Foxglove — a beautiful flower that saves the heart or stops it?

Aim of the study: Cardiac glycosides have undergone one of the most paradoxical trajectories in cardiovascular therapeutics, evolving from foundational heart failure therapy to near abandonment in the modern era.

Results: Contemporary evidence now supports a more disciplined reassessment. Recent randomized trials, including Digitoxin to Improve Outcomes in Patients with Advanced Chronic Heart Failure (DIGIT-HF) and Digoxin Evaluation in Chronic Heart Failure: Investigational Study in Outpatients in the Netherlands (DECISION), together with a contemporary meta-analysis, demonstrate consistent directional reductions in worsening heart failure events with low-dose digitalis therapy, without excess mortality when serum concentrations are carefully controlled. These findings suggest that the historical toxicity narrative largely reflected excessive drug exposure rather than intrinsic biologic hazard. Digitalis glycosides should not be viewed as mortality-reducing "foundational" therapy but rather as complementary agents for selected patients with persistent residual risk despite optimized guideline-directed therapy, particularly those with recurrent decompensation or concomitant atrial fibrillation.

Aim of the study: Digitalis glycosides are among the oldest therapies for heart failure (HF) with reduced ejection fraction, yet their contemporary role remains debated.

Results: Finally, this review also provides valuable insights from a 2025 survey of Portuguese HF specialists into real-world clinical practice regarding digitalis use. With 55 experts responding, the survey highlights a predominant, selective application of digitalis glycosides, primarily after optimization of foundational HF therapies, consistent with guideline recommendations. Perceived benefits focus on rate control and symptom relief, while concerns about toxicity, the need for monitoring, and gaps in modern trial evidence continue to restrict broader adoption. Together, current data support a repositioning of digitalis as a low-dose, concentration-guided, neurohormonal modulator and rate-control agent for carefully selected patients with HF with reduced ejection fraction, an approach that ongoing and future trials should further refine.

Aim of the study: Cardiac Na+,K(+)-ATPase, the receptor molecule for digitalis glycosides, have isoforms with different intrinsic affinities for the glycosides. Expression of these isoforms are under developmental and hormonal regulation.

Results: Reserve capacity of the sodium pump is also reduced by pathological conditions or aging, resulting in reduced margin of safety for the glycoside. Events that follow sodium pump inhibition also affect sensitivity of the heart to digitalis toxicity. These are hypercalcemia and magnesium depletion. It is now feasible to predict digitalis sensitivity of the heart, not empirically but based on the understanding of the mechanisms responsible for the positive inotropic and toxic actions of the glycoside.

Aim of the study: Cardiac glycosides represent one of the oldest therapeutic pillars in medicine, although their role has progressively diminished in the modern era of neurohormonal therapy for heart failure (HF).

Results: Following publication of the Digitalis Investigation Group (DIG) trial in 1997, no randomized clinical trials evaluating this drug class were conducted for almost three decades, while observational studies and meta-analyses accumulated, often yielding conflicting results. The DIGIT-HF randomized clinical trial (2025) addressed a major unmet need by evaluating digitoxin in patients with HF with reduced ejection fraction in the contemporary era of guideline-directed medical therapy. Treatment with digitoxin was associated with favourable outcomes, including a reduction in the composite endpoint of all-cause mortality and hospitalizations for HF, thereby reopening a long-standing debate on the role of digitalis, which had remained marginal for many years. This article reviews the history of digitalis, the main evidence generated over recent decades, the evolution of clinical guidelines from 1997 to 2022, and the conceptual and clinical implications of the DIGIT-HF trial.