Digitalis Glycosides in Heart Failure With and Without Atrial Fibrillation

Background: Atrial fibrillation or flutter (AF/AFL) is the most common arrhythmia in patients with heart failure (HF). Patients with concomitant HF and AF/AFL represent a distinct clinical phenotype associated with worse prognosis. Recent randomized trials have renewed interest in the role of digitalis glycosides in HF. However, whether these benefits could be generalized to the AF subgroup remains uncertain. Research Question: Among patients with HF, do patients with baseline AF/AFL derive more clinical benefits from digitalis glycosides when compared with those without? Methods: PubMed, Embase, Cochrane Library, and ClinicalTrials.gov were searched from inception to May 30, 2026, for randomized controlled trials of digitalis glycosides versus placebo in HF. The primary outcome was death or worsening HF. Random-effects meta-analysis used restricted maximum likelihood. Number needed to treat was derived from pooled relative risks when effects were significant. To explore whether baseline AF/AFL modifies the treatment effect of digitalis glycosides, we conducted a prespecified subgroup analysis stratified by baseline AF/AFL status. We also conducted a meta-regression investigating the interaction between baseline AF/AFL status and the treatment effect of digitalis glycosides vs placebo. Meta-regression was conducted utilizing a mixed-effects model employing REML as the heterogeneity estimator and the Hartung-Knapp-Sidik-Jonkman method to adjust the standard errors of estimated coefficients. Results: Five double-blind RCTs including 11,770 participants were included (digitalis, 5,887; placebo, 5,883). DIG, DIGIT-HF, and DECISION exclusively enrolled participants with HF with reduced or mid-range ejection fraction (EF); whereas DIG-Ancillary enrolled patients with preserved EF. Additionally, DIG and DIG-Ancillary enrolled HF patients in sinus rhythm before contemporary GDMT era, DIGIT-HF and DECISION enrolled contemporary HF populations, and Dig-RHD enrolled a younger population with symptomatic rheumatic heart disease, with HF or AF/AFL.Overall, digitalis glycosides reduced death or worsening HF compared with placebo (RR, 0.91; 95% CI, 0.87-0.94; I 2 =0%; NNT, 21 [95% CI, 15-30]) (Figure 2A). Benefit was greater in patients with baseline AF/AFL (RR, 0.80; 95% CI, 0.71-0.90; I 2 =0%; NNT, 13 [95% CI, 9-26]) than in those without AF/AFL (RR, 0.91; 95% CI, 0.87-0.94; I 2 =0%; NNT, 23 [95% CI, 16-34]), with evidence of subgroup interaction ( P-interaction =0.04) (Figure 2B). Conclusion: In this meta-analysis, digitalis glycoside use was associated with a lower risk of death or worsening HF, with a more pronounced benefit observed among patients with baseline AF/AFL. Further analyses using individual participant-level data are warranted to determine whether AF/AFL truly modifies the treatment effect of digitalis glycosides in HF.