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Completed

NCT Number: NCT03514108

DANHEART (H-HeFT and 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.

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Key information

Conditions

Heart Failure Cardiovascular Diseases Diabetes Diabetes Mellitus Endocrine System Diseases Glucose Metabolism Disorders Heart Diseases Hyperinsulinism Insulin Resistance Metabolic Diseases Nutritional and Metabolic Diseases

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 4

Primary location

Holbæk Hospital, Holbæk, Region Sjælland, Denmark

Loading trial locations.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

Hydralazine Isosorbide Dinitrate

Drug

Tablet BiDil (Hydralazine 37.5 mg/ Isosorbide Dinitrate (ISDN) 20 mg) 2 tablets x 3 daily

Other names: BiDil

Placebo oral tablet

Drug

2 tablets x 3 daily

Metformin Hydrochloride

Drug

Tablet Metformin hydrochloride 500 mg 2 tablets x 2 daily (eGFR 35-60 ml/min: 500 mg x 2 daily)

Primary outcomes

  1. 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.

  2. 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

Secondary outcomes

  1. H-HeFT Death

    Time frame: Through study completion, an average of 4 years

    Death

  2. 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

  3. 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

  4. 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.

  5. H-HeFT: All-cause, total (first and subsequent) hospitalizations

    Time frame: Through study completion, an average of 4 years

    Any hospitalization

  6. 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

  7. H-HeFT: Cardiovascular hospitalizations

    Time frame: Through study completion, an average of 4 years

    Any cardiovascular hospitalization

  8. 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

  9. Met-HeFT secondary endpoint: Death

    Time frame: Through study completion, an average of 4 years

    Death

  10. 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

  11. 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.

  12. Met-HeFT secondary endpoint: Acute myocardial infarction

    Time frame: Through study completion, an average of 4 years

    Acute myocardial infarction

  13. Met-HeFT secondary endpoint: Stroke

    Time frame: Through study completion, an average of 4 years

    Stroke

  14. Met-HeFT secondary endpoint: New onset type 2 diabetes

    Time frame: Through study completion, an average of 4 years

    New onset type 2 diabetes

  15. 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.

  16. Met-HeFT: All-cause, total (first and subsequent) hospitalizations

    Time frame: Through study completion, an average of 4 years

    Any hospitalization

  17. 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

  18. Met-HeFT: Cardiovascular hospitalizations

    Time frame: Through study completion, an average of 4 years

    Any cardiovascular hospitalization

Sponsors and collaborators

Lead sponsor

Henrik Wiggers

Other

Collaborators

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

Registry information

Official study title

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)

Acronym: DANHEART

Important dates

Study start
2018
Primary completion
2025
Study completion
2025
First posted
May 2, 2018
Registry last updated
Jun 11, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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