Digoxin for HF Ups Rehospitalizations in Cohort, Survival Not Affected

September 19, 2016

ORLANDO, FL — After more than 200 years, medicine is still figuring out how to use digoxin in patients with heart failure. A new retrospective analysis adds to the debate over whether the drug, also used in atrial fibrillation, offers clinical benefit in systolic heart failure enough to compensate for its well-recognized risk of toxicity[1].

In more than 1000 patients with heart failure and reduced ejection fraction (HFrEF) admitted for acute decompensation at a major medical center from 2004 through 2015, about one-third were on digoxin. Its use was associated with about a 50% increase in rehospitalization within 30 days (P=0.02) and a 70% jump at 180 days (P=0.003), compared with digoxin nonuse.

In short, digoxin didn't seem to seem to help the patients clinically and may have harmed by raising the risk of readmission, primarily from cardiac causes and mostly likely from recurrent HF, Dr Hassan Alkhawam (Icahn School of Medicine at Mount Sinai, New York, NY) told heartwire from Medscape.

Alkhawam, lead author on the study presented here at the Heart Failure Society of America 2016 Scientific Meeting, said that the analysis adjusted for a range of conditions, including chronic kidney disease, diabetes, hypertension, dyslipidemia, atrial fibrillation, heart-failure medications, and history of trauma or surgery.

There were no differences in hospital length of stay or 30-day or 180-day mortality by digoxin use, although other analyses have seen increased mortality with digoxin in HFrEF. The increased rehospitalizations in the current analysis contrasts with the Digitalis Investigation Group (DIG) randomized trial, which saw rehospitalizations for worsening heart failure decrease for patients who received digoxin. But the DIG trial from the 1990s predated the use ACE inhibitors and beta-blockers in most patients with heart failure.

One limitation of the current analysis, in fact of many analyses of outcomes associated with digoxin for heart failure, is a lack of information about patients' digoxin serum levels, according to Dr Paul J Hauptman (Saint Louis University School of Medicine, St Louis, MO). Typically, he said to heartwire , "there's not even a snapshot of the dig level."

The therapeutic range for digoxin level is well recognized to be fairly narrow and should be below 0.9 ng/mL for safety, said Hauptman, who wasn't involved in the current analysis. He's "pretty convinced," he said, that a lot of patients who show adverse effects from digoxin in the literature have digoxin levels that are too high.

If analyses of digoxin in heart failure were to control for serum levels, he said, "you might actually get your answer, finally, about digoxin."

In the current analysis, the adjusted odds ratio (OR) for 30-day readmission in digitalis-treated patients compared with those who didn't get the drug was 1.5 (95% CI 1.1–2.2). For patients aged 65 or greater, the corresponding OR was 2.02 (95% CI 1.3–3.0).

The adjusted OR for 180-day readmission, digitalis vs no digitalis, was 1.7 (95% CI 1.2–2.0).

Outcomes at 30 Days and 180 Days by Digitalis vs No Digitalis in Heart Failure With Reduced Ejection Fraction

End points Digitalis, n=356 (%) No digitalis, n=683 (%) P
Outcomes at 30 d
Readmission 30 16 0.02
Mortality 2.5 3.0 0.7
Outcomes at 180 d
Readmission 45 32 0.003
Mortality 6.5 5.7 0.6

Hauptman and coauthors recently reported that 93% of 60 laboratories at top-rated US hospitals that responded to their questionnaire considered serum concentrations exceeding 2.0 ng/mL or higher as being in the "normal" range[2]. That, despite DIG data suggesting no benefit from levels higher than 0.9 ng/mL and possible harm at levels higher than 1.2 ng/mL, according to the group.

"We find that the 0.5 to 0.8 [ng/mL] is the sweet zone, 0.9 to 1.1 [ng/mL] is neutral, and at greater than 1.1 [ng/mL] there is increased mortality," Hauptman said to heartwire , emphasizing that he is referring to digoxin use in heart failure, not necessarily atrial fibrillation.

According to his chart review, Alkhawam said when interviewed, until 2010 "the majority of patients" with systolic heart failure at his center were on digoxin, but the number fell off sharply in later years.

Alkhawam has no relevant financial relationships. Hauptman discloses being a consultant or on an advisory board for Sensible Medical.

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