Clinical trial NCT05276219: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Pulmonary Edema
Congestive Heart Failure
Acute Heart Failure
Keywords: acute heart failure
Pulmonary edema
Lead sponsor: Rigshospitalet, Denmark
Sponsor class: OTHER
Collaborators: name: Zealand University Hospital
name: Copenhagen University Hospital, Hvidovre
name: Bispebjerg Hospital
First posted: 2022-03-11
Enrollment: 1104
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 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.
Primary purpose: TREATMENT

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.

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.

Eligibility 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

Primary outcomes:
measure: Days alive and outside hospital
timeFrame: 30 days
Secondary outcomes:
measure: A composite outcome consisting of 1. all-cause mortality, 2. in-hospital worsening heart failure (WHF) or 3. hospital readmission for HF through Day 30.
timeFrame: 30 days
measure: Worsening heart failure until day 30
timeFrame: 30 days
measure: Rehospitalization for heart failure until day 30
timeFrame: 30 days
measure: Death from all causes until day 30
timeFrame: 30 days
measure: Days alive out-of-intensive care unit until day 30
timeFrame: 30 days
measure: Renal replacement therapy until day 30
timeFrame: 30 days
measure: Quality of life at 30-day follow-up (5Q-DL)
timeFrame: 30 days
measure: Congestion assessed by Lung Ultrasound
timeFrame: 1 day
measure: Time from inclusion to freedom from supplemental oxygen with a saturation >93%
timeFrame: Up to 30 days
Other outcomes:
measure: Pulmonary congestion on chest x-ray the next day
timeFrame: 1 day
measure: Duration of index admission, including hospital-based rehabilitation
timeFrame: Up to 30 days
measure: FiO2, Blood pressure, respiratory rate, heart rate after 1 hour
timeFrame: 1 hours
measure: Echocardiographic parameters (LVEF, %)
timeFrame: After 24 hours after hospital-admission
measure: NT-pro-BNP
timeFrame: After 24 hours after hospital-admission
measure: Myocardial infarction within 48 hours
timeFrame: 2 days
measure: Change in bodyweight from baseline until 2 days (kg)
timeFrame: 2 days
Locations:
city: Copenhagen
country: Denmark
facility: Bispebjerg Hospital
city: Copenhagen
country: Denmark
facility: Hvidovre Hospital
city: Hillerød
country: Denmark
facility: Nordsjællands Hospital
city: Roskilde
country: Denmark
facility: Roskilde Hospital
Study officials:
affiliation: Hvidovre University Hospital
name: Johannes Grand, PhD
role: PRINCIPAL_INVESTIGATOR
References: