CardioExchange Archive

Digoxin is one of the oldest medicines in the cardiovascular arsenal. When William Withering identified it as the active ingredient in the foxglove plant more than 200 years ago, he was only codifying a longstanding folk remedy for heart failure, or “dropsy” as it was known then.

Digoxin fully entered the modern era with the publication of the DIG trial in 1997. The trial found that digoxin reduced hospitalization for heart failure but did not have an impact on mortality. On the basis of the trial, digoxin received recommendations in U.S. and European guidelines for use in patients with systolic heart failure who remain symptomatic despite optimal therapy. However, the epidemiology and treatment of heart failure have evolved considerably since then. Now, the authors of a new study, supported by an accompanying editorial, say that these recommendations need to be reconsidered.

In the study, published in Circulation: Cardiovascular Quality and Outcomes, James Freeman and colleagues followed 2891 patients with newly diagnosed systolic heart failure, 18% of whom received digoxin. After 2.5 years, the digoxin users had a higher rate of death and hospitalization for heart failure:

• Death: 14.2 versus 11.3 per 100 person-years
• HF hospitalization: 28.2 versus 24.4 per 100 person-years

After adjustment for other factors, the increase in mortality — but not the increase in hospitalization — remained significant:

• Digoxin hazard ratio for mortality: 1.72, CI 1.25–2.36
• Digoxin hazard ratio for hospitalization: 1.05, CI 0.82–1.34

The overall findings were consistent for both men and women and for beta-blocker users and nonusers.

The authors acknowledged that because they performed an observational study, they were unable to demonstrate a direct cause-and-effect relationship with digoxin. However, they pointed out that since the DIG trial, “substantial improvements in HF treatment have occurred,” including increased use of beta-blockers, ACE inhibitors, ARBs, and aldosterone antagonists, which “may substantially modify the independent effect of digoxin on death and HF hospitalization.”  They write that their “community-based systolic HF cohort is more likely to represent patients with systolic HF in the modern era with regard to pathogenesis and treatment patterns.” They recommend that the use of digoxin for systolic heart failure should be “re-evaluated.”

In an accompanying editorial, Lionel Opie writes that the new study “is of considerable importance” because the evidence base for the current use of digoxin is “highly unsatisfactory.” He agrees with the study authors that it is time to “seriously question” the U.S. and European guidelines that support the current use of digoxin.