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

University Medical Center Groningen982 enrolled

Overview

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%).

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

982

Conditions

Heart Failure

Interventions

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Age ≥18year 2. Outpatients with chronic HF, New York Heart Association \[NYHA\] class II - ambulatory IV 3. LVEF\<50% 4. 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. 5. ≥14 days stable on guideline-recommended therapy (doses and number of therapies as tolerated by each patient) Exclusion Criteria: 1. Heart rate ≤60bpm (if sinus rhythm); heart rate ≤70bpm (if AF) 2. History of HF hospitalization ≤7days 3. History of myocardial infarction, myocarditis, percutaneous intervention, RCT, pacemaker/ICD implantation, cardiac surgery or stroke ≤30 days 4. Estimated glomerular filtration rate (eGFR), ≤30ml/min/1.73m2 5. The presence of a mechanical assist device 6. Use of inotropic drugs (dopamine, dobutamine, (nor)adrenaline, and milrinon) 7. Scheduled for mechanical assist device or heart transplant 8. Other non-cardiac conditions with limited life expectancy (≤ duration of the study) 9. Amyloid, hypertrophic obstructive or constrictive cardiomyopathy 10. Accessory atrio-ventricular pathway (e.g. Wolf-Parkinson-White syndrome) 11. (Intermittent) complete heart block or second-degree AV block type Mobitz without pace maker or ICD 12. Severe (grade III/III) aortic valve disease 13. Complex congenital heart disease 14. Proven hypersensitivity to digoxin (prior side effects) 15. Concomitant medication that interacts with digoxin 16. Use of digoxin ≤6 months prior to inclusion 17. Participation in another (intervention) clinical trial (registry studies not included) 18. Women who are pregnant, breastfeeding or may be considering pregnancy during the study period

Locations (44)

Noordwest Ziekenhuisgroep

Alkmaar, Netherlands

Zorggroep Twente

Almelo, Netherlands

Meander Medisch Centrum

Amersfoort, Netherlands

BovenIJ Ziekenhuis

Amsterdam, Netherlands

Gelre Ziekenhuizen

Apeldoorn, Netherlands

Rijnstate Ziekenhuis

Outcomes

Primary Outcomes

To demonstrate whether low-dose digoxin compared to placebo reduces the rate of the composite CV outcome

The composite of total worsening heart failure events (with an event defined as a first or recurrent unplanned hospitalization or urgent visit for heart failure) and death from cardiovascular causes (amount of events)

Time frame: Median of 3 years

Secondary Outcomes

To determine whether low-dose digoxin compared to placebo reduces the rate of the ranked clinical outcomes: composite of all repeated HF hospitalizations and repeated urgent HF visits

composite of all repeated HF hospitalizations and repeated urgent HF visits (amount)

Time frame: Median of 3 years

To determine whether low-dose digoxin compared to placebo reduces the rate of the ranked clinical outcomes: composite of all repeated CV hospitalizations and repeated urgent CV hospital visits

composite of all repeated CV hospitalizations and repeated urgent CV hospital visits (amount)

Time frame: Median of 3 years

To determine whether low-dose digoxin compared to placebo reduces the rate of the ranked clinical outcomes: first-time occurrence of any of the composite of CV-mortality, HF hospitalization or urgent HF hospital visit

first-time occurrence of any of the composite of CV-mortality, HF hospitalization or urgent HF hospital visit

Time frame: Median of 3 years

To determine whether low-dose digoxin compared to placebo reduces the rate of the ranked clinical outcomes: first-time occurrence of any of the composite of all-cause mortality, HF hospitalization or urgent HF hospital visit

first-time occurrence of any of the composite of all-cause mortality, HF hospitalization or urgent HF hospital visit

Time frame: Median of 3 years

To determine whether low-dose digoxin compared to placebo reduces the rate of the ranked clinical outcomes: first-time occurrence of any of the composite of HF hospitalization or urgent HF hospital visit

first-time occurrence of any of the composite of HF hospitalization or urgent HF hospital visit

Time frame: Median of 3 years

To determine whether low-dose digoxin compared to placebo reduces the rate of the ranked clinical outcomes: first time event to CV mortality

first time event to CV mortality

Time frame: Median of 3 years

To determine whether low-dose digoxin compared to placebo reduces the rate of the ranked clinical outcomes: first-time event to all-cause mortality

first-time event to all-cause mortality

Time frame: Median of 3 years