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

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.
2. The second hypothesis is that treatment of underlying insulin resistance/ type 2 diabetes with metformin in heart failure patients with moderately to severely reduced LVEF 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: Recruiting
• Conditions: Heart Failure; Diabetes
• Intervention / Treatment: Drug: Hydralazine Isosorbide Dinitrate; Drug: Placebo Oral Tablet; Drug: Placebo Oral Tablet; Drug: Metformin Hydrochloride

• Study Type: Interventional
• Enrollment (Estimated): 1500
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Henrik Wiggers, MD, PhD; Phone Number: +45 40136627; Email: henrikwiggers@dadlnet.dk

Study Locations

• Denmark
  • Aabenraa, Denmark
    • Recruiting
    • Sygehus Sønderjylland, Aabenraa
    • Contact: Bartlomiej Jonczy
  • Aalborg, Denmark
    • Recruiting
    • Aalborg University Hospital
    • Contact: Søren Vraa
  • Aarhus, Denmark
    • Recruiting
    • Aarhus University Hospital
    • Contact: Henrik Wiggers; Phone Number: +45 40136627; Email: henrikwiggers@dadlnet.dk
    • Sub-Investigator: Anders Jorsal
  • Copenhagen, Denmark
    • Recruiting
    • Rigshospitalet
    • Contact: Lars Køber
    • Principal Investigator: Finn Gustafsson
  • Copenhagen, Denmark
    • Recruiting
    • Bispebjerg Hospital
    • Contact: Olav Wendelbo Nielsen
  • Copenhagen, Denmark
    • Recruiting
    • Gentofte Hospital
    • Contact: Morten Schou
  • Copenhagen, Denmark
    • Recruiting
    • Hvidovre Hospital
    • Contact: Anette Sjøl
  • Copenhagen, Denmark
    • Recruiting
    • Amager Hospital
    • Contact: Jens Broennum-Schou
  • Copenhagen, Denmark
    • Recruiting
    • Glostrup Hospital
    • Contact: Jawdat Abdulla
  • Copenhagen, Denmark
    • Recruiting
    • Herlev Hospital
    • Contact: Morten Schou
  • Esbjerg, Denmark
    • Recruiting
    • Sydvestjysk Sygehus, Esbjerg
    • Contact: Kirsten Vilain Mikkelsen
  • Herning, Denmark
    • Recruiting
    • Herning Hospital
    • Contact: Morten Bøttcher
  • Hillerød, Denmark
    • Recruiting
    • Nordsjællands Hospital Hillerød
    • Contact: Nis Stride
  • Hjørring, Denmark
    • Recruiting
    • Regionshospital Nordjylland, Hjørring
    • Contact: Gitte Nielsen
  • Holbæk, Denmark
    • Recruiting
    • Holbæk Hospital
    • Contact: Walter Bjørn Nielsen
  • Horsens, Denmark
    • Recruiting
    • Horsens Hospital
    • Contact: Karen Kaae Dodt
  • Kolding, Denmark
    • Recruiting
    • Kolding Hospital
    • Contact: Monica Petronela Poenaru
  • Nykøbing Falster, Denmark
    • Not yet recruiting
    • Nykøbing Falster Hospital
    • Contact: Lisbeth Tingsted
  • Odense, Denmark
    • Recruiting
    • Odense University Hospital
    • Contact: Mikael Kjær Poulsen
  • Randers, Denmark
    • Recruiting
    • Randers Hospital
    • Contact: Kiomars Mahboubi
  • Roskilde, Denmark
    • Recruiting
    • Sjællands Universitetshospital, Roskilde
    • Contact: Niels Eske Bruun
  • Silkeborg, Denmark
    • Terminated
    • Silkeborg Hospital
  • Slagelse, Denmark
    • Recruiting
    • Slagelse Sygehus
    • Contact: Dennis Mikkelsen
  • Vejle, Denmark
    • Recruiting
    • Vejle Hospital
    • Contact: Vibeke Brogaard
  • Viborg, Denmark
    • Recruiting
    • Viborg Hospital
    • Contact: Malene Hollingdal

Participation Criteria

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

How is the study designed?

Design Details

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

Number of Arms

4

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 endpoint: Death or hospitalization with worsening heart failure or urgent heart failure visit	Death or hospitalization with worsening heart failure or urgent heart failure visit resulting in intravenous therapy or metolazone treatment for heart failure.	Through study completion, an average of 4 years
Met-HeFT combined endpoint: Death or hospitalization with worsening heart failure or acute myocardial infarction or stroke or urgent heart failure visit	Death or hospitalization with worsening heart failure or acute myocardial infarction or stroke or urgent visit resulting in intravenous therapy or metolazone treatment for heart failure	Through study completion, an average of 4 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
H-HeFT secondary endpoint: Death	Death	Through study completion, an average of 4 years
H-HeFT secondary endpoint: Hospitalization with worsening heart failure or urgent visit resulting in intravenous therapy or metolazone therapy for heart failure	Hospitalization with worsening heart failure or urgent visit resulting in intravenous therapy or metolazone therapy for heart failure	Through study completion, an average of 4 years
H-HeFT secondary endpoint: Combined endpoint: Death or cardiovascular hospitalization or urgent heart failure visit	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	Through study completion, an average of 4 years
Met-HeFT secondary endpoint: Extended clinical endpoint: The primary endpoint or coronary revascularization or non-coronary revascularization or limb amputation.	Extended clinical endpoint: The primary endpoint or coronary revascularization or non-coronary revascularization or limb amputation.	Through study completion, an average of 4 years
Met-HeFT secondary endpoint: Death	Death	Through study completion, an average of 4 years
Met-HeFT secondary endpoint: Hospitalization with worsening heart failure or urgent visit resulting in intravenous therapy or metolazone therapy for heart failure	Hospitalization with worsening heart failure or urgent visit resulting in intravenous therapy or metolazone therapy for heart failure	Through study completion, an average of 4 years
Met-HeFT secondary endpoint: Acute myocardial infarction	Acute myocardial infarction	Through study completion, an average of 4 years
Met-HeFT secondary endpoint: Stroke	Stroke	Through study completion, an average of 4 years
Met-HeFT secondary endpoint: New onset type 2 diabetes	New onset type 2 diabetes	Through study completion, an average of 4 years
Met-HeFT secondary endpoint: Hospitalization or death caused by lactate acidosis.	Hospitalization or death caused by lactate acidosis.	Through study completion, an average of 4 years

Collaborators and Investigators

• 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

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2018
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2026

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): May 31, 2023
• Last Update Submitted That Met QC Criteria: May 30, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: Diabetes; Insulin resistance; Heart failure; Metformin; Isosorbide Dinitrate; Hydralazine
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Vasodilator Agents; Natriuretic Agents; Diuretics, Osmotic; Diuretics; Nitric Oxide Donors; Metformin; Isosorbide; Isosorbide Dinitrate; Isosorbide-5-mononitrate; Hydralazine
• 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