Digoxin Reduces Heart Failure Worsening in Rheumatic Heart Disease

Key Takeaways

• Digoxin was associated with fewer primary composite events than placebo in the randomized comparison.
• The between-group difference appeared to reflect fewer new or worsening heart failure events, while all-cause death was similar.
• Suspected toxicity was uncommon, but the authors cautioned against broad generalization beyond this relatively young Indian trial population.

In a recent JAMA trial, digoxin added to usual care was associated with a lower risk of the primary composite outcome than placebo in symptomatic rheumatic heart disease. The randomized comparison included 1759 analyzed adults, with a median follow-up of 2.1 years and outcome assessment through 36 months. The hazard ratio for all-cause death or new-onset or worsening heart failure was 0.82. The difference centered on the composite outcome rather than mortality alone.

The Dig-RHD study was an investigator-initiated, multicenter, randomized, double-blind, placebo-controlled, parallel-group superiority trial at 12 tertiary care hospitals in India. Eligible participants were adults aged 18 years or older with echocardiography-confirmed rheumatic heart disease who were already taking digoxin or had heart failure, atrial fibrillation, or atrial flutter. Patients were assigned 1:1 to oral digoxin 0.125 to 0.25 mg once daily or matching placebo on a background of usual care. Of 1769 enrolled patients, 1759 entered the primary analysis; mean age was about 46 years, about 72% were female, about 70% had atrial fibrillation or flutter, and about 90% were in NYHA class II to IV. Most had mixed valvular disease, many had moderate to severe mitral stenosis, and the primary endpoint was all-cause death or new-onset or worsening heart failure within 36 months or until study end.

The primary composite occurred in 276 of 880 patients receiving digoxin and 312 of 879 receiving placebo, or 31.4% versus 35.5%. That corresponded to a hazard ratio of 0.82, with a 95% confidence interval of 0.70 to 0.97 and P=.02. New-onset or worsening heart failure occurred in 227 of 880 patients, or 25.8%, with digoxin and 257 of 879, or 29.2%, with placebo, for a hazard ratio of 0.82 and a 95% confidence interval of 0.69 to 0.98. All-cause death was 88 of 880, or 10.0%, with digoxin and 91 of 879, or 10.4%, with placebo, for a hazard ratio of 0.94, a 95% confidence interval of 0.70 to 1.26, and P=.69. A secondary composite of heart failure-related death or new-onset or worsening heart failure was 28.3% with digoxin and 32.3% with placebo, with a hazard ratio of 0.82. Most worsening heart failure episodes were treated with augmentation of oral or intravenous diuretics without hospitalization. The pattern points to fewer worsening heart failure events rather than a mortality difference.

Suspected digoxin toxicity was uncommon. Overall, 24 patients had suspected toxicity; study medication was permanently discontinued in 10 patients in the digoxin group and 1 in the placebo group because of suspected toxicity. Serum digoxin levels were not measured in patients with suspected toxicity. Temporary discontinuation occurred in 189 patients and permanent discontinuation occurred in 197, most often after valve surgery or return to sinus rhythm. Prespecified subgroup analyses suggested larger apparent effects among patients already taking digoxin at baseline and among those with baseline atrial fibrillation or atrial flutter, but these remained subgroup signals. The authors also noted the relatively young population, excellent kidney function, absence of screening logs, and lack of multiple-testing adjustment. They interpreted the findings as showing less heart failure worsening in this study population, with little reported toxicity.