EXPERT CONSENSUS DECISION PATHWAY 2021 Update to the 2017 ACC Expert Consensus Decision Pathway for Optimization of Heart Failure Treatment: Answers to 10 Pivotal Issues About Heart Failure With Reduced Ejection Fraction A Report of the American College of Cardiology Solution Set Oversight Committee Writing Committee Thomas M. Maddox, MD, MSC, FACC, Chair James L. Januzzi, JR, MD, FACC, Vice Chair Larry A. Allen, MD, MHS, FACC Khadijah Breathett, MD, MS, FACC Javed Butler, MD, MBA, MPH, FACC Leslie L. Davis, PHD, RN, ANP-BC, FACC Gregg C. Fonarow, MD, FACC Nasrien E. Ibrahim, MD, FACC JoAnn Lindenfeld, MD, FACC Frederick A. Masoudi, MD, MSPH, FACC Shweta R. Motiwala, MD, MPH Estefania Oliveros, MD, MSC J. Herbert Patterson, PHARMD Mary Norine Walsh, MD, MACC Alan Wasserman, MD, FACC Clyde W. Yancy, MD, MSC, MACC Quentin R. Youmans, MD Solution Set Oversight Committee Ty J. Gluckman, MD, FACC, Chair Niti R. Aggarwal, MD, FACC Nicole M. Bhave, MD, FACC Gregory J. Dehmer, MD, MACC Olivia N. Gilbert, MD, MSc, FACC Chayakrit Krittanawong, MD Dharam J. Kumbhani, MD, SM, FACC Javier A. Sala-Mercado, MD, PhD David E. Winchester, MD, MS, FACC Martha Gulati, MD, MS, FACC Ex Of cio This document was approved by the American College of Cardiology Clinical Policy Approval Committee in November 2020. The American College of Cardiology requests that this document be cited as follows: Maddox TM, Januzzi JL Jr., Allen LA, Breathett K, Butler J, Davis LL, Fonarow GC, Ibrahim NE, Lindenfeld J, Masoudi FA, Motiwala SR, Oliveros E, Patterson JH, Walsh MN, Wasserman A, Yancy CW, Youmans QR. 2021 update to the 2017 ACC expert consensus decision pathway for optimization of heart failure treatment: answers to 10 pivotal issues about heart failure with reduced ejection fraction: a report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol 2021;77:772 810. Copies: This document is available on the website of the American College of Cardiology (http://www.acc.org). For copies of this document, please contact Elsevier Inc. Reprint Department via fax (212 633-3820) or e-mail (reprints@elsevier.com). Permissions: Multiple copies, modi cation, alteration, enhancement, and/or distribution of this document are not permitted without the express permission of the American College of Cardiology. Requests may be completed online via the Elsevier site (https://www.elsevier.com/about/policies/ copyright/permissions). J O U R N A L O F 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 V O L . 7 7 , N O . 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. General Approaches to Improving Adherence 794 5.5.3. System and Policy to Promote Adherence 796 5.6. What Is Needed in Speci c Patient Cohorts: African Americans, Older Adults, and the Frail . 796 5.7. How to Manage Your Patients Cost and Access to HF Medications 797 5.8. How to Manage the Increasing Complexity of HF Management 798 5.9. How to Manage Common Comorbidities 800 5.10. How to Integrate Palliative Care and Transition to Hospice Care 800 6. DISCUSSIONS AND IMPLICATIONS OF PATHWAY 802 ACC PRESIDENT AND STAFF 802 Author Relationships With Industry and Other Entities (RELEVANT) 807 Peer Reviewer Information 809 Abbreviations 810 PREFACE The American College of Cardiology (ACC) has a long history of developing documents (e.g., decision path- ways, health policy statements, appropriate use criteria) J Maddox et al. to provide members with guidance on both clinical and nonclinical topics relevant to cardiovascular (CV) care. In most circumstances, these documents have been created to complement clinical practice guidelines and to inform clinicians about areas where evidence may be new and evolving or where suf cient data may be more limited. Despite this, numerous care gaps continue to exist, highlighting the need for more streamlined and ef cient processes to implement best practices in service to improved patient care. Central to the ACC s strategic plan is the generation of actionable knowledge a concept that places emphasis on making clinical information easier to consume, share, integrate, and update. To this end, the ACC has evolved from developing isolated documents to developing inte- grated solution sets. Solution sets are groups of closely related activities, policy, mobile applications, decision support, and other tools necessary to transform care and/ or improve heart health. Solution sets address key ques- tions facing care teams and attempt to provide practical guidance to be applied at the point of care. They use both established and emerging methods to disseminate infor- mation for CV conditions and their related management. The success of the solution sets rests rmly on their ability to have a measurable impact on the delivery of care. Because solution sets re ect current evidence and ongoing gaps in care, the associated content will be re ned over time to best match changing evidence and member needs. Expert consensus decision pathways (ECDPs) represent a key component of solution sets. The methodology for ECDPs is grounded in assembling a group of clinical ex- perts to develop content that addresses key questions facing our members across a range of high-value clinical topics (1). This content is used to inform the development of various tools that accelerate real-time use of clinical policy at the point of care. They are not intended to pro- vide a single correct answer; rather, they encourage cli- nicians to ask questions and consider important factors as they de ne treatment plans for their patients. Whenever appropriate, ECDPs seek to provide uni ed articulation of clinical practice guidelines, appropriate use criteria, and other related ACC clinical policy. In some cases, covered topics will be addressed in subsequent clinical practice guidelines as the evidence base evolves. In other cases, these will serve as stand-alone policy. Ty J. Gluckman, MD, FACC Chair, ACC Solution Set Oversight Committee ABSTRACT The 2017 ACC Expert Consensus Decision Pathway for Optimization of Heart Failure Treatment was created to provide a practical, streamlined resource for clinicians managing patients with heart failure with reduced ejec- tion fraction (HFrEF) (2). The 2017 ECDP was based on the 2013 ACCF/American Heart Association (AHA) Guideline for the Management of Heart Failure and the 2017 ACC/ AHA/Heart Failure Society of America (HFSA) Focused Update of the 2013 Guideline (3,4). The 2017 ECDP pro- vided guidance on introducing the numerous evidence- based therapies, improving adherence, overcoming treatment barriers, acknowledging contraindications and situations for which little data exist, affording expensive therapies, treating special cohorts, and making the tran- sition to palliative care. Rather than focusing on extensive text, the document provided practical tips, tables, and gures to make clear the steps, tools, and provisos needed to successfully and expeditiously treat the patient with HFrEF. Many of the pivotal issues addressed in the ECDP were not the substance of clinical trials; rather, they represent the challenge of clinical practice. Since the 2017 ECDP, new therapies for HFrEF have emerged that expand the armamentarium for the treat- ment of patients with HFrEF. In particular, the emergence of angiotensin receptor-neprilysin inhibitors (ARNIs), sodium-glucose cotransporter-2 (SGLT2) inhibitors, and percutaneous therapy for mitral regurgitation (MR) represent signi cant advances in the treatment of HFrEF. As such, a focused update to the 2017 ECDP that in- corporates these advances into the recommendations is warranted. This update can serve as interim guidance to clinicians while we await the comprehensive and de ni- tive heart failure (HF) guideline update under develop- ment by the ACC. The treatment of HFrEF can feel overwhelming, and many opportunities to improve pa- tient outcomes are being missed; hopefully, this ECDP will streamline care to realize the best possible patient outcomes in HF. The prevalence of HF is escalating rapidly (5). Com- pounding this, HF is an illness that consumes substantial healthcare resources, in icts considerable morbidity and mortality, and greatly affects quality of life. Important breakthroughs have rede ned opportunities to change Maddox et al. J the natural history of the disease with a broad range of medical therapies, devices, and care strategies. The purpose of this focused ECDP update is to sup- plement the 2017 ECDP with data from emerging studies and to continue to provide succinct, practical guidance for managing patients with HFrEF. The format of the 10 Pivotal Issues in the 2017 ECDP was preserved, and their associated treatment algorithms and tables have been updated to accommodate this new, evolving evidence. Ten Pivotal Issues in HFrEF 1. How to initiate, add, or switch therapies to new evidence-based guideline-directed treatments for HFrEF. 2. How to achieve optimal therapy given multiple drugs for HF including augmented clinical assessment (e.g., imaging data, biomarkers, and lling pressures) that may trigger additional changes in guideline-directed therapy. 3. When to refer to an HF specialist. 4. How to address challenges of care coordination. 5. How to improve medication adherence. 6. What is needed in speci c patient cohorts: African Americans, older adults, and the frail. 7. How to manage your patients costs and access to HF medications. 8. How to manage the increasing complexity of HF. 9. How to manage common comorbidities. 10. How to integrate palliative care and the transition into hospice care. The original 2017 ACC ECDP was drafted using a struc- tured format that was created subsequent to the release of the 2016 and 2017 ACC/AHA/HFSA focused updates of the 2013 ACCF/AHA HF guideline (2,4,6). The evolution of that ECDP involved developing questions to identify ev- idence gaps and convening a multidisciplinary panel of stakeholders who carried out a literature review to aggregate relevant evidence addressing contemporary HF care. At that time, the references were separately reviewed by the Chair and Vice Chair of the ECDP, and an agreed-upon compendium was developed. Print copies of the references were provided to each member of the panel before a live roundtable meeting held on July 19, 2016, at the ACC Heart House. Participants attending the HF roundtable included cardiologists, internists, emergency physicians, hospitalists, nurses, representatives from pa- tient advocacy groups, pharmacists, fellows-in-training, quality improvement experts, epidemiologists, and biostatisticians. Since the publication of the 2017 ECDP, numerous clinical trials have been reported, providing updated knowledge to inform the clinical management of patients with HFrEF. In addition, more knowledge is now available regarding biomarkers and imaging, management of comorbidities, and the mitigation of dif culties encoun- tered in care coordination. Lastly, the considerable impact of the coronavirus disease 2019 (COVID-19) pandemic on outpatient management of chronic disease states such as HFrEF justi es its consideration in this document. To address these newer data and how they relate to prior logic for clinical management of HFrEF, the ACC convened structured discussions to address new thera- pies, unanswered questions, adherence, and imple- mentation strategies. The College also convened multidisciplinary panel discussions, which have been archived for online distribution (https://www.acc.org/ tools-and-practice-support/quality-programs/succeed-in- managing-heart-failure-initiative/emerging-strategies-for- heart-failure-roundtable). Based on those discussions, a writing committee was formed to provide practical guid- ance to address gaps in care related to optimal manage- ment of HF treatment. For this 2021 update, the writing committee convened in mid-2020 on con dential con- ference calls attended only by writing committee mem- bers and ACC staff. When consensus within the writing committee was deemed necessary by the Chair and Vice Chair, either a roll call vote or an email-generated ballot was implemented. A simple majority prevailed; in the presence of a tie, the Chair s prerogative reconciled the nal decision. The formal peer-review process was completed consistent with ACC policy and included a public comment period to obtain further feedback. Following reconciliation of all comments, this document was approved for publication by the Clinical Policy Approval Committee. The ACC and the Solution Set Oversight Committee (SSOC) recognize the importance of avoiding real or J Maddox et al. perceived relationships with industry (RWI) or other en- tities that may affect clinical policy. The ACC maintains a database that tracks all relevant relationships for ACC members and persons who participate in ACC activities, including those involved in the development of ECDPs. ECDPs follow ACC RWI Policy in determining what con- stitutes a relevant relationship, with additional vetting by the SSOC. ECDP writing groups must be chaired or co-chaired by an individual with no relevant RWI. Although vice chairs and writing group members may have relevant RWI, they must constitute <50% of the writing group. Relevant disclosures for the writing group, external reviewers, and SSOC members can be found in Appendixes 1 and 2. To ensure complete transparency, a full list of disclosure in- formation, including relationships not pertinent to this document, is available in Supplemental Appendix 1. Participants are discouraged from acquiring relevant RWI throughout the writing process. 3. ASSUMPTIONS AND DEFINITIONS To limit inconsistencies in interpretation, speci c as- sumptions (e.g., treatment effects in varied populations) were considered by the writing group in development of the ECDP. References are supplied when applicable or appropriate. 3.1. General Clinical Assumptions 1. Although many topics are generalizable to all patients with HF, the focus of this effort, including pathway recommendations, is on patients with HFrEF. 2. Although some of the recommendations may be rele- vant to patients hospitalized with acute HF or in those with left ventricular ejection fractions (LVEFs) higher than 40%, this document mainly focuses on the man- agement of patients with chronic ambulatory HFrEF with LVEF #40%. 3. The expert consensus writing committee endorses the evidence-based approaches to HF therapy and man- agement enumerated in the 2013 ACC/AHA HF guide- line (3) and the subsequent 2016 and 2017 ACC/AHA/ HFSA focused updates (4,6). 4. These algorithms assume the clinician will seek input as needed from a pharmacist, a cardiologist, an HF specialist, and/or a disease management program, and/ or other relevant medical specialists (e.g., endocrinol- ogists or nephrologists) to guide clinical management. 5. In all cases, patient preferences and values, in part- nership with evidence-based clinical judgment, should guide clinical decision-making. 6. At any point in time, these suggestions and algorithms may be superseded by new data. ACC/AHA Stages of HF: n Stage A: At high risk for HF but without structural heart disease or symptoms of HF. n Stage B: Structural heart disease but without signs or symptoms of HF. n Stage C: Structural heart disease with prior or current symptoms of HF. n Stage D: Refractory HF requiring specialized interventions. GDMT: Guideline-directed medical therapy, repre- senting treatment options supported for use by clinical practice guidelines. HFrEF: Clinical diagnosis of HF and LVEF #40%. New York Heart Association (NYHA) functional classi cation: n Class I: No limitation of physical activity. Ordinary physical activity does not cause symptoms of HF. n Class II: Slight limitation of physical activity. Comfort- able at rest, but ordinary physical activity results in symptoms of HF. n Class III: Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes symptoms of HF. n Class IV: Unable to perform any physical activity without symptoms of HF, or symptoms of HF at rest. Optimal therapy: Treatment provided at either the target or the highest-tolerated dose for a given patient. Target dose: Doses targeted in clinical trials. 4. PATHWAY SUMMARY GRAPHIC Figure 1 is an update of the 2017 ACC ECDP Summary Graphic outlining the 10 pivotal issues about HFrEF. Maddox et al. J 5. 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. Another important development since the publication of the 2017 ECDP is the Food and Drug Administration s approval of a candidate SGLT2 inhibitor and its addition to the armamentarium of medications available for the treatment of patients with HFrEF. In the DAPA-HF (Study to Evaluate the Effect of Dapagli ozin on the Incidence of Worsening HF or CV Death in Patients with Chronic HF) trial, dapagli ozin demonstrated a reduction in CV death and HF hospitalization in patients with and without type 2 diabetes (T2D) (12). In addition, the EMPEROR-Reduced (Empagli ozin Outcome Trial in Patients With Chronic HFrEF) trial demonstrated a reduction in HF hospitaliza- tion/CV death from empagli ozin treatment in patients with HFrEF with and without diabetes (13). As such, it is clear that SLGT2 inhibitors exhibit a bene cial class effect in patients with HFrEF. In light of these developments, an update on when and how to add, switch, and titrate all HFrEF therapies to maximally tolerated, and ideally target, doses (Figure 1, Table 1) was deemed important. Starting and Target Doses of Select GDMT and Novel Therapies for HF (choice and timing of each therapy and in whom they should be added discussed in the text)* Starting Dose Target Dose Beta-Blockers Bisoprolol 1.25 mg once daily 10 mg once daily Carvedilol 3.125 mg twice daily 25 mg twice daily for weight <85 kg and 50 mg twice daily for weight $85 kg Metoprolol succinate 12.5 25 mg daily 200 mg daily ARNIs Sacubitril/valsartan 24/26 mg 49/51 mg twice daily 97/103 mg twice daily ACEIs Enalapril 2.5 mg twice daily 10 20 mg twice daily Lisinopril 2.5 5 mg daily 20 40 mg daily Ramipril 1.25 mg daily 10 mg daily ARBs Candesartan 4 8 mg daily 32 mg daily Losartan 25 50 mg daily 150 mg daily Valsartan 40 mg twice daily 160 mg twice daily Aldosterone antagonists Eplerenone 25 mg daily 50 mg daily Spironolactone 12.5 25 mg daily 25 50 mg daily Dapagli ozin 10 mg daily 10 mg daily Empagli ozin 10 mg daily 10 mg daily Vasodilators Isosorbide dinitrate Fixed-dose combination isosorbide dinitrate/hydralazine Ivabradine Ivabradine 2.5 5 mg twice daily Titrate to heart rate 50 60 beats/min. Maximum dose 7.5 mg twice daily *Digoxin remains indicated for HFrEF, but there are no contemporary data to warrant additional comment in this document. The reader is referred to already available guideline statements (3). Isosorbide mononitrate is not recommended by the ACC/AHA/HFSA guideline. The ACC/AHA/HFSA guideline considers either the xed-dose combination or the separate combination of isosorbide dinitrate and hydralazine as appropriate guideline-directed therapy for HF. ACC American College of Cardiology; ACEI angiotensin-converting enzyme inhibitor; AHA American Heart Association; ARB angiotensin receptor blocker; ARNI angiotensin receptor-neprilysin inhibitor; GDMT guideline-directed medical therapy; HF heart failure; HFrEF heart failure with reduced ejection fraction; HFSA Heart Failure Society of America; SGLT2 sodium-glucose cotransporter-2. Maddox et al. J HF is a complex syndrome typically associated with multiple comorbidities; most patients are on multiple medications. No clinical trials have speci cally evaluated the potential for greater bene t or excessive risk of indi- cated therapies among patients with multimorbidity. To assess tolerability of medications and best assess the trajectory of HF, it is often necessary for patients to have more frequent follow-ups, especially after initiation or titration of therapy. 5.1.1. Initiating GDMT Recommendations for starting GDMT in a patient with a new diagnosis of symptomatic HFrEF are detailed in Figure 2. In a patient with new-onset stage C HFrEF, a common question is whether to initiate a beta-blocker or an in- hibitor of the renin-angiotensin system (ARNI/ACEI/ARB) rst. The writing committee recommends that either an ARNI/ACEI/ARB or beta-blocker should be started. In some cases, an ARNI/ACEI/ARB and a beta-blocker can be started at the same time. Regardless of the initiation sequence, both classes of agent should be up-titrated to the maximum tolerated or target doses in a timely fashion (e.g., every 2 weeks). Initiation of an ARNI/ACEI/ARB (Table 1, Figures 2 and 3) is often better tolerated when the patient is still congested ( wet ), whereas beta-blockers are better tolerated when the patient is less congested ( dry ) with an adequate resting heart rate; FIGURE 2 Treatment Algorithm for Guideline-Directed Medical Therapy Including Novel Therapies Green color identi es a Class I therapy from clinical practice guidelines, whereas yellow color indicates a Class II therapy. J Maddox et al. beta-blockers should not be initiated in patients with decompensated signs or symptoms. Only evidence-based beta-blockers should be used in patients with HFrEF (Table 1, Figures 2 and 3). Titration of ARNIs/ACEIs/ARBs and beta-blockers is discussed in Section 5.2. With recent clinical trial data supporting the use of SGLT2 inhibitors in a reasonably broad spectrum of HFrEF severity, the addition of this class of therapy to the regimens of pa- tients with HFrEF provides improvements in clinical outcomes and in patient-reported outcome measures. FIGURE 3 Guideline-Directed Medical Therapy Including Novel Therapies in the Expert Consensus Decision Pathway for Chronic Heart Failure ARNIs are the preferred agents, but for patients in whom ARNI administration is not possible, an ACEI/ARB is recommended. Maddox et al. J 5.1.2. Angiotensin Receptor-Neprilysin Inhibitor Neprilysin, also known as neutral endopeptidase, is a zinc-dependent metalloprotease that inactivates several vasoactive peptides, including the natriuretic peptides, adrenomedullin, bradykinin, and substance P, each of which has an important role in the pathogenesis and progression of HF (14). Because angiotensin II is also a substrate for neprilysin, neprilysin inhibitors raise angiotensin levels, which explains the rationale for coadministration of an ARB. Neprilysin inhibitors are not combined with an ACEI due to a higher risk of angioe- dema (15). Sacubitril/valsartan (16,17) was tested among patients with chronic HFrEF in a randomized controlled trial, FIGURE 3 Continued J Maddox et al. FIGURE 3 Continued Maddox et al. J PARADIGM HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in HF). The trial enrolled patients with NYHA class II to IV symptoms with an ejection fraction (EF) #40% (modi ed to #35% 1 year into the trial), stable on doses of ACEIs/ARBs, and on other background GDMT. Patients with a history of angioedema, estimated , symptomatic hypotension or systolic blood pressure <100 mm Hg, or current decompensated HF were excluded. The trial began with a sequential run-in period to ensure that every patient who was randomized could tolerate target doses of both sacubitril/valsartan and the compar- ator enalapril. Of the 10,513 candidates screened, 2,079 were not randomized due to inability to achieve target dose therapy on enalapril or sacubitril/valsartan. Most patients enrolled in PARADIGM-HF had NYHA class II to III symptoms (<100 patients with NYHA class IV symptoms). PARADIGM-HF demonstrated an absolute 4.7% reduc- tion in the primary outcome of CV death or HF hospital- ization (hazard ratio: 0.80; 95% con dence interval [CI]: 0.73 to 0.87; p < 0.001) in patients treated with sacubitril/ valsartan versus enalapril. The number of patients who would need to be treated to prevent 1 primary endpoint over 27 months was 21. These differences in outcomes included a 20% reduction in sudden cardiac death. Symptomatic hypotension was more common with sacubitril/valsartan (14.% vs. 9.2%; p < 0.001) but was not associated with a worsening of renal function. Angioe- dema was numerically higher but not statistically signif- icantly different from enalapril in the sacubitril/valsartan group. The 2016 update to the HF guidelines (6) recom- mended an ARNI, ACEI, or ARB to reduce morbidity and mortality in patients with chronic HFrEF and that patients with NYHA class II to III symptoms who can tolerate an ACEI or ARB should transition to an ARNI to further reduce morbidity and mortality (Class I, Level of Evi- dence: B-R) (3,4,7,8). ARNIs have been associated with improvement in diastolic function, left ventricular (LV) function, quality of life, and burden of ventricular ar- rhythmias (8,10,11,18,19). In the PROVE-HF (Prospective Study of Biomarkers, Symptom Improvement, and Ven- tricular Remodeling During Sacubitril/Valsartan Therapy for HF) study, after 12 months of therapy with sacubitril/ valsartan, the median LVEF increased from 28.2% to 0.001), while the median LV end-diastolic volume index [interquartile range: 12.92 to 11.58]; p < 0.001) and the median LV end-systolic volume index decreased [95% CI: 16.03 to 14.55]; p < 0.001). Indexed left atrial volume by body surface area and the E/e0 ratio also decreased signi cantly (11). These results were demon- strated in important subgroups not represented in the PARADIGM-HF trial, such as those with de novo HF or naive to ACEIs/ARBs, those with lower enrollment N-ter- minal pro B-type natriuretic peptide (NT-proBNP) con- centrations, or those not attaining the target dose in the course of the study. The results from PROVE-HF were further substantiated by evidence from the randomized EVALUATE-HF (Effects of Sacubitril/Valsartan vs. Ena- lapril on Aortic Stiffness in Patients With Mild to Moder- ate HF With Reduced Ejection Fraction) trial, which demonstrated an improvement in echocardiographic pa- rameters of reverse cardiac remodeling as early as 12 weeks with treatment of sacubitril/valsartan compared with enalapril (20). A frequent question is whether established use of an aldosterone antagonist is mandatory before initiation of an ARNI. As there is no existing predicate data to suggest an aldosterone antagonist is mandatory before ARNI therapy, lack of treatment with an aldosterone antagonist should not delay initiating or switching a patient to an ARNI. Guidance for the transition from an ACEI or ARB to an ARNI is detailed in Figures 2 and 3 and in Tables 1 to 4. When making the transition from an ACEI to an ARNI, a 36-hour washout period should be strictly observed to avoid angioedema, a delay that is not required when switching from an ARB to an ARNI. In a recent study (21), a comparison between condensed and conservative ap- proaches to initiation of sacubitril/valsartan was explored. The investigators compared titration to a target dose between 3 and 6 weeks. Both approaches were tolerated similarly, but the gradual titration approach maximized attainment of the target dose of sacubitril/ valsartan in patients previously receiving low doses of an ACEI/ARB. Indications for ARNI, Ivabradine, and SGLT2 Inhibitor Use Indications for Use of an ARNI n HFrEF (EF #40%) n NYHA class II IV HF n Administered in conjunction with a background of GDMT for HF in place of an ACEI or ARB Indications for Use of Ivabradine n HFrEF (EF #35%) n On maximum tolerated dose of beta-blocker n Sinus rhythm with a resting heart rate $70 beats/min n NYHA class II or III HF Indications for Use of an SGLT2 Inhibitor n HFrEF (EF #40%) with or without diabetes n NYHA class II IV HF n Administered in conjunction with a background of GDMT for HF ACEI angiotensin-converting-enzyme inhibitor; ARB angiotensin receptor blocker; ARNI angiotensin receptor-neprilysin inhibitor; EF ejection fraction; GDMT guideline-directed medical therapy; HF heart failure; HFrEF heart failure with reduced ejection fraction; NYHA New York Heart Association; SGLT2 sodium- glucose cotransporter-2. J Maddox et al. An ideal time to consider therapy optimization is during hospitalization for HFrEF, and the reader is directed to the 2019 ACC Expert Consensus Decision Pathway on Risk Assessment, Management, and Clinical Trajectory of Pa- tients Hospitalized With Heart Failure (22). Although dis- cussion of hospital-based initiation of sacubitril/valsartan is outside of the scope of this document, it is important to prioritize ongoing titration of GDMT for patients during the hospital-to-home transition. The PIONEER-HF (Compari- son of Sacubitril Valsartan versus Enalapril on Effect on NT-proBNP in Patients Stabilized from an Acute HF Episode) trial established that the initiation of ARNI during an acute decompensated HF hospitalization is feasible (23) after the patient has been hemodynamically stabilized; in PIONEER-HF, up to 25% of patients developed hypotension when treated with sacubitril/valsartan. Therefore, ensuring patients are not volume-depleted at the time of initiation may help to avoid this issue. Notably, the TRANSITION (Comparison of Pre- and Post-discharge Initiation of LCZ696 Therapy in HFrEF Patients After an Acute Decompensation Event) study demonstrated that about one-half of the patients could achieve the target dose within 10 weeks after in-hospital initiation or soon after discharge (24). Accordingly, following the patient s discharge from the hospital, ongoing efforts toward GDMT optimization (including titration to target doses whenever possible) should continue. Clinicians should be advised that sacubitril/valsartan may exert a more noteworthy effect on blood pressure when compared with ACEIs/ARBs. Therefore, in patients with borderline blood pressure (e.g., systolic blood pressure #100 mm Hg), careful administration and follow-up are advised. In noncongested patients with otherwise stable clinical pro les, empiric modest lowering of loop diuretic agents has been found to miti- gate the hypotensive effects of sacubitril/valsartan. Lastly, although the number of patients in studies of ARNI with chronic HFrEF and NYHA class IV symptoms is limited, sacubitril/valsartan remains indicated in this higher-risk population; the role of sacubitril/ valsartan in more advanced forms of HFrEF continues to be explored (25). 5.1.3. Initiation of an ARNI De Novo Without Prior Exposure to an ACEI or ARB It is possible that a patient may be identi ed who meets all criteria for initiation of an ARNI but has not yet been treated with an ACEI or ARB. Recent data from clinical studies (7 9), along with aggregate clinical experience, suggest that directly initiating an ARNI, rather than a pretreatment period ACEI or ARB, is a safe and effective strategy. In a prospective study comparing the tolera- bility of different initiation strategies of sacubitril/val- sartan (21), patients with de novo HFrEF or those who were naive to ACEIs/ARBs demonstrated no unexpected adverse effects compared with those already taking an ACEI/ARB. In a similar fashion, in an open-label pro- spective study of patients eligible for ARNI therapy, the PROVE-HF study demonstrated tolerability and signi - cant reverse cardiac remodeling among those with de novo HFrEF or those naive to ACEIs/ARBs, in whom an average 12% increase in LVEF by 1 year was noted. These results are also supported by data from studies of acute HFrEF that indicate ef cacy and tolerability for those not previously treated with an ACEI/ARB (9,26). In a pre- speci ed subanalysis from PIONEER-HF, patients with de novo HF who underwent in-hospital initiation of an ARNI had a greater reduction in natriuretic peptide concentra- tions, a comparable safety pro le, and a signi cant improvement in early clinical outcomes compared with those on enalapril (23); such improvement in early clin- ical outcomes would be lost in a scenario of ACEI/ARB pre-treatment. Because of this totality of data, a direct-to-ARNI approach is now recommended. When de novo initiation of ARNI is performed, close follow-up and serial assess- ments (blood pressure, electrolytes, and renal function) should be considered, and any such usage should consider concerns regarding the risk of angioedema or hypotension (Figures 2 and 3, Tables 1 to 4). When making a recommendation to initiate an ARNI (either as a switch or as de novo treatment), the Writing Committee recommends the decision occurs within a Dose Adjustments of Sacubitril/Valsartan for Speci c Patient Populations Population Initial Dose High-dose ACEI > Enalapril 10-mg total daily dose or therapeutically equivalent dose of another ACEI twice daily High-dose ARB > Valsartan 160-mg total daily dose or therapeutically equivalent dose of another ARB De novo initiation of ARNI 24/26 mg twice daily Low- or medium-dose ACEI # Enalapril 10-mg total daily dose or therapeutically equivalent dose of another ACEI Low- or medium-dose ARB # Valsartan 160-mg total daily dose or therapeutically equivalent dose of another ARB ACEI/ARB naive Severe renal impairment* ) Moderate hepatic impairment (Child-Pugh Class B) Elderly (age $75 years) *This population was not studied in the PARADIGM-HF trial. The statement is consistent with FDA-approved labeling indications. ACEI angiotensin-converting enzyme inhibitor; ARB angiotensin receptor blocker; ARNI angiotensin receptor-neprilysin inhibitor; eGFR estimated glomerular ltration rate; FDA Food and Drug Administration; PARADIGM-HF Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in HF. Maddox et al. J framework of shared decision-making (https://www. cardiosmart.org/topics/heart-failure/assets/decision-aid/ drug-options-for-patients-with-heart-failure). The writing committee is aware that an ARNI may not be easily accessible to all patients with HFrEF due to challenges with payer coverage and unaffordable copays. Although an ARNI is the preferred renin-angiotensin antagonist in HFrEF, an ACEI/ARB should be used to reduce morbidity and mortality in patients with HFrEF in such cases where the decision is not to use an ARNI. Heart rate independently predicts outcomes in HFrEF. A meta-analysis of beta-blocker trials suggests that heart rate lowering is directly related to improved outcomes (27). A dose-response relationship for evidence-based beta-blockers used in HFrEF has been demonstrated (i.e., the higher the dose, the better the outcome) (27). Before initiating ivabradine, the dose of an evidence- based beta-blocker should be optimized and increased to the target dose as long as excessive bradycardia is not an issue. Some apparently well-compensated patients on optimal beta-blocker therapy continue to have a persis- tent resting heart rate over 70 beats/min, and some pa- tients do not tolerate up-titration of beta-blockade to the target dose and have an elevated heart r ate. In patients on low-dose beta-blockers who may have heart rates below 70 beats/min, a beta-blocker should continue to be TABLE 4 Contraindications and Cautions for Sacubitril/Valsartan, Ivabradine, and SGLT2 inhibitors A) Sacubitril/Valsartan Contraindications Cautions n Within 36 hours of ACEI use n History of angioedema with or without an ACEI or ARB n Pregnancy n Lactation (no data) n Severe hepatic impairment (Child-Pugh C) n Concomitant aliskiren use in patients with diabetes n Known hypersensitivity to either ARBs or ARNIs n Renal impairment: ): no starting dose adjustment required ): reduce starting dose to 24/26 mg twice daily; double the dose every 2 4 weeks to target maintenance dose of 97/103 mg twice daily, as tolerated n Hepatic impairment:  Mild (Child-Pugh A): no starting dose adjustment required  Moderate (Child-Pugh B): reduce starting dose to 24/26 mg twice daily; double the dose every 2 4 weeks to target maintenance dose of 97/103 mg twice daily, as tolerated n Renal artery stenosis n Systolic blood pressure <100 mm Hg n Volume depletion B) Ivabradine Contraindications Cautions n HFpEF n Presence of angina with normal EF n Hypersensitivity n Severe hepatic impairment (Child-Pugh C) n Acute decompensated HF n Blood pressure <90/50 mm Hg n Sick sinus syndrome without a pacemaker n Sinoatrial node block n 2nd or 3rd degree block without a pacemaker n Resting heart rate <60 beats/min n Persistent AF or utter n Atrial pacemaker dependence n Sinus node disease n Cardiac conduction defects n Prolonged QT interval C) SGLT2 Inhibitors Contraindications Cautions n Not approved for use in patients with type I diabetes due to increased risk of diabetic ketoacidosis n Known hypersensitivity to drug n Lactation (no data) n On dialysis n For HF care, dapagli ozin, eGFR <30 mL/min/1.73 m2 n For HF care, empagli ozin, eGFR <20 mL/min/1.73 m2 n Pregnancy n Increased risk of mycotic genital infections n May contribute to volume depletion. Consider altering diuretic dose if applicable n Ketoacidosis in patients with diabetes: n Temporary discontinuation before scheduled surgery is recommended to avoid potential risk for ketoacidosis n Assess patients who present with signs and symptoms of metabolic acidosis for ketoacidosis, regardless of blood glucose level n Acute kidney injury and impairment in renal function: consider temporarily discontinuing in settings of reduced oral intake or uid losses n Urosepsis and pyelonephritis: evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated n Necrotizing fasciitis of the perineum (Fournier s gangrene): rare, serious, life-threatening cases have occurred in both female and male patients; assess patients presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise *This population was not studied in PARADIGM-HF. The statement is consistent with FDA-approved labeling indications. ACEI angiotensin converting enzyme inhibitor; AF atrial brillation; ARB angiotensin receptor blocker; EF ejection fraction; eGFR estimated glomerular ltration rate; ESRD end-stage renal disease; FDA Food and Drug Administration; HF heart failure; HFpEF heart failure with preserved ejection fraction; PARADIGM-HF Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in HF; SGLT2 sodium-glucose cotransporter-2. J Maddox et al. up-titrated to the maximum tolerated or target dose as long as the patients remain asymptomatic. Ivabradine is an adjunctive means to reduce the heart rate in patients with chronic HFrEF who are in sinus rhythm. Ivabradine is a speci c inhibitor of the If current involved in sinoatrial nodal activity and reduces the heart rate of patients in normal sinus rhythm without lowering blood pressure. In the SHIFT (Systolic HF Treatment with the If Inhibitor Ivabradine) trial of 6,505 subjects with stable, chronic, predominantly NYHA class II and III HFrEF, ivabradine therapy, when added to GDMT, resul- ted in a signi cant reduction in HF hospitalizations (28). Bene ts were noted especially for those patients with contraindications to beta-blockers, on beta-blocker doses #50% of GDMT targets (29), and with resting heart rate $77 beats/min at study entry (30). It is important to emphasize that ivabradine is indicated only for patients mainly in sinus rhythm, not in those with persistent or chronic AF, those experiencing 100% atrial pacing, or unstable patients. A history of paroxysmal AF is not a contraindication to ivabradine; in the SHIFT study, nearly 10% of patients had a history of paroxysmal AF. In this study, there was a requirement for sinus rhythm at least 40% of the time. From a safety standpoint, patients treated with ivabradine had greater rates of bradycardia and transient blurring of vision (28). In the 2016 ACC/AHA/HFSA HF guideline update (6), ivabradine was recommended as a Class IIa, Level of Ev- idence: B-R (3,4) therapy to reduce the risk of HF hospi- talization in patients with HFrEF (LVEF #35%) already receiving GDMT (including a beta-blocker at the maxi- mally tolerated dose), and who are in sinus rhythm with a heart rate greater than 70 beats/min at rest (Figures 2 and 3, Tables 1, 2, and 5). The contraindications to ivabradine are enumerated in Table 4. The use of SGLT2 inhibitors for general CV risk reduction was recently covered in the ACC s 2020 Expert Consensus Decision Pathway on Novel Therapies for Cardiovascular Risk Reduction in Patients With Type 2 Diabetes (31). This document, however, was not speci cally focused on the emerging role of SGLT2 inhibitors for HFrEF care. Among patients with prevalent HFrEF, data support an SGLT2 inhibitor as valuable therapy, with evidence showing a reduced risk for major events (such as hospi- talization or death) regardless of the presence of diabetes. Although the mechanism of bene t from these agents in HFrEF remains uncertain, treatment with SGLT2 in- hibitors leads to osmotic diuresis and natriuresis, de- creases in arterial pressure and stiffness, and a shift to ketone-based myocardial metabolism (32). Further bene- ts may be due to reduction of preload and afterload blunting of cardiac stress/injury with less hypertrophy and brosis, which would have favorable effects on myocardial remodeling. The rst study to demonstrate a bene t of SGLT2 in- hibitors for HFrEF care examined the role of dapagli ozin in patients with HFrEF. The DAPA-HF study demon- strated that among 4,744 patients with HFrEF, the risk of worsening HF or death from CV causes was lower among those who received dapagli ozin than among those who received placebo, regardless of the presence or absence of T2D (16.3% in the dapagli ozin group versus 21.2% in the placebo group; hazard ratio: 0.74; 95% CI: 0.65 to 0.85). In addition, dapagli ozin demonstrated a signi cant reduc- tion in each of the individual components of the com- posite endpoint, with a 30% decrease in the risk of experiencing a rst episode of worsening HF (hospitali- zation for HF/urgent HF visit) and an 18% decrease in the risk of CV death (12). The DEFINE-HF (Dapagli ozin Effect on Symptoms and Biomarkers in Patients with HF) study demonstrated that dapagli ozin increased the proportion of patients experiencing clinically meaningful improve- ments in HF-related health status or natriuretic peptide concentrations in patients with HFrEF, regardless of the presence of diabetes (33). In the EMPEROR-Reduced trial in which 3,730 patients with chronic HFrEF were ran- domized to empagli ozin versus placebo, empagli ozin was found to signi cantly reduce the composite endpoint of CV death or HF hospitalization in adults with and without diabetes (19.4% in the empagli ozin group versus 24.7% in the placebo group; hazard ratio: 0.75; 95% CI: 0.65 to 0.86). The trial also showed that treatment with empagli ozin slowed the decline in the eGFR over time (13). A subsequent meta-analysis of DAPA-HF and EMPEROR-Reduced suggested that the effects of empa- gli ozin and dapagli ozin on hospitalization for HF were consistent and that these agents reduced all-cause and CV death and improved renal outcomes in patients (34). The dosing for SGLT2 inhibitors is detailed in Table 1, whereas cautions and contraindications for SGLT2 in- hibitors are enumerated in Table 4. The DAPA-HF trial did not enroll patients with an eGFR <30 mL/min/1.73 , yet dapagli ozin is approved for HFrEF care in pa- tients with worse renal function. The lower limit of eGFR for inclusion in the EMPEROR-Reduced trial was . The writing committee recognizes that glucosuric effects of SGLT2 inhibitors may be TABLE 5 Recommended Starting Dose of Ivabradine Population Initial Dose Maximally tolerated beta-blocker dose with persistent resting heart rate $70 beats/min 5 mg twice daily with meals History of conduction defects 2.5 mg twice daily with meals Age $75 years Maddox et al. J attenuated in those with eGFRs below these thresholds; bene ts of SGLT2 inhibitors for HFrEF management in those with more advanced renal dysfunction than the patients in these recent studies remains less clear. Caution is advised when using SGLT2 inhibitors in pa- tients with eGFRs below the inclusion criteria from pivotal studies, particularly as SGLT2 inhibitors have been associated with mild worsening of renal function during the rst year of use. 5.1.6. Consensus Pathway Algorithm for Initiation and Titration of HFrEF Therapies Figures 2 and 3 depict a strategy for initiating and titrating evidence-based therapies for patients with HFrEF. As noted in the previous text, after a diagnosis of HF is made, adjustment of therapies should occur every 2 weeks, and some patients may tolerate more rapid titration of GDMT. Clinicians should aim to achieve optimal GDMT within 3 to 6 months of an initial diagnosis of HF (however, this rapid timeline may not be logistically feasible for some patients). GDMT should continue to be up-titrated to achieve maximally tolerated or targeted doses of these therapies. During follow-up, frequent reassessment of the clinical status of the patient, blood pressure, and kidney function (and electrolytes) should be performed. Struc- tured medication titration plans embedded in disease management programs that articulate a strategy for drug initiation and strategies for follow-up have been shown to be useful in obtaining target doses of GDMT within 6 months of hospital discharge (35). Reassessment of ventricular function should occur 3 to 6 months after target (or maximally tolerated) doses of GDMT are achieved to determine the need for device therapies such as implantable cardioverter-de brillators and cardiac resynchronization therapy. For those at higher risk for sudden death (e.g., with ischemic cardio- myopathy, LVEF <30%, evidence for ventricular ectopy), the time to follow-up imaging might be shorter (e.g., 3 months), whereas in those at lower risk, time to follow-up might be longer (e.g., 6 months) (3). In patients who already have such devices, reimaging might be deferred even further. 5.1.7. Severe Mitral Regurgitation and the Use of Transcatheter Mitral Valve Repair Surgical treatment is recommended in cases of severe primary chronic MR resulting in HFrEF (36). The treat- ment for severe chronic functional MR is somewhat controversial; initial steps should incorporate optimiza- tion of GDMT and participation in team management de- cisions before the use of percutaneous transcatheter repair. In 2018, 2 large randomized clinical trials of percuta- neous mitral valve repair were published. The MITRA-FR (Percutaneous Repair with the MitraClip Device for Se- vere Functional/Secondary MR) and COAPT (CV Out- comes Assessment of the MitraClip Percutaneous Therapy for HF Patients with Functional MR) trials reported divergent results. Whereas no bene t from percutaneous clipping of the mitral valve was observed in MITRA-FR, the COAPT study investigators reported that, in a popu- lation with maximally-tolerated GDMT and device ther- apy, there was a reduction in HF hospitalization and mortality in symptomatic HF patients with grade 3 to 4 MR (37,38). Substantial differences exist between MITRA-FR and COAPT, but a primary difference relates to the require- ment in COAPT for optimized GDMT before the use of percutaneous mitral valve edge-to-edge reapposition; in COAPT, 90% of study participants received a beta- blocker, 70% received an ARNI/ACEI/ARB, and 50% received an aldosterone antagonist before the procedure. Optimal GDMT leads to reversal of cardiac remodeling, reduction of LV volumes (7), and a concomitant reduction in functional MR (39); thus, although percutaneous mitral valve repair is of bene t in patients with optimized GDMT and persistent symptoms with severe MR, it is essential that GDMT is optimized before referral for the procedure to ensure the greatest likelihood that patients will receive the combined bene ts of optimal GDMT together with edge-to-edge repair. 5.1.8. Patients in Whom New Therapies May Not Be Indicated Contraindications may preclude the initiation of some agents among some patients. Additionally, after being presented with all evidence for and against these thera- pies, a well-informed patient may make a personal judg- ment, in terms of bene ts and risks, and decide against initiation. In a patient whose life expectancy is short (<1 year) due to other comorbidities, some therapies (such as implant- able devices) may not be appropriate. Similarly, in pa- tients with NYHA class IV and Stage D HF being considered for advanced therapies (i.e., transplant or LV assist device), home inotropes, hospice, or initiation of new drug therapies may not be appropriate, especially given the absence of evidence addressing their ef cacy in such patients. 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) 5.2.1. Target Doses To achieve the maximal bene ts of GDMT in patients with chronic HFrEF, therapies must be initiated and titrated to maximally tolerated doses (16,40 42). Doses of GDMT J Maddox et al. higher than those studied in randomized clinical trials, even if tolerated, are not known to provide incremental bene ts, and are generally not recommended. Strategies for titration are detailed in Figures 2 and 3. Achieving target or maximally tolerated doses of GDMT is the goal of titration. Beta-blocker doses should be adjusted every 2 weeks (43) in a patient with no evidence of decompensated HF and no contraindications to higher doses. Longer time periods may be needed for frail pa- tients or those with marginal hemodynamics, whereas more rapid titration may be reasonable in clinically stable patients without hypotension. Following adjustment, patients should be cautioned that there may be a transient worsening of HF symptoms such as dyspnea, fatigue, erectile dysfunction, or dizziness. An ARNI is the preferred renin-angiotensin inhibitor in the absence of hypotension, electrolyte/renal instability, or prior angioedema on an ACEI or ARB. If administration of an ARNI is not possible, then an ACEI or ARB should be used, barring contraindication. An ARNI/ACEI/ARB may be titrated similarly to beta-blockers with monitoring of renal function, potassium, and blood pressure; more rapid titration is also reasonable in clinically stable patients. For those taking an ARNI, doses can be increased every 2 weeks to allow time for adjustment to the vasodilatory effects of the combined inhibition of the angiotensin receptor and neprilysin while also monitoring renal function, potassium, and especially blood pressure. For optimal titration of an ARNI/ACEI/ARB, lower loop diuretic doses may be necessary to permit titration; in this circumstance, careful attention to potassium concentra- tions is needed, as the kaliuretic effects of loop diuretics may no longer be present, and restriction of supplemental and/or dietary potassium may be necessary. Aldosterone antagonists are added in as part of the therapy for patients with symptomatic chronic HFrEF who are already receiving beta-blockers and an ARNI/ ACEI/ARB and who do not have contraindications to this therapy (3). It is not necessary to achieve target or maxi- mally tolerated doses of other drugs before adding aldo- sterone antagonists. The doses of aldosterone antagonists used in clinical trials, which are typically below those that might in uence blood pressure, are suf cient for clinical ef cacy. Adherence to the guideline recommendations for monitoring of renal function and potassium is required (4). SGLT2 inhibitors are added in as part of the therapy for patients with chronic HFrEF who are already receiving beta-blockers, an ARNI/ACEI/ARB, and aldosterone an- tagonists, if not contraindicated. There is little data addressing the combination of an ARNI and an SGLT2 inhibitor. However, in both DAPA-HF and EMPEROR- Reduced, the bene t of SGLT2 inhibition was consistent in patients already treated with an ARNI, and a meta- analysis of the 2 trials af rms this nding (12,34,44). In the DAPA-HF trial, among the small number of patients receiving an ARNI, additive bene t was seen across each timepoint from the addition of dapagli ozin (45). Achieving target or maximally tolerated doses of other drugs is not necessary before adding SGLT2 inhibitors. The loop diuretic dose may need to be adjusted based on close monitoring of weight and symptoms (46). In pa- tients using insulin or insulin-secretagogues (such as sulfonylureas), coordinating care through the inclusion of endocrinologists and primary care providers may be helpful in order to minimize the risk of hypoglycemia in patients with diabetes. For several reasons, HYD/ISDN-indicated therapy for HF is often neglected in eligible patients. However, given the bene ts of this combination (43% relative reduction in mortality and 33% relative reduction in HF hospitali- zation) and the favorable impact on health status (47), African-American patients should receive these drugs once target or maximally tolerated doses of beta-blocker, ARNI/ACEI/ARB, and aldosterone antagonists are ach- ieved (3). This combination of drugs is especially impor- tant for those patients with NYHA class III to IV symptoms. Finally, in patients whose heart rate remains $70 beats/min on target or maximally tolerated doses of beta- blockers, ivabradine (6) can be added and titrated at 2 weeks to lower the heart rate. 5.2.2. Barriers to Medication Titration In some instances, it may not be possible to titrate GDMT to the target doses achieved in clinical trials. Patients seen in clinical practice may differ substantially from those enrolled in trials. For example, patients seen in clinical practice are typically older, may experience more side effects including hypotension, and are likely to have more comorbidities that will limit titration. Although data are lacking, it is logical to assume that below-target doses of multiple classes of GDMT are likely more effective in reducing risk than large doses of 1 or 2 agents. Abnormal renal function and/or hyperkalemia are common barriers to initiation and titration of GDMT. In patients with hyperkalemia, education regarding a low potassium diet should be provided. In addition, newer potassium binders (patiromer and sodium zirconium cyclosilicate) are now approved by the Food and Drug Administration and may be considered; however, more data are needed regarding use of such agents in patients with HFrEF, as their use has not been shown to increase GDMT use or have an impact on outcomes in patients. Additionally, these agents raise concerns in terms of cost/ access and their contribution to polypharmacy. A trial examining whether a strategy of potassium binding will potentiate GDMT prescription and improve HFrEF Maddox et al. J outcomes is ongoing, and more data may be available in the future. For patients with established renal disease, caution may be necessary when starting GDMT. In patients with ), no adjustment is needed when deciding the starting dose of the ARNI sacubitril/valsar- tan. In those with severe renal impairment (eGFR <30 mL/ ), the starting dose of sacubitril/valsartan should be reduced to 24/26 mg twice daily (Table 4). ACEIs/ARBs are generally considered safe in patients with severe renal impairment, although de nitive data are lacking. Aldosterone antagonists are contraindicated in patients with severe renal impairment (eGFR <30 mL/ , or creatinine >2.5 mg/dL in men or creati- nine >2 mg/dL in women) or with potassium >5.0 mEq/L (Figure 2). Renal function and potassium should be assessed within 1 to 2 weeks after initiation or dose increase of an ARNI/ACEI/ARB. In patients with preserved renal func- tion or mild to moderate renal impairment, renal function and potassium after initiation and titration of aldosterone antagonists should be assessed within 2 to 3 days and again at 7 days. The schedule for subsequent monitoring should be dictated by the clinical stability of renal func- tion and volume status but should occur at least monthly for the rst 3 months and every 3 months thereafter (3). During the initiation and titration of agents that affect renal function, a decrease in eGFR of >30% or the development of hyperkalemia should alert the clinician that a reduction in doses may be necessary, even though short-term changes in eGFR during intense diuretic therapy or with the initiation of an ACEI or ARB do not predict longer-term adverse outcomes (48), and initial mild worsening of renal function after SGLT2 inhibitor initiation may also occur before longer-term renal func- tion preservation (13). In patients with evidence of hypovolemia, the dose of diuretic agents should be reduced. The ARNI dose may also need to be reduced in the setting of renal insuf ciency or hypotension. Hyper- kalemia may also require changes in medical therapy. Among SGLT2 inhibitors for patients with chronic HFrEF, clinical trial experience with dapagli ozin is lacking in , whereas for empagli ozin, there is a similar lack of clinical trial data for those with an eGFR <20 mL/min/1.73 m2 . Volume status should be closely monitored, as intravascular vol- ume contraction may necessitate a reduction in loop diuretic dosing. Clinical assessment and renal stability in each patient dictates whether clinicians may need to monitor certain patients more closely than others. Socioeconomic barriers to care may undermine the ability to achieve GDMT. For example, the cost of thera- pies poses a substantial barrier to care, particularly for an ARNI, SGLT2 inhibitor, and ivabradine (see the discussion on costs of care in Section 5.7). In such cases, if all solu- tions are exhausted, optimizing care with the most nancially manageable program is recommended. Simi- larly, some patients have a limited ability to attend frequent of ce visits for GDMT optimization. For example, homebound patients or those with limited ability to travel may be unable to have blood pressure, heart rate, or renal function assessed in a timely fashion. In these cases, options such as virtual care and home visiting nurse services may aid in remote optimization of GDMT (49). Virtual care in particular may be a more viable strategy, with the recent increases in its use due to the COVID-19 pandemic. Useful guidance exists regarding the use of virtual visits to allow for medical access, moni- toring of symptoms/signs, and adjustments of GDMT (50). 5.2.3. Clinical Assessment Figure 4 details a reasonable strategy for patient evalua- tion and management following a diagnosis of HFrEF. After GDMT is initiated and titrated with the goal of achieving clinical trial doses or maximally tolerated doses, patients with chronic HFrEF should be evaluated on a regularly scheduled basis. For most patients, a reasonable interval is every 3 to 6 months, although many may require more frequent follow-up to monitor clinical stability and revisit opportunities for further GDMT titration. Cardiac rehabilitation is helpful to support drug titration, monitor symptoms, improve health status, and increase exercise tolerance, but remains underused in terms of both prescription and access (51). During the COVID-19 pandemic, virtual care to allow for outpatient GDMT titration has been useful in certain patients (52) and will likely take on a larger role in HFrEF care post- pandemic. High-risk features (conveniently summarized by the acronym I NEED HELP in Figure 4 and Table 6) should trigger consideration for referral for an advanced HF consultation (53). Features triggering referral to advanced HF care are also discussed in Section 5.3 and Table 6. 5.2.4. Imaging When to Order an Echocardiogram An echocardiogram, with strain imaging when available, is recommended in the evaluation of the patient with incident HF to assess LVEF, diastolic function, chamber size, ventricular wall thickness, valvular abnormalities, and hemodynamic parameters including estimated right ventricular systolic pressure, central venous pressure, and LV lling pressures. Once optimal doses of GDMT have been achieved for 3 to 6 months, repeat imaging can be useful in making decisions regarding device therapy (implantable cardioverter de brillator, cardiac resynch- ronization therapy, or transcatheter mitral valve repair) or referral for advanced therapies (ventricular assist device J Maddox et al. or transplant). In some patients, it may be reasonable to wait longer for such decisions if there is an expectation that LV remodeling might further progress. For example, in the PROVE-HF study, increases in LVEF and reduction in LV volumes continued over 12 months in some patients (11). Repeat imaging may also be considered at the time of important changes in clinical status (3). Routine surveil- lance echocardiograms (e.g.