Friend or Foe? Digoxin for Systolic HF Ups Mortality in Cohort Study

September 19, 2013

OAKLAND, CA — Introduction of digoxin therapy in patients with new systolic heart failure was associated with a significant 72% jump in all-cause mortality but no effect on HF-hospitalization risk in a community-based cohort study, in both women and men and regardless of whether patients were also taking beta-blockers [1].

This analysis and other recent studies provide "no good evidence that digoxin improves outcomes" and suggest that "it's associated, at least theoretically, with different types of harm," according to Dr Alan S Go (Kaiser Permanente Northern California, Oakland). The use of digoxin should be reevaluated, he told heartwire , to determine "whether or not it is really helping patients with heart failure."

The current study adds to a database that had been fraught with uncertainty about the role digoxin might play in heart failure and at what dosages in patients on contemporary medications. After ups and downs in acceptance as an HF treatment, digoxin currently occupies places in both US and European guidelines as no more than a second-line agent for systolic HF.

Those indications are based on interpretations as well as post hoc analyses of the Digitalis Investigation Group (DIG) randomized trial, which dates from the early 1990s when ACE inhibitors were the latest thing and beta-blockers still aroused suspicion in HF. In that trial, digoxin didn't cut mortality but did lower the risk of hospitalization for worsening heart failure.

The DIG trial was important in its day as the largest randomized trial of digoxin, according to Go. "But it was in the context of what we'd say today was suboptimal therapy. The concern is that in more optimally managed patients, digoxin may be associated with worse outcomes."

The current study, he said, controlled for a wide range of possible confounders in a contemporary population. "It is real practice--this is what's happening in a large community-based population." The report was published online September 10, 2013 in Circulation: Cardiovascular Quality and Outcomes with first author Dr James V Freeman (Stanford University School of Medicine, CA).

The analysis suggests "therapy for HF that includes beta-blockade and full angiotensin-II modulation dispenses with the need for taking the risks of adding digoxin therapy," according to an accompanying editorial from Dr Lionel H Opie (University of Cape Town Medical School, South Africa)[2]. "The data at our disposal, taking into account the current study, allow us to seriously question the advice on digoxin given by both the current and influential guidelines, European and American."

Freeman et al looked at 2891 digoxin-naive adults with recently diagnosed systolic heart failure from 2006 to 2008, 18% of whom were started on digoxin; they were followed for a median of 2.5 years.

Hazard ratio* (95% CI) for Outcomes, Digoxin (n=529) vs No Digoxin (n=2362) for Recent-Onset Systolic Heart Failure

Population All-cause mortality HF hospitalization
Overall cohort 1.72 (1.25–2.36) 1.05 (0.82–1.34)
Concurrently on beta-blockers 1.55 (1.11–2.18) 1.08 (0.83–1.42)
Not concurrently on beta-blockers 2.49 (1.20–5.17) 0.88 (0.46–1.69)

*Median follow-up, 2.5 years. Adjusted for LVEF, sex, race, ethnicity, body-mass index, ischemic or arrhythmic heart disease, implanted cardiac device use, history of PCI or CABG, renal function, other cardiovascular medication use, serum electrolytes, outpatient visits per year before cohort entry, and propensity score for digoxin initiation

The causes of death in the study aren't known, but there are clues. "We do know that digoxin theoretically at least can increase the risk of certain types of arrhythmias," Go said. Sudden cardiac death as a cause would be consistent with the increased all-cause mortality without an effect on HF hospitalization. And patients who received digoxin showed a preponderance of atrial fibrillation or flutter at baseline (p<0.001) that could well have driven the drug's use. "If a patient has both systolic heart failure and atrial fibrillation, providers [might] be more likely to prescribe [digoxin], to try to treat both."

But that's probably not an effective strategy, anyway. Go pointed to evidence, notably from his group and the AFFIRM trial, that digoxin isn't good at rate control in treating AF, is less effective than alternatives like beta-blockers or calcium-channel blockers, and may worsen clinical outcomes in AF much as it does in heart failure.

The study was supported by grants through the American Heart Association/Pharmaceutical Roundtable-Spina Outcomes Research Center program. The authors had no disclosures. Opie reports that his report was supported by the University of Cape Town; he had no other disclosures.


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