Treatment with digitalis glycosides was associated with a lower risk of worsening heart failure events among patients with heart failure with reduced ejection fraction or heart failure with mildly reduced ejection fraction, according to a meta-analysis published in JAMA. Researchers found no reduction in cardiovascular or all-cause mortality.
Researchers pooled data from 3 placebo-controlled randomized clinical trials — DIG, DIGIT-HF, and DECISION — involving 9,013 patients who received digoxin or digitoxin in addition to background heart failure therapy. The weighted mean age was 64.5 years, and 22% of patients were women.
The primary endpoint was time to cardiovascular death or first worsening heart failure event. Because the included trials used different original primary endpoints, the pooled primary outcome represented a harmonized contemporary endpoint rather than one that was prespecified consistently across all studies.
The primary composite outcome occurred in 41% of patients receiving digitalis glycosides compared with 45% of patients receiving placebo, corresponding to a hazard ratio (HR) of 0.85. Researchers reported that the reduction was driven primarily by worsening heart failure events rather than mortality.
First worsening heart failure events occurred in 26% of patients treated with digitalis glycosides vs 33% of patients receiving placebo, corresponding to an HR of 0.75. Cardiovascular death occurred in 27% of patients in both groups, corresponding to an HR of 0.99, while all-cause mortality occurred in 32% of patients receiving digitalis glycosides vs 33% of patients receiving placebo, corresponding to an HR of 0.97.
The findings were directionally consistent across treatment eras and types of digitalis glycosides, although the researchers noted that the analysis had limited power to detect heterogeneity because only 3 studies were included.
The DIG trial, published in 1997, contributed most of the patients and statistical weight in the meta-analysis. Unlike the more contemporary DIGIT-HF and DECISION trials, DIG excluded patients with atrial fibrillation and was conducted before beta-blockers, mineralocorticoid receptor antagonists, angiotensin receptor-neprilysin inhibitors, and sodium-glucose cotransporter-2 inhibitors became standard background therapy.
Despite those differences, researchers reported similar relative reductions in the primary composite outcome in the contemporary trials, which enrolled patients receiving more guideline-directed therapy and included patients with atrial fibrillation.
The DECISION trial also differed from the earlier studies by requiring N-terminal pro–brain natriuretic peptide threshold criteria for enrollment, stratified by rhythm status and recent hospitalization history.
The researchers noted that prior post hoc analyses from DIG suggested the greatest benefit occurred among patients with serum digoxin concentrations below 1.2 ng/mL. Both DIGIT-HF and DECISION evaluated low-dose digitalis regimens.
The authors also argued that, by contemporary heart failure trial standards that accept reductions in worsening heart failure events as clinically meaningful outcomes, digitalis glycosides might have been considered a foundational therapy if DIG had been evaluated using modern endpoint frameworks rather than mortality reduction alone.
Researchers compared the approximately 15% relative reduction in the primary composite endpoint with effects seen in other heart failure therapies, noting that the magnitude appeared smaller than that reported with sodium-glucose cotransporter-2 inhibitors, similar to ivabradine, and larger than pooled findings reported with vericiguat.
Safety findings were generally similar between treatment groups. Serious adverse events and cardiovascular hospitalizations did not differ substantially across studies. In DIG, supraventricular arrhythmias occurred more often among patients receiving digoxin, although this pattern was not observed in the contemporary trials.
Researchers noted several limitations. The meta-analysis included only 3 studies, and DIG contributed most of the statistical weight. The analysis also relied on study-level rather than patient-level data, limiting subgroup assessment. In addition, the included trials differed in design and definitions of worsening heart failure events, and the pooled primary outcome was a post hoc harmonized endpoint rather than a uniformly prespecified one.
“Treatment with digitalis glycosides was associated with a lower risk of the composite of cardiovascular death or first worsening HF event in patients with HFmrEF or HFrEF, mainly through a lower risk of worsening HF events,” wrote lead study author Kevin Damman, MD, of University Medical Center Groningen in the Netherlands, and colleagues.
Disclosures: Several researchers reported research support, consulting fees, speaking fees, grants, advisory relationships, or travel support from pharmaceutical and medical device companies. The meta-analysis itself was supported by academic and research organizations, including the Dutch Heart Foundation and European Research Council, without reported pharmaceutical industry funding.
Source: JAMA
