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| ID | Type | Description | Link |
|---|---|---|---|
| 2022-500035-36-01 | Other Identifier | euclinicaltrials.eu |
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| Name | Class |
|---|---|
| Zealand University Hospital | OTHER |
| Copenhagen University Hospital, Hvidovre | OTHER |
| Bispebjerg Hospital | OTHER |
| Herlev Hospital |
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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. |
|
| 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. |
|
| 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Furosemide Injection | Drug | A diuretic (iv furosemide) strategy for decongestion in acute heart failure |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | 72 hours |
Inclusion criteria
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) *
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
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Johannes Grand, MD, Phd, MPH | Contact | +4535452121 | johannes.grand@regionh.dk | |
| Jens Jakob Thune, MD, PhD | Contact | jens.jakob.thune@regionh.dk |
| Name | Affiliation | Role |
|---|---|---|
| Johannes Grand, PhD | Hvidovre University Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Bispebjerg Hospital | Recruiting | Copenhagen | Copenhagen | 2000 | Denmark |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 42044762 | Derived | Olesen ASO, Lukoschewitz JD, Taraldsen IA, Najim A, El Caidi NO, Haastrup SB, Tonning S, Mottlau RG, Nygaard H, Doleman B, Nielsen SJ, Thomsen JH, Hove JD, Seven E, Folke F, Lindholm MG, Jakobsen JC, Thune JJ, Grand J. Vasodilation, loop diuretics, or their combination in acute heart failure: Rationale and design of the randomized placebo-controlled DECONGEST-AHF trial. Am Heart J. 2026 Sep;299:107461. doi: 10.1016/j.ahj.2026.107461. Epub 2026 Apr 25. |
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| ID | Term |
|---|---|
| D011654 | Pulmonary Edema |
| D006333 | Heart Failure |
| ID | Term |
|---|---|
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| D006331 | Heart Diseases |
| D002318 | Cardiovascular Diseases |
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| ID | Term |
|---|---|
| D005665 | Furosemide |
| D007548 | Isosorbide Dinitrate |
| ID | Term |
|---|---|
| D013424 | Sulfanilamides |
| D013449 | Sulfonamides |
| D000577 | Amides |
| D009930 | Organic Chemicals |
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| OTHER |
Inter-regional collaborative, randomized, placebo-controlled trial with 1:1:1 allocation
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Matching and identical placebo (saline)
| Isosorbide Dinitrate | Drug | Vasodilation (iv isosorbide dinitrate) strategy for decongestion in acute heart failure |
|
| 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 |
|
| 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 | 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 needing medical therapy • Renal impairment: Need for continuous renal replacement therapy or intermittent hemodialysis • Electrolyte disorders: Hypokalemia (<2.5 mM), hyperkalemia (>6.0 mM) • Cardiac arrhythmias: VF, VT and AF requiring DC conversion, new need for pacing • Respiratory: Intubation and mechanical ventilation during admission • Headache requiring treatment, • Loss of hearing • Anaphylaxis | 30 days |
| 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 = - | 24 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. | 24 hours |
| FiO2, Blood pressure, respiratory rate, heart rate after 1 hour | 1 hours |
| Myocardial infarction within 48 hours | Assessed by the treating clinician | 2 days |
| FiO2, Blood pressure, respiratory rate, heart rate after 6 hours | 6 hours |
| Number of patients where intervention is terminated (opt out) before 6 hours | 1 day |
| All-cause mortality, | 30 days |
| Days alive out-of-ICU | Day 30 |
| Change from inclusion to t24 in creatinine and CRP at the next day after inclusion. | 24 hours |
| Hvidovre Hospital | Recruiting | Copenhagen | Copenhagen | 2650 | Denmark |
|
| Nordsjællands Hospital | Recruiting | Hillerød | Denmark |
|
| Roskilde Hospital | Not yet recruiting | Roskilde | Denmark |
|
| D000814 |
| Aniline Compounds |
| D000588 | Amines |
| D013450 | Sulfones |
| D013457 | Sulfur Compounds |
| D007547 | Isosorbide |
| D013012 | Sorbitol |
| D013402 | Sugar Alcohols |
| D000438 | Alcohols |
| D002241 | Carbohydrates |