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.148 In a very large RCT of hypertensive patients, omapatrilat was associated with a 3-fold increased risk of angioedema as compared with enalapril.149 Blacks and smokers were particularly at risk. The high incidence of angioedema ultimately led to cessation of the clinical development of In light of these observations, angioedema was an exclusion criterion in the first large trial assessing ARNI therapy in patients with hypertension153 and then in the large trial that demonstrated clinical benefit of ARNI therapy in HFrEF.138 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. 7.3.2.11. Ivabradine: Recommendation Recommendation for Ivabradine COR LOE Recommendation Comment/Rationale IIa B-R Ivabradine can be beneficial to reduce HF hospitalization for patients with symptomatic (NYHA class II-III) stable chronic HFrEF (LVEF 35%) who are receiving GDEM*, including a beta blocker at maximum tolerated dose, and who are in sinus rhythm with a heart rate of 70 bpm or greater at rest.154 157 NEW: New clinical trial data. See Online Data Supplement 4. Ivabradine is a new therapeutic agent that selectively inhibits the If current in the sinoatrial node, providing heart rate reduction. One RCT demonstrated the efficacy of ivabradine in reducing the composite endpoint of cardiovascular death or HF The benefit of ivabradine was driven by a reduction in HF hospitalization. 