Heart failure management has changed dramatically over the past three decades, yet digoxin — one of medicine's oldest cardiac drugs — has never been fully retired from clinical use. Whether a modern, carefully dosed strategy could rehabilitate it remained an open question, particularly as older trials used higher, potentially toxic serum concentrations. The DECISION trial offers the most rigorous answer to date, and it is sobering.
In this double-blind, placebo-controlled trial published in Nature Medicine, 1,001 patients with symptomatic chronic heart failure and left ventricular ejection fraction ≤50% were randomized to low-dose digoxin (targeting serum concentrations of 0.5–0.9 ng/mL) or placebo, with a median follow-up of 36.5 months. The composite primary endpoint — total worsening heart failure hospitalizations, urgent visits, and cardiovascular mortality — showed a rate ratio of 0.81 favoring digoxin, but the 95% confidence interval (0.61–1.07) crossed unity and the p-value was 0.133, falling short of statistical significance. Worsening heart failure events alone trended in digoxin's favor (rate ratio 0.76), and cardiovascular mortality was nearly identical between arms (17% vs. 18%).
This result lands in a historically contested landscape. The landmark DIG trial (1997) enrolled over 6,800 patients and found digoxin reduced heart failure hospitalizations without improving mortality — a neutral-to-modest profile that largely shaped its declining use. The DECISION trial's narrower cohort, modern background therapy, and lower target concentrations represent a methodologically cleaner test, yet the directional signal without statistical significance leaves the clinical picture unresolved rather than clarified. A rate ratio of 0.81 in a 1,001-patient trial may simply reflect insufficient statistical power to detect a modest but real benefit — or it may confirm genuine inefficacy. The trial's inclusion of mildly reduced ejection fraction (HFmrEF, 40–50%) patients adds contemporary relevance but also heterogeneity. Practically, the safety finding — that low-dose digoxin was well tolerated — removes one historical barrier to its use, but clinicians will reasonably await either a larger confirmatory trial or pre-specified subgroup analyses before reconsidering digoxin's role. This is a high-quality, incremental trial that narrows uncertainty without eliminating it.