Optimized Treatment of Pulmonary Edema or Congestion (Decongest)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Congestive Heart Failure; Pulmonary Edema; Acute Heart Failure
• Intervention / Treatment: Drug: Furosemide Injection; Drug: Isosorbide Dinitrate; Drug: Furosemide and isosorbide dinitrate

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.

• Study Type: Interventional
• Enrollment (Estimated): 1104
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Johannes Grand, MD, Phd; Phone Number: +4522817126; Email: johannes.grand@regionh.dk
• Study Contact Backup: Name: Olav Nielsen, MD, PhD, DmSC; Email: olav.wendelboe.nielsen@regionh.dk

Study Locations

• Denmark
  • Copenhagen, Denmark, 2000
    • Recruiting
    • Hvidovre Hospital
    • Contact: Johannes Grand, MD, PhD; Phone Number: 22817126; Email: johannes.grand@regionh.dk
  • Copenhagen, Denmark, 2000
    • Recruiting
    • Bispebjerg Hospital
    • Contact: Olav Nielsen
    • Sub-Investigator: Jens Jakob Thune
  • Roskilde, Denmark
    • Not yet recruiting
    • Roskilde Hospital
    • Contact: Matias Lindholm; Email: matiasgl@dadlnet.dk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Furosemide only; • Boluses of 40 mg furosemide given as soon as possible and repeated up to 10 times by the discretion of the treating physician.	Drug: Furosemide Injection; A diuretic (iv furosemide) strategy for decongestion in acute heart failure
Active Comparator: isosorbide dinitrate; • 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.	Drug: Isosorbide Dinitrate; Vasodilation (iv isosorbide dinitrate) strategy for decongestion in acute heart failure
Active Comparator: isosorbide dinitrate + furosemide; • 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.	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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Days alive and outside hospital	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.	30 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	WHF was defined as progress in signs and/or symptoms of heart failure that lead to an intensification of treatment for heart failure. Such treatment was defined as initiation of mechanical ventilation, renal replacement therapy, vasopressors, inotropes, or mechanical heart failure treatment.	30 days
Worsening heart failure until day 30	WHF was defined as progress in signs and/or symptoms of heart failure that lead to an intensification of treatment for heart failure. Such treatment was defined as initiation of mechanical ventilation, renal replacement therapy, vasopressors, inotropes, or mechanical heart failure treatment.	30 days
Rehospitalization for heart failure until day 30	Any visit to the hospital due to heart failure.	30 days
Death from all causes until day 30		30 days
Days alive out-of-intensive care unit until day 30		30 days
Renal replacement therapy until day 30		30 days
Quality of life at 30-day follow-up (5Q-DL)	The descriptive system comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. The patient is asked to indicate his/her health state by ticking the box next to the most appropriate statement in each of the five dimensions. This decision results in a 1-digit number that expresses the level selected for that dimension. The digits for the five dimensions can be combined into a 5-digit number that describes the patient's health state. The EQ VAS records the patient's self-rated health on a vertical visual analogue scale, where the endpoints are labelled 'The best health you can imagine' and 'The worst health you can imagine'. The VAS can be used as a quantitative measure of health outcome that reflect the patient's own judgement.	30 days
Congestion assessed by Lung Ultrasound	Multiple b-lines in at least two windows (yes/no)	1 day
Time from inclusion to freedom from supplemental oxygen with a saturation >93%		Up to 30 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pulmonary congestion on chest x-ray the next day		1 day
Duration of index admission, including hospital-based rehabilitation		Up to 30 days
FiO2, Blood pressure, respiratory rate, heart rate after 1 hour		1 hours
Echocardiographic parameters (LVEF, %)		After 24 hours after hospital-admission
NT-pro-BNP	Measured and analysed at each site	After 24 hours after hospital-admission
Myocardial infarction within 48 hours	Assessed by the treating clinician	2 days
Change in bodyweight from baseline until 2 days (kg)	Measured at admission and after 48 hours	2 days

Collaborators and Investigators

• Sponsor: Johannes Grand
• Collaborators: Zealand University Hospital; Bispebjerg Hospital; Copenhagen University Hospital, Hvidovre
• Investigators: Principal Investigator: Johannes Grand, PhD, Hvidovre University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): September 14, 2023
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: January 31, 2022
• First Submitted That Met QC Criteria: March 2, 2022
• First Posted (Actual): March 11, 2022

Study Record Updates

• Last Update Posted (Actual): October 25, 2023
• Last Update Submitted That Met QC Criteria: October 24, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: acute heart failure; Pulmonary edema
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Respiratory Tract Diseases; Lung Diseases; Heart Failure; Edema; Pulmonary Edema; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Natriuretic Agents; Membrane Transport Modulators; Diuretics, Osmotic; Diuretics; Sodium Potassium Chloride Symporter Inhibitors; Nitric Oxide Donors; Furosemide; Isosorbide; Isosorbide Dinitrate; Isosorbide-5-mononitrate
• Other Study ID Numbers: 08102021_ver2.5; 2022-500035-36-01 (Other Identifier: euclinicaltrials.eu)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No