Pulmonary Edema, Congestive Heart Failure, Acute Heart Failure
Conditions
Keywords
acute heart failure, Pulmonary edema
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.
Interventions
A diuretic (iv furosemide) strategy for decongestion in acute heart failure
Vasodilation (iv isosorbide dinitrate) strategy for decongestion in acute heart failure
DRUGFurosemide 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
Sponsors
Rigshospitalet, Denmark
Zealand University Hospital
Copenhagen University Hospital, Hvidovre
Bispebjerg Hospital
Herlev Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Matching and identical placebo (saline)
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Days alive and outside hospital | 30 days | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. | 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 | 30 days | 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 |
| 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 | — |
Countries
Denmark
Contacts
CONTACTJohannes Grand, MD, Phd, MPH
CONTACTJens Jakob Thune, MD, PhD
PRINCIPAL_INVESTIGATORJohannes Grand, PhD
Hvidovre University Hospital
Outcome results
None listed