Optimized Treatment of Pulmonary Edema or Congestion

Official title

Vasodilation or Loop-diuretics for Initial Treatment of Pulmonary Edema or Congestion Due to Acute Heart Failure - a Randomized Placebo-controlled Trial

Overview

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.

Detailed description

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.

Interventions

• Drug Furosemide Injection
  A diuretic (iv furosemide) strategy for decongestion in acute heart failure
• Drug Isosorbide Dinitrate
  Vasodilation (iv isosorbide dinitrate) strategy for decongestion in acute heart failure
• Drug Furosemide and isosorbide dinitrate
  Vasodilation (iv isosorbide dinitrate) strategy for decongestion in acute heart failure AND A diuretic (iv furosemide) strategy for decongestion in acute heart failure

Primary outcome measures

• Days alive and outside hospital [Time frame: 30 days]

Secondary outcome measures (6)

• 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 1-3 [Time frame: 30 days]
• Early Warning Score measured 6-24 hours after start of intervention. [Time frame: 24 hours]
• Adverse events [Time frame: 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 = - [Time frame: 24 hours]

Eligibility criteria

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) \*

• by the best assessment from a medical doctor. Inclusion must not wait on x-ray or other measures: patients suspected of pulmonary congestion should be included immediately.

Exclusion criteria

• 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.

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

Denmark · 4 centers

• Bispebjerg Hospital — Copenhagen
• Hvidovre Hospital — Copenhagen
• Nordsjællands Hospital — Hillerød
• Roskilde Hospital — Roskilde

Publications

• 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;299:10 PMID 42044762

Identifiers

NCT: NCT05276219 · 08102021_ver2.5 · 2022-500035-36-01

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗