In-Depth and Fresh Look at Heart Failure Clinical Trials

By Justin L. Grodin, M.D., M.P.H.

Associate Professor of Internal Medicine
Medical Director, Internal Medicine Clinical Trials Unit

At #AHA22, I co-chaired a Featured Science session with Alanna Morris, M.D., M.Sc., from Emory University. Principal investigators of several, recently published pivotal clinical trials in heart failure presented their findings of pre-specified, secondary analyses. These data provided important new insights into both evolving and established treatments for the management of decompensated and chronic heart failure, including: 1) intravenous acetazolamide added to conventional intravenous loop diuretic treatment as treatment for congestion; 2) sodium glucose cotransporter 2 inhibitors; and 3) utility of percutaneous coronary revascularization for the management of ischemic cardiomyopathy.

Two of the studies I want to highlight are pre-specified post hoc analyses from the Acetazolamide in Acute Decompensated Heart Failure with Volume Overload (ADVOR) clinical trial. The first tested whether left ventricular ejection fraction (LVEF) modified the superior decongestive efficacy of acetazolamide versus placebo when added to loop diuretics. The key finding of this analysis was that the benefits of acetazolamide were consistent across the spectrum of LVEF – a clinically important finding that extends this treatment strategy to patients with either heart failure with reduced or preserved LVEF (HFREF or HFPEF, respectively). The second study sought to establish whether the benefits of acetazolamide on decongestion were mediated by natriuresis. Of the 519 ADVOR participants, 460 had urinary collections and urine sodium (UNa) measurements during treatment. There were three key findings from this analysis: 1) greater UNa concentration during treatment was associated with a greater likelihood of successful decongestion (defined as the absence of signs of volume overload within three days after randomization); 2) greater UNa during treatment was associated with lower risk of death or heart failure rehospitalization after discharge; and 3) the superior decongestive efficacy of acetazolamide treatment was mediated by enhanced natriuresis.

The ADVOR study is an important multicenter clinical trial in decompensated heart failure because it demonstrated the superiority of one management strategy over another. These two pre-specified studies advanced our understanding about the role of acetazolamide, when combined with loop diuretics, as a therapy for patients with decompensated heart failure. Specifically, they support the generalizability of this treatment strategy to patients with HFREF and HFPEF, an important observation because both phenotypes are represented equally among patients hospitalized for decompensated heart failure. In addition, these new data emphasized the importance of achieving a negative sodium balance through natriuresis to achieve successful decongestion and clarified that acetazolamide, when added to loop diuretics, facilitates successful decongestion via enhancement of natriuresis.

Email: justin.grodin@utsouthwestern.edu

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