Clinical trial NCT03783429: Digoxin Evaluation in Chronic Heart Failure: Investigational Study In Outpatients in the Netherlands
Official title: Digoxin Evaluation in Chronic Heart Failure: Investigational Study In Outpatients in the Netherlands
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE4
Conditions: Heart Failure
Keywords: Heart Failure
Digoxin
Atrial fibrillation
Lead sponsor: University Medical Center Groningen
Sponsor class: OTHER
Collaborators: name: Disphar International B.V.
name: Teva Nederland BV
name: Tiofarma BV
name: Netherlands Heart Foundation
name: Werkgroep Cardiologische centra Nederland
First posted: 2018-12-21
Enrollment: 982
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: A national, multicenter, randomized, double-blind placebo controlled, clinical trial.
Primary purpose: TREATMENT

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%).


Eligibility criteria: 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

Primary outcomes:
measure: Composite of repeated HF hospitalizations, urgent HF Visits, and cardiovascular death
timeFrame: Median of 3 years
Secondary outcomes:
measure: All-cause mortality
timeFrame: Median of 3 years
measure: Cardiovascular death
timeFrame: Median of 3 years
measure: (Repeated) HF hospitalization
timeFrame: Median of 3 years
measure: Cost-effectiveness assessed by the Medical Consumption Questionnaire
timeFrame: Median of 3 years
measure: Urgent HF hospital visits
timeFrame: Median of 3 years
Other outcomes:
measure: All-cause hospitalizations
timeFrame: Median of 3 years
measure: Unscheduled cardiovascular hospital visits
timeFrame: Median of 3 years
measure: Days alive out of hospital
timeFrame: Median of 3 years
measure: Quality of Life assessed by the EUROQOL-5D-5L questionnaire
timeFrame: Median of 3 years
measure: Heart rate in both AF and sinus rhythm
timeFrame: Median of 3 years
measure: To assess side effects (SUSARs) associated with study medication
timeFrame: Median of 3 years
measure: Initiation of (recurrence of) AF in patients with sinus rhythm at baseline
timeFrame: Median of 3 years
measure: Conversion to sinus rhythm and maintenance of sinus rhythm in patients with AF at baseline
timeFrame: Median of 3 years
Locations:
city: Alkmaar
country: Netherlands
facility: Noordwest Ziekenhuisgroep
city: Almelo
country: Netherlands
facility: Zorggroep Twente
city: Amersfoort
country: Netherlands
facility: Meander Medisch Centrum
city: Amsterdam
country: Netherlands
facility: BovenIJ Ziekenhuis
city: Apeldoorn
country: Netherlands
facility: Gelre Ziekenhuizen
city: Arnhem
country: Netherlands
facility: Rijnstate Ziekenhuis
city: Beverwijk
country: Netherlands
facility: Rode Kruis Ziekenhuis
city: Blaricum
country: Netherlands
facility: Tergooi
city: Breda
country: Netherlands
facility: Amphia Ziekenhuis
city: Capelle Aan Den IJssel
country: Netherlands
facility: Ijsselland Ziekenhuis
city: Delft
country: Netherlands
facility: Reinier de Graaf Gasthuis
city: Den Haag
country: Netherlands
facility: Haaglanden Medisch Centrum
city: Deventer
country: Netherlands
facility: Deventer Ziekenhuis
city: Dirksland
country: Netherlands
facility: Van Weel Bethesda
city: Doetinchem
country: Netherlands
facility: Slingeland Ziekenhuis
city: Ede
country: Netherlands
facility: Ziekenhuis Gelderse Vallei
city: Emmen
country: Netherlands
facility: Scheper Ziekenhuis
city: Goes
country: Netherlands
facility: Admiraal de Ruyter Ziekenhuis
city: Gorinchem
country: Netherlands
facility: Beatrix Ziekenhuis
city: Gouda
country: Netherlands
facility: Groene Hart Ziekenhuis
city: Groningen
country: Netherlands
facility: Martini Ziekenhuis
city: Groningen
country: Netherlands
facility: University Medical Center Groningen
city: Haarlem
country: Netherlands
facility: Spaarne Gasthuis
city: Hardenberg
country: Netherlands
facility: Saxenburgh MC
city: Harderwijk
country: Netherlands
facility: Ziekenhuis St Jansdal
city: Heerlen
country: Netherlands
facility: Zuyderland Medisch Centrum
city: Helmond
country: Netherlands
facility: Elkerliek Ziekenhuis
city: Hoogeveen
country: Netherlands
facility: Bethesda
city: Leeuwarden
country: Netherlands
facility: Medisch Centrum Leeuwarden
city: Leiden
country: Netherlands
facility: Alrijne Ziekenhuis
city: Maastricht
country: Netherlands
facility: Maastricht UMC+
city: Meppel
country: Netherlands
facility: Isala Diaconessenhuis
city: Nijmegen
country: Netherlands
facility: Radboud University Medical Center
city: Roosendaal
country: Netherlands
facility: Bravis ziekenhuis
city: Rotterdam
country: Netherlands
facility: Erasmus Medisch Centrum
city: Rotterdam
country: Netherlands
facility: Franciscus Gasthuis
city: Rotterdam
country: Netherlands
facility: Ikazia Ziekenhuis
city: Schiedam
country: Netherlands
facility: Franciscus Vlietland
city: Sneek
country: Netherlands
facility: Antonius Ziekenhuis Sneek
city: Stadskanaal
country: Netherlands
facility: Refaja
city: Tilburg
country: Netherlands
facility: Elisabeth-Tweesteden Ziekenhuis
city: Utrecht
country: Netherlands
facility: Diak. Utrecht
city: Veldhoven
country: Netherlands
facility: Máxima Medisch Centrum
city: Zaandam
country: Netherlands
facility: Zaans Medisch Centrum
Study officials:
affiliation: University Medical Center Groningen
name: Michiel Rienstra, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University Medical Center Groningen
name: Peter van der Meer, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University Medical Center Groningen
name: Dirk J van Veldhuisen, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: