6 , 2 0 2 1 2 0 2 1 B Y T H E A M E R I C A N C O L L E G E O F C A R D I O L O G Y F O U N D A T I O N P U B L I S H E D B Y E L S E V I E R TABLE OF CONTENTS PREFACE 773 ABSTRACT 774 1. INTRODUCTION 774 2. METHODS 775 3. ASSUMPTIONS AND DEFINITIONS 776 3.1. General Clinical Assumptions 776 3.2. De nitions 776 4. PATHWAY SUMMARY GRAPHIC 776 5. DESCRIPTION AND RATIONALE: ANSWERS TO 10 PIVOTAL ISSUES IN HF 777 5.1. How to Initiate, Add, or Switch to New Evidence-Based Guideline-Directed Therapy for HFrEF 777 5.1.1. Initiating GDMT 779 5.1.2. Angiotensin Receptor-Neprilysin Inhibitor 781 5.1.3. Initiation of an ARNI De Novo Without Prior Exposure to ACEI or ARB 784 5.1.4. Ivabradine 785 Inhibitors 786 5.1.6. Consensus Pathway Algorithm for Initiation and Titration of HFrEF Therapies 787 5.1.7. Severe Mitral Regurgitation and the Use of Transcatheter Mitral Valve Repair . 787 5.1.8. Patients in Whom New Therapies May Not Be Indicated 787 5.2. How to Achieve Optimal Therapy Given Multiple Drugs for HF Including Augmented Clinical Assessment That May Trigger Additional Changes in GDMT (e.g., Imaging Data, Biomarkers, and Filling Pressures) 787 5.2.1. Target Doses 787 5.2.2. Barriers to Medication Titration 788 5.2.3. Clinical Assessment 789 5.2.4. Imaging When to Order an Echocardiogram 789 5.2.5. Biomarkers When to Order Natriuretic Peptides 791 5.2.6. Filling Pressure Assessment When and How to Measure Filling Pressures 792 5.3. When to Refer to an HF Specialist 792 5.4. How to Address Challenges of Care Coordination 792 5.5. How to Improve Adherence 794 5.5.1. Medication Nonadherence 794 5.5.2. 