Revival of Digoxin in Heart Failure Management: Is It Justified

Building upon the experience with foxglove (Digitalis-like plant) in dropsy, digoxin, a cardiac glycoside, went through nearly two centuries of unrestricted routine use, with frequent toxicities and inconsistent results, for the treatment of heart failure (HF). Digoxin, being a potent inotropic drug with chronotropic effects, stood out as the core drug along with diuretics in the clinical management of HF. It became the choice drug for the treatment of atrial fibrillation, irrespective of the baseline ventricular function. The clinical outcomes included a neutral impact on cardiac mortality and improvement in symptoms in refractory HF. Two clinical trials published in 1993—RADIANCE and PROVED formed the basis for its continued use.^{1, 2} The DIG trial, including 6,800 patients with chronic HF, who were on angiotensin-converting enzyme (ACE) inhibitors and diuretics, published a few years later in 1997, showed a decrease in hospitalizations without a change in mortality in patients with HF (left ventricular ejection fraction (LVEF) <45%) in sinus rhythm. ³ By the mid-20th century, digoxin became the mainstay for HF with atrial fibrillation in the absence of better alternatives. However, evidence from large randomized trials was lacking for such extensive use. Over the years, clinicians realized the potential for digoxin toxicity due to its narrow therapeutic index, renal dependency of serum levels, and individual variability in toxicity.

The concept of neurohormonal modification as a target for HF became popular in the late 1980s and early 1990s. With the entry of ACE inhibitors and angiotensin receptor blockers (based on CONSENSUS, SOLVED, AIRE, Val-HeFT, CHARM, and VALIANT trials), beta-blockers (based on the US Carvedilol program, CIBIS, MERIT-HF, and COPERNICUS trials), and mineralocorticoid receptor antagonists (RALES, EPHESUS, and EMPHASIS-HF trials), which promised survival benefit and favorable re-modeling, digoxin was relegated to a backup role for persistent symptoms despite guideline-directed medical therapy (GDMT), in the presence of hypotension limiting the uptitration of GDMT drugs, or if atrial fibrillation is present concurrently. Landmark trials like PARADIGM (2014), DAPA-HF (2019), and Emperor-Reduced (2020) crystallized the concept of the four pillars of foundational drugs for chronic HF, and the need for digoxin became more irrelevant. ⁴

Concurrently, digoxin use was also reevaluated in the era of modern GDMT in the mid-2000s. A meta-analysis in 2015 reviewing over 300,000 patients with atrial fibrillation (AF), congestive HF, or both showed that digoxin was associated with an overall 21% increased relative risk of all-cause mortality (HR = 1.21, 95% CI: 1.07-1.38, P < .01). ⁵ Rate-AF trial was published in late 2025, which showed that low-dose digoxin improves cardiac function and quality of life for certain patients with HFpEF with permanent atrial fibrillation. ⁶ More recently, the DIGIT-HF trial proved that digitoxin reduced all-cause mortality and worsening HF hospitalizations when carefully titrated in advanced HF patients. ⁷ These trial results renewed interest in low-dose digitalis therapy in HF. The DECISION trial (n = 1,001 patients) was published in 2026, which threw up unexpected results. In this first placebo-controlled randomized controlled trial study, patients with chronic HF with LVEF <50% were randomized to low-dose digoxin (target serum levels of 0.5-0.9 ng/mL) or placebo. Baseline therapy included GDMT drugs at maximum tolerated doses. The digoxin group showed a trend for reduction in the composite of worsening HF events/cardiovascular (CV) death, but the difference was not statistically significant. The message of the trial was that the routine addition of digoxin to improve outcomes was not justified in contemporarily treated HF patients. ⁷ However, a blinded analysis had shown clinical deterioration following stopping the drug in those who were on digoxin for a long time. The authors advocated caution while stopping the drug. ⁸

A recent 2026 meta-analysis from three large trials (DIG, DIGIT-HF, and DECISION) that included 9,013 participants revealed that digitalis treatment resulted in a lower risk of CV death or first worsening HF events in patients with either HFmrEF or HFrEF, mainly through a lower risk of worsening HF events. ⁹ Interestingly, a subgroup of patients with rheumatic valvular heart disease and atrial fibrillation (Dig-RHD trial) reported fewer composite events (death or new/worsening HF) with digoxin treatment. ¹⁰ This trial suggests that digoxin still has a place in HF management due to rheumatic valve disease, which has relevance for India.

To conclude from the trials described above, I have three takeaways for digoxin usage in HF.

Digoxin does not give additional survival benefit over modern GDMT established for the treatment of chronic HF. But the HF worsening events are fewer.

If a patient is on long-term digoxin, it is not safe to suddenly withdraw it. Exercise caution.

There is still some clinical role for digoxin in HF with permanent atrial fibrillation and HF associated with chronic rheumatic valve disease.