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Optimized Treatment of Pulmonary Edema or Congestion (Decongest)

Primary Purpose

Pulmonary Edema, Congestive Heart Failure, Acute Heart Failure

Status
Recruiting
Phase
Phase 4
Locations
Denmark
Study Type
Interventional
Intervention
Furosemide Injection
Isosorbide Dinitrate
Furosemide and isosorbide dinitrate
Sponsored by
Johannes Grand
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Pulmonary Edema focused on measuring acute heart failure, Pulmonary edema

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Bispebjerg HospitalRecruiting
  • Hvidovre HospitalRecruiting
  • Roskilde Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Active Comparator

Active Comparator

Arm Label

Furosemide only

isosorbide dinitrate

isosorbide dinitrate + furosemide

Arm Description

• 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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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.
Rehospitalization for heart failure until day 30
Any visit to the hospital due to heart failure.
Death from all causes until day 30
Days alive out-of-intensive care unit until day 30
Renal replacement therapy until day 30
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.
Congestion assessed by Lung Ultrasound
Multiple b-lines in at least two windows (yes/no)
Time from inclusion to freedom from supplemental oxygen with a saturation >93%

Full Information

First Posted
January 31, 2022
Last Updated
October 24, 2023
Sponsor
Johannes Grand
Collaborators
Zealand University Hospital, Copenhagen University Hospital, Hvidovre, Bispebjerg Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT05276219
Brief Title
Optimized Treatment of Pulmonary Edema or Congestion
Acronym
Decongest
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

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Recruiting
Study Start Date
September 14, 2023 (Actual)
Primary Completion Date
December 31, 2026 (Anticipated)
Study Completion Date
December 31, 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Johannes Grand
Collaborators
Zealand University Hospital, Copenhagen University Hospital, Hvidovre, Bispebjerg Hospital

4. Oversight

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
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pulmonary Edema, Congestive Heart Failure, Acute Heart Failure
Keywords
acute heart failure, Pulmonary edema

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
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.
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Masking Description
Matching and identical placebo (saline)
Allocation
Randomized
Enrollment
1104 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Furosemide only
Arm Type
Active Comparator
Arm Description
• Boluses of 40 mg furosemide given as soon as possible and repeated up to 10 times by the discretion of the treating physician.
Arm Title
isosorbide dinitrate
Arm Type
Active Comparator
Arm 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.
Arm Title
isosorbide dinitrate + furosemide
Arm Type
Active Comparator
Arm 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.
Intervention Type
Drug
Intervention Name(s)
Furosemide Injection
Intervention Description
A diuretic (iv furosemide) strategy for decongestion in acute heart failure
Intervention Type
Drug
Intervention Name(s)
Isosorbide Dinitrate
Intervention Description
Vasodilation (iv isosorbide dinitrate) strategy for decongestion in acute heart failure
Intervention Type
Drug
Intervention Name(s)
Furosemide and isosorbide dinitrate
Intervention Description
Vasodilation (iv isosorbide dinitrate) strategy for decongestion in acute heart failure AND A diuretic (iv furosemide) strategy for decongestion in acute heart failure
Primary Outcome Measure Information:
Title
Days alive and outside hospital
Description
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.
Time Frame
30 days
Secondary Outcome Measure Information:
Title
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.
Description
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.
Time Frame
30 days
Title
Worsening heart failure until day 30
Description
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.
Time Frame
30 days
Title
Rehospitalization for heart failure until day 30
Description
Any visit to the hospital due to heart failure.
Time Frame
30 days
Title
Death from all causes until day 30
Time Frame
30 days
Title
Days alive out-of-intensive care unit until day 30
Time Frame
30 days
Title
Renal replacement therapy until day 30
Time Frame
30 days
Title
Quality of life at 30-day follow-up (5Q-DL)
Description
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.
Time Frame
30 days
Title
Congestion assessed by Lung Ultrasound
Description
Multiple b-lines in at least two windows (yes/no)
Time Frame
1 day
Title
Time from inclusion to freedom from supplemental oxygen with a saturation >93%
Time Frame
Up to 30 days
Other Pre-specified Outcome Measures:
Title
Pulmonary congestion on chest x-ray the next day
Time Frame
1 day
Title
Duration of index admission, including hospital-based rehabilitation
Time Frame
Up to 30 days
Title
FiO2, Blood pressure, respiratory rate, heart rate after 1 hour
Time Frame
1 hours
Title
Echocardiographic parameters (LVEF, %)
Time Frame
After 24 hours after hospital-admission
Title
NT-pro-BNP
Description
Measured and analysed at each site
Time Frame
After 24 hours after hospital-admission
Title
Myocardial infarction within 48 hours
Description
Assessed by the treating clinician
Time Frame
2 days
Title
Change in bodyweight from baseline until 2 days (kg)
Description
Measured at admission and after 48 hours
Time Frame
2 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion criteria Age ≥ 18 years Acute (within minutes to days) onset or worsening of subjective dyspnea* Systolic blood pressure ≥100 mmHg Oxygen saturation <94% or need of oxygen 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 More than 40 mg IV furosemide within the last three hours before randomization including prehospital treatment. More than 3 hours from hospital-admission to randomization Ongoing ventricular taky- or brady-arrythmias or supraventricular arrhythmias with HR > 180 or < 40 bpm. 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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Johannes Grand, MD, Phd
Phone
+4522817126
Email
johannes.grand@regionh.dk
First Name & Middle Initial & Last Name or Official Title & Degree
Olav Nielsen, MD, PhD, DmSC
Email
olav.wendelboe.nielsen@regionh.dk
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Johannes Grand, PhD
Organizational Affiliation
Hvidovre University Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Bispebjerg Hospital
City
Copenhagen
ZIP/Postal Code
2000
Country
Denmark
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Olav Nielsen
First Name & Middle Initial & Last Name & Degree
Jens Jakob Thune
Facility Name
Hvidovre Hospital
City
Copenhagen
ZIP/Postal Code
2000
Country
Denmark
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Johannes Grand, MD, PhD
Phone
22817126
Email
johannes.grand@regionh.dk
Facility Name
Roskilde Hospital
City
Roskilde
Country
Denmark
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Matias Lindholm
Email
matiasgl@dadlnet.dk

12. IPD Sharing Statement

Plan to Share IPD
No

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Optimized Treatment of Pulmonary Edema or Congestion

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