Digoxin Swings Toward Benefit in HFrEF, But Lack of Clarity Remains

Patrice Wendling

July 30, 2019

The use of digoxin for hospitalized patients with heart failure with reduced ejection fraction (HFrEF) has garnered some support with the publication of a new study suggesting that discontinuation of treatment is associated with significantly worse outcomes.

The study, a propensity-matched analysis of the OPTIMIZE-HF registry, showed that patients on contemporary guideline-directed medical therapy (GDMT) taken off digoxin at discharge had risks 21% higher for hospital readmission from worsening heart failure, 16% higher for readmission from all causes, and 20% higher for the composite of HF readmission and all-cause death after 4 years of follow-up.

An association with mortality was significant at 30 days but disappeared after the first year. The associations with readmissions became significant at 6 months and lasted for 4 years, the authors report in the August 6 issue of the Journal of the American College of Cardiology.

"Findings from our study are consistent with those from the RADIANCE and PROVED trials, in which discontinuation of digoxin therapy increased the risk of adverse outcomes in ambulatory patients with chronic HFrEF not receiving GDMT. However, our study is the first to demonstrate that in hospitalized patients with HFrEF receiving GDMT," senior author Ali Ahmed, MD, Veterans Affairs Medical Center and George Washington University, both in Washington, DC, said.

National HF guidelines recommend the use of digoxin based on the PROVED, RADIANCE, and the 1990s Digitalis Investigation Group (DIG) randomized trial, which predated the use of more contemporary GDMTs, such as angiotensin-converting-enzyme (ACE) inhibitors, beta-blockers, and mineralocorticoid receptor antagonists (MRAs), in most patients with HF. It found significantly fewer hospitalizations with digoxin use but a neutral effect on mortality.

"If I had a heart failure patient with low ejection fraction, I would start an ACE inhibitor, a beta-blocker, and not start digoxin and let them be," Ahmed told theheart.org | Medscape Cardiology. "However, if I see that that patient continues to be symptomatic, as the guidelines say, and is being hospitalized, would I consider digoxin? Absolutely. There is solid evidence from the DIG trial that it reduces the risk of hospitalization both for heart failure and all-cause hospitalization."

Numerous studies, however, have reported conflicting results regarding mortality and digoxin in HF and atrial fibrillation, further contributing to both the enthusiasm and vilification that have characterized the use of digitalis for more than 250 years.

A new analysis of the DIG trial takes aim at the inability to control prescription bias in many observational digoxin studies reporting higher mortality risks, concluding the data are unlikely to yield any firm conclusions about the effects of cardiac glycosides. Ahmed counters the point in a newly published letter, noting that no mortality association is seen when looking at new use of digoxin, rather than prevalent use of the drug, as the exposure.

Propensity Matching

For the present study, the researchers took a different tack, linking the OPTIMIZE-HF registry with Medicare data for 3499 patients with HFrEF (ejection fraction ≤45%) who were receiving digoxin before admission. Of these, 721 patients had digoxin discontinued at discharge.

A matched cohort of 698 pairs of patients was assembled using propensity scores for digoxin discontinuation and balanced on 50 baseline characteristics, including previous HF hospitalizations. The team also assembled a sensitivity cohort, comprising 602 matched pairs of patients, that accounted for acute kidney injury, a common reason that digoxin may be discontinued in hospital.

At 30 days after discharge, digoxin discontinuation had no association with HF or all-cause readmissions but was associated with a higher risk for all-cause mortality (hazard ratio [HR], 1.80; 95% CI, 1.26 - 2.57).

At 6 and 12 months, discontinuation of digoxin was associated with higher risks of HF and all-cause readmission, all-cause mortality, and the composite of HF readmission or all-cause mortality.

Notably, fewer patients in the digoxin discontinuation group were receiving ACE inhibitors/angiotensin II receptor blockers, beta-blockers, and MRAs, which one would expect could contribute to poor outcomes and thus increase the risk for death, but this was not the case at 4 years.

"We felt that the association we were seeing was more due to digoxin than the confounding of ACE inhibitors and beta-blockers," Ahmed said.

Outcomes by Digoxin Discontinuation
End Point Hazard Ratio (95% CI) P Value
6 months
HF readmission 1.31 (1.08–1.57) .005
All-cause readmission 1.18 (1.03–1.36) .019
All-cause mortality 1.25 (1.02–1.52) .028
HF readmission or all-cause mortality 1.28 (1.10–1.48) .001
4 years
HF readmission 1.21 (1.05–1.39) .007
All-cause readmission 1.16 (1.04–1.31) .010
All-cause mortality 1.09 (0.97–1.24) .163
HF readmission or all-cause mortality 1.20 (1.07–1.34) .002

A Differential Effect

Overall, findings from the sensitivity cohort were similar to the main analysis. In subgroup analyses, digoxin withdrawal led to significantly worse outcomes in patients not on beta-blockers at discharge (composite end point HR, 1.38; 95% CI, 1.14 - 1.66) but showed no adverse effect on those on beta-blockers. Results of subgroup analyses need to be interpreted with caution because they may be false positive owing to multiple comparisons and false negative owing to inadequate power, the authors note.

Reached for comment, Clyde Yancy, MD, MSc, chief of cardiology at Northwestern University, Feinberg School of Medicine, Chicago, said via email: "The findings are provocative," but subject to "a number of limitations" well described by the authors.

Specifically, these are older observational data; despite propensity matching, residual and important confounders may be present; and background GDMT use may not have been uniform across the patients. But the observations are not to be dismissed, as previous randomized trials did demonstrate a higher event rate among patients withdrawn from digoxin, he said.

"The takeaway? Given the declination in use of digoxin, this concern is limited to those still exposed to digoxin," Yancy said. "If withdrawal is contemplated, optimizing contemporary evidence-based medical therapy and proceeding slowly would seem to be the best steps."

In an accompanying editorial, Barry Uretsky, MD, and Srikanth Vallurupalli, MD, Central Arkansas Veterans Health System, University of Arkansas for Medical Sciences, Little Rock, describe the beta-blocker finding as "intriguing" and note that a possible mechanism of worse outcomes after digoxin withdrawal is increased sympathetic activity — a notion supported by an increase in heart rate with drug cessation.

"The current study further supports this hypothesis insofar as outcomes were worsened in patients not on beta-blockers, that is, in patients with high uninhibited sympathetic tone, whereas digoxin withdrawal showed no worsening in the subgroup on beta-blockers," they write. "The current study thus raises the possibility that digoxin might be particularly useful in patients with HFrEF who cannot be treated with beta-blockers."

Commenting further, Uretsky and Vallurupalli suggest the study's "take-home message" will likely depend on whether a clinician is convinced of digoxin's efficacy in HFrEF. For believers, it will reinforce their conviction, whereas the message for those less convinced is that stopping digoxin "may cause clinical deterioration; it does not demonstrate that the drug is truly effective in the digoxin-naïve HFrEF patient."

They argue that digoxin withdrawal studies were necessary 30 years ago because digoxin use was "ubiquitous" in HFrEF, but that its declining use — from 33.7% in 2004 to 10.4% in 2014 — provides the opportunity now to prospectively evaluate its efficacy.

"The current study suggests that we may have prematurely abandoned this drug class before its role in the treatment of HFrEF in the modern era has been completely delineated," the editorialists say.

Considering the limited role of digoxin in contemporary patients with HFrEF on GDMT, it is unlikely that new randomized trials of digoxin withdrawal will be conducted to confirm the new findings, Ahmed said. However, the double-blind, randomized DIGIT-HF trial of another cardiac glycoside, digitoxin, which unlike digoxin is not eliminated by the kidneys, is expected to provide further evidence about the role of these drugs in HFrEF on top of standard of care treatment.

The study was sponsored by GlaxoSmithKline, which the authors report had no role in the design, conduct, analyses, or interpretation of the study. Ahmed was supported in part by grants from the National Institutes of Health. The editorialists report having no relevant disclosures.

J Am Coll Cardiol. 2019;74;617-627 and 628-630. Abstract, Editorial

Follow Patrice Wendling on Twitter: @pwendl. For more from theheart.org | Medscape Cardiology, join us on Twitter and Facebook.

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