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.