Digoxin Evaluation in Chronic Heart Failure: Investigational Study In Outpatients in the Netherlands

Study Overview
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Brief Summary
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Digoxin is the oldest, market-authorized drug for heart failure (HF), and very cheap. A large trial with digoxin, the DIG trial, executed in the early nineties revealed a highly significant reduction in HF hospitalizations, but no effect on mortality. A post-hoc analysis of the DIG trial suggests that low serum concentrations of digoxin may not only improve HF hospitalizations but also mortality in chronic HF patients. To confirm these retrospective analyses, a prospective, randomized, placebo-controlled trial is necessary to establish the position of digoxin in the contemporary treatment of HF. Therefore, the investigators examine whether low-level, aiming for serum concentrations 0.5-0.9ng/mL, digoxin is beneficial in HF patients with reduced or mid-range ejection fractions (LVEF <50%).

Official Title
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Digoxin Evaluation in Chronic Heart Failure: Investigational Study In Outpatients in the Netherlands

Conditions
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Heart Failure

Intervention / Treatment
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* Drug: Digoxin
* Drug: Placebos


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18year Outpatients with chronic HF, New York Heart Association [NYHA] class II - ambulatory IV LVEF<50% Serum NT-proBNP concentrations: Previous HF hospitalization ≤ 1 year before randomisation ≥400pg/mL if sinus rhythm; ≥800pg/mL if AF Previous HF hospitalization > 1 year before randomisation or in the absence of HF hospitalizations ≥ 600pg/mL if sinus rhythm; ≥1000 pg/mL if AF BNP concentrations: Previous HF hospitalization ≤ 1 year before randomisation ≥100pg/mL if sinus rhythm; ≥200pg/mL if AF Previous HF hospitalization > 1 year before randomisation or in absence of HF hospitalization ≥150pg/mL if sinus rhythm; ≥250pg/mL if AF. ≥14 days stable on guideline-recommended therapy (doses and number of therapies as tolerated by each patient) Exclusion Criteria: Heart rate ≤60bpm (if sinus rhythm); heart rate ≤70bpm (if AF) History of HF hospitalization ≤7days History of myocardial infarction, myocarditis, percutaneous intervention, RCT, pacemaker/ICD implantation, cardiac surgery or stroke ≤30 days Estimated glomerular filtration rate (eGFR), ≤30ml/min/1.73m2 The presence of a mechanical assist device Use of inotropic drugs (dopamine, dobutamine, (nor)adrenaline, and milrinon) Scheduled for mechanical assist device or heart transplant Other non-cardiac conditions with limited life expectancy (≤ duration of the study) Amyloid, hypertrophic obstructive or constrictive cardiomyopathy Accessory atrio-ventricular pathway (e.g. Wolf-Parkinson-White syndrome) (Intermittent) complete heart block or second-degree AV block type Mobitz without pace maker or ICD Severe (grade III/III) aortic valve disease Complex congenital heart disease Proven hypersensitivity to digoxin (prior side effects) Concomitant medication that interacts with digoxin Use of digoxin ≤6 months prior to inclusion Participation in another (intervention) clinical trial (registry studies not included) Women who are pregnant, breastfeeding or may be considering pregnancy during the study period

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A national, multicenter, randomized, double-blind placebo controlled, clinical trial.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Intervention group<br>The intervention group will receive low-dose digoxin | Drug: Digoxin<br>* Digoxin tablets will be given orally<br>|
| Placebo Comparator: Placebo group<br>The placebo group will receive a matching placebo | Drug: Placebos<br>* Placebo tablets will be given orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite of repeated HF hospitalizations, urgent HF Visits, and cardiovascular death |  | Median of 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All-cause mortality |  | Median of 3 years | 
| Cardiovascular death |  | Median of 3 years | 
| (Repeated) HF hospitalization |  | Median of 3 years | 
| Cost-effectiveness assessed by the Medical Consumption Questionnaire |  | Median of 3 years | 
| Urgent HF hospital visits |  | Median of 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Heart Failure, Digoxin, Atrial fibrillation