DESCRIPTION AND RATIONALE: ANSWERS TO 10 PIVOTAL ISSUES IN HF 5.1. How to Initiate, Add, or Switch to New Evidence-Based Guideline-Directed Therapy for HFrEF Established therapies for chronic HFrEF include ARNIs, angiotensin-converting enzyme inhibitors (ACEIs), angio- tensin receptor blockers (ARBs), beta-blockers, loop di- uretics, aldosterone antagonists, hydralazine/isosorbide dinitrate (HYD/ISDN), and ivabradine, an If channel blocker highly selective for the sinoatrial node pacemaker current. With the exception of loop diuretics, all of these therapies have been shown in randomized controlled trials to improve symptoms, reduce hospitalizations, and/or prolong survival (3). Use of digoxin as a treatment for HFrEF lacks new data; most of its use in modern HFrEF management focuses on its role as a rate control agent for atrial brillation (AF) in those with low blood pressure. Following the publication of the 2017 ECDP focused on optimizing therapy for HFrEF, more data have emerged to support an expanded role for ARNIs in pa- tients with HFrEF. These data include their use as a de novo therapy in some patients naive to ACEIs or ARB therapies (7 10), evidence for rapid improvement in patient-reported outcome measures (e.g., symptoms, physical functioning, and quality of life), and the FIGURE 1 10 Pivotal Issues About Heart Failure With Reduced Ejection Fraction J Maddox et al. demonstration of a reverse-remodeling effect of ARNIs in chronic HFrEF, independent of background therapy with ACEIs/ARBs (11). It is not yet clear that de novo initiation is best for all patients with HFrEF (such as those with hypotension or very advanced HF), and we do recognize access challenges for some patients with regards to payer coverage and associated costs of ARNIs. 