CardioExchange Archive

CardioExchange editor John Ryan interviewed James Freeman about his research group’s evaluation of the contemporary effectiveness and safety of digoxin therapy among a large, diverse, community-based cohort of adults with newly diagnosed systolic heart failure (HF). The study found that digoxin use in patients with incident systolic HF was independently associated with a higher risk of death, but revealed no difference in HF hospitalization. The paper appears in Circulation: Cardiovascular Quality and Outcomes.

Ryan: AHA HF guidelines for 2013 state as a Class IIa indication that “Digoxin can be beneficial in patients with HFrEF, unless contraindicated, to decrease hospitalizations for HF (484-491). (Level of Evidence: B).” Do you agree with this and are your data sufficient to change this recommendation?

Freeman: The current guideline recommendations for the use of digoxin in patients with HFrEF are largely based on the findings of the DIG randomized trial, which showed that digoxin had no effect on the risk of death but a lower risk of hospitalization for HF. However, the DIG trial enrolled patients between 1991 and 1993 before several significant advances in HF therapy and a significant shift in the epidemiology of systolic HF towards more ischemic cardiomyopathy, which may significantly influence the effects of digoxin.

Our cohort differed in a number of very important ways from that older, very sub-selected trial population and more likely represents the current patient characteristics and concurrent HF treatment of contemporary patients treated with digoxin for HFrEF. Our findings that incident digoxin use was associated with a higher risk of death were consistent with a secondary analysis of the Valsartan Heart Failure Trial (Val-HeFT) and other recent observational studies. Taken together, we believe these recent studies suggest that the use of digoxin should be re-evaluated for the treatment of systolic HF in the modern era and that this should be reflected in the guidelines.

Ryan: It has been more than 10 years since digoxin therapy has been shown to be associated with an increased risk of death among women. With these data readily available, and lack of demonstrated benefit with digoxin, why do you think it is still prescribed so frequently? 

Freeman: A post-hoc analysis of the DIG trial by Rathore and associates showed that digoxin was associated with a significantly higher risk of death among women (HR 1.23; CI, 1.02 to 1.47), but not men (HR 0.93; CI 0.85 to 1.02; P=0.014 for the interaction). The authors suggested that their results may be due to gender-associated differences in the pharmacokinetics of digoxin, which would suggest that lower dosing may be required for women to maintain an optimal SDC.

These data certainly raised concern regarding digoxin use over a decade ago, however, differential pharmacokinetics for digoxin by patient gender has not been well demonstrated in subsequent years, and because the data were from a secondary analysis of a trial population, the scientific and clinical communities may have been seeking multiple studies confirming this finding. Our results showed that the increased risk of mortality associated with digoxin use did not vary in men and women. We are hopeful that our work, combined with other recent studies, will serve as a sufficient body of evidence to change clinical practice.

Ryan: Who would you give digoxin to now? 

Freeman: Our study suggests that digoxin use may not be safe for the treatment of patients with HF and that we critically need more data to determine whether digoxin use is safe in other clinical contexts, such as atrial fibrillation.