Cardiac Glycosides in HFrEF: A Systematic Review and Meta-Analysis

Authors, Journal, Affiliations, Type, DOI

• Dayang Wang, Xiaoqing Xu, Jingyao Lu, Jiayi Gao, Yingyu Li, Guozhong Pan, Wenhua Peng
• Frontiers in Cardiovascular Medicine (2026; 13:1746467)
• Dongzhimen Hospital, Beijing University of Chinese Medicine; Beijing Hepingli Hospital
• Type: Systematic review and meta-analysis (PRISMA 2020); pre-registered PROSPERO CRD420251142262
• DOI: https://doi.org/10.3389/fcvm.2026.1746467

Overview

This 2026 systematic review and meta-analysis pooled 6 RCTs (n=8,488 patients) evaluating cardiac glycosides (predominantly digoxin; one digitoxin trial) versus placebo on top of GDMT in HFrEF. The primary finding is that cardiac glycosides reduce HF hospitalization (HR=0.79) but do not reduce all-cause mortality (HR=0.98). An exploratory network meta-analysis found no significant advantage of digitoxin over digoxin for either mortality or hospitalization. The DIGIT-HF trial (2025) — the sole RCT conducted within contemporary GDMT — dominates the modern evidence base but was underpowered to detect individual component benefits.

Keywords

Cardiac glycosides, digitoxin, digoxin, heart failure and reduced ejection fraction, meta-analysis, prognosis

Key Takeaways

Introduction

• Cardiac glycosides enhance myocardial contractility by inhibiting Na⁺/K⁺-ATPase → increases intracellular calcium in cardiomyocytes and sarcoplasmic reticulum; also reduces heart rate via indirect sympathetic tone suppression
• The DIG trial (1997) established no mortality benefit with digoxin; current guidelines classify glycosides as symptom-modifying, not prognosis-modifying
• Digitoxin has distinct pharmacokinetics from digoxin: lipophilic → higher intestinal absorption, stronger serum protein binding, predominantly hepatic clearance (not renal) → more stable plasma concentrations especially in renal impairment
• The DIGIT-HF trial (2025) showed digitoxin reduced the composite of all-cause mortality and HF rehospitalization in HFrEF on contemporary GDMT, challenging the conventional position

Methods

• Databases: PubMed, EMBASE, Cochrane Library, Web of Science; up to September 12, 2025
• Inclusion: RCTs only; HFrEF population; cardiac glycoside + GDMT vs placebo + GDMT; all-cause mortality or HF rehospitalization reported
• Quality: RoB-2 tool; all 6 trials classified as "low risk of bias"
• Statistical: random-effects model; pooled HR; I² heterogeneity; network meta-analysis (mvmeta/network packages in STATA 17) for indirect digoxin vs digitoxin comparison
• Publication bias: funnel plots + Egger's test (p=0.204 — no significant bias)

Results

Study characteristics

• 6 RCTs included from 1,181 identified studies (after removing duplicates and applying eligibility criteria)
• Total 8,488 patients; follow-up ranged 6 months to 4 years
• 5 trials evaluated digoxin; 1 trial (DIGIT-HF) evaluated digitoxin
• Key trials:
  • DIG trial (1997): n=6,800; digoxin; 37-month follow-up; United States/Canada
  • DIGIT-HF (2025): n=1,212; digitoxin; 48-month follow-up; Austria/Germany/Serbia; ARNi 39.5%, SGLT2i 19.3%
  • Smaller trials: Captopril-Dig Group 1988 (n=196), DIBianco 1989 (n=111), Blackwood 1990 (n=61), DIMT 1993 (n=108)
• Mean age 56.8–65.9 years; LVEF <30–45% across studies

Primary outcome: All-cause mortality

• HR = 0.98 (95% CI 0.92–1.04) — no significant difference vs placebo
• Result robust on leave-one-out sensitivity analysis across all 6 trials

Secondary outcome: HF hospitalization

• HR = 0.79 (95% CI 0.67–0.94) — significant reduction vs placebo
• Sensitivity analysis: result sensitive to exclusion of DIG trial (HR shifts to 0.71 [0.44–1.15] when DIG removed, crossing the null)

Indirect comparison: digitoxin vs digoxin

• All-cause mortality: HR = 0.93 (95% CI 0.77–1.13) — NS
• HF hospitalization: HR = 1.35 (95% CI 0.70–2.60) — NS
• Indirect comparison methodology limited by 30-year GDMT evolution gap between DIG (1997) and DIGIT-HF (2025)

Discussion

• Pooled results consistent with DIG trial conclusions: glycosides reduce HF hospitalization but not mortality
• DIGIT-HF contributed unique context: only trial in contemporary GDMT with therapeutic drug monitoring (TDM) — TDM may explain more pronounced benefits in that trial versus older studies
• Digitoxin's pharmacokinetic advantages (hepatic clearance, higher bioavailability) did not translate to clinical superiority in indirect comparison; limited by single digitoxin trial with only 613 patients
• GDMT evolution (ARNi, SGLT2i, vericiguat, ICD/CRT device therapy) between 1997 and 2025 lowered annual HF mortality from 33.4 to 23.8 per 100,000 (Swedish National Patient Register), potentially attenuating absolute benefit of glycosides
• Ongoing DECISION trial (low-dose digoxin in HFrEF, contemporary GDMT) will provide additional evidence for direct digoxin comparison
• Current 2022 AHA/ACC/HFSA guidelines: digoxin COR IIb in symptomatic HFrEF despite GDMT (or GDMT intolerance) — to decrease HF hospitalizations
• Vamos 2015 meta-analysis suggested increased mortality with digoxin, but that study included observational data; RCT-only analyses (Ziff 2015; this study) show no mortality signal

Limitations of the document

• Study-level (not patient-level) meta-analysis; unable to perform subgroup analyses for specific HFrEF populations
• All five digoxin trials are dated (1988–1997); conducted before ARNi, SGLT2i, CRT, ICD became standard
• Wide range of follow-up durations (6 months–4 years) introduces temporal bias
• Only one digitoxin trial (DIGIT-HF, n=1,212 with 613 in digitoxin arm) — indirect comparison underpowered
• No head-to-head RCTs between digoxin and digitoxin exist
• GDMT evolution across trials makes indirect comparison unreliable
• HF hospitalization result sensitive to DIG trial exclusion (loses significance without it)
• Frontiers in Cardiovascular Medicine is a lower-tier journal; no independent replication yet

Key Concepts Mentioned

• concepts/Cardiac-Glycosides-in-HFrEF — primary concept page for this topic
• concepts/Iron-Deficiency-in-HF — context for GDMT landscape in HFrEF
• concepts/Cardiac-Resynchronization-Therapy — device therapy evolution context
• concepts/Pharmacogenomics-in-HF — GDMT framework

Key Entities Mentioned

• DIG trial (1997) — landmark digoxin RCT; dominant contributor to all-cause mortality pooled result
• DIGIT-HF trial (2025) — see sources/digitoxin-hfref-digithf-nejm-2025; only contemporary GDMT digitoxin trial
• DECISION trial — ongoing low-dose digoxin RCT in HFrEF; will enable direct digoxin comparison

Wiki Pages Updated

• Created wiki/sources/cardiac-glycosides-hfrEF-fcvm-2026.md
• Created wiki/concepts/Cardiac-Glycosides-in-HFrEF.md
• Updated wiki/sourceindex.md
• Updated wiki/wikiindex.md