DANHEART (H-HeFT and Met-HeFT)

Overview

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.

Full Title of Study: “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)”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Factorial Assignment
    • Primary Purpose: Treatment
    • Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
  • Study Primary Completion Date: December 31, 2026

Interventions

  • Drug: Hydralazine Isosorbide Dinitrate
    • Tablet BiDil (Hydralazine 37.5 mg/ Isosorbide Dinitrate (ISDN) 20 mg) 2 tablets x 3 daily
  • Drug: Placebo Oral Tablet
    • 2 tablets x 3 daily
  • Drug: Metformin Hydrochloride
    • Tablet Metformin hydrochloride 500 mg 2 tablets x 2 daily (eGFR 35-60 ml/min: 500 mg x 2 daily)
  • Drug: Placebo Oral Tablet
    • 2 tablets x 2 daily (eGFR 35-60 ml/min: 500 mg x 2 daily)

Arms, Groups and Cohorts

  • 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.
  • Placebo Comparator: Placebo (Hydralazine Isosorbide Dinitrate)
    • Tablet Placebo 2 tablets x 3 daily. Average treatment period 4 years.
  • 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.
  • 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.

Clinical Trial Outcome Measures

Primary Measures

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

Secondary Measures

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

Participating in This Clinical Trial

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.

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Henrik Wiggers
  • Collaborator
    • Danish Heart Foundation
  • Provider of Information About this Clinical Study
    • Sponsor-Investigator: Henrik Wiggers, Consultant, Associate professor, MD, PhD, DMSc – Aarhus University Hospital
  • Overall Official(s)
    • Henrik Wiggers, MD, PhD, Study Chair, Dept. of Cardiology, Aarhus University Hospital, Aarhus, Denmark
    • Lars Køber, MD, PhD, Study Chair, Dept. of Cardiology, Rigshospitalet, Copenhagen, Denmark
    • Finn Gustafsson, MD, PhD, Principal Investigator, Dept. of Cardiology, Rigshospitalet, Copenhagen, Denmark
    • Søren Mellemkjaer, MD, PhD, Principal Investigator, Dept. of Cardiology, Aarhus University Hospital, Aarhus, Denmark
    • Gunnar Gislason, MD, PhD, Study Chair, The Danish Heart Foundation, Copenhagen, Denmark
  • Overall Contact(s)
    • Henrik Wiggers, MD, PhD, +45 40136627, henrikwiggers@dadlnet.dk

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