Rationale and design of the DIGIT‐HF trial (DIGitoxin to Improve ouTcomes in patients with advanced chronic Heart Failure): a randomized, double‐blind, placebo‐controlled study

Abstract

Aims Despite recent advances in the treatment of chronic heart failure (HF), mortality and hospitalizations still remain high. Additional therapies to improve mortality and morbidity are urgently needed. The efficacy of cardiac glycosides – although regularly used for HF treatment – remains unclear. DIGIT‐HF was designed to demonstrate that digitoxin on top of standard of care treatment improves mortality and morbidity in patients with HF and a reduced ejection fraction (HFrEF). Methods Patients with chronic HF, New York Heart Association (NYHA) functional class III–IV and left ventricular ejection fraction (LVEF) ≤ 40%, or patients in NYHA functional class II and LVEF ≤ 30% are randomized 1:1 in a double‐blind fashion to treatment with digitoxin (target serum concentration 8–18 ng/mL) or matching placebo. Randomization is stratified by centre, sex, NYHA functional class (II, III, or IV), atrial fibrillation, and treatment with cardiac glycosides at baseline. A total of 2190 eligible patients will be included in this clinical trial (1095 per group). All patients receive standard of care treatment recommended by expert guidelines upon discretion of the treating physician. The primary outcome is a composite of all‐cause mortality or hospital admission for worsening HF (whatever occurs first). Key secondary endpoints are all‐cause mortality, hospital admission for worsening HF, and recurrent hospital admission for worsening HF. Conclusion The DIGIT‐HF trial will provide important evidence, whether the cardiac glycoside digitoxin reduces the risk for all‐cause mortality and/or hospital admission for worsening HF in patients with advanced chronic HFrEF on top of standard of care treatment.

Clinical practice update on heart failure 2019: pharmacotherapy, procedures, devices and patient management. An expert consensus meeting report of the Heart Failure Association of the European Society of Cardiology

“…The group believes that a series of randomized controlled trials is required comparing ‘non‐aggressive’ pharmacological rate control, avoiding amiodarone or Class I antiarrhythmic agents and higher doses or plasma concentrations of digoxin with the following procedures: PV (and/or AV node) ablation for paroxysmal AF and HF vs ‘non‐aggressive’ pharmacological rate control (and avoiding all of: amiodarone, Class I antiarrhythmic agents, higher doses or higher plasma concentrations of digoxin). PV (and/or AV node) ablation for persistent AF and HF with or without a back‐up pacing device vs ‘non‐aggressive’ pharmacological rate control (and avoiding all of: amiodarone, Class I antiarrhythmic agents, higher doses or higher plasma concentrations of digoxin). PV (and/or AV node) ablation in HF patients with CRT vs. usual care. There is also a need for randomized controlled trials comparing different rate control strategies, including: high‐ vs. low‐dose beta‐blocker; addition of digoxin to beta‐blockers. The ongoing DIGIT‐HF (DIGitoxin to Improve ouTcomes in patients with advanced chronic Heart Failure) trial includes patients with AF, but excludes patients in need of rate control with digitalis glycosides There is also a need for randomized controlled trials investigating: new agents for pharmacological rhythm control (double‐blind vs. placebo); prevention of AF (double‐blind vs. placebo); better treatments to prevent AF recurrence (double‐blind vs. placebo). …”

“…The ongoing DIGIT-HF (DIGitoxin to Improve ouTcomes in patients with advanced chronic Heart Failure) trial includes patients with AF, but excludes patients in need of rate control with digitalis glycosides. 78 5 There is also a need for randomized controlled trials investigating:…”

Digoxin–mortality: randomized vs. observational comparison in the DIG trial

“…Conflict of interest: L.A.D., K.W., U.B., J.B., and A.K. are involved in the conduct of the DIGIT-HF trial 28 (Eudra-CT: 2013-005326-38) funded by the Federal Ministry of Education and Research (BMBF), Germany.…”

Heart rate control in heart failure with reduced ejection fraction: the bright and the dark side of the moon

“…Digitalis glycosides are used quite often for this purpose; however, as the DIG trial did not include patients with AF, current evidence is scarce. The ongoing DIGIT‐HF trial (http://www.digit-hf.de, EudraCT‐No. : 2013–005326‐38) as well as the DECISION trial (http://ClinicalTrials.gov Identifier: NCT03783429) will provide data in the future.…”