Diabetes, Heart Failure
Conditions
Keywords
Heart failure, Diabetes, Insulin resistance, Metformin, Hydralazine, Isosorbide Dinitrate
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. 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.
Interventions
DRUGHydralazine Isosorbide Dinitrate
Tablet BiDil (Hydralazine 37.5 mg/ Isosorbide Dinitrate (ISDN) 20 mg) 2 tablets x 3 daily
DRUGPlacebo Oral Tablet
2 tablets x 3 daily
DRUGMetformin Hydrochloride
Tablet Metformin hydrochloride 500 mg 2 tablets x 2 daily (eGFR 35-60 ml/min: 500 mg x 2 daily)
Sponsors
Henrik Wiggers
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
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| H-HeFT combined primary endpoint | 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. |
| Met-HeFT combined primary endpoint | 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
| Measure | Time frame | Description |
|---|---|---|
| H-HeFT Death | Through study completion, an average of 4 years | Death |
| H-HeFT: Heart failure events | 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 |
| H-HeFT: Death or cardiovascular hospitalization | 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 |
| H-HeFT combined primary endpoint of total (first and recurrent) events | 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. |
| H-HeFT: All-cause, total (first and subsequent) hospitalizations | Through study completion, an average of 4 years | Any hospitalization |
| H-HeFT: Change in NT-proBNP from baseline to final follow-up | Through study completion, an average of 4 years | Change in NT-proBNP from baseline to final follow-up |
| H-HeFT: Cardiovascular hospitalizations | Through study completion, an average of 4 years | Any cardiovascular hospitalization |
| Met-HeFT combined endpoint of total (first and recurrent) events in the primary endpoint | 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 |
| Met-HeFT secondary endpoint: Death | Through study completion, an average of 4 years | Death |
| 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 | 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 |
| Met-HeFT Extended clinical endpoint (first event analysis): The primary endpoint or coronary revascularization or non-coronary revascularization or limb amputation. | 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. |
| Met-HeFT secondary endpoint: Acute myocardial infarction | Through study completion, an average of 4 years | Acute myocardial infarction |
| Met-HeFT secondary endpoint: Stroke | Through study completion, an average of 4 years | Stroke |
| Met-HeFT secondary endpoint: New onset type 2 diabetes | Through study completion, an average of 4 years | New onset type 2 diabetes |
| Met-HeFT secondary endpoint: Hospitalization or death caused by lactic acidosis. | Through study completion, an average of 4 years | Hospitalization or death caused by lactic acidosis. |
| Met-HeFT: All-cause, total (first and subsequent) hospitalizations | Through study completion, an average of 4 years | Any hospitalization |
| Met-HeFT: Change in NT-proBNP from baseline to final follow-up | Through study completion, an average of 4 years | Change in NT-proBNP |
| Met-HeFT: Cardiovascular hospitalizations | Through study completion, an average of 4 years | Any cardiovascular hospitalization |
Countries
Denmark
Contacts
STUDY_CHAIRHenrik Wiggers, MD, PhD
Dept. of Cardiology, Aarhus University Hospital, Aarhus, Denmark
STUDY_CHAIRLars Køber, MD, PhD
Dept. of Cardiology, Rigshospitalet, Copenhagen, Denmark
PRINCIPAL_INVESTIGATORFinn Gustafsson, MD, PhD
Dept. of Cardiology, Rigshospitalet, Copenhagen, Denmark
PRINCIPAL_INVESTIGATORSøren Mellemkjaer, MD, PhD
Dept. of Cardiology, Aarhus University Hospital, Aarhus, Denmark
STUDY_CHAIRGunnar Gislason, MD, PhD
The Danish Heart Foundation, Copenhagen, Denmark
Outcome results
None listed