Combination Angiotensin Receptor Blocker‐Neutral Endopeptidase Inhibitor Provides Additive Blood Pressure Reduction Over Angiotensin Receptor Blocker Alone

COMBINATION ANGIOTENSIN RECEPTOR BLOCKER–NEUTRAL ENDOPEPTIDASE INHIBITOR PROVIDES ADDITIVE BLOOD PRESSURE REDUCTION OVER ANGIOTENSIN RECEPTOR BLOCKER ALONE Hypertension continues to be the single most important cause of morbidity and mortality worldwide. The most recent United States National Health and Nutrition Examination Survey (NHANES) data suggests that blood pressure (BP) control continues to improve in all demographic groups, with 50% of all persons with hypertension and more than 65% of persons also being treated for hypertension currently controlled to the minimum goal of <140 ⁄90 mm Hg. Despite these successes, the pathogenesis of hypertension remains extremely heterogeneous and, since most patients require 2 antihypertensive agents to control BP, the hypertension community continues to look for new and innovative pathophysiologic approaches for BP control. Vasopeptidase inhibitors simultaneously block 2 key enzymes involved in the regulation of cardiac function: (1) neprilysin (neutral endopeptidase [NEP]), which increases concentrations of natriuretic peptides and also inhibits the renin-angiotensin-aldosterone and sympathetic nervous system, and (2) angiotensin-converting enzyme (ACE). The most widely studied vasopeptidase inhibitor, omapatrilat, has been found to be a potent BP-lowering agent; however, since its use was associated with an increased risk for angioedema, believed to occur as a result of bradykinin upregulation, it was never approved for clinical use. Because angiotensin receptor blockers (ARBs) are believed to have less effect on bradykinin metabolism, agents that combine NEP inhibition with agents that block the angiotensin II receptor (ARBs) might be associated with the cardiac benefits of vasopeptidase inhibition without the increased risk for angioedema. Developed using a radiographic crystallographic technique, LCZ696 is a first-in-class dual-acting angiotensin II receptor and NEP inhibitor (ARNI) that combines the ARB valsartan with AHU377, its NEP inhibitor moiety. The present industry sponsored proof-of-concept trial was designed to establish whether LCZ696 leads to greater reduction of BP compared with the ARB valsartan. Recruited from 134 sites in 18 countries (including the United States) between September 2007 and March 2008, eligible patients had to be aged between 18 and 75 years and have uncomplicated essential hypertension (mean sitting diastolic BP 90–109 mm Hg after antihypertensive drug washout or 95–109 mm Hg if untreated). Exclusion criteria included severe hypertension (mean sitting systolic BP 180 mm Hg), history of angioedema or allergy to an ARB or NEP inhibitor, type 1 or 2 diabetes, secondary hypertension, a serious structural or functional cardiac disorder, significant hepatic or renal disease, clinically important anemia, or abnormal serum sodium or potassium concentrations. In addition, use of certain medications were prohibited, including antihypertensives other than those specified in the protocol, antiarrhythmics, tricyclic antidepressants and monoamine oxidase inhibitors, systemic corticosteroids, nonsteroidal anti-inflammatory drugs, chronic sympathomimetic use, bile acid resins, a-blockers, and phosphodiesterase inhibitors taken within 48 hours of scheduled visits. From the Department of Internal Medicine, University of Nevada School of Medicine, Medical Director, Risk Reduction Center, Saint Mary’s Regional Medical Center; and the Seinsheimer Cardiovascular Health Program, Division of General Internal Medicine ⁄ Geriatrics, Medical University of South Carolina, Ralph H. Johnson VA Medical Center, Charleston, SC Address for correspondence: Michael J. Bloch, MD, Risk Reduction Center, Saint Mary’s Regional Medical Center, 645 North Arlington Street, Suite 460, Reno, NV 89503 E-mail: mbloch@aol.com