Optimized Treatment of Pulmonary Edema or Congestion

NCT05276219 | Recruiting Phase 4 DMC

• 2 other identifiers: 08102021_ver2.52022-500035-36-01
• Study Type: interventional
• Target: 1,104
• Locations: 1 country
• Sites: 4

Brief Summary

Background: Intravenous (IV) loop-diuretics have been a key component in treating pulmonary edema since the nineteen sixties and has a Class 1 recommendation in the 2021 European Society of Cardiology guidelines for heart failure. Conversely, vasodilation was downgraded in the treatment of acute heart failure due to a lack of trials that compare vasodilation with loop-diuretics in a hyperacute clinical setting. This clinical equipoise will be tested in a trial including patients with pulmonary congestion immediately at hospital admission. Primary objective: To determine the superior strategy of loop-diuretics (furosemide), vasodilation (nitrates) or the combination during emergency treatment. Design: Investigator-initiated, randomized, double-blinded, placebo-controlled trial with 1:1:1 allocation. Intervention: Intervention-phase will last 6 hours from study-inclusion, and patients will be allocated to one of three groups:

• Boluses of 40 mg IV furosemide + nitrate-placebo as soon as possible and repeated up to 10 times.
• Boluses of 3 mg IV isosorbide dinitrate + furosemide-placebo as soon as possible.
• Boluses of both 3 mg IV isosorbide dinitrate + of 40 mg as soon as possible.

Conditions

Pulmonary Edema; Congestive Heart Failure; Acute Heart Failure

Keywords

acute heart failure; Pulmonary edema

Outcome Measures

Primary Outcomes (1)

• Days alive and outside hospital

  The primary end point is the number of days alive and out of hospital during the 30-day period after the hospital-visit. The choice of this end point allow capturing the burden of acute heart failure in terms of mortality, hospital length of stay, and early readmission to the hospital. Patients who died before day 30 will be counted as having zero days alive and out of hospital. A return visit to the emergency department was considered as 1 day in the hospital, using the same approach as a recent trial of acute heart failure.

  30 days

Secondary Outcomes (6)

• Intensification of therapy defined as at least one of: mechanical ventilation, renal replacement therapy, vasopressors, inotropes, or mechanical heart failure treatment.

  30 days

• Clinical benefit at 30 days, consisting of a composite of 1. All-cause death, 2. Intubation with mechanical ventilation, and 3. rehospitalization, assessed using a 'win-ratio' approach.

  30 days

• NT-proBNP at day 1-3

  30 days

• Early Warning Score measured 6-24 hours after start of intervention.

  24 hours

• Adverse events

  30 days

Other Outcomes (9)

• Echocardiographic substudy

  72 hours

• Research biobank-parameters

  24 hours

• FiO2, Blood pressure, respiratory rate, heart rate after 1 hour

  1 hours

Study Arms (3)

Furosemide only

ACTIVE COMPARATOR

• Boluses of 40 mg furosemide given as soon as possible and repeated up to 10 times by the discretion of the treating physician.

Drug: Furosemide Injection

isosorbide dinitrate

ACTIVE COMPARATOR

• Boluses of 3 mg IV isosorbide dinitrate given as soon as possible and repeated up to 10 times by the discretion of the treating physician.

Drug: Isosorbide Dinitrate

isosorbide dinitrate + furosemide

ACTIVE COMPARATOR

• Boluses of both 3 mg IV isosorbide dinitrate + of 40 mg furosemide given as soon as possible and repeated up to 10 times by the discretion of the treating physician.

Drug: Furosemide and isosorbide dinitrate

Interventions

Furosemide Injection DRUG

A diuretic (iv furosemide) strategy for decongestion in acute heart failure

Furosemide only

Isosorbide Dinitrate DRUG

Vasodilation (iv isosorbide dinitrate) strategy for decongestion in acute heart failure

isosorbide dinitrate

Furosemide and isosorbide dinitrate DRUG

Vasodilation (iv isosorbide dinitrate) strategy for decongestion in acute heart failure AND A diuretic (iv furosemide) strategy for decongestion in acute heart failure

isosorbide dinitrate + furosemide

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥ 18 years
• Acute (within minutes to days) onset or worsening of subjective dyspnea\*
• Systolic blood pressure ≥100 mmHg
• Oxygen saturation \<94% or need of oxygen
• Signs or suspicion of congestion (peripheral edema, rales, and/or clinical suspicion of congestion) \*

You may not qualify if:

• More than 40 mg IV furosemide within the last three hours before randomization including prehospital treatment.
• More than 3 hours from hospital-admission to randomization
• Ongoing ventricular taky- or brady-arrythmias or supraventricular arrhythmias with HR \> 180 or \< 40 bpm.
• Suspected severe infection or sepsis.
• If blood pressure drops below 90 mmHg in 2 measurements with 5 minutes apart and/or if urine production is below 50 ml after 1 hour, the intervention will be stopped, and patients can receive furosemide and nitrates freely.
• We purposely chose not to exclude patients with aortic stenosis, since observational studies did not find excess risk of given nitrates to patients with pulmonary edema and aortic stenosis

Sponsors & Collaborators

• Zealand University Hospital: collaborator
• Copenhagen University Hospital, Hvidovre: collaborator
• Bispebjerg Hospital: collaborator
• Rigshospitalet, Denmark: lead
• Herlev Hospital: collaborator

Study Sites (4)

Bispebjerg Hospital

Copenhagen, Copenhagen, 2000, Denmark

RECRUITING

Hvidovre Hospital

Copenhagen, Copenhagen, 2650, Denmark

RECRUITING

Nordsjællands Hospital

Hillerød, Denmark

RECRUITING

Roskilde Hospital

Roskilde, Denmark

NOT YET RECRUITING

MeSH Terms

Conditions

Pulmonary Edema; Heart Failure

Interventions

Furosemide; Isosorbide Dinitrate

Condition Hierarchy (Ancestors)

Lung Diseases; Respiratory Tract Diseases; Heart Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Sulfanilamides; Sulfonamides; Amides; Organic Chemicals; Aniline Compounds; Amines; Sulfones; Sulfur Compounds; Isosorbide; Sorbitol; Sugar Alcohols; Alcohols; Carbohydrates

Study Officials

• Johannes Grand, PhD

  Hvidovre University Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Johannes Grand, MD, Phd, MPH

CONTACT

+4535452121; johannes.grand@regionh.dk

Jens Jakob Thune, MD, PhD

CONTACT

jens.jakob.thune@regionh.dk

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Matching and identical placebo (saline)
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal investigator

Model Details: Inter-regional collaborative, randomized, placebo-controlled trial with 1:1:1 allocation * Boluses of 40 mg furosemide given as soon as possible and repeated up to 10 times by the discretion of the treating physician. * Boluses of 3 mg IV isosorbide dinitrate given as soon as possible and repeated up to 10 times by the discretion of the treating physician. * Boluses of both 3 mg IV isosorbide dinitrate + of 40 mg furosemide given as soon as possible and repeated up to 10 times by the discretion of the treating physician.

Study Record Dates

• First Submitted: January 31, 2022
• First Posted: March 11, 2022
• Study Start: September 14, 2023
• Primary Completion (Estimated): May 31, 2027
• Study Completion (Estimated): May 31, 2027
• Last Updated: April 22, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

DK (4)