A Phase 4 interventional study of Furosemide Injection and Isosorbide Dinitrate in Pulmonary Edema, Congestive Heart Failure and Acute Heart Failure, sponsored by Rigshospitalet, Denmark. Recruiting at 5 sites in Denmark. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2026-08-17.
Sponsored by Rigshospitalet, Denmark · Phase 4, Interventional, and Treatment
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:
IV-loop diuretics are a central part of acute treatment of pulmonary edema and is recommended in guidelines (Class 1 recommendation) with a higher recommendation as compared to vasodilation, which was downgraded from Ia to IIb in the 2021 guidelines for heart failure. However, the effects of loop-diuretics alone or in combination with nitrates compared to nitrates alone is unknown and should be investigated in adequately powered prospective trials to optimize acute treatment of these patients.
Trial objective The primary objective is to determine the superior strategy of urgent treatment (starting within 3 hours after hospital-admission) of pulmonary edema. Strategies are: 1. Diuretics (Furosemide), 2. Vasodilation (nitrates), 3. A combination of both furosemide and nitrates. Patient-outcome will be evaluated through the primary endpoint as described elsewhere.
Hypothesis:
Iv nitrates in combination with iv furosemide are superior compared to iv furosemide alone or iv nitrates alone during initial (first 6 hours) in-hospital treatment of pulmonary edema. "Superior" is defined as a significant benefit on the primary outcome.
Study design The study is an investigator-initiated, randomized, placebo-controlled, double-blinded, multicenter, interventional, clinical trial. Following successful completion of screening procedures, patients will be randomized in a 1:1:1 fashion to receive either of the 3 treatments-strategies.
Since patients are in cardio-respiratory and mental stress, informed consent prior to the intervention will be impossible. Instead, a legal guardian will be contacted and asked for consent in addition to next of kind and patients regaining mental ability.
Signs or suspicion of congestion (peripheral edema, rales, and/or clinical suspicion of congestion) *
Exclusion criteria
Exclusion criteria are purposely liberal, so patients can be included in accordance with everyday clinical practice. However, a safety criterion will be implemented:
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
• 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
• 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
• 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
A diuretic (iv furosemide) strategy for decongestion in acute heart failure
Vasodilation (iv isosorbide dinitrate) strategy for decongestion in acute heart failure
Vasodilation (iv isosorbide dinitrate) strategy for decongestion in acute heart failure AND A diuretic (iv furosemide) strategy for decongestion in acute heart failure
Days alive and outside hospital
The number of days during the 30-day period after the index emergency-department visit that the participant is alive and outside hospital. The outcome captures mortality, duration of the index admission and subsequent hospital readmissions. A return visit to an emergency department is counted as one hospital day.
Time frame: 30 days
Intensification of therapy defined as at least one of: mechanical ventilation, renal replacement therapy, vasopressors, inotropes, or mechanical heart failure treatment.
Time frame: 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.
Time frame: 30 days
NT-proBNP at day 3
Time frame: 3 days
Early Warning Score measured 6-24 hours after start of intervention.
Time frame: 24 hours
Adverse events
An adverse event means any untoward medical occurrence in a subject to whom a medicinal product is administered, and which does not necessarily have a causal relationship with this treatment. Adverse events (AE) will be categorized according to the definitions below. To assess specific adverse events possibly related to the trial intervention, we will collect data on the following during the first 24 hours after inclusion in the trial: Symptomatic hypotension requiring medical treatment Dialysis or renal replacement therapy Potassium below 2.5 mmol/L or above 6.0 mmol/L VF, VT or AF requiring DC conversion New need for pacing Intubation and mechanical ventilation Headache requiring treatment Hearing loss Anaphylaxis
Time frame: First 24 hours after inclusion
Patient-reported dyspnea assessment after 12-24 hours (7-point Likert scales in a standardized position: marked improvement from admission = 3, moderate improvement = 2, slight improvement = 1, no change = 0, slight worsening = -1, moderate worsening = -
Time frame: 24 hours
Echocardiographic substudy
parameters at day 0-3: LVEF, TAPSE, TR-gradient, VCI-size and compressibility, e/é. At Hvidovre and Bispebjerg sites, a transthoracic echocardiography will be performed at 12-72 hours after randomization. o Multiple B-lines in at least two areas on lung ultrasound identifying interstitial syndrome (yes/no) after 12-72 hours.
Time frame: 72 hours
Research biobank-parameters
IL-6, IL-10, copeptin, Soluble CD146 \[43\], carbohydrate antigen-125 \[44\], adrenomedullin \[45\], NT-proBNP \[46\], Neutrophil gelatinase-associated lipocalin (NGAL) \[47\]. Several biomarkers will be analyzed from the research biobank. Blood will be collected at admission day 1 (T24). The research biobank will be analyzed for biomarkers of inflammation, organ injury and other organ specific markers. The research biobank will only be collected at Bispebjerg and Hvidovre sites.
Time frame: 24 hours
FiO2, Blood pressure, respiratory rate, heart rate after 1 hour
Time frame: 1 hours
Myocardial infarction within 48 hours
Assessed by the treating clinician
Time frame: 2 days
FiO2, Blood pressure, respiratory rate, heart rate after 6 hours
Time frame: 6 hours
Number of patients where intervention is terminated (opt out) before 6 hours
Time frame: 1 day
All-cause mortality,
Time frame: 30 days
Days alive out-of-ICU
Time frame: Day 30
Change from inclusion to t24 in creatinine and CRP at the next day after inclusion.
Time frame: 24 hours
Plan to share: No
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Rigshospitalet, Denmark