DANHEART (H-HeFT and Met-HeFT)

NCT03514108 | Completed Phase 4 DMC FDA Drug

• 2 other identifiers: DANHEART2015-002150-12
• Study Type: interventional
• Target: 1,100
• Locations: 1 country
• Sites: 26

Brief Summary

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. 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. 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.

Conditions

Heart Failure; Diabetes

Keywords

Heart failure; Diabetes; Insulin resistance; Metformin; Hydralazine; Isosorbide Dinitrate

Outcome Measures

Primary Outcomes (2)

• H-HeFT combined primary endpoint

  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

  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 Outcomes (18)

• H-HeFT Death

  Through study completion, an average of 4 years

• H-HeFT: Heart failure events

  Through study completion, an average of 4 years

• H-HeFT: Death or cardiovascular hospitalization

  Through study completion, an average of 4 years

• H-HeFT combined primary endpoint of total (first and recurrent) events

  Through study completion, an average of 4 years

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

  Through study completion, an average of 4 years

Study Arms (4)

Hydralazine Isosorbide Dinitrate

ACTIVE COMPARATOR

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

Placebo (Hydralazine Isosorbide Dinitrate)

PLACEBO COMPARATOR

Tablet Placebo 2 tablets x 3 daily. Average treatment period 4 years.

Drug: Placebo Oral Tablet

Metformin

ACTIVE COMPARATOR

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

Placebo (Metformin)

PLACEBO COMPARATOR

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

Interventions

Hydralazine Isosorbide Dinitrate DRUG

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

Also known as: BiDil

Hydralazine Isosorbide Dinitrate

Placebo Oral Tablet DRUG

2 tablets x 3 daily

Placebo (Hydralazine Isosorbide Dinitrate)

Metformin Hydrochloride DRUG

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

Metformin

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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)
• 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

Sponsors & Collaborators

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

Study Sites (26)

Holbæk Hospital

Holbæk, Region Sjælland, Denmark

Location

Sygehus Sønderjylland, Aabenraa

Aabenraa, Denmark

Location

Aalborg University Hospital

Aalborg, Denmark

Location

Aarhus University Hospital

Aarhus, Denmark

Location

Amager Hospital

Copenhagen, Denmark

Location

Bispebjerg Hospital

Copenhagen, Denmark

Location

Gentofte Hospital

Copenhagen, Denmark

Location

Glostrup Hospital

Copenhagen, Denmark

Location

Herlev Hospital

Copenhagen, Denmark

Location

Hvidovre Hospital

Copenhagen, Denmark

Location

Rigshospitalet

Copenhagen, Denmark

Location

Sydvestjysk Sygehus, Esbjerg

Esbjerg, Denmark

Location

Herning Hospital

Herning, Denmark

Location

Nordsjællands Hospital Hillerød

Hillerød, Denmark

Location

Regionshospital Nordjylland, Hjørring

Hjørring, Denmark

Location

Holbæk Hospital

Holbæk, Denmark

Location

Horsens Hospital

Horsens, Denmark

Location

Kolding Hospital

Kolding, Denmark

Location

Nykøbing Falster Hospital

Nykøbing Falster, Denmark

Location

Odense University Hospital

Odense, Denmark

Location

Randers Hospital

Randers, Denmark

Location

Sjællands Universitetshospital, Roskilde

Roskilde, Denmark

Location

Silkeborg Hospital

Silkeborg, Denmark

Location

Slagelse Sygehus

Slagelse, Denmark

Location

Vejle Hospital

Vejle, Denmark

Location

Viborg Hospital

Viborg, Denmark

Location

Related Publications (1)

• Wiggers H, Kober L, Gislason G, Schou M, Poulsen MK, Vraa S, Nielsen OW, Bruun NE, Norrelund H, Hollingdal M, Barasa A, Bottcher M, Dodt K, Hansen VB, Nielsen G, Knudsen AS, Lomholdt J, Mikkelsen KV, Jonczy B, Bronnum-Schou J, Poenaru MP, Abdulla J, Raymond I, Mahboubi K, Sillesen K, Serup-Hansen K, Madsen JS, Kristensen SL, Larsen AH, Botker HE, Torp-Petersen C, Eiskjaer H, Moller J, Hassager C, Steffensen FH, Bibby BM, Refsgaard J, Hofsten DE, Mellemkjaer S, Gustafsson F. The DANish randomized, double-blind, placebo controlled trial in patients with chronic HEART failure (DANHEART): A 2 x 2 factorial trial of hydralazine-isosorbide dinitrate in patients with chronic heart failure (H-HeFT) and metformin in patients with chronic heart failure and diabetes or prediabetes (Met-HeFT). Am Heart J. 2021 Jan;231:137-146. doi: 10.1016/j.ahj.2020.09.020. Epub 2020 Oct 9.

  PMID: 33039340 DERIVED

MeSH Terms

Conditions

Heart Failure; Diabetes Mellitus; Insulin Resistance

Interventions

isosorbide-hydralazine combination; Metformin

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Hyperinsulinism

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals

Study Officials

• Henrik Wiggers, MD, PhD

  Dept. of Cardiology, Aarhus University Hospital, Aarhus, Denmark

  STUDY CHAIR

• Lars Køber, MD, PhD

  Dept. of Cardiology, Rigshospitalet, Copenhagen, Denmark

  STUDY CHAIR

• Finn Gustafsson, MD, PhD

  Dept. of Cardiology, Rigshospitalet, Copenhagen, Denmark

  PRINCIPAL INVESTIGATOR

• Søren Mellemkjaer, MD, PhD

  Dept. of Cardiology, Aarhus University Hospital, Aarhus, Denmark

  PRINCIPAL INVESTIGATOR

• Gunnar Gislason, MD, PhD

  The Danish Heart Foundation, Copenhagen, Denmark

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor, Consultant, MD, PhD, DMSc

Model Details: Patients can be allocated to either 1. both Hydralazine Isosorbide Dinitrate / Placebo and Metformin hydrochloride / Placebo 2. to only Hydralazine Isosorbide Dinitrate / Placebo. 3. to only Metformin hydrochloride / Placebo. Patient characteristics are entered in an electronic CRF. According to in- and exclusion criteria they are randomized in three blocks: 1. Patients receiving both Hydralazine Isosorbide Dinitrate / Placebo and Metformin hydrochloride / Placebo 2. Patients receiving only Hydralazine Isosorbide Dinitrate / Placebo and 3. Patients receiving only Metformin hydrochloride / Placebo Analysis will be performed in: 1. all patients who have received Hydralazine Isosorbide Dinitrate / Placebo (H-HeFT) and 2. all patients who have received Metformin hydrochloride / Placebo (Met-HeFT) The study is event driven. Anticipated: both H-HeFT and Met-HeFT 900, only H-HeFT 400, only Met-HeFT 200 patients.

Study Record Dates

• First Submitted: February 20, 2018
• First Posted: May 2, 2018
• Study Start: March 1, 2018
• Primary Completion: December 31, 2025
• Study Completion: December 31, 2025
• Last Updated: February 20, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will not share

Locations

DK (26)