was examined in the DIG trial, what else might be behind this curious report from a large group of prominent heart-failure specialists? (You can see all their names in the article published online simultaneous to Dr. Ahmed’s ACC report [Am. J. Med. 2013;126 (doi:10.1016/j.amjmed.2013.02.001)]).

The answer seems to be their desire to promote digoxin, keep it current in cardiology chatter, and build pressure for a new, prospective study that reexamines the incremental benefit of digoxin on top everything else that heart failure patients receive today. They see current heart failure management, especially efforts to cut hospitalizations for acute decompensation and also cut the rate at which decompensated patients wind up back in the hospital a second time, as woefully inadequate and stand discouraged after many new agents have failed to make a dent in this problem.

"Dismissing digoxin, which was approved by the FDA only 10 years ago and has been used for 2,000 years, in the face of a high event rate [among heart failure patients] when we cannot find any new drugs, is not a wise clinical decision," said Dr. Mihai Gheorghiade, a cardiologist with Northwestern University, Evanston, Ill., who coauthored the new analysis and is a leader of the movement to resurrect digoxin. Using digoxin "isn’t controversial if you see benefit from it and if we are desperate to find something for these patients," he said during a press conference at the meeting.

Efforts to rehabilitate and reevaluate digoxin in heart failure have been going on since the mid-2000s. Dr. Ahmed, Dr. Gheorghiade, and their associates published their first reanalysis of the DIG data in 2005 (Eur. Heart J. 2006;27:178-86), which was recognized by an editorialist at the time as a call to "rehabilitate" digoxin (Eur. Heart J. 2006;27:127-9). In 2006, Dr. Gheorghiade lamented digoxin’s neglect and fall from standard heart failure management, having been muscled out by treatments with big-pocket backers – beta-blockers, ACE inhibitors, and cardiac resynchronization devices; concerns over digoxin’s safety (which he says is obviated by using low dosages), and most of all the absence of any company with enough of a financial interest in digoxin to promote it and fund more studies (Circulation 2006;113:2556-64).


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