Cardiac glycosides in heart failure with reduced ejection fraction in the era of contemporary guideline-directed medical therapy: a systematic review and meta-analysis
B Lage Garcia, L Pinheiro, E Mata, M Castro, A M Pinto, B Resende, J Portugues, M Tinoco, F Cardoso, O Azevedo, L Calvo, A LourencoAbstract
Introduction
Heart failure (HF) with reduced ejection fraction (HFrEF) remains a major challenge despite widespread use of the four pillars of contemporary guideline-directed medical therapy (GDMT). Cardiac glycosides, historically used for their inotropic and neurohormonal effects, have largely fallen out of favor with the DIG trial (1997), showing reduction of HF hospitalizations (HFH) but no mortality benefit. However, that trial predated modern GDMT and device therapy. Recent data, including the DIGIT-HF trial (2023), have renewed interest in this drug class by suggesting a potential benefit of digitoxin in optimally treated patients.
Aim
To evaluate the impact of cardiac glycosides on patients with HFrEF receiving contemporary background therapy.
Methods
Four databases were searched for randomized trials (RCT)or propensity-matched studies recruiting adults with HFrEF (LVEF < 50%) after 2000, comparing cardiac glycosides with standard care and reporting at least one primary outcome (all-cause mortality or heart-failure hospitalization). Data were pooled using an inverse-variance random-effects model.
Results
Six studies met inclusion criteria, one RCT (DIGIT-HF) and five propensity-matched observational cohorts (2000–2023), encompassing ~10000 patients (4500 cardiac glycoside users, 5500 controls). DIGIT-HF assessed digitoxin; the remaining studies evaluated digoxin. Pooled analysis demonstrated no significant difference in all-cause mortality (HR 1.01 [0.67–1.53] I² = 77%) with cardiac glycosides significantly reducing HFH (HR 0.84 [0.76–0.93] I² = 0%). No significant effect was observed for all-cause hospitalizations (HR 0.95 [0.83–1.10] I² = 53%). Cardiovascular mortality, reported only in DIGIT-HF, was similar between groups (HR 0.87 [0.67–1.11]).
Discussion
This post-2000 era meta-analysis suggests that cardiac glycosides may still provide benefit by reducing HFH among patients with HFrEF receiving contemporary GDMT. The interpretation of mortality outcomes is, however, limited by the high heterogeneity observed across studies. Digoxin dosing differences, potential residual bias despite propensity matching, and differences in pharmacokinetics between digoxin and digitoxin, together with wide variation in recruitment periods, may have influenced the results and contributed to heterogeneity. These findings highlight the crucial need for contemporary RCTs to clarify the role of cardiac glycosides as adjunctive therapy in contemporary HFrEF.For image description, please refer to the figure legend and surrounding text.