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Heart FailurePhase 4DANHEARTNCT03514108

DANHEART (H-HeFT and Met-HeFT)

A Phase 4 study testing Hydralazine Isosorbide Dinitrate and Metformin Hydrochloride in people with Heart Failure and Diabetes, run by Henrik Wiggers at 26 sites in Denmark.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Heart Failure, Diabetes
What is being tested?
Hydralazine Isosorbide Dinitrate and Metformin Hydrochloride
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
1,100 participants
Where
26 sitesDenmark
Study dates
1 Mar 2018to 31 Dec 2025
Phase
Phase 4
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.
Show all 20Show fewer
  • 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.

Who cannot join

None listed.

Trial locations and contacts

26 sites in 1 country.

26 sites in 1 country

Denmark26 sites

  • Sygehus Sønderjylland, Aabenraa

    Aabenraa

  • Aalborg University Hospital

    Aalborg

  • Aarhus University Hospital

    Aarhus

  • Amager Hospital

    Copenhagen

  • Bispebjerg Hospital

    Copenhagen

  • Gentofte Hospital

    Copenhagen

  • Glostrup Hospital

    Copenhagen

  • Herlev Hospital

    Copenhagen

  • Hvidovre Hospital

    Copenhagen

  • Rigshospitalet

    Copenhagen

  • Sydvestjysk Sygehus, Esbjerg

    Esbjerg

  • Herning Hospital

    Herning

  • Nordsjællands Hospital Hillerød

    Hillerød

  • Regionshospital Nordjylland, Hjørring

    Hjørring

  • Holbæk Hospital

    Holbæk, Region Sjælland

  • Holbæk Hospital

    Holbæk

  • Horsens Hospital

    Horsens

  • Kolding Hospital

    Kolding

  • Nykøbing Falster Hospital

    Nykøbing Falster

  • Odense University Hospital

    Odense

  • Randers Hospital

    Randers

  • Sjællands Universitetshospital, Roskilde

    Roskilde

  • Silkeborg Hospital

    Silkeborg

  • Slagelse Sygehus

    Slagelse

  • Vejle Hospital

    Vejle

  • Viborg Hospital

    Viborg

Other trials in Denmark

About this study

Official title: 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 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.
Being tested
Hydralazine Isosorbide Dinitrate, Placebo Oral Tablet, Metformin Hydrochloride
Keywords
Heart failure, Diabetes, Insulin resistance, Metformin, Hydralazine, Isosorbide Dinitrate
Medical subject headings
Heart Failure, Diabetes Mellitus, Insulin Resistance

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Hydralazine Isosorbide DinitrateDrug

    Also called BiDil

    Tablet BiDil (Hydralazine 37.5 mg/ Isosorbide Dinitrate (ISDN) 20 mg) 2 tablets x 3 daily

  • Placebo Oral TabletDrug

    2 tablets x 3 daily

  • Metformin HydrochlorideDrug

    Tablet Metformin hydrochloride 500 mg 2 tablets x 2 daily (eGFR 35-60 ml/min: 500 mg x 2 daily)

  • Placebo Oral TabletDrug

    2 tablets x 2 daily (eGFR 35-60 ml/min: 500 mg x 2 daily)

Study groups in NCT03514108
Study groupRoleWhat they receive
Hydralazine Isosorbide DinitrateActive comparatorTablet BiDil (Hydralazine 37.5 mg/ isosorbide dinitrate (ISDN) 20 mg) 2 tablets x 3 daily. Average treatment period 4 years.
Receives: Drug: Hydralazine Isosorbide Dinitrate
Placebo (Hydralazine Isosorbide Dinitrate)Placebo comparatorTablet Placebo 2 tablets x 3 daily. Average treatment period 4 years.
Receives: Drug: Placebo Oral Tablet
MetforminActive comparatorTablet Metformin hydrochloride 500 mg 2 tablets x 2 daily (eGFR 35-60 ml/min: 500 mg x 2 daily). Average treatment period 4 years.
Receives: Drug: Metformin Hydrochloride
Placebo (Metformin)Placebo comparatorTablet Placebo 500 mg 2 tablets x 2 daily (eGFR 35-60 ml/min: 500 mg x 2 daily). Average treatment period 4 years.
Receives: Drug: Placebo Oral Tablet

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. H-HeFT combined primary endpoint

    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.

    Measured: Through study completion, an average of 4 years

  2. Met-HeFT combined primary endpoint

    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

    Measured: Through study completion, an average of 4 years

Secondary outcomes (18)

  1. H-HeFT Death

    Death

    Measured: Through study completion, an average of 4 years

  2. H-HeFT: Heart failure events

    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

    Measured: Through study completion, an average of 4 years

  3. H-HeFT: Death or cardiovascular hospitalization

    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

    Measured: Through study completion, an average of 4 years

  4. H-HeFT combined primary endpoint of total (first and recurrent) events

    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.

    Measured: Through study completion, an average of 4 years

  5. H-HeFT: All-cause, total (first and subsequent) hospitalizations

    Any hospitalization

    Measured: Through study completion, an average of 4 years

  6. H-HeFT: Change in NT-proBNP from baseline to final follow-up

    Change in NT-proBNP from baseline to final follow-up

    Measured: Through study completion, an average of 4 years

  7. H-HeFT: Cardiovascular hospitalizations

    Any cardiovascular hospitalization

    Measured: Through study completion, an average of 4 years

  8. Met-HeFT combined endpoint of total (first and recurrent) events in the primary endpoint

    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

    Measured: Through study completion, an average of 4 years

  9. Met-HeFT secondary endpoint: Death

    Death

    Measured: Through study completion, an average of 4 years

  10. 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

    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

    Measured: Through study completion, an average of 4 years

  11. Met-HeFT Extended clinical endpoint (first event analysis): The primary endpoint or coronary revascularization or non-coronary revascularization or limb amputation.

    Met-HeFT: Extended clinical endpoint (first event analysis): The primary endpoint or coronary revascularization or non-coronary revascularization or limb amputation.

    Measured: Through study completion, an average of 4 years

  12. Met-HeFT secondary endpoint: Acute myocardial infarction

    Acute myocardial infarction

    Measured: Through study completion, an average of 4 years

  13. Met-HeFT secondary endpoint: Stroke

    Stroke

    Measured: Through study completion, an average of 4 years

  14. Met-HeFT secondary endpoint: New onset type 2 diabetes

    New onset type 2 diabetes

    Measured: Through study completion, an average of 4 years

  15. Met-HeFT secondary endpoint: Hospitalization or death caused by lactic acidosis.

    Hospitalization or death caused by lactic acidosis.

    Measured: Through study completion, an average of 4 years

  16. Met-HeFT: All-cause, total (first and subsequent) hospitalizations

    Any hospitalization

    Measured: Through study completion, an average of 4 years

  17. Met-HeFT: Change in NT-proBNP from baseline to final follow-up

    Change in NT-proBNP

    Measured: Through study completion, an average of 4 years

  18. Met-HeFT: Cardiovascular hospitalizations

    Any cardiovascular hospitalization

    Measured: Through study completion, an average of 4 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted2 May 2018
  2. Study start1 Mar 2018
  3. Primary completion31 Dec 2025
  4. Study completion31 Dec 2025

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 4
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Factorial
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.
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
1,100 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03514108
Sponsor's protocol ID
DANHEART
Other IDs
2015-002150-12, 2015
Acronym
DANHEART
Status last verified
Apr 2026
First submitted
20 Feb 2018
Last updated
11 Jun 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

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.

    PubMed 33039340

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Hydralazine Isosorbide Dinitrate and Metformin Hydrochloride in people with Heart Failure and Diabetes, run by Henrik Wiggers at 26 sites in Denmark.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 20 inclusion and 0 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 11 Jun 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 26 sites in Denmark. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

H-HeFT combined primary endpoint (time frame: Through study completion, an average of 4 years). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03514108, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Jun 2026; AzTrials last refreshed its copy on 3 Nov 2026.

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