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

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 Overview

• Status: Completed
• Conditions: Heart Failure
• Intervention / Treatment: Drug: Digoxin; Drug: Placebos

• Study Type: Interventional
• Enrollment (Actual): 982
• Phase: Phase 4

Contacts and Locations

Study Locations

• Netherlands
  • Alkmaar, Netherlands
    • Noordwest Ziekenhuisgroep
  • Almelo, Netherlands
    • Zorggroep Twente
  • Amersfoort, Netherlands
    • Meander Medisch Centrum
  • Amsterdam, Netherlands
    • BovenIJ ziekenhuis
  • Apeldoorn, Netherlands
    • Gelre Ziekenhuizen
  • Arnhem, Netherlands
    • Rijnstate Ziekenhuis
  • Beverwijk, Netherlands
    • Rode Kruis Ziekenhuis
  • Blaricum, Netherlands
    • Tergooi
  • Breda, Netherlands
    • Amphia Ziekenhuis
  • Capelle aan den IJssel, Netherlands
    • IJsselland Ziekenhuis
  • Delft, Netherlands
    • Reinier de Graaf Gasthuis
  • Deventer, Netherlands
    • Deventer Ziekenhuis
  • Dirksland, Netherlands
    • Van Weel Bethesda
  • Doetinchem, Netherlands
    • Slingeland Ziekenhuis
  • Ede, Netherlands
    • Ziekenhuis Gelderse Vallei
  • Emmen, Netherlands
    • Scheper Ziekenhuis
  • Goes, Netherlands
    • Admiraal De Ruyter Ziekenhuis
  • Gorinchem, Netherlands
    • Beatrix Ziekenhuis
  • Gouda, Netherlands
    • Groene Hart Ziekenhuis
  • Groningen, Netherlands
    • Martini Ziekenhuis
  • Groningen, Netherlands
    • University Medical Center Groningen
  • Haarlem, Netherlands
    • Spaarne Gasthuis
  • Hardenberg, Netherlands
    • Saxenburgh MC
  • Harderwijk, Netherlands
    • Ziekenhuis St Jansdal
  • Heerlen, Netherlands
    • Zuyderland Medisch Centrum
  • Helmond, Netherlands
    • Elkerliek Ziekenhuis
  • Hoogeveen, Netherlands
    • Bethesda
  • Leeuwarden, Netherlands
    • Medisch Centrum Leeuwarden
  • Leiden, Netherlands
    • Alrijne Ziekenhuis
  • Maastricht, Netherlands
    • Maastricht UMC+
  • Meppel, Netherlands
    • Isala Diaconessenhuis
  • Nijmegen, Netherlands
    • Radboud University Medical Center
  • Roosendaal, Netherlands
    • Bravis ziekenhuis
  • Rotterdam, Netherlands
    • Erasmus Medisch Centrum
  • Rotterdam, Netherlands
    • Ikazia Ziekenhuis
  • Rotterdam, Netherlands
    • Franciscus Gasthuis
  • Schiedam, Netherlands
    • Franciscus Vlietland
  • Sneek, Netherlands
    • Antonius Ziekenhuis Sneek
  • Stadskanaal, Netherlands
    • Refaja
  • The Hague, Netherlands
    • Haaglanden Medisch Centrum
  • Tilburg, Netherlands
    • Elisabeth-TweeSteden Ziekenhuis
  • Utrecht, Netherlands
    • Diak. Utrecht
  • Veldhoven, Netherlands
    • Maxima Medisch Centrum
  • Zaandam, Netherlands
    • Zaans Medisch Centrum

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)	Median of 3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)	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)	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	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	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	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	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	Median of 3 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
To determine whether low-dose digoxin compared to placebo improves the exploratory outcomes: all-cause hospitalizations and urgent hospital visits	Amount of events per patient years, incidence rate	Median of 3 years
To determine whether low-dose digoxin compared to placebo improves the exploratory outcomes: days alive and out of hospital	amount of days alive and out of hospital	Median of 3 years
To determine whether low-dose digoxin compared to placebo improves the exploratory outcomes: Quality of Life assessed by the EUROQOL-5D-5L questionnaire	Quality of Life is assessed by questions about mobility, selfcare, daily activity, pain and anxiety. The questions about mobility, selfcare and daily activity range from 'no problem doing activity' to 'not able to do activity'. The questions about pain and anxiety range from 'not at all present' to 'extremely present'. The last question in the questionnaire asks how a person rates his or her health in the present day, ranging from 0-100, where 0 is the worst health imaginable, and 100 is the best health imaginable. EQ5DL index value and EQ5DL VAS score (0-100). The EQ-5D-5L is a 2-part instrument, if only one part is used you cannot claim to have used EQ-5D-5L in your publications, therefore this outcome is listed as 1 outcome measure.	Median of 3 years
To determine whether low-dose digoxin compared to placebo improves the exploratory outcomes: Reported Suspected Unexpected Serious Adverse Reactions (SUSARs)	incidence rate (IR) amount of events per patient years	Median of 3 years
To determine whether low-dose digoxin compared to placebo improves the exploratory outcomes: Heart rate in both AF and sinus rhythm	in beats per minute	Median of 3 years
To determine whether low-dose digoxin compared to placebo improves the exploratory outcomes: Initiation of (and/of recurrence of) AF in patients with sinus rhythm at baseline	Amount of events per patient years, incidence rate (IR)	Median of 3 years
To determine whether low-dose digoxin compared to placebo improves the exploratory outcomes: Conversion to sinus rhythm and maintenance of sinus rhythm in patients with AF at baseline	Amount of events per patient years, incidence rate (IR)	Median of 3 years
To determine whether low-dose digoxin compared to placebo improves the exploratory outcomes: Implantation of pacemaker, ICD, CRT or LVAD	Amount of events per patient years, incidence rate (IR)	Median of 3 years

Collaborators and Investigators

• Sponsor: University Medical Center Groningen
• Collaborators: Netherlands Heart Foundation; Disphar International B.V.; Teva Nederland BV; Tiofarma BV; Werkgroep Cardiologische centra Nederland
• Investigators: Principal Investigator: Michiel Rienstra, MD, PhD, University Medical Center Groningen; Principal Investigator: Peter van der Meer, MD, PhD, University Medical Center Groningen; Principal Investigator: Dirk J van Veldhuisen, MD, PhD, University Medical Center Groningen

Publications and helpful links

General Publications

• van Veldhuisen DJ, Rienstra M, Mosterd A, Alings AM, van Asselt ADJ, Bouvy ML, Tijssen JGP, Schaap J, van der Wall EE, Voors AA, Boorsma EM, Lok DJA, Crijns HJGM, Schut A, Vijver MAT, Voordes GHD, de Vos AH, Maas-Soer EL, Smit NW, Touw DJ, Samuel M, van der Meer P; DECISION Investigators and Committees. Efficacy and safety of low-dose digoxin in patients with heart failure. Rationale and design of the DECISION trial. Eur J Heart Fail. 2024 Oct;26(10):2223-2230. doi: 10.1002/ejhf.3428. Epub 2024 Aug 30.

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2020
• Primary Completion (Actual): November 13, 2025
• Study Completion (Actual): November 13, 2025

Study Registration Dates

• First Submitted: December 13, 2018
• First Submitted That Met QC Criteria: December 18, 2018
• First Posted (Actual): December 21, 2018

Study Record Updates

• Last Update Posted (Actual): April 27, 2026
• Last Update Submitted That Met QC Criteria: April 21, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Heart Failure; Atrial fibrillation; Digoxin
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Pathologic Processes; Heart Diseases; Arrhythmias, Cardiac; Pathological Conditions, Signs and Symptoms; Heart Failure; Atrial Fibrillation; Carbohydrates; Polycyclic Compounds; Glycosides; Steroids; Fused-Ring Compounds; Digitalis Glycosides; Cardenolides; Cardiac Glycosides; Cardanolides; Digoxin
• Other Study ID Numbers: DECISION trial

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No