N/A Omapatrilat, a neprilysin inhibitor (as well as an ACE inhibitor and aminopeptidase P inhibitor), was associated with a higher frequency of angioedema than that seen with enalapril in an RCT of patients with HFrEF.31 In a very large RCT of hypertensive patients, ompatrilat was associated with a 3-fold increased risk of angioedema as compared with Blacks and smokers were particularly at risk. The high incidence of angioedema ultimately led to cessation of the clinical development of omapatrilat.34,35 In light of these observations, angioedema was an exclusion criterion in the first large trial assessing ARNI therapy in patients with hypertension36 and then in the large trial that demonstrated clinical benefit of ARNI therapy in HFrEF.19 ARNI therapy should not be administered in patients with a history of angioedema because of the concern that it will increase the risk of a recurrence of angioedema. Recommendations for Renin-Angiotensin System Inhibition With ACE Inhibitor or ARB or ARNI (Continued) COR LOE Recommendations Yancy et al Morgane Cibotti-Sun, MPH, Project Manager, Clinical Practice Guidelines American Heart Association Mark A. Creager, MD, FACC, FAHA, President Nancy Brown, Chief Executive Officer Rose Marie Robertson, MD, FAHA, Chief Science and Medical Officer Gayle R. Whitman, PhD, RN, FAHA, FAAN, Senior Vice Presi- dent, Office of Science Operations Comilla Sasson, MD, PhD, FACEP, Vice President, Science and Medicine Jody Hundley, Production Manager, Scientific Publications, Office of Science Operations FOOTNOTES This document was approved by the American College of Cardiology Board of Trustees and Executive Committee, the American Heart Association Science Advisory and Coordinating Committee and Executive Committee, and the Heart Failure Society of America Executive Committee in April 2016. The Comprehensive RWI Data Supplement table is available with this article at http://circ.ahajournals.org/lookup/suppl/ doi:10.1161/CIR.0000000000000435/-/DC1. The Data Supplement is available with this article at CIR.0000000000000435/-/DC2. 