Study Results
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Basic Information
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RECRUITING
PHASE4
1500 participants
INTERVENTIONAL
2018-03-01
2026-12-31
Brief Summary
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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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Detailed Description
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Conditions
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Study Design
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RANDOMIZED
FACTORIAL
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.
TREATMENT
QUADRUPLE
Study Groups
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Hydralazine Isosorbide Dinitrate
Tablet BiDil (Hydralazine 37.5 mg/ isosorbide dinitrate (ISDN) 20 mg) 2 tablets x 3 daily.
Average treatment period 4 years.
Hydralazine Isosorbide Dinitrate
Tablet BiDil (Hydralazine 37.5 mg/ Isosorbide Dinitrate (ISDN) 20 mg) 2 tablets x 3 daily
Placebo (Hydralazine Isosorbide Dinitrate)
Tablet Placebo 2 tablets x 3 daily. Average treatment period 4 years.
Placebo Oral Tablet
2 tablets x 3 daily
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.
Metformin Hydrochloride
Tablet Metformin hydrochloride 500 mg 2 tablets x 2 daily (eGFR 35-60 ml/min: 500 mg x 2 daily)
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.
Placebo Oral Tablet
2 tablets x 2 daily (eGFR 35-60 ml/min: 500 mg x 2 daily)
Interventions
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Hydralazine Isosorbide Dinitrate
Tablet BiDil (Hydralazine 37.5 mg/ Isosorbide Dinitrate (ISDN) 20 mg) 2 tablets x 3 daily
Placebo Oral Tablet
2 tablets x 3 daily
Metformin Hydrochloride
Tablet Metformin hydrochloride 500 mg 2 tablets x 2 daily (eGFR 35-60 ml/min: 500 mg x 2 daily)
Placebo Oral Tablet
2 tablets x 2 daily (eGFR 35-60 ml/min: 500 mg x 2 daily)
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* 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
* 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.
18 Years
ALL
No
Sponsors
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Danish Heart Foundation
OTHER
Danish Council for Independent Research
OTHER
The Danish Regions: Foundation for Medical Research
UNKNOWN
The Novo Nordisk Foundation
UNKNOWN
The Aase og Ejnar Danielsen Foundation
UNKNOWN
Henrik Wiggers
OTHER
Responsible Party
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Henrik Wiggers
Professor, Consultant, MD, PhD, DMSc
Principal Investigators
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Henrik Wiggers, MD, PhD
Role: STUDY_CHAIR
Dept. of Cardiology, Aarhus University Hospital, Aarhus, Denmark
Lars Køber, MD, PhD
Role: STUDY_CHAIR
Dept. of Cardiology, Rigshospitalet, Copenhagen, Denmark
Finn Gustafsson, MD, PhD
Role: PRINCIPAL_INVESTIGATOR
Dept. of Cardiology, Rigshospitalet, Copenhagen, Denmark
Søren Mellemkjaer, MD, PhD
Role: PRINCIPAL_INVESTIGATOR
Dept. of Cardiology, Aarhus University Hospital, Aarhus, Denmark
Gunnar Gislason, MD, PhD
Role: STUDY_CHAIR
The Danish Heart Foundation, Copenhagen, Denmark
Locations
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Holbæk Hospital
Holbæk, Region Sjælland, Denmark
Sygehus Sønderjylland, Aabenraa
Aabenraa, , Denmark
Aalborg University Hospital
Aalborg, , Denmark
Aarhus University Hospital
Aarhus, , Denmark
Amager Hospital
Copenhagen, , Denmark
Bispebjerg Hospital
Copenhagen, , Denmark
Gentofte Hospital
Copenhagen, , Denmark
Glostrup Hospital
Copenhagen, , Denmark
Herlev Hospital
Copenhagen, , Denmark
Hvidovre Hospital
Copenhagen, , Denmark
Rigshospitalet
Copenhagen, , Denmark
Sydvestjysk Sygehus, Esbjerg
Esbjerg, , Denmark
Herning Hospital
Herning, , Denmark
Nordsjællands Hospital Hillerød
Hillerød, , Denmark
Regionshospital Nordjylland, Hjørring
Hjørring, , Denmark
Holbæk Hospital
Holbæk, , Denmark
Horsens Hospital
Horsens, , Denmark
Kolding Hospital
Kolding, , Denmark
Nykøbing Falster Hospital
Nykøbing Falster, , Denmark
Odense University Hospital
Odense, , Denmark
Randers Hospital
Randers, , Denmark
Sjællands Universitetshospital, Roskilde
Roskilde, , Denmark
Silkeborg Hospital
Silkeborg, , Denmark
Slagelse Sygehus
Slagelse, , Denmark
Vejle Hospital
Vejle, , Denmark
Viborg Hospital
Viborg, , Denmark
Countries
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Central Contacts
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Facility Contacts
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Walter B Nielsen, MD
Role: primary
Bartlomiej Jonczy
Role: primary
Søren Vraa
Role: primary
Jens Broennum-Schou
Role: primary
Olav Wendelbo Nielsen
Role: primary
Morten Schou
Role: primary
Jawdat Abdulla
Role: primary
Morten Schou
Role: primary
Jens Hove, MD, PhD
Role: primary
Lars Køber
Role: primary
Kirsten Vilain Mikkelsen
Role: primary
Morten Bøttcher
Role: primary
Nis Stride
Role: primary
Gitte Nielsen
Role: primary
Walter Bjørn Nielsen
Role: primary
Karen Kaae Dodt
Role: primary
Monica Petronela Poenaru
Role: primary
Lisbeth Tingsted
Role: primary
Mikael Kjær Poulsen
Role: primary
Kiomars Mahboubi
Role: primary
Niels Eske Bruun
Role: primary
Dennis Mikkelsen
Role: primary
Vibeke Brogaard
Role: primary
Malene Hollingdal
Role: primary
References
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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.
Other Identifiers
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2015-002150-12
Identifier Type: EUDRACT_NUMBER
Identifier Source: secondary_id
DANHEART
Identifier Type: -
Identifier Source: org_study_id
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