DANHEART (H-HeFT and Met-HeFT) (DANHEART)

June 9, 2026 updated by: Henrik Wiggers

A Randomized, Double-blind, Placebo Controlled Study (DANHEART): Hydralazine-ISDN in Patients With Chronic Heart Failure - Hydralazine Heart Failure Trial (H-HeFT) and Metformin in Patients With Chronic Heart Failure and Diabetes or Insulin Resistance - Metformin Heart Failure Trial (Met-HeFT)

The present study is testing in a combined design to types of drugs in patients with chronic heart failure: 1) Hydralazine in combination with isosorbide dinitrate (BiDil) and 2) Metformin hydrochloride. The study is double blind, placebo controlled.

  1. The first hypothesis is that hydralazine in combination with isosorbide dinitrate can reduce mortality and hospitalization with worsening heart failure in chronic heart failure patients with reduced LVEF.
  2. The second hypothesis is that treatment with metformin in chronic heart failure patients with reduced LVEF and type 2 diabetes / diabetes risk / insulin resistance can reduce mortality and cardiovascular hospitalizations. Among secondary endpoints are reduction in new-onset diabetes in heart failure patients with insulin resistance and diabetes risk profile and patient safety.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

1100

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Denmark
      • Aabenraa, Denmark
        • Sygehus Sønderjylland, Aabenraa
      • Aalborg, Denmark
        • Aalborg University Hospital
      • Aarhus, Denmark
        • Aarhus University Hospital
      • Copenhagen, Denmark
        • Rigshospitalet
      • Copenhagen, Denmark
        • Bispebjerg Hospital
      • Copenhagen, Denmark
        • Herlev Hospital
      • Copenhagen, Denmark
        • Gentofte Hospital
      • Copenhagen, Denmark
        • Hvidovre Hospital
      • Copenhagen, Denmark
        • Glostrup Hospital
      • Copenhagen, Denmark
        • Amager Hospital
      • Esbjerg, Denmark
        • Sydvestjysk Sygehus, Esbjerg
      • Herning, Denmark
        • Herning Hospital
      • Hillerød, Denmark
        • Nordsjællands Hospital Hillerød
      • Hjørring, Denmark
        • Regionshospital Nordjylland, Hjørring
      • Holbæk, Denmark
        • Holbæk Hospital
      • Horsens, Denmark
        • Horsens Hospital
      • Kolding, Denmark
        • Kolding Hospital
      • Nykøbing Falster, Denmark
        • Nykøbing Falster Hospital
      • Odense, Denmark
        • Odense University Hospital
      • Randers, Denmark
        • Randers Hospital
      • Roskilde, Denmark
        • Sjællands Universitetshospital, Roskilde
      • Silkeborg, Denmark
        • Silkeborg Hospital
      • Slagelse, Denmark
        • Slagelse Sygehus
      • Vejle, Denmark
        • Vejle Hospital
      • Viborg, Denmark
        • Viborg Hospital
    • Region Sjælland
      • Holbæk, Region Sjælland, Denmark
        • Holbæk Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

General inclusion criteria for both H-HeFT and Met-HeFT

  • Patients with chronic heart failure
  • NYHA-class II, III or IV
  • LVEF </= 40% within 12 months prior to screening. The echocardiography should (i) be performed after uptitration in heart failure medication and (ii) LVEF from the most recently performed echocardiographic study should be used and (iii) LVEF must not be measured during rapid atrial fibrillation, i.e. heart rate >110/min) and (iiii) the echocardiography should be performed at least 3 months after CRT-implantation.
  • Patients should be uptitrated to recommended or maximally tolerated dose of ACE-I/ARB/ARNI (unless contraindicated) and beta-blocker (unless contraindicated). If indicated, an aldosterone receptor antagonist should be given (unless contraindicated).
  • A CRT device should be implanted, if indicated and accepted by the patient and patients with a CRT device should be treated for > 3 months.
  • Implantation of an ICD unit should be planned or already done, if indicated and accepted by the patient. The patient can be included in the study before a planned ICD implantation has been performed.
  • Informed consent

Specific inclusion criteria for only H-HeFT:

  • Systolic blood pressure ≥100 mmHg
  • NT-proBNP > 350 pg/ml or BNP > 80 pg/ml (in patients treated with ARNI, NT-proBNP must be used)

Specific inclusion criteria for only Met-HeFT:

Patients must have a diagnosis of type 2 diabetes or insulin resistance or diabetes risk. This includes 1 or more of any of the following:

  • A previous diagnosis of type 2 diabetes at any time without Metformin treatment during the last 3 months
  • HbA1c ≥ 5.5 % (≥ 37 mmol/mol) within 12 months prior to screening
  • Fasting P-glucose ≥ 5.6 mmol/l within 12 months prior to screening (measured when the patient in stable condition / has no intercurrent illness)
  • Body mass index ≥ 30 kg/m2
  • If oral glucose tolerance testing (OGTT) has been performed at any time prior to randomization: 2 hour P-glucose ≥ 7.8 mmol/l
  • In addition, patients in Met-HeFT must have eGFR ≥ 35 ml/min (MDRD)

Patients are randomized through an internet based randomization module. Patients can be allocated to a) both H-HeFT and Met-HeFT or to b) only H-HeFT or to c) only Met-HeFT.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Hydralazine Isosorbide Dinitrate

Tablet BiDil (Hydralazine 37.5 mg/ isosorbide dinitrate (ISDN) 20 mg) 2 tablets x 3 daily.

Average treatment period 4 years.
Drug: Hydralazine Isosorbide Dinitrate
Tablet BiDil (Hydralazine 37.5 mg/ Isosorbide Dinitrate (ISDN) 20 mg) 2 tablets x 3 daily
Other Names:
  • BiDil
Placebo Comparator: Placebo (Hydralazine Isosorbide Dinitrate)
Tablet Placebo 2 tablets x 3 daily. Average treatment period 4 years.
Drug: Placebo Oral Tablet
2 tablets x 3 daily
Drug: Placebo Oral Tablet
2 tablets x 2 daily (eGFR 35-60 ml/min: 500 mg x 2 daily)
Active Comparator: Metformin
Tablet Metformin hydrochloride 500 mg 2 tablets x 2 daily (eGFR 35-60 ml/min: 500 mg x 2 daily). Average treatment period 4 years.
Drug: Metformin Hydrochloride
Tablet Metformin hydrochloride 500 mg 2 tablets x 2 daily (eGFR 35-60 ml/min: 500 mg x 2 daily)
Placebo Comparator: Placebo (Metformin)
Tablet Placebo 500 mg 2 tablets x 2 daily (eGFR 35-60 ml/min: 500 mg x 2 daily). Average treatment period 4 years.
Drug: Placebo Oral Tablet
2 tablets x 3 daily
Drug: Placebo Oral Tablet
2 tablets x 2 daily (eGFR 35-60 ml/min: 500 mg x 2 daily)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
H-HeFT combined primary endpoint
Time Frame: Through study completion, an average of 4 years
Combined endpoint: Death or hospitalization with worsening heart failure or an urgent visit resulting in intravenous therapy or metolazone therapy for heart failure or heart transplantation or implantation of a LVAD.
Through study completion, an average of 4 years
Met-HeFT combined primary endpoint
Time Frame: Through study completion, an average of 4 years
Combined endpoint: Death or hospitalization with worsening heart failure or an urgent visit resulting in intravenous therapy or metolazone therapy for heart failure or heart transplantation or implantation of a LVAD or acute myocardial infarction or stroke
Through study completion, an average of 4 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Met-HeFT secondary endpoint: Death
Time Frame: Through study completion, an average of 4 years
Death
Through study completion, an average of 4 years
Met-HeFT secondary endpoint: Acute myocardial infarction
Time Frame: Through study completion, an average of 4 years
Acute myocardial infarction
Through study completion, an average of 4 years
Met-HeFT secondary endpoint: Stroke
Time Frame: Through study completion, an average of 4 years
Stroke
Through study completion, an average of 4 years
Met-HeFT secondary endpoint: New onset type 2 diabetes
Time Frame: Through study completion, an average of 4 years
New onset type 2 diabetes
Through study completion, an average of 4 years
H-HeFT: All-cause, total (first and subsequent) hospitalizations
Time Frame: Through study completion, an average of 4 years
Any hospitalization
Through study completion, an average of 4 years
Met-HeFT secondary endpoint: Hospitalization or death caused by lactic acidosis.
Time Frame: Through study completion, an average of 4 years
Hospitalization or death caused by lactic acidosis.
Through study completion, an average of 4 years
Met-HeFT: All-cause, total (first and subsequent) hospitalizations
Time Frame: Through study completion, an average of 4 years
Any hospitalization
Through study completion, an average of 4 years
Met-HeFT: Change in NT-proBNP from baseline to final follow-up
Time Frame: Through study completion, an average of 4 years
Change in NT-proBNP
Through study completion, an average of 4 years
H-HeFT Death
Time Frame: Through study completion, an average of 4 years
Death
Through study completion, an average of 4 years
H-HeFT: Heart failure events
Time Frame: Through study completion, an average of 4 years
Hospitalization with worsening heart failure or urgent visit resulting in intravenous therapy or metolazone therapy for heart failure or heart transplantation or implantation of LVAD
Through study completion, an average of 4 years
H-HeFT: Death or cardiovascular hospitalization
Time Frame: Through study completion, an average of 4 years
Combined endpoint: Death or cardiovascular hospitalizations (hospitalization with worsening heart failure, acute myocardial infarction, or stroke) or urgent visit resulting in intravenous therapy or metolazone therapy for heart failure or or heart transplantation or implantation of LVAD
Through study completion, an average of 4 years
H-HeFT combined primary endpoint of total (first and recurrent) events
Time Frame: Through study completion, an average of 4 years

Composite of total (first and recurrent) events in the primary endpoint:

Death or hospitalization with worsening heart failure or an urgent visit resulting in intravenous therapy or metolazone therapy for heart failure or heart transplantation or implantation of a LVAD.
Through study completion, an average of 4 years
H-HeFT: Change in NT-proBNP from baseline to final follow-up
Time Frame: Through study completion, an average of 4 years
Change in NT-proBNP from baseline to final follow-up
Through study completion, an average of 4 years
H-HeFT: Cardiovascular hospitalizations
Time Frame: Through study completion, an average of 4 years
Any cardiovascular hospitalization
Through study completion, an average of 4 years
Met-HeFT combined endpoint of total (first and recurrent) events in the primary endpoint
Time Frame: Through study completion, an average of 4 years
Combined endpoint of total (first and recurrent) events: Death or hospitalization with worsening heart failure or an urgent visit resulting in intravenous therapy or metolazone therapy for heart failure or heart transplantation or implantation of a LVAD or acute myocardial infarction or stroke
Through study completion, an average of 4 years
Met-HeFT: Hospitalization with worsening heart failure or urgent visit resulting in intravenous therapy or metolazone therapy for heart failure or heart transplantation or implantation of a LVAD
Time Frame: Through study completion, an average of 4 years
Hospitalization with worsening heart failure or urgent visit resulting in intravenous therapy or metolazone therapy for heart failure or heart transplantation or implantation of a LVAD
Through study completion, an average of 4 years
Met-HeFT Extended clinical endpoint (first event analysis): The primary endpoint or coronary revascularization or non-coronary revascularization or limb amputation.
Time Frame: Through study completion, an average of 4 years
Met-HeFT: Extended clinical endpoint (first event analysis): The primary endpoint or coronary revascularization or non-coronary revascularization or limb amputation.
Through study completion, an average of 4 years
Met-HeFT: Cardiovascular hospitalizations
Time Frame: Through study completion, an average of 4 years
Any cardiovascular hospitalization
Through study completion, an average of 4 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Henrik Wiggers

Collaborators

Danish Heart Foundation
Danish Council for Independent Research
The Danish Regions: Foundation for Medical Research
The Novo Nordisk Foundation
The Aase og Ejnar Danielsen Foundation

Investigators

  • Study Chair: Henrik Wiggers, MD, PhD, Dept. of Cardiology, Aarhus University Hospital, Aarhus, Denmark
  • Study Chair: Lars Køber, MD, PhD, Dept. of Cardiology, Rigshospitalet, Copenhagen, Denmark
  • Principal Investigator: Finn Gustafsson, MD, PhD, Dept. of Cardiology, Rigshospitalet, Copenhagen, Denmark
  • Principal Investigator: Søren Mellemkjaer, MD, PhD, Dept. of Cardiology, Aarhus University Hospital, Aarhus, Denmark
  • Study Chair: Gunnar Gislason, MD, PhD, The Danish Heart Foundation, Copenhagen, Denmark

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

March 1, 2018

Primary Completion (Actual)

December 31, 2025

Study Completion (Actual)

December 31, 2025

Study Registration Dates

First Submitted

February 20, 2018

First Submitted That Met QC Criteria

April 20, 2018

First Posted (Actual)

May 2, 2018

Study Record Updates

Last Update Posted (Actual)

June 11, 2026

Last Update Submitted That Met QC Criteria

June 9, 2026

Last Verified

April 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • DANHEART
  • 2015-002150-12 (EudraCT Number)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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