Nitroglycerin vs. Furosemide Using Lung Ultrasound Pilot Trial

The primary goal of the N-FURIOUS pilot trial is to determine whether a nitrate intense strategy safely reduces congestion, defined by LUS B-lines, better than a diuretic intense strategy.

This pilot trial is designed to provide the necessary and sufficient information for a larger, definitive trial.

PUBLIC HEALTH IMPACT:

Over one million hospitalizations for AHF occur every year in the US. Within 30 days after hospitalization, over 25% of AHF patients will be dead or re-hospitalized. By one year after hospitalization, up to 67% of patients will be re-hospitalized and 36% will be dead. Worldwide, the costs of AHF exceed 100 billion annually. For patients aged 65 years and older, AHF is the most common and most expensive reason for hospitalization. Despite major reductions in morbidity and mortality for chronic HF, considerably less progress has been seen in AHF.

The emergency department (ED) initiates diagnosis and management for the vast majority of AHF patients. Nearly 80% of all admissions originate from the ED. Delays in diagnosis, misdiagnosis, and delayed or improper treatment are costly, associated with greater morbidity and mortality. Despite this crucial starting role, ED AHF pharmacological management today is largely the same as 40 years ago. In fact, guidelines state: "the treatment of AHF remains largely opinion-based with little good evidence to guide therapy." Consensus statements from the American Heart Association as well as a working group from the NHLBI on ED AHF management further corroborate this lack of evidence: "the evidence base on which this foundation of acute care is built is astonishly thin." There remains a critical unmet need for evidence based ED AHF management.

Limitations of Current AHF Therapy:

There are currently no Class I, Level of Evidence A therapeutic guideline recommendations for AHF, highlighting the unmet need. In fact, therapeutic recommendations from the ACCF/AHA begin with hospital based management, highlighting the absence of ED based evidence. The last ED based guidelines were published in 2007 and have yet to be updated. The investigators argue this lack of evidence leads to tremendous variation in ED care. Combined, this contributes to worse outcomes.

Targeting Congestion in AHF:

Freedom from congestion is associated with improved outcomes; yet many patients leave the hospital inadequately decongested. In fact, many patients leave the hospital without a pre-discharge assessment of congestion. The investigators would argue, many ED AHF patients are poorly assessed prior to hospitalization. The absence of robust, reliable methods to assess congestion is a primary reason why it is not assessed. A recent consensus statement published in 2010 highlights this fact: "…no method to assess congestion prior to discharge has been validated." While physical exam is currently the cornerstone of congestion assessment, it lacks sensitivity and inter-rater reliability. The ED is the beginning of AHF management for >75% of admitted patients; delays in diagnosis, misdiagnosis, and resultant delays in management are associated with greater morbidity and mortality.

Initial Therapy:

IV loop diuretics are the mainstay of AHF management. Yet emergency physicians are often reluctant to use IV loop diuretics, largely influenced by small studies and retrospective studies suggesting an association with harm. Nitrates are either recommended above diuretics or even to replace diuretics in popular blogs, podcasts, or online forums. Arguably, neither IV loop diuretics nor nitrates have definitive outcome data regarding efficacy or harm. This is evident in guidelines, where IV loop diuretics receive a class I, B indication, and nitrates a IIb, A recommendation. The evidence that does exist supports their use. Whether one should be used before another, both, how to combine them, and in whom, is not well defined.

Lung Ultrasound as an Endpoint:

For years, the lungs have been considered 'off-limits' to ultrasound: with aerated lungs, the ultrasound beam is reflected and scattered due to acoustic mismatch. However, in the setting of pulmonary congestion, extra vascular lung water (EVLW) can be directly visualized and quantitated. Lung ultrasound measurement of B-lines are an objective, semi-quantitative measure of extra vascular lung water (EVLW). B-lines are well-defined, vertical echogenic lines, originating from water-thickened interlobular septa. They are a marker of congestion.

• Nitrates (Drug), also known as SL or IV Nitrates: For patients randomized to the Nitrate intense arm, the treatment protocol will be initiated and continued until there is a decrease in B-lines to ≤ 15 or 6 hours of care has been delivered, whichever comes first. Treatment protocol: 1. IV furosemide (unless already given) (All patients receive at minimum 20 mg IV furosemide or equivalent) 2. SL nitroglycerin (400 ucg) will be given every 5 minutes, a total of three times. (May be repeated) (Held if SBP decreases to < 120 mmHg) 3. Reassessment every 2 hours. If LUS B-lines >15, repeat step 2. If < 15, stop algorithm.
• Loop Diuretics (Drug), also known as IV Loop Diuretics: For patients randomized to the Diuretic intense arm, the treatment protocol will be initiated and continued until there is a decrease in B-lines to ≤ 15 or 6 hours of care has been delivered, whichever comes first. Treatment protocol: 1. Patients receive 1 inch topical nitropaste 2. IV Loop diuretic dose = patients total oral dose (max dose of 200 mg IV) 3. Reassessment every 2 hours. If LUS B-lines >15, repeat step 2. If < 15, stop algorithm.

Primary outcomes

• The Total Number of B-lines at the Conclusion of ED AHF Management [During the ED phase of management, no more than 6 hours]: The total number of B-lines at the conclusion of ED AHF management or maximum of 6 hours after enrollment, whichever comes first.

Secondary outcomes

• Dyspnea Assessment [During the ED phase of management, no more than 6 hours]: A patient reported measurement of dyspnea using 7-point Likert scales in a standardized position, ranging from Markedly worse, Moderately Worse, Minimally Worse, No Change to Minimally Improved, Moderately Improved, Markedly Improved
• B-lines <= 15 at the Conclusion of ED AHF Management [During the ED phase of management, no more than 6 hours]: B-lines <= 15 at the conclusion of ED AHF management or maximum of 6 hours after enrollment, whichever comes first

Other outcomes

• Total DAOOH [Up through 30 days post discharge]: Total days alive and out of hospital through 30 days post-discharge
• Association of B-lines at Discharge and 30-day Outcome [Up through 30 days post discharge]
• Time to Reach B-lines <15 [Throughout hospitalization, on average 5-7 days]
• Association of Baseline, Discharge, and Change of B-lines With 30-day Outcomes [Up through 30 days post discharge]
• All Cause Readmissions, All Cause ED Re-visits [30 days post discharge]
• Change in Physical Exam Findings and Body Weight From Presentation to Pre-discharge [From admission to pre-discharge from the hospital, on average 5 to 7 days]: Physical exam includes peripheral edema, jugular venous distention, pulmonary and cardiac auscultation

Sex: All, ages: 21 Years to any

Inclusion Criteria:

* Age ≥ 21 years
* Presents with shortness of breath at rest or with minimal exertion
* Clinical diagnosis of AHF and presence of > 15 total bilateral B-lines distributed in at least 4 zones on initial LUS
* Hx of chronic HF and ANY ONE OF THE FOLLOWING:
* \[Chest radiograph consistent with AHF
* Jugular venous distension
* Pulmonary rales on auscultation
* Lower extremity edema
* BNP > 500pg/mL\]

Exclusion Criteria:

* Chronic renal dysfunction, including ESRD or eGFR < 20 ml//min/1.73m2.
* Shock of any kind. Any requirement for vasopressors or inotropes.
* SBP < 120
* Need for immediate intubation
* Acute Coronary Syndrome OR new ST-segment elevation/depression on EKG. (troponin release outside of ACS is allowed)
* Fever >101.5ºF
* End stage HF: transplant list, ventricular assist device
* Anemia requiring transfusion
* Known interstitial lung disease
* Suspected acute lung injury or acute respiratory distress syndrome (ARDS)
* Pregnant or recently pregnant within the last 6 months
* Severe valvular disease
* Anuria
* Allergy or hypersensitivity to nitroglycerin, furosemide or sulfa
* Concern for cardiac tamponade or restrictive cardiomyopathy
* Elevated intracranial pressure
* Recent use of PDE5 inhibitors

Participant flow

Outcome results

• The Total Number of B-lines at the Conclusion of ED AHF Management (Primary), Mean, Number of B-lines: Nitrate Intense Strategy 29 +/- 22.5; Diuretic Intense Strategy 32 +/- 19.4
• Dyspnea Assessment (Secondary), Number, participants: Nitrate Intense Strategy 3; Diuretic Intense Strategy 1
• B-lines <= 15 at the Conclusion of ED AHF Management (Secondary), Count of participants, Participants: Nitrate Intense Strategy 2; Diuretic Intense Strategy 0
• Total DAOOH (Other pre specified)
• Association of B-lines at Discharge and 30-day Outcome (Other pre specified)
• Time to Reach B-lines <15 (Other pre specified)
• Association of Baseline, Discharge, and Change of B-lines With 30-day Outcomes (Other pre specified)
• All Cause Readmissions, All Cause ED Re-visits (Other pre specified)
• Change in Physical Exam Findings and Body Weight From Presentation to Pre-discharge (Other pre specified)

Adverse events

Time frame: The study period during which AEs must be reported begins after informed consent is obtained and initiation of study treatment and for 5 days after ending study treatment. Patients will be followed for 30 days for ED visits, re-hospitalization, and mortality. Subject's hospital discharge summaries will be examined at hospital discharge and all non-exempt AEs will be investigated by examining necessary medical records.

Serious adverse events by term

Other adverse events by term

Limitations and caveats: Due to the COVID-19 pandemic, enrollment was halted. The nature of the study was to enroll patients with AHF signs and symptoms. The principle symptom is shortness of breath, a common symptom during the peak of COVID-19. Further, employees were not allowed into the ED setting to enroll patients, when much less was known about COVID-19.

• Study Protocol and Statistical Analysis Plan (PDF, 2019-07-30)

• Peter S Pang, MD, Principal investigator, Indiana University