Heart Failure
Conditions
Keywords
Heart Failure, Digoxin, Atrial fibrillation
Brief summary
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%).
Interventions
DRUGDigoxin
Digoxin tablets will be given orally
DRUGPlacebos
Placebo tablets will be given orally
Sponsors
University Medical Center Groningen
Disphar International B.V.
Teva Nederland BV
Tiofarma BV
Netherlands Heart Foundation
Werkgroep Cardiologische centra Nederland
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Double blind, placebo controlled
Intervention model description
A national, multicenter, randomized, double-blind placebo controlled, clinical trial.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| To demonstrate whether low-dose digoxin compared to placebo reduces the rate of the composite CV outcome | Median of 3 years | 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) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Median of 3 years | composite of all repeated HF hospitalizations and repeated urgent HF visits (amount) |
| 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 | Median of 3 years | composite of all repeated CV hospitalizations and repeated urgent CV hospital visits (amount) |
| 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 | Median of 3 years | first-time occurrence of any of the composite of CV-mortality, HF hospitalization or urgent HF hospital visit |
| 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 | Median of 3 years | first-time occurrence of any of the composite of all-cause mortality, HF hospitalization or urgent HF hospital visit |
| 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 | Median of 3 years | first-time occurrence of any of the composite of HF hospitalization or urgent HF hospital visit |
| To determine whether low-dose digoxin compared to placebo reduces the rate of the ranked clinical outcomes: first time event to CV mortality | Median of 3 years | first time event to CV mortality |
| To determine whether low-dose digoxin compared to placebo reduces the rate of the ranked clinical outcomes: first-time event to all-cause mortality | Median of 3 years | first-time event to all-cause mortality |
Countries
Netherlands
Contacts
PRINCIPAL_INVESTIGATORMichiel Rienstra, MD, PhD
University Medical Center Groningen
PRINCIPAL_INVESTIGATORPeter van der Meer, MD, PhD
University Medical Center Groningen
PRINCIPAL_INVESTIGATORDirk J van Veldhuisen, MD, PhD
University Medical Center Groningen
Outcome results
None listed