INTRODUCTION
Heart failure with reduced ejection fraction (HFrEF) remains a major global health burden despite remarkable advances in drug therapies and device-based therapies. (1, 2) According to the Heart Failure Association (HFA) Atlas, the median annual number of HF hospitalizations (HFH) in Europe is 2671 per million inhabitants, underscoring the magnitude of this condition. (2, 3) Given its clinical and economic impact, effective strategies to optimize HF management have become increasingly necessary.
The widespread implementation of contemporary guideline-directed medical therapy (GDMT), including angiotensin receptor-neprilysin inhibitors (ARNIs), angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), beta-blockers, mineralocorticoid receptor antagonists (MRAs), and sodium-glucose linked transporter-2 inhibitors (SGLT2i), has significantly improved survival and reduced hospitalizations over the past two decades. (1) Nevertheless, a substantial proportion of patients continue to experience recurrent decompensations, frequent hospitalizations, and progressive functional decline, highlighting the need for further therapeutic optimization. (1, 2)
Cardiac glycosides have occupied a distinctive role in the management of HF for two centuries. (4) By inhibiting the Na+/K+-ATPase pump, these agents increase intracellular calcium availability, thereby enhancing myocardial contractility. Their vagotonic effects also provide rate control in patients with concomitant atrial fibrillation (AF). (5)
The landmark Digitalis Investigation Group (DIG) trial published in 1997 demonstrated that digoxin reduced HFH but did not confer a survival benefit. (6) However, subsequent observational studies and meta-analyses have yielded conflicting results, with some suggesting a potential association between digoxin use and increased mortality, particularly among patients with AF, leading to a progressive decline in its clinical use. (7-12) In contrast, the RATE-AF trial suggested that digoxin may remain a safe and effective option for rate control in selected patients with permanent AF, and demonstrated greater cost-effectiveness than beta-blockers and fewer adverse events and hospitalizations, without compromising quality of life. (13) Importantly, the DIG trial was conducted more than two decades ago, when background HF therapy was limited to ACEI and diuretics. Its findings may therefore not reflect outcomes in the era of contemporary GDMT and device-based therapies, including implantable cardioverter-defibrillators (ICD) and cardiac resynchronization therapy (CRT). (1, 14, 15) Furthermore, the trial had relevant methodological limitations, including substantial crossover to digoxin in the placebo arm, which may have attenuated treatment differences. (6) Post hoc analyses suggested worse outcomes among patients with higher serum digoxin concentrations, raising concerns about dose–response effects and the narrow therapeutic range of the drug. (16, 17)
Growing evidence has renewed interest in this therapeutic class. In particular, the DIGIT-HF trial, which evaluated digitoxin versus placebo in patients with chronic HFrEF receiving optimal GDMT, demonstrated a significant reduction in the composite endpoint of all-cause mortality or HFH (hazard ratio [HR]: 0.82 [95% CI 0.69-0.98]; p=0.03) without an excess of major adverse events. (18) Notably, digitoxin, a glycoside structurally related to digoxin but with a longer half-life and more stable pharmacokinetics, may overcome some of the safety concerns historically associated with digoxin. (19-22)
Additionally, findings from a recent umbrella review of 12 meta-analyses suggest that previously reported mortality risks may have been confounded by indication bias, comorbidities, and outdated treatment contexts rather than reflecting a true causal relationship. (23)
Accordingly, the present meta-analysis aims to assess the effect of cardiac glycosides on clinical outcomes in patients with HFrEF and mildly reduced ejection fraction (HFmrEF) in the context of contemporary management by integrating data from modern randomized controlled trials and propensity score-matched observational studies.
METHODS
Search Strategy
This systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (24) (Supplementary Table 1) and was registered in PROSPERO (CRD420251185713).
A systematic search of four electronic databases (Cochrane Central Register of Controlled Trials (CENTRAL), Scopus, EMBASE, and PubMed) was performed between October 10 and November 10, 2025. The search strategy included studies containing the terms "heart failure" and "cardiac glycosides" and was restricted to publications from 2000 onward to ensure inclusion of contemporary cohorts, consistent with the first modern ACC/AHA HF guideline issued in 2001. (25) That guideline incorporated evidence from pivotal trials of the 1990s (MERIT-HF, CIBIS-II, RALES, and Val-HeFT), which established beta-blockers, MRAs, and ARBs as disease-modifying therapies in addition to ACE inhibitors. The full search strategies are provided in Supplementary Table 2. No language restrictions were applied. Reference lists of included studies were manually screened to identify additional eligible records.
Inclusion and Exclusion Criteria
Eligible studies included randomized controlled trials (RCTs) or propensity score-matched cohort studies evaluating the effects of cardiac glycosides in patients with HF with reduced or mildly reduced left ventricular ejection fraction (LVEF <50%). Studies were required to report at least one of the predefined primary outcomes.
The primary outcomes were all-cause mortality and HFH. The secondary outcomes included all-cause hospitalizations and cardiovascular mortality.
Studies were excluded if they lacked a control group, did not provide sufficient data for outcome extraction, evaluated alternative therapeutic interventions, had a recruitment period beginning before 2000, or focused exclusively on a specific subgroup of patients with HF with reduced or mildly reduced LVEF.
Study selection process and data collection
Two reviewers independently screened titles and abstracts after removing duplicate records. Full-text articles of potentially eligible studies were then independently assessed by the same reviewers for inclusion according to the predefined criteria. Disagreements at the full-text stage were resolved based on consensus. No automation tools were used during the screening process. All references were managed using EndNote X9 (Clarivate Analytics).
Three reviewers independently extracted data from each included study using a standardized data extraction form. Extracted information included study design, population characteristics, baseline demographics and clinical features, interventions, and outcomes. For studies with multiple publications, care was taken to avoid duplication of data.
Data were analyzed according to the intention-to-treat principle whenever applicable; otherwise, an as-treated approach was used. For observational studies, only results derived from propensity score-matched analyses were included. All relevant data are presented in the main text and supplementary material.
Quality assessment
Two authors independently assessed the risk of bias of the DIGIT-HF trial using the Cochrane Risk of Bias tool, version 1 (RoB 1). For observational studies, risk of bias was independently evaluated using the Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) tool. Publication bias was not formally assessed because fewer than ten studies were included, which limited the reliability of the funnel plot and Egger's regression test. According to established guidance, such tests lack statistical power when applied to a small number of studies and may yield misleading results.
Synthesis methods
A narrative synthesis was used to describe and interpret findings across studies, particularly when analysis was limited by heterogeneity in outcome reporting, study populations, or outcome definitions.
When appropriate, a meta-analysis was conducted using a random-effects model to account for anticipated between-study variability in treatment effects. Summary outcome measures were expressed as HR with the corresponding 95% confidence interval ( 95% CI), calculated using the inverse-variance method. HRs and incidence rate ratios were considered approximately equivalent estimates of relative risk under the assumption of proportional hazards and were therefore pooled together.
Statistical heterogeneity was assessed by visual inspection of forest plots and quantified using the I² statistic (<25% low, 25%-50% moderate, >50% high heterogeneity).
The meta-analysis was conducted using the software package Review Manager (RevMan), version 5.4.1 (The Cochrane Collaboration). All data were evaluated at a 5% significance level (p<0.05). Pooled HRs with 95% CI were recalculated for each scenario, and heterogeneity was reassessed using the I² statistic. A leave-one-out analysis was also performed for the primary outcomes to evaluate the robustness of the findings.
Ethical considerations
This study is a systematic review and meta-analysis that did not involve direct interaction with human participants or animals, therefore, no ethical approval or informed consent was required. However, the study was conducted in accordance with established standards for ethical scientific reporting outlined by the International Committee of Medical Journal Editors (ICMJE; http://www.icmje.org/).
RESULTS
Search results
Figure 1 shows the study selection process. After removing duplicates, 3301 records were screened according to the predefined eligibility criteria. Six studies met the inclusion criteria: the recently published RCT DIGIT-HF, (18) and five propensity score-matched observational studies: one multicenter (26) and four single-center studies. (27-30) The recruitment periods ranged from 2000 to 2023 and included approximately 4500 patients in the cardiac glycoside group and 5500 in the control group. Except for the DIGIT-HF trial, which investigated digitoxin, all other studies evaluated digoxin. Table 1 summarizes the main characteristics of the included studies.
Table 1.
Summary of included studies
| Study | Inclusion and Exclusion Criteria | Patient Groups and Intervention | Primary outcome |
|---|---|---|---|
| DIGIT-HF (18) 2025 Austria, Germany, Serbia 65 Centers FU: 3 (0-110) years | Inclusion Criteria:
- NYHA III-IV and a LVEF ≤40%; - NYHA II and a LVEF ≤30%; - GDMT for a duration of at least 6 months. Exclusion Criteria: - Recent MI/revascularization/device therapy, planned cardiac surgery, myocarditis or complex CHD; - advanced AV block or ventricular arrhythmia; - severe hepatic/renal disease, major electrolyte imbalance; - amiodarone use. |
Digitoxin
- 613 Control: - 599 Recruitment period: 2015-2023 | - Composite of death or first HFH |
| Qamer, S. Z. et al.
2019 (26) United States 259 Centers FU: 2.4 (0-6) years | Inclusion Criteria:
- Medicare-linked OPTIMIZE-HF patients with LVEF ≤45%; - discharged alive. Exclusion Criteria: - Pre-admission digoxin use; - for sensitivity analysis: bradycardia (<60 bpm) or severe renal dysfunction (eGFR <15 mL/min/1.73m²). | Digoxin
- 1531 Control: - 1531 Recruitment period: 2003-2004 | - HF readmission at 30 days, 1 year, and 6 years. |
| Georgiopoulou et al.
2009 (27) United States 1 Center FU: 2.3 (1.3-3.5) years | Inclusion Criteria:
- Adults 18-70 years; - LVEF ≤30%; - NYHA II-IV, on maximally tolerated HF therapy; - referred for heart transplant evaluation. Exclusion Criteria: - CHD or planned cardiac surgery within 6 months. | Digoxin
- 161 Control: - 161 Recruitment period: 2000-2006 | - Death, urgent heart transplantation, or LVAD implantation. |
| Andrey, J. L. et al.
2011 (28) Spain 1 Center FU: 3.8 (3.1-4.7) years | Inclusion Criteria:
- ≥14 years; newly diagnosed with HF according to Framingham criteria. Exclusion Criteria: - Patients non-permanent resident in the community of reference. | Digoxin
- 1421 Control: - 1421 Recruitment period: 2001-2008 | - All cause death |
| Freeman, J. V. et al.
2013 (29) United States 1 Center FU: 2.5 (1.4-3.5) years | Inclusion Criteria:
- Adults ≥21 years old with ≥1 inpatient admission with a primary discharge for HF or ≥3 outpatient encounters for HF; - LVEF ≤40%. Exclusion Criteria: - <12 months of continuous drug benefit before index date; - no follow-up after diagnosis; - prior cardiac/renal transplantation. | Digoxin
- 529 Control: - 2362 Recruitment period: 2006-2008 | - All cause mortality |
| May Al-khateeb et al.
2017 (30) Saudi Arabia 750+ Centers FU: 3.6 (1.6-6.3) years | Inclusion Criteria:
- HF and LVEF < 45%. Exclusion Criteria: - If their vital status could not be verified. | Digoxin
- 325 Control: - 750 Recruitment period: 2000-2015 | - All-cause mortality |
AV: atrio-ventricular; CHD: congenital heart disease; FU: follow-up; GDMT: guideline-directed medical therapy; HF: heart failure; HFH: heart failure hospitalization; LVEF: left ventricular ejection fraction; LVAD: left ventricular assist device; MI: myocardial infarction; NYHA: New York Heart As- sociation.
Population characteristics
Table 2 summarizes the characteristics of the study population. Mean age ranged from 52 to 76 years, with a predominance of male participants (47-80%). Hypertension and diabetes mellitus were common comorbidities, reported in approximately 47-67% and 30-70% of patients, respectively, while dyslipidemia affected 36-72%. Atrial fibrillation or flutter was observed in 12-60% of participants, and chronic kidney disease in 5-47%. When reported, ischemic etiology accounted for approximately half of the cases. Baseline LVEF was markedly reduced across studies, generally ranging from 18% to 29%. Most patients were receiving contemporary GDMT. Beta-blocker use ranged from 43% to 97%, ACE inhibitor or ARB use ranged from 70% to 80%, whereas MRA use varied widely from 10 to 76%. SGLT2i use was reported only in DIGIT-HF trial, reaching up to 20%. Device therapy (ICD and/or CRT) ranged from 1% to 29%, reflecting temporal differences in the study design and population characteristics.
Table 2.
Summary of baseline characteristics of included patients
| DIGIT-HF (18) | Qamer et al (26) | Georgiopoulou et al. (27) | Andrey et al. (28) | Freeman et al. (29) | Al-khateeb et al. (30) | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Digitoxin
(n=613) | Control
(n=599) | Digoxin
(n=1531) | Control
(n=1531) | Digoxin
(n=161) | Control
(n=161) | Digoxin
(n=1421) | Control
(n=1421) | Digoxin
(n=529) | Control
(n=2362) | Digoxin
(n=325) | Control
(n=750) |
|
| Age, years. (mean ± SD) | 66.0 ± 11.1 | 65.8 ± 11.4 | 75 ± 10 | 76 ± 10 | 51.9 ± 12.7 | 52.2 ± 11.9 | 70.7 ± 7.4 | 70.6 ± 7.3 | 68.2 ± 14.8 | 69.8 ± 14.4 | 54.7 ± 13.7 | 55.5 ± 13.4 |
| Male - n.º total | 491/613 | 474/599 | 856/1531 | 855/1531 | 112/161 | 112/161 | 663/1421 | 665/1421 | 354/529 | 1583/2362 | 231/325 | 528/750 |
| HTN | -- | -- | 987/1531
(64.5 %) | 949/1531
(62.0 %) | -- | -- | 668/1421
(47.0 %) | 665/1421
(46.8 %) | 316/529
(59.7 %) | 1577/2362
(66.8 %) | 194/325
(59.7 %) | 454/750
(60.5 %) |
| T2DM | -- | -- | 555/1531
(36.3 %) | 534/1531
(34.9 %) | -- | -- | 520/1421
(36.6 %) | 519/1421
(36.5 %) | 157/529
(29.7 %) | 806/2362
(34.1 %) | 226/325
(69.5 %) | 543/750
(72.4 %) |
| DLP | 377/613
(61.7 %) | 343/599
(57.6 %) | -- | -- | -- | -- | 511/1421
(36.0 %) | 513/1421
(36.1 %) | 329/529
(62.2 %) | 1647/2362
(69.7 %) | 214/325
(65.8 %) | 536/750
(71.5 %) |
| AF/AFL | 169/613
(27.6 %) | 161/599
(26.9 %) | 552/1531
(36.1 %) | 554/1531
(36.2 %) | 60/161
(37.3 %) | 58/161
(36.0 %) | 849/1421
(59.7 %) | 850/1421
(59.8 %) | 209/529
(39.5 %) | 454/2362
(19.2 %) | 56/325
(17.2 %) | 91/750
(12.1 %) |
| Tobacco use | -- | -- | 248/1531
(16.2 %) | 267/1531
(17.4 %) | -- | -- | 435/1421
(30.6 %) | 435/1421
(30.6 %) | -- | -- | 102/325
(31.4 %) | 228/750
(30.4 %) |
| Prior MI | -- | -- | -- | -- | -- | -- | -- | -- | 42/529
(7.9 %) | 355/2362
(15.0 %) | 98/325
(30.2 %) | 266/750
(35.5 %) |
| ihd | 323/608
(53.1 %) | 310/592
(52.4 %) | -- | -- | 59/161
(36.6 %) | 65/161
(40.4 %) | 695/1421
(48.9 %) | 696/1421
(49.0 %) | -- | -- | -- | -- |
| CKD | -- | -- | -- | -- | -- | -- | 107/1421
(7.5 %) | 107/1421
(7.5 %) | 228/529
(43.1 %) | 1115/2362
(47.2 %) | 15/325
(4.6 %) | 41/750
(5.5 %) |
| LVEF (%) | 28.4 ± 6.9
(n=613) | 28.9 ± 6.7
(n=599) | 27 ± 10
(n=1531) | 27 ± 10
(n=1531) | 18.3 ± 8.7
(n=161) | 18.7 ± 7.9
(n=161) | -- | -- | 28.2 ± 6.4
(n=529) | 25.9 ± 6.1
(n=2362) | --
(n=325) | --
(n=750) |
| NYHA III/IV | 432/613
(70.5 %) | 421/599
(70.3 %) | -- | -- | -- | -- | -- | -- | -- | -- | 232/325
(7.2 %) | 36/750
(4.8 %) |
| ICD/CRT | -- | -- | 98/1531
(6.4 %) | 101/1531
(6.6 %) | 43/161
(26.7 %) | 47/161
(29.2 %) | -- | -- | 4/529
(0.8 %) | 41/2362
(1.7 %) | 54/325
(16.6 %) | 108/750
(14.4 %) |
| Guideline-directed Medical Therapy | ||||||||||||
| Betablocker | 593/613
(96.7 %) | 567/599
(94.7 %) | 1120/1531
(73.2 %) | 1145/1531
(74.8 %) | 149/161
(92.5 %) | 147/161
(91.3 %) | 613/1421
(43.1 %) | 614/1421
(43.2 %) | 209/529
(39.5 %) | 1205/2362
(51.0 %) | 313/325
(96.3 %) | 724/750
(96.5 %) |
| ARNI | 248/613
(40.5 %) | 231/599
(38.6 %) | -- | -- | -- | -- | -- | -- | -- | -- | -- | -- |
| ACEi | 222/613
(36.2 %) | 213/599
(35.6 %) | -- | -- | 117/161
(72.7 %) | 119/161
(73.9 %) | -- | -- | 196/529
(37.1 %) | 1112/2362
(47.1 %) | 262/325
(80.6 %) | 589/750
(78.5 %) |
| ARB | 113/613
(18.4 %) | 115/599
(19.2 %) | -- | -- | 34/161
(21.1 %) | 33/161
(20.5 %) | -- | -- | 40/529
(7.6 %) | 236/2362
(10.0 %) | 115/325
(35.4 %) | 282/750
(37.6 %) |
| ACEi or ARB | -- | -- | 1125/1531
(73.5 %) | 1095/1531
(71.5 %) | -- | -- | 1119/1421
(78.7 %) | 1120/1421
(78.8 %) | -- | -- | -- | -- |
| MRA | 466/613
(76.0 %) | 458/599
(76.5 %) | 319/1531
(20.8 %) | 317/1531
(20.7 %) | 73/161
(45.3 %) | 74/161
(46.0 %) | 146/1421
(10.3 %) | 147/1421
(10.3 %) | -- | -- | 245/325
(75.5 %) | 553/750
(73.7 %) |
| SGLT2 Inhibitor | 121/613
(19.7 %) | 113/599
(18.9 %) | -- | -- | -- | -- | -- | -- | -- | -- | -- | -- |
ACEi, angiotensin-converting enzyme inhibitor; AF/AFL, atrial fibrillation/flutter; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor-neprilysin inhibitor; CKD, chronic kidney disease; CRT, cardiac resynchronization therapy; DLP, dyslipidemia; HTN, hypertension; ICD, implantable cardioverter-defibrillator; IHD, ischemic heart disease; LVEF, left ventricular ejection fraction; MI, myocardial infarction; MRA, mineralocorticoid receptor antagonist; NYHA, New York Heart Association; SD: standard deviation; SGLT2, sodium-glucose linked cotransporter 2; T2DM, type 2 diabetes mellitus.
Primary outcomes
Across five studies, (18, 26, 28-30) the pooled estimate for all-cause mortality showed no significant difference between the cardiac glycoside therapy group and the control group (HR 1.01, 95% CI 0.67-1.53; I² = 77%), indicating substantial heterogeneity (Figure 2A). Cardiac glycoside therapy was associated with a significant reduction in HFH (HR 0.84, 95% CI 0.76-0.93; I² = 0%), with no evidence of heterogeneity (Figure 2B).
Fig. 2.
Meta-analysis of cardiac glycoside therapy in heart failure patients with reduced ejection fraction, including randomized controlled trials and propensity-matched cohort studies. Hazard ratios (HR) and incidence rate ratios (IRR) were considered approximately equivalent effect measures and were pooled using a random-effects model with inverse-variance weighting. Forest plots display pooled estimates and 95% confidence intervals (CIs) for (A) all-cause mortality, (B) heart failure hospitalizations, and (C) all-cause hospitalizations
IV: inverse variance; SE: standard error
The leave- one- out sensitivity analysis demonstrated that the statistical significance of the pooled results for all- cause mortality remained robust across all iterations. For HFH, exclusion of the Georgiopoulou study 27 did not change the direction or statistical significance of the pooled effect estimate; however, exclusion of any of the remaining studies led to loss of statistical significance.
Secondary outcomes
For all-cause hospitalizations, there was no significant difference between treatment and control groups (HR 0.95, 95% CI 0.83-1.10; I² = 53%) (Figure 2C). Cardiovascular mortality was reported only in the DIGIT-HF trial (18) and showed no statistically significant difference between groups (HR 0.87, 95% CI 0.67-1.11).
Quality assessment
The DIGIT-HF trial was judged to have an unclear risk of bias (Supplementary Table 3). Among the five observational studies, three were judged to have a moderate risk of bias and two a high risk of bias (Supplementary Table 4).
DISCUSSION
Mortality and heart failure hospitalizations
This meta-analysis provides an updated assessment of cardiac glycosides in patients with HF, LVEF < 50% and contemporary GDMT. Consistent with the original DIG trial, our findings suggest that cardiac glycosides may reduce HFH without a consistent impact on all-cause mortality.
Despite pooled available data, definitive conclusions regarding the effect of cardiac glycosides on all-cause mortality cannot be drawn from the current evidence base. The meta-analytic estimates for mortality are undermined by substantial between-study heterogeneity and the limited number of contemporary high-quality trials. These limitations increase the risk of imprecise and potentially biased estimates, thereby reducing confidence in any pooled mortality effect.
Importantly, the reduction in HFH associated with cardiac glycosides was a consistent finding across heterogeneous study populations. This reproducible finding observed despite variability across studies suggests a robust signal for symptomatic improvement and event reduction that appears less sensitive to between-study differences than mortality outcomes. Nevertheless, the magnitude and clinical implications of HFH reduction should be cautiously interpreted.
Key sources of heterogeneity
Although the included studies generally reflect populations treated with contemporary pharmacotherapy, including beta-blockers, renin–angiotensin–aldosterone system inhibitors, and SGLT2 inhibitors, patients included in this meta-analysis represent a broad and clinically heterogeneous spectrum.
Baseline characteristics , including age, comorbidities, renal function, and rhythm status varied substantially across studies and may influence both the efficacy and safety of cardiac glycosides. Recruitment periods spanned more than two decades, during which HF management evolved considerably, resulting in differences in absolute risk, event rates, and concomitant drug therapy.
Differences in study design, covariate adjustment strategies, and completeness of reporting further contributed to heterogeneity. In addition, the methodological quality of the included studies raises concerns that may undermine the robustness of our findings.
Finally, a key source of variability arises from the specific cardiac glycoside evaluated (digoxin versus digitoxin), which differs in pharmacokinetics, dosing requirements, and safety profiles.
Digoxin and digitoxin
The declining use of digoxin in contemporary HF practice reflects ongoing uncertainty regarding its safety profile. Observational studies and prior meta-analyses have suggested an association between digoxin therapy and increased mortality, particularly in patients with AF, (23, 31-33) an effect that appears more pronounced at higher serum levels.
Values exceeding the therapeutic range have been associated with pro-arrhythmogenic and pro-thrombotic mechanisms, including enhanced endothelial and platelet activation, which may contribute to increased cardiovascular risk. (34-36) These findings are consistent with post hoc analyses of the DIG trial, in which low serum digoxin levels (0.5-0.9 ng/mL) were associated with improved outcomes, whereas higher levels (>1.0 ng/mL) appeared to be harmful. (11, 16, 37) Although the safety and efficacy of cardiac glycosides likely depend on the appropriate serum drug level and dosing, this study was unable to evaluate dose-response relationships due to limited reporting of dosing strategies across studies.
In contrast, recent randomized evidence from the DIGIT-HF trial suggests that low-dose digitoxin may represent a potentially safe and effective therapeutic option. (18) Among patients with chronic HFrEF receiving GDMT, digitoxin significantly reduced the composite endpoint of all-cause mortality or hospitalization for worsening HF, with consistent benefits across prespecified subgroups.
Notably, the DIGIT-HF population exhibited a high symptomatic burden despite optimized GDMT, yet the absolute risk reduction and corresponding number needed to treat were comparable to those observed with other contemporary therapies, including ARNIs and SGLT2i. (18, 38-40) Importantly, these benefits were achieved with few major safety events, particularly in patients with renal dysfunction.
These findings may herald a therapeutic shift from digoxin to digitoxin, a more lipophilic cardiac glycoside with potentially improved safety characteristics.
Other important effect modifiers and interactions
Several clinical variables may meaningfully modify the effects of cardiac glycosides, although available data remain insufficient to elucidate these interactions.
The use of implantable cardiac devices, including ICD and CRT, present in up to 29% of participants in some cohorts, substantially alters the risk of sudden death and HF mortality, and may therefore modify the observed impact of glycoside therapy.
Similarly, the presence of AF and overall rhythm status influence both the clinical indication for glycoside use and dosing strategies, which in turn affect serum concentrations and pharmacodynamic responses. Variability in baseline renal function, together with the absence of standardized drug therapy monitoring further complicates interpretation, as glycoside clearance and toxicity are closely linked to renal function and serum levels.
Finally, concomitant medications that alter glycoside pharmacokinetics or affect renal function may introduce additional residual confounding, thereby influencing outcomes.
Limitations
This meta-analysis has several important limitations. First, the overall quality was suboptimal, as only one contemporary randomized controlled trial was included while the remaining studies were observational and therefore susceptible to selection bias and residual confounding despite the use of propensity score matching.
Second, the substantial between-study heterogeneity, likely attributable to differences in study design, patient characteristics, recruitment periods spanning more than two decades, and evolving background therapies, limits the interpretability of the results.
Third, safety endpoints were not systematically assessed, which is relevant given ongoing concerns regarding glycoside-related toxicity and potential mortality risk signals.
In addition, variability in covariate adjustment strategies across studies may have further contributed to heterogeneity. Finally, the limited number of included studies precluded a formal assessment of publication bias.
Clinical and research implications
Despite these limitations, our findings have relevant clinical and research implications. Cardiac glycosides may continue to provide therapeutic benefit in selected patients with HF and LVEF < 50% receiving contemporary GDMT, primarily through reduction of HFH. This observation suggests that indiscriminate discontinuation of these agents may overlook a niche population: patients who remain symptomatic, have inadequate rate control in AF, or are intolerant to alternative treatments.
Moreover, digoxin remains an inexpensive and widely available medication that may be particularly valuable in healthcare systems with limited access to the full spectrum of disease-modifying therapies.
Nevertheless, the current evidence base is insufficient to support routine use. Well-designed, adequately powered RCTs are urgently needed to reassess the safety and efficacy of digoxin and/or digitoxin in the context of modern HF management. Future studies should ideally incorporate pharmacokinetic-guided dosing strategies, stratification according to rhythm status, and evaluation of potential interactions with device therapy.
CONCLUSIONS
In conclusion, in this contemporary meta-analysis, cardiac glycosides conferred clinical benefits in patients with HFrEF and HFmrEF, primarily by reducing HFH, an effect consistently observed across diverse populations and time periods. However, no consistent mortality benefit was demonstrated, and the certainty of the evidence is limited by substantial heterogeneity, incomplete dosing data, and the predominance of observational studies. These findings underscore the need for powered randomized controlled trials to more definitively define the role of cardiac glycosides as adjunctive therapy in HF management.
Author contributions
EM and MC contributed equally to this work and shared first authorship.
MC: conceptualization, study design, data curation, formal analysis, methodology, data interpretation, project administration, writing: original draft.
EM: conceptualization, study design, data curation, formal analysis, methodology, data interpretation, project administration, writing: original draft.
LP: data curation, formal analysis, data interpretation, writing: original draft.
BR: data curation, formal analysis, data interpretation, writing: original draft.
AMP: data curation, formal analysis, data interpretation, writing: original draft.
SR: supervision, formal analysis, methodological revision of the manuscript.
JP: supervision, formal analysis, methodological revision of the manuscript.
AL: supervision, writing: review and editing, final approval of the manuscript, guarantor of the study overall content.
All authors reviewed and approved the final manuscript. All authors accept responsibility for the accuracy, reliability and validity of the research data and analysis.
Conflicts of interest
None declared. (See authors' conflict of interests forms on the web).
Funding
This research received no public or public financial support.
