Approximately half of all patients with heart failure (HF) have normal left ventricular ejection fraction (LVEF)-'diastolic HF'. Traditionally, these patients have been excluded from clinical drug trials and, therefore, evidence-based treatment recommendations are lacking. The digitalis glycoside, digoxin, has been previously studied in patients with systolic HF, but this paper by Ahmed et al. represents the first analysis of digoxin therapy in patients with diastolic HF.OBJECTIVE
To evaluate the efficacy of digoxin in patients with diastolic HF.DESIGN
This was an ancillary study conducted as part of the randomized, placebo-controlled Digitalis Investigation Group (DIG) trial of digoxin in patients with chronic HF. The results of the main DIG trial, which enrolled patients with systolic HF, have already been reported. Between January 1991 and August 1993, the ancillary study enrolled ambulatory patients with HF, LVEF greater than 45%, and normal sinus rhythm at baseline. Patients were recruited from 186 centers in the US and 116 centers in Canada.INTERVENTION
Patients were randomized to receive daily doses of digoxin or placebo in doses of 0.125 mg, 0.25 mg, 0.375 mg, or 0.50 mg depending on age, sex, weight, and serum creatinine level.OUTCOME MEASURES
The primary composite outcome measure was hospitalization and mortality caused by HF. Secondary endpoints, which were not prespecified in the trial design, were all-cause and cardiovascular-related hospitalization and mortality.RESULTS
The ancillary trial enrolled 988 patients, 59% of whom were male. The median age was 67 years. Concomitant medication use included angiotensin-converting-enzyme inhibitors (>85% of patients) and diuretics (>80% of patients). There were 492 patients randomized to digoxin and 496 to placebo. Baseline characteristics did not differ significantly between the two groups. During the first 2 years of the trial, patients receiving digoxin had a significantly lower incidence of HF hospitalization and mortality than patients on placebo (14% versus 18%, respectively; P = 0.034). After a mean follow-up of 37 months, however, there were no significant differences between the two groups in the number of patients who experienced the primary outcome (21% versus 24%, respectively; P = 0.136). Digoxin was not associated with a difference in cardiovascular-related or all-cause mortality or hospitalizations when compared with placebo. Notably, there was a trend towards increased hospitalization for unstable angina in patients receiving digoxin compared with those in the placebo group (17% versus 13%, respectively; P = 0.061). Suspected or confirmed toxicity was experienced by 66 (7%) of patients receiving digoxin, but this led to hospitalization in only one patient.CONCLUSION
Digoxin has no significant effect on HF, cardiovascular-related or all-cause hospitalization or mortality in patients with diastolic HF and normal sinus rhythm.