DECONGEST-AHF is an investigator-initiated, pragmatic, randomized, placebo-controlled, double-blinded, multicenter, interventional, clinical trial. Patients will be randomized in a 1:1:1 fashion to receive either of the 3 strategies: intravenous furosemide, intravenous nitrates, or the combination of the 2.

The trial includes patients in the hyper-acute emergency setting, where inclusion occurs directly in the emergency departments at participating sites. Due to the severity of the patients’ condition, informed consent prior to intervention is neither feasible nor ethical. In accordance with current European and Danish regulations on emergency research, eligible patients will be enrolled without prior consent. Immediately upon inclusion, an independent trial guardian is electronically notified and provides surrogate consent on behalf of the patient. Consent from the patient will be obtained as soon as capacity is regained, or alternatively from a next of kin.

The participating centers include Copenhagen University Hospital––Amager and Hvidovre, Copenhagen University Hospital––Bispebjerg and Frederiksberg, North Zealand Hospital, Zealand University Hospital, and Copenhagen University Hospital––Herlev and Gentofte.

Patients are eligible if they are adults presenting with acute or worsening dyspnea, systolic blood pressure ≥100 mmHg, oxygen saturation <94% on room air, or a clinical need for supplemental oxygen, and signs or suspicion of congestion, with enrollment occurring within 3 hours of hospital arrival. Eligibility is determined based on bedside clinical assessment in the emergency department. Acute dyspnea refers to symptom onset or worsening within minutes to days prior to presentation. In Danish emergency departments, oxygen is administered based on documented hypoxemia or clinical respiratory compromise and is not routinely given in the absence of an indication. Clinical signs of congestion are assessed by the treating physician and may include peripheral edema, pulmonary rales, orthopnea, increased work of breathing, or an overall clinical impression of fluid overload consistent with acute heart failure. Additional diagnostic examinations, such as chest radiography, lung ultrasound, or echocardiography, may support the diagnosis but are not required for enrollment to avoid delaying treatment in the hyper-acute setting.

Patients are excluded if they have received more than 50 mg of intravenous furosemide in the previous 3 hours or have severe arrhythmia or suspected sepsis. Inclusion and exclusion criteria are provided in Table 1 .

When a patient arrives at the emergency department or is admitted directly to the department of cardiology with suspicion of acute heart failure, the treating physician will assess trial eligibility based on the inclusion and exclusion criteria ( Table 1 ). If the patient meets the criteria, the treating physician selects a sealed study box containing the trial medicine, and the patient is enrolled in the study. As inclusion is based solely on routine clinical assessment and requires no additional procedures, the trial intervention can be initiated immediately upon admission.

The study medication is centrally prepared, labeled, and packaged by the Pharmacy of the Capital Region of Copenhagen (Marielundvej 25, DK-2730 Herlev), which is approved by the Danish Health Authorities. Study drugs and matching placebos are pre-packaged into individually sealed, sequentially numbered boxes according to a computer-generated randomization sequence generated using the online tool Sealed Envelope ( www.sealedenvelope.com ). The boxes are prepared by trained healthcare professionals at the pharmacy and validated by an independent staff member before sealing. Each box contains the complete treatment course for 1 participant, thereby ensuring that repeated dosing within the 6-hour intervention window is administered from the same randomized allocation.

Labeling includes a study ID and a unique box number linked to the participant ID in the electronic case report form. No information on treatment allocation is visible on the packaging. As active treatment and placebo are visually indistinguishable, neither the treating clinician, the participant, nor the study investigators can identify the allocated treatment.

Patients receive trial medication from the selected study box and are thereby randomly allocated to 1 of 3 intervention strategies ( Figure 1 ). One dosage of the study drug consists of either:

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  Loop diuretics only: 40 mg intravenous furosemide + nitrate-placebo.

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  Nitrates only: 3 mg intravenous isosorbide dinitrate + furosemide-placebo.

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  Combination: 3 mg intravenous isosorbide dinitrate + 40 mg intravenous furosemide.

Trial flow chart. ED , Emergency Department; ICU , intensive care unit; IV , intravenous.

Administration can be repeated up to 10 times within a 6-hour intervention window, depending on clinical need. During this period, non-study diuretics and vasodilators are withheld, while other standard treatments remain at the physician’s discretion.

If clinical deterioration occurs or the treating physician deems it necessary to deviate from the study protocol, the intervention will be discontinued, and standard treatment resumed. The time of treatment discontinuation will be recorded as an outcome. Criteria for early termination of the intervention are outlined in Table 2 . The trial medication is visually identical to standard hospital preparations, with some containing saline as a placebo, ensuring that all study medications will be administered in a double-blinded manner by clinical staff. In case of medical urgency, unblinding is possible but not anticipated, as treatment can be adjusted by simply discontinuing study medication and initiating standard therapy.

At Copenhagen University Hospitals––Amager and Hvidovre, and Bispebjerg and Frederiksberg, a predefined echocardiography sub-study will be conducted. Transthoracic echocardiography will be performed by study personnel within the first 3 days of hospitalization, with specific parameters outlined in Table 3 . Lung ultrasound will be performed concurrently to evaluate the decongestive effects of the intervention.

At these sites, blood samples for biobanking will be collected 24 hours after the intervention, as detailed in Table 3 . NT-proBNP will be measured at all sites 24 hours after the intervention.

The primary outcome is the number of days alive and out of the hospital at day 30, calculated from the date of index hospitalization. This composite measure encompasses mortality, length of hospital stays, and early readmission, in line with the European Society of Cardiology consensus paper.

Secondary outcomes include therapy intensification, defined as the initiation of mechanical ventilation, renal replacement therapy, vasopressors, inotropes, or mechanical circulatory support. Clinical benefit at 30 days will be assessed as a composite of all-cause mortality, mechanical ventilation, or rehospitalization, using a win-ratio analysis. Patient-reported dyspnea will also be evaluated once within 12 to 24 hours postintervention. Patients rate their current level of breathlessness compared with their condition at admission using a standardized 7-point Likert-scale, thereby capturing change relative to baseline status. Additional secondary outcomes include NT-proBNP levels, primarily measured on day 1, with samples obtained up to day 3 accepted if necessary. National Early Warning Score is recorded repeatedly during the first 24 hours as part of routine clinical monitoring (at arrival, at intervention, and at 2, 4, and 6 hours after intervention, as well as the latest assessment on day 0 and the routine morning assessment on day 1 (approximately 08:00). The Early Warning Score is a standardized clinical tool used in regional hospitals to detect early signs of patient deterioration by producing an aggregated score based on vital parameters, including respiratory rate, blood pressure, heart rate, temperature, oxygen saturation, and level of consciousness.

Safety outcomes will include 1 of the following: symptomatic hypotension requiring medical treatment, renal impairment requiring dialysis, significant electrolyte disturbances (hypokalemia <2.5 mmol/L or hyperkalemia >6.0 mmol/L), cardiac arrhythmia requiring intervention, respiratory failure requiring mechanical ventilation, headache requiring treatment, hearing loss, and anaphylaxis. Adverse events will be monitored from the first study dose and for 24 hours following the final study dose. Serious adverse events will be recorded during the initial hospitalization and assessed for potential relation to the intervention. Full details for the endpoints are provided in Table 3 .