Angiotensin receptor neprilysin inhibition in heart failure: mechanistic action and clinical impact.
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2015-09
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Heart failure (HF) is an increasingly common syndrome associated with high mortality and economic burden, and there has been a paucity over the past decade of new pharmacotherapies that improve outcomes. However, recent data from a large randomized controlled trial compared the novel agent LCZ696, a dual-acting angiotensin receptor blocker and neprilysin inhibitor (ARNi), with the well established angiotensin-converting enzyme (ACE) inhibitor enalapril and found significant reduction in mortality among the chronic reduced ejection fraction HF population. Preclinical and clinical data suggest that neprilysin inhibition provides beneficial outcomes in HF patients by preventing the degradation of natriuretic peptides and thereby promoting natriuresis and vasodilatation and counteracting the negative cardiorenal effects of the up-regulated renin-angiotensin-aldosterone system. Agents such as omapatrilat combined neprilysin and ACE inhibition but had increased rates of angioedema. Goals of an improved safety profile provided the rationale for the development of the ARNi LCZ696. Along with significant reductions in mortality and hospitalizations, clinical trials suggest that LCZ696 may improve surrogate markers of HF severity. In this paper, we review the preclinical and clinical data that led to the development of LCZ696, the understanding of the underlying mechanistic action, and the robust clinical impact that LCZ696 may have in the near future.
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Buggey, Jonathan, Robert J Mentz, Adam D DeVore and Eric J Velazquez (2015). Angiotensin receptor neprilysin inhibition in heart failure: mechanistic action and clinical impact. J Card Fail, 21(9). pp. 741–750. 10.1016/j.cardfail.2015.07.008 Retrieved from https://hdl.handle.net/10161/11016.
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Adam David DeVore
Adam D. DeVore, MD, MHS
Dr. DeVore is a cardiologist and Associate Professor of Medicine in the Department of Medicine, Division of Cardiology, at Duke University School of Medicine. His clinical interests include caring for patients and families with heart failure, including those with left ventricular assist devices and heart transplants. He is involved in and leads multiple large studies of patients with heart failure at both Duke University Medical Center and the Duke Clinical Research Institute. He currently serves as the medical director of the Duke Heart Transplant program.
He attended medical school at the University of Chicago Pritzker School of Medicine and completed internal medicine residency at Brigham and Women’s Hospital. He then pursued cardiology training at Duke University and solidified his interests in clinical research and heart failure. He completed a research fellowship at the Duke Clinical Research Institute and a Masters of Health Sciences in Clinical Research before completing an advanced heart failure fellowship at Duke University.
The overarching goals of his research are to advance the current understanding of heart failure through clinical trials as well as develop an evidence base for implementation strategies that addresses the gap between heart failure trial results and clinical practice. For example, he has served on the Steering Committees for large clinical trials, including PIONEER-HF and SPIRRIT-HFpEF. Dr. DeVore also published the first clinical trial conducted within the American Heart Association’s Get With The Guidelines-Heart Failure program, a registry-based cluster randomized trial of quality improvement interventions. He was also the principal investigator for CONNECT-HF, a large-scale, pragmatic, cluster-randomized trial at 161 sites in the US evaluating heart failure quality improvement initiatives. Outside of his work on heart failure, Dr. DeVore is married with 4 children and spends his time corralling them all and coaching youth baseball.
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