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