Optimized Treatment of Pulmonary Edema or Congestion (Decongest)

Johannes Grand

Status and phase: Enrolling; Phase 4

Conditions: Acute Heart Failure; Pulmonary Edema; Congestive Heart Failure

Treatments: Drug: Furosemide and isosorbide dinitrate; Drug: Furosemide Injection; Drug: Isosorbide Dinitrate

Study type: Interventional

Funder types: Other

Identifiers

NCT05276219

2022-500035-36-01 (Other Identifier)

08102021_ver2.5

Details and patient eligibility

About

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.

Full 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.

Enrollment: 1,104 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Inclusion criteria

1. Age ≥ 18 years

2. Acute (within minutes to days) onset or worsening of subjective dyspnea*

3. Systolic blood pressure ≥100 mmHg

4. Oxygen saturation <94% or need of oxygen

5. 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

1. More than 40 mg IV furosemide within the last three hours before randomization including prehospital treatment.
2. More than 3 hours from hospital-admission to randomization
3. Ongoing ventricular taky- or brady-arrythmias or supraventricular arrhythmias with HR > 180 or < 40 bpm.
4. 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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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1,104 participants in 3 patient groups

Furosemide only

Active Comparator group

Description:

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

Treatment:

Drug: Furosemide Injection

isosorbide dinitrate

Active Comparator group

Description:

• 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.

Treatment:

Drug: Isosorbide Dinitrate

isosorbide dinitrate + furosemide

Active Comparator group

Description:

• 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.

Treatment:

Drug: Furosemide and isosorbide dinitrate