CLINICAL STATEMENTS AND GUIDELINES WRITING GROUP MEMBERS* Clyde W. Yancy, MD, MSc, MACC, FAHA, FHFSA, Chair Mariell Jessup, MD, FACC, FAHA, Vice Chair Biykem Bozkurt, MD, PhD, FACC, FAHA* Javed Butler, MD, MBA, MPH, FACC, FAHA* Donald E. Casey Jr, MD, MPH, MBA, FACC Monica M. Colvin, MD, FAHA Mark H. Drazner, MD, MSc, FACC, FAHA, FHFSA Gerasimos S. Filippatos, MD* Gregg C. Fonarow, MD, FACC, FAHA, FHFSA* Michael M. Givertz, MD, FACC, FHFSA* Steven M. Hollenberg, MD, FACC# JoAnn Lindenfeld, MD, FACC, FAHA, FHFSA* Frederick A. Masoudi, MD, MSPH, FACC** Patrick E. McBride, MD, MPH, FACC Pamela N. Peterson, MD, FACC, FAHA Lynne Warner Stevenson, MD, FACC* Cheryl Westlake, PhD, RN, ACNS-BC, FAHA, FHFSA Developed in Collaboration with the American Academy of Family Physicians, American College of Chest Physicians, and International Society for Heart and Lung Trans- plantation ACC/AHA Task Force Members, see page e150 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America 2017 by the American College of Cardiology Foundation, the American Heart Association, Inc., and the Heart Failure Society of America ACC/AHA/HFSA FOCUSED UPDATE Key Words: AHA Scientific Statements angioedema angiotensin-converting enzyme inhibitors angiotensin receptor blockers angiotensin receptor- neprilysin inhibitor beta blockers ferric carboxymaltose focused update heart failure hypertension iron deficiency ivabradine natriuretic peptides natriuretic peptide biomarker sleep apnea *Writing group members are required to recuse themselves from voting on sections to which their specific relationships with industry may apply; see Appendix 1 for detailed information. ACC/AHA Task Force on Clinical Practice Guidelines Liaison. ACC/AHA Representative. ACP Representative. ISHLT Representative. HFSA Representative. #CHEST Representative. **ACC/AHA Task Force on Performance Measures Representative. AAFP Representative. The American Heart Association requests that this document be cited as follows: Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Colvin MM, Drazner MH, Filippatos GS, Fonarow GC, Givertz MM, Hollenberg SM, Lindenfeld J, Masoudi FA, McBride PE, Peterson PN, Stevenson LW, Westlake C. 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation. 2017;136:e137 e161. DOI: 10.1161/CIR.0000000000000509. Yancy et al TABLE OF CONTENTS Preamble e138 Methodology and Evidence Review e140 Organization of the Writing Group e141 Document Review and Approval e141 Initial and Serial Evaluation of the HF Patient e141 Biomarkers for Prevention: Recommendation e142 Biomarkers for Diagnosis: Recommendation e142 Biomarkers for Prognosis or Added Risk Stratification: Recommendations e142 Treatment of Stages A to D e144 Pharmacological Treatment for Stage C HF With Reduced Ejection Fraction: 7.3.2.10. Renin-Angiotensin System Inhibition With Angiotensin- Converting Enzyme Inhibitor or Angiotensin Receptor Blocker or ARNI: Recommendations e144 Pharmacological Treatment for Stage C HFpEF: Recommendations e146 Important Comorbidities in HF e147 Hypertension (New Section) e149 Treating Hypertension to Reduce the Incidence of HF: Recommendation e149 Treating Hypertension in Stage C HFrEF: Recommendation e149 Treating Hypertension in Stage C HFpEF: Recommendation e149 9.6. Sleep-Disordered Breathing: Appendix 1. Author Relationships With Industry and Other Entities (Relevant) e156 Appendix 2. Reviewer Relationships With Industry and Other Entities (Comprehensive) e158 PREAMBLE Since 1980, the American College of Cardiology (ACC) and American Heart Association (AHA) have translat- ed scientific evidence into clinical practice guidelines (guidelines) with recommendations to improve cardio- vascular health. These guidelines, which are based on systematic methods to evaluate and classify evidence, provide a cornerstone for quality cardiovascular care. The ACC and AHA sponsor the development and pub- lication of guidelines without commercial support, and members of each organization volunteer their time to the writing and review efforts. Guidelines are official policy of the ACC and AHA. Intended Use Practice guidelines provide recommendations applica- ble to patients with or at risk of developing cardiovas- cular disease. The focus is on medical practice in the United States, but guidelines developed in collabora- tion with other organizations may have a global impact. Although guidelines may be used to inform regulatory or payer decisions, their intent is to improve patients quality of care and align with patients interests. Guide- lines are intended to define practices meeting the needs of patients in most, but not all, circumstances and should not replace clinical judgment. Clinical Implementation Guideline recommended management is effective only when followed by healthcare providers and patients. Adherence to recommendations can be enhanced by shared decision making between healthcare providers and patients, with patient engagement in selecting interventions based on individual values, preferences, and associated conditions and comorbidities. Methodology and Modernization The ACC/AHA Task Force on Clinical Practice Guidelines (Task Force) continuously reviews, updates, and modi- fies guideline methodology on the basis of published standards from organizations including the Institute of and on the basis of internal reevaluation. Similarly, the presentation and delivery of guidelines are reevaluated and modified on the basis of evolving tech- nologies and other factors to facilitate optimal dissemi- nation of information at the point of care to healthcare professionals. Given time constraints of busy healthcare providers and the need to limit text, the current guideline format delineates that each recommendation be support- ed by limited text (ideally, <250 words) and hyperlinks to supportive evidence summary tables. Ongoing efforts to further limit text are underway. Recognizing the impor- tance of cost-value considerations in certain guidelines, when appropriate and feasible, an analysis of the value of a drug, device, or intervention may be performed in accordance with the ACC/AHA methodology.3 To ensure that guideline recommendations remain current, new data are reviewed on an ongoing basis, with full guideline revisions commissioned in approxi- mately 6-year cycles. Publication of new, potentially practice-changing study results that are relevant to an existing or new drug, device, or management strategy will prompt evaluation by the Task Force, in consultation with the relevant guideline writing committee, to de- termine whether a focused update should be commis- sioned. For additional information and policies regard- ing guideline development, we encourage readers to 2017 ACC/AHA/HFSA Heart Failure Focused Update CLINICAL STATEMENTS AND GUIDELINES consult the ACC/AHA guideline methodology manual4 and other methodology articles.5 8 Selection of Writing Committee Members The Task Force strives to avoid bias by selecting experts from a broad array of backgrounds. Writing commit- tee members represent different geographic regions, sexes, ethnicities, races, intellectual perspectives/biases, and scopes of clinical practice. The Task Force may also invite organizations and professional societies with re- lated interests and expertise to participate as partners, collaborators, or endorsers. Relationships With Industry and Other Entities The ACC and AHA have rigorous policies and meth- ods to ensure that guidelines are developed without bias or improper influence. The complete relationships with industry and other entities (RWI) policy can be found online. Appendix 1 of the current document lists writing committee members relevant RWI. For the purposes of full transparency, writing committee mem- bers comprehensive disclosure information is available online. Comprehensive disclosure information for the Task Force is also available online. Evidence Review and Evidence Review Committees When developing recommendations, the writing com- mittee uses evidence-based methodologies that are based on all available data.4 7 Literature searches focus on randomized controlled trials (RCTs) but also include registries, nonrandomized comparative and descriptive studies, case series, cohort studies, systematic reviews, and expert opinion. Only key references are cited. An independent evidence review committee (ERC) is commissioned when there are 1 or more questions deemed of utmost clinical importance that merit formal systematic review. This systematic review will strive to de- termine which patients are most likely to benefit from a drug, device, or treatment strategy and to what degree. Criteria for commissioning an ERC and formal systematic review include: a) the absence of a current authoritative systematic review, b) the feasibility of defining the ben- efit and risk in a time frame consistent with the writing of a guideline, c) the relevance to a substantial number of patients, and d) the likelihood that the findings can be translated into actionable recommendations. ERC members may include methodologists, epidemiologists, healthcare providers, and biostatisticians. When a formal systematic review has been commissioned, the recom- mendations developed by the writing committee on the basis of the systematic review are marked with SR . Guideline-Directed Management and Therapy The term guideline-directed management and therapy (GDMT) encompasses clinical evaluation, diagnostic testing, and pharmacological and procedural treat- ments. For these and all recommended drug treat- ment regimens, the reader should confirm the dosage by reviewing product insert material and evaluate the treatment regimen for contraindications and interac- tions. The recommendations are limited to drugs, de- vices, and treatments approved for clinical use in the United States. Class of Recommendation and Level of Evidence The Class of Recommendation (COR) indicates the strength of the recommendation, encompassing the estimated magnitude and certainty of benefit in pro- portion to risk. The Level of Evidence (LOE) rates the quality of scientific evidence that supports the inter- vention on the basis of the type, quantity, and con- sistency of data from clinical trials and other sources Glenn N. Levine, MD, FACC, FAHA Chair, ACC/AHA Task Force on Clinical Practice Guidelines The purpose of this focused update is to update the 2013 ACCF/AHA Guideline for the Management of (2013 HF guideline) in areas in which new evidence has emerged since its publication. For this update and future heart failure (HF) guidelines, the Heart Failure Society of America (HFSA) has partnered with the ACC and AHA to provide coordinated guid- ance on the management of HF. The scope of the focused update includes revision to the sections on biomarkers; new therapies indicated for stage C HF with reduced ejection fraction (HFrEF); updates on HF with preserved ejection fraction (HFpEF); new data on important comorbidities, including sleep apnea, anemia, and hypertension; and new insights into the prevention of HF. This focused update represents the second part of a 2-stage publication; with the first part having been pub- lished as the 2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure, 10 which introduced guidance on new therapies, specifi- cally for the use of an angiotensin receptor neprilysin inhibitor (ARNI) (valsartan/sacubitril) and a sinoatrial node modulator (ivabradine). That focused update was published concurrently with the European Society of Cardiology s complete guideline, 2016 ESC Guidelines Yancy et al for the Diagnosis and Treatment of Acute and Chronic 1.1. Methodology and Evidence Review To identify key data that influence guideline recommen- dations, the Task Force and members of the 2013 HF guideline writing committee reviewed clinical trials that were presented at the annual scientific meetings of the ACC, AHA, and European Society of Cardiology and other scientific meetings and that were published in peer-reviewed format from April 2013 through Novem- ber 2016. The evidence is summarized in tables in the Online Data Supplement. All recommendations (new, modified, and unchanged) for each clinical section are included to provide a comprehensive assessment. The text explains new and modified recommendations, whereas recommendations from the previous guideline Table 1. Applying Class of Recommendation and Level of Evidence to Clinical Strategies, Interventions, Treatments, or Diagnostic Testing in Patient Care* (Updated August 2015) 2017 ACC/AHA/HFSA Heart Failure Focused Update CLINICAL STATEMENTS AND GUIDELINES that have been deleted or superseded no longer ap- pear. Please consult the full-text version of the 2013 for text and evidence tables supporting the unchanged recommendations and for clinical areas not addressed in this focused update. Individual recom- mendations in this focused update will be incorporated into the full-text guideline in the future. Recommenda- tions from the prior guideline that remain current have been included for completeness, but the LOE reflects the COR/LOE system used when the recommendations were initially developed. New and modified recommen- dations in this focused update reflect the latest COR/ LOE system, in which LOE B and C are subcategorized for greater specificity.4 6 The section numbers corre- spond to the full-text guideline sections. 1.2. Organization of the Writing Group For this focused update, representative members of the 2013 HF guideline writing committee were invit- ed to participate. They were joined by additional in- vited members to form a new writing group, which is referred to as the 2017 HF focused update writing group. Members were required to disclose all RWI rel- evant to the data under consideration. The group was composed of experts representing general cardiolo- gists, HF and transplantation specialists, electrophysi- ologists, pharmacists, and general internists. The 2017 HF focused update writing group included representa- tives from the ACC, AHA, and HFSA, as well as the American Academy of Family Physicians, American College of Chest Physicians, American College of Phy- sicians, and International Society for Heart and Lung Transplantation. 1.3. Document Review and Approval The focused update was reviewed by 2 official reviewers each nominated by the ACC, AHA, and HFSA; 1 reviewer each from the American Academy of Family Physicians, American College of Chest Physicians, and International Society for Heart and Lung Transplantation; and 19 in- dividual content reviewers. Reviewers RWI information is published in this document (Appendix 2). This document was approved for publication by the governing bodies of the ACC, AHA, and HFSA. 6. INITIAL AND SERIAL EVALUATION OF THE HF PATIENT Assays for BNP (B-type natriuretic peptide) and NT- proBNP (N-terminal pro-B-type natriuretic peptide), which are both natriuretic peptide biomarkers, have been used increasingly to establish the presence and severity of HF. In general, both natriuretic peptide bio- marker values track similarly, and either can be used in patient care settings as long as their respective ab- solute values and cutpoints are not used interchange- ably. Notably, BNP, but not NT-proBNP, is a substrate for neprilysin. Therefore, ARNI increases BNP levels12 but not NT-proBNP levels.13 Note that the type of natri- uretic peptide assay that has been performed must be considered during interpretation of natriuretic peptide biomarker levels in patients on ARNI. In 2 studies with ARNI, NT-proBNP levels were reduced,12,14 with the reduction in 1 study being associated with improved A substantial evidence base exists that supports the use of natriuretic peptide biomarkers to assist in the di- agnosis or exclusion of HF as a cause of symptoms (eg, dyspnea, weight gain) in the setting of chronic ambula- or in the setting of acute care with decom- especially when the cause of dyspnea is unclear. The role of natriuretic peptide biomarkers in population screening to detect incident HF is emerg- Elevated plasma levels of natriuretic peptide biomarkers are associated with a wide variety of cardiac and noncardiac causes (Table 2).38 42 Obesity may be as- sociated with lower natriuretic peptide concentrations, and this may modestly reduce diagnostic sensitivity in morbidly obese patients.42 Table 2. Selected Potential Causes of Elevated Natriuretic Peptide Levels38 41 Cardiac HF, including RV syndromes Acute coronary syndromes Heart muscle disease, including LVH Valvular heart disease Pericardial disease Atrial fibrillation Myocarditis Cardiac surgery Cardioversion Toxic-metabolic myocardial insults, including cancer chemotherapy Noncardiac Advancing age Anemia Renal failure Pulmonary: obstructive sleep apnea, severe pneumonia Pulmonary hypertension Critical illness Bacterial sepsis Severe burns Modified from Table 8 of the 2013 HF guideline.9 HF, indicates heart failure; LVH, left ventricular hypertrophy; and RV, right ventricular. Yancy et al Because of the absence of clear and consistent evi- dence for improvement in mortality and cardiovascular there are insufficient data to inform spe- cific guideline recommendations related to natriuretic peptide guided therapy or serial measurements of BNP or NT-proBNP levels for the purpose of reducing hospi- talization or deaths in the present document. Like natriuretic peptides, cardiac troponin levels may be elevated in the setting of chronic or acute decom- pensated HF, suggesting myocyte injury or necrosis.63 Troponins I and T respond similarly for acute coronary syndromes and acute decompensated HF. Elevations in either troponin I or T levels in the setting of acute HF are of prognostic significance and must be interpreted in the clinical context.64 In addition to natriuretic peptides and troponins,65 67 multiple other biomarkers, including those of inflam- mation, oxidative stress, vascular dysfunction, and myo- cardial and matrix remodeling, have been implicated in Biomarkers of myocardial fibrosis, soluble ST2 receptor, and galectin-3 are predictive of hospitaliza- tion and death and may provide incremental prognos- tic value over natriuretic peptide levels in patients with Strategies that combine multiple biomarkers may ultimately prove beneficial in guiding HF therapy in the future, but multicenter studies with larger deri- vation and validation cohorts are needed.75,76 Several emerging biomarkers await validation with well-defined outcome measures and prognostic accuracy before they can reach the clinical arena.77 84 This section categorizes the role of biomarkers into prevention, diagnosis, prognosis, and added risk strati- fication to clarify evidence-based objectives of their use in clinical practice. 6.3.1 Biomarkers for Prevention: Recommendation Biomarkers: Recommendation for Prevention of HF COR LOE Recommendation Comment/Rationale IIa B-R For patients at risk of developing HF, natriuretic peptide biomarker based screening followed by team-based care, including a cardiovascular specialist optimizing GDMT, can be useful to prevent the development of left ventricular dysfunction (systolic or diastolic) or NEW: New data suggest that natriuretic peptide biomarker screening and early intervention may prevent HF. See Online Data Supplements A and B. In a large-scale unblinded single-center study (STOP-HF [The St Vincent s Screening to Prevent Heart Failure]),85 patients at risk of HF (identified by the presence of hypertension, diabetes mellitus, or known vascular disease [eg, stage A HF]), but without established left ventricular systolic dysfunction or symptomatic HF at baseline, were randomly assigned to receive screening with BNP testing or usual primary care. Intervention-group participants with BNP levels of 50 pg/mL underwent echocardiography and were referred to a cardiovascular specialist who decided on further investigation and management. All patients received further coaching by a specialist nurse who emphasized individual risk and the importance of adherence to medication and healthy lifestyle behaviors. BNP-based screening reduced the composite endpoint of asymptomatic left ventricular dysfunction (systolic or diastolic) with or without newly diagnosed HF.85 Similarly, in another small, single-center RCT, accelerated up-titration of renin-angiotensin-aldosterone system antagonists and beta blockers reduced cardiac events in patients with diabetes mellitus and elevated NT-proBNP levels but without cardiac disease at Developing a standardized strategy to screen and intervene in patients at risk of HF can be difficult because of different definitions of HF risk, heterogeneity of prevalence in different populations, variable duration until clinical HF or left ventricular dysfunction develops, and variable interventions for risk factor modification or treatment. Further studies are needed to determine cost-effectiveness and risk of such screening, as well as its impact on quality of life (QoL) and mortality rate. 6.3.2 Biomarkers for Diagnosis: Recommendation Biomarkers: Recommendation for Diagnosis COR LOE Recommendation Comment/Rationale I A In patients presenting with dyspnea, measurement of natriuretic peptide biomarkers is useful to support a diagnosis or exclusion MODIFIED: 2013 acute and chronic recommendations have been combined into a diagnosis section. See Online Data Supplements A and B. Natriuretic peptide biomarker testing in the setting of chronic ambulatory HF provides incremental diagnostic value to clinical judgment, especially when the etiology of dyspnea is unclear.15 21 In emergency settings, natriuretic peptide biomarker levels usually have higher sensitivity than specificity and may be more useful for ruling out than ruling in HF.20 Although lower values of natriuretic peptide biomarkers exclude the presence of HF, and higher values have reasonably high positive predictive value to diagnose HF, clinicians should be aware that elevated plasma levels for both natriuretic peptides have been associated with a wide variety of cardiac and noncardiac causes (Table 2).38 41 6.3.3 Biomarkers for Prognosis or Added Risk Stratification: Recommendations Biomarkers: Recommendations for Prognosis COR LOE Recommendations Comment/Rationale I A Measurement of BNP or NT-proBNP is useful for establishing prognosis or disease severity in chronic HF.16,87 92 2013 recommendation remains current. 2017 ACC/AHA/HFSA Heart Failure Focused Update CLINICAL STATEMENTS AND GUIDELINES Figure 1. Biomarkers Indications for Use. Colors correspond to COR in Table 1. *Other biomarkers of injury or fibrosis include soluble ST2 receptor, galectin-3, and high- sensitivity troponin. ACC indicates American College of Cardiology; AHA, American Heart Association; ADHF, acute decom- pensated heart failure; BNP, B-type natriuretic peptide; COR, Class of Recommendation; ED, emergency department; HF, heart failure; NT-proBNP, N-terminal pro-B-type natriuretic peptide; NYHA, New York Heart Association; and pts, patients. I A Measurement of baseline levels of natriuretic peptide biomarkers and/ or cardiac troponin on admission to the hospital is useful to establish a prognosis in acutely decompensated HF.27,93 100 MODIFIED: Current recommendation emphasizes that it is admission levels of natriuretic peptide biomarkers that are useful. See Online Data Supplements A and B. Higher levels of natriuretic peptide biomarkers on admission are usually associated with greater risk for clinical outcomes, including all-cause and cardiovascular mortality, morbidity, and composite outcomes, across different time intervals in patients with decompensated HF.20,27,29,93 101 Similarly, abnormal levels of circulating cardiac troponin are commonly found in patients with acute decompensated HF, often without obvious myocardial ischemia or underlying coronary artery disease (CAD), and this is associated with worse clinical outcomes and higher risk of death.95,99,102,103 Studies have demonstrated incremental prognostic value of these biomarkers to standard approaches of cardiovascular disease risk assessment.29,95 However, there were differences in the risk prediction models, assay cutpoints, and lengths of follow-up.29 Furthermore, not all patients may need biomarker measurement for prognostication, especially if they already have advanced HF with established poor prognosis or persistently elevated levels of biomarkers in former settings. Therefore, assays of natriuretic peptide biomarkers for incremental prognostication should not preclude good clinical judgment; an individualized approach to each patient is paramount. IIa B-NR During a HF hospitalization, a predischarge natriuretic peptide level can be useful to establish a postdischarge prognosis.93,96,104 113 NEW: Current recommendation reflects new observational studies. See Online Data Supplements A and B. Predischarge natriuretic peptide biomarker levels and the relative change in levels during hospital treatment are strong predictors of the risk of death or hospital readmission for HF.93,96,104 113 Several studies have suggested that predischarge natriuretic peptide biomarker levels had higher reclassification and discrimination value than clinical variables in predicting outcomes.96,106,108 111 Patients with higher predischarge levels and patients who do not have a decrease in natriuretic peptide biomarker levels during hospitalization have worse outcomes.96,106,108 111 Although observational or retrospective studies have suggested that patients with natriuretic peptide biomarker reduction had better outcomes than those without any changes or with a biomarker rise,93,107,112,113 targeting a certain threshold, value, or relative change in these biomarker levels during hospitalization may not be practical or safe for every patient and has not been tested in a prospective large-scale trial. Clinical assessment and adherence to GDMT should be the emphasis, and the prognostic value of a predischarge value or relative changes does not imply the necessity for serial and repeated biomarker measurements during hospitalization. IIb B-NR In patients with chronic HF, measurement of other clinically available tests, such as biomarkers of myocardial injury or fibrosis, may be considered for additive risk stratification.27,95,98,99,103,114 119 MODIFIED: 2013 recommendations have been combined into prognosis section, resulting in LOE change from A to B-NR. See Online Data Supplements A and B. Biomarkers of myocardial fibrosis (eg, soluble ST2 receptor, galectin-3, high-sensitivity cardiac troponin, and others) are predictive of hospitalization and death in patients with HF and also are additive to natriuretic peptide biomarker levels in their prognostic value.117,119 126 A combination of biomarkers may ultimately prove to be more informative than single biomarkers.127 Biomarkers: Recommendations for Prognosis (Continued) COR LOE Recommendations Comment/Rationale Yancy et al 7. Treatment of Stages A to D 7.3. Stage C 7.3.2. Pharmacological Treatment for Stage C HF With Reduced Ejection Fraction: Recommendations (See Figure 2 and Table 3). 7.3.2.10. Renin-Angiotensin System Inhibition With Angiotensin-Converting Enzyme Inhibitor or Angiotensin Receptor Blocker or ARNI: Recommendations Recommendations for Renin-Angiotensin System Inhibition With ACE Inhibitor or ARB or ARNI COR LOE Recommendations Comment/Rationale I ACE-I: A The clinical strategy of inhibition of the renin-angiotensin system with ACE inhibitors (Level of Evidence: A),128 133 OR ARBs (Level of Evidence: OR ARNI (Level of Evidence: B-R)138 in conjunction with evidence- based beta blockers,9,139,140 and aldosterone antagonists in selected is recommended for patients with chronic HFrEF to reduce morbidity and mortality. NEW: New clinical trial data prompted clarification and important updates. ARB: A ARNI: B-R See Online Data 18-20. Angiotensin-converting enzyme (ACE) inhibitors reduce morbidity and mortality in heart failure with reduced ejection fraction (HFrEF). Randomized controlled trials (RCTs) clearly establish the benefits of ACE inhibition in patients with mild, moderate, or severe symptoms of HF and in patients with or without coronary artery disease.128 133 ACE inhibitors can produce angioedema and should be given with caution to patients with low systemic blood pressures, renal insufficiency, or elevated serum potassium. ACE inhibitors also inhibit kininase and increase levels of bradykinin, which can induce cough but also may contribute to their beneficial effect through vasodilation. Angiotensin receptor blockers (ARBs) were developed with the rationale that angiotensin II production continues in the presence of ACE inhibition, driven through alternative enzyme pathways. ARBs do not inhibit kininase and are associated with a much lower incidence of cough and angioedema than ACE inhibitors; but like ACE inhibitors, ARBs should be given with caution to patients with low systemic blood pressure, renal insufficiency, or elevated serum potassium. Long-term therapy with ARBs produces hemodynamic, neurohormonal, and clinical effects consistent with those expected after interference with the renin-angiotensin system and have been shown in RCTs134 137 to reduce morbidity and mortality, especially in ACE inhibitor intolerant patients. In ARNI, an ARB is combined with an inhibitor of neprilysin, an enzyme that degrades natriuretic peptides, bradykinin, adrenomedullin, and other vasoactive peptides. In an RCT that compared the first approved ARNI, valsartan/sacubitril, with enalapril in symptomatic patients with HFrEF tolerating an adequate dose of either ACE inhibitor or ARB, the ARNI reduced the composite endpoint of cardiovascular death or HF hospitalization significantly, by 20%.138 The benefit was seen to a similar extent for both death and HF hospitalization and was consistent across subgroups. The use of ARNI is associated with the risk of hypotension and renal insufficiency and may lead to angioedema, as well. I ACE-I: A The use of ACE inhibitors is beneficial for patients with prior or current symptoms of chronic HFrEF to reduce morbidity and mortality.128 133,143 2013 recommendation repeated for clarity in this section. See Online Data Supplement 18. ACE inhibitors have been shown in large RCTs to reduce morbidity and mortality in patients with HFrEF with mild, moderate, or severe symptoms of HF, with or without coronary artery disease.128 133 Data suggest that there are no differences among available ACE inhibitors in their effects on symptoms or survival.143 ACE inhibitors should be started at low doses and titrated upward to doses shown to reduce the risk of cardiovascular events in clinical trials. ACE inhibitors can produce angioedema and should be given with caution to patients with low systemic blood pressures, renal insufficiency, or elevated serum potassium (>5.0 mEq/L). Angioedema occurs in <1% of patients who take an ACE inhibitor, but it occurs more frequently in blacks and women.144 Patients should not be given ACE inhibitors if they are pregnant or plan to become pregnant. ACE inhibitors also inhibit kininase and increase levels of bradykinin, which can induce cough in up to 20% of patients but also may contribute to beneficial vasodilation. If maximal doses are not tolerated, intermediate doses should be tried; abrupt withdrawal of ACE inhibition can lead to clinical deterioration and should be avoided. Although the use of an ARNI in lieu of an ACE inhibitor for HFrEF has been found to be superior, for those patients for whom ARNI is not appropriate, continued use of an ACE inhibitor for all classes of HFrEF remains strongly advised. I ARB: A The use of ARBs to reduce morbidity and mortality is recommended in patients with prior or current symptoms of chronic HFrEF who are intolerant to ACE inhibitors because of cough or angioedema.134 137,145,146 2013 recommendation repeated for clarity in this section. See Online Data Supplements 2 and 19. ARBs have been shown to reduce mortality and HF hospitalizations in patients with HFrEF in large RCTs.134 137 Long-term therapy with ARBs in patients with HFrEF produces hemodynamic, neurohormonal, and clinical effects consistent with those expected after interference with the renin-angiotensin system.145,146 Unlike ACE inhibitors, ARBs do not inhibit kininase and are associated with a much lower incidence of cough and angioedema, although kininase inhibition by ACE inhibitors may produce beneficial vasodilatory effects. Patients intolerant to ACE inhibitors because of cough or angioedema should be started on ARBs; patients already tolerating ARBs for other indications may be continued on ARBs if they subsequently develop HF. ARBs should be started at low doses and titrated upward, with an attempt to use doses shown to reduce the risk of cardiovascular events in clinical trials. ARBs should be given with caution to patients with low systemic blood pressure, renal insufficiency, or elevated serum potassium (>5.0 mEq/L). Although ARBs are alternatives for patients with ACE inhibitor induced angioedema, caution is advised because some patients have also developed angioedema with ARBs. Head-to-head comparisons of an ARB versus ARNI for HF do not exist. For those patients for whom an ACE inhibitor or ARNI is inappropriate, use of an ARB remains advised. 2017 ACC/AHA/HFSA Heart Failure Focused Update CLINICAL STATEMENTS AND GUIDELINES I ARNI: B-R In patients with chronic symptomatic HFrEF NYHA class II or III who tolerate an ACE inhibitor or ARB, replacement by an ARNI is recommended to further reduce morbidity and mortality.138 NEW: New clinical trial data necessitated this recommendation. See Online Data Supplements 1 and 18. Benefits of ACE inhibitors with regard to decreasing HF progression, hospitalizations, and mortality rate have been shown consistently for patients across the clinical spectrum, from asymptomatic to severely symptomatic HF. Similar benefits have been shown for ARBs in populations with mild-to-moderate HF who are unable to tolerate ACE inhibitors. In patients with mild-to- moderate HF (characterized by either 1) mildly elevated natriuretic peptide levels, BNP [B-type natriuretic peptide] >150 pg/mL or NT-proBNP [N-terminal pro-B-type natriuretic peptide] 600 pg/mL; or 2) BNP 100 pg/mL or NT-proBNP 400 pg/mL with a prior hospitalization in the preceding 12 months) who were able to tolerate both a target dose of enalapril (10 mg twice daily) and then subsequently an ARNI (valsartan/sacubitril; 200 mg twice daily, with the ARB component equivalent to valsartan 160 mg), hospitalizations and mortality were significantly decreased with the valsartan/sacubitril compound compared with enalapril. The target dose of the ACE inhibitor was consistent with that known to improve outcomes in previous landmark clinical trials.129 This ARNI has been approved for patients with symptomatic HFrEF and is intended to be substituted for ACE inhibitors or ARBs. HF effects and potential off-target effects may be complex with inhibition of the neprilysin enzyme, which has multiple biological targets. Use of an ARNI is associated with hypotension and a low-frequency incidence of angioedema. To facilitate initiation and titration, the approved ARNI is available in 3 doses that include a dose that was not tested in the HF trial; the target dose used in the trial was 97/103 mg twice daily.147 Clinical experience will provide further information about the optimal titration and tolerability of ARNI, particularly with regard to blood pressure, adjustment of concomitant HF medications, and the rare complication of angioedema.14 III: Harm B-R ARNI should not be administered concomitantly with ACE inhibitors or within 36 hours of the last dose of an ACE inhibitor.148,149 NEW: Available evidence demonstrates a potential signal of harm for a concomitant use of ACE inhibitors and ARNI. See Online Data Supplement 3. Oral neprilysin inhibitors, used in combination with ACE inhibitors can lead to angioedema and concomitant use is contraindicated and should be avoided. A medication that represented both a neprilysin inhibitor and an ACE inhibitor, omapatrilat, was studied in both hypertension and HF, but its development was terminated because of an unacceptable incidence of angioedema148,149 and associated significant morbidity. This adverse effect was thought to occur because both ACE and neprilysin break down bradykinin, which directly or indirectly can cause angioedema.149,150 An ARNI should not be administered within 36 hours of switching from or to an ACE inhibitor. III: Harm C-EO ARNI should not be administered to patients with a history of angioedema. NEW: New clinical trial data. 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. The study included patients with HFrEF (NYHA class II-IV, albeit with only a modest representation of NYHA class IV HF) and left ventricular ejection fraction (LVEF) 35%, in sinus rhythm with a resting heart rate of 70 beats per minute. Patients enrolled included a small number with paroxysmal atrial fibrillation (<40% of the time) but otherwise in sinus rhythm and a small number experiencing ventricular pacing but with a predominant sinus rhythm. Those with a myocardial infarction within the preceding 2 months were excluded. Patients enrolled had been hospitalized for HF in the preceding 12 months and were on stable GDEM* for 4 weeks before initiation of ivabradine therapy. The target of ivabradine is heart rate slowing (the presumed benefit of action), but only 25% of patients studied were on optimal doses of beta-blocker therapy.9,139,140,155 Given the well-proven mortality benefits of beta-blocker therapy, it is important to initiate and up titrate these agents to target doses, as tolerated, before assessing the resting heart rate for consideration of Recommendations for Renin-Angiotensin System Inhibition With ACE Inhibitor or ARB or ARNI (Continued) COR LOE Recommendations Comment/Rationale *In other parts of the document, the term GDMT has been used to denote guideline-directed management and therapy. In this recommendation, however, the term GDEM has been used to denote this same concept in order to reflect the original wording of the recommendation that initially appeared in the 2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure: An Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure. 10 Yancy et al 7.3.3. Pharmacological Treatment for Stage C HFpEF: Recommendations Recommendations for Stage C HFpEF COR LOE Recommendations Comment/Rationale I B Systolic and diastolic blood pressure should be controlled in patients with HFpEF in accordance with published clinical practice guidelines to 2013 recommendation remains current. I C Diuretics should be used for relief of symptoms due to volume overload in patients with HFpEF. 2013 recommendation remains current. IIa C Coronary revascularization is reasonable in patients with CAD in whom symptoms (angina) or demonstrable myocardial ischemia is judged to be having an adverse effect on symptomatic HFpEF despite GDMT. 2013 recommendation remains current. IIa C Management of AF according to published clinical practice guidelines in patients with HFpEF is reasonable to improve symptomatic HF. 2013 recommendation remains current (Section 9.1 in the 2013 HF guideline). IIa C The use of beta-blocking agents, ACE inhibitors, and ARBs in patients with hypertension is reasonable to control blood pressure in patients with HFpEF. 2013 recommendation remains current. Figure 2. Treatment of HFrEF Stage C and D. Colors correspond to COR in Table 1. For all medical therapies, dosing should be optimized and serial assessment exercised. *See text for important treatment directions. Hydral-Nitrates green box: The combination of ISDN/HYD with ARNI has not been robustly tested. BP response should be carefully monitored. See 2013 HF guideline.9 Participation in investigational studies is also appropriate for stage C, NYHA class II and III HF. ACEI indicates angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor-blocker; ARNI, angiotensin receptor-neprilysin inhibitor; BP, blood pressure; bpm, beats per minute; C/I, contraindication; COR, Class of Recommendation; CrCl, creatinine clearance; CRT-D, cardiac resynchronization therapy device; Dx, diagnosis; GDMT, guideline-directed management and therapy; HF, heart failure; HFrEF, heart failure with reduced ejection fraction; ICD, implantable cardioverter-defibrillator; ISDN/HYD, isosorbide dinitrate hydral-nitrates; K+, potassium; LBBB, left bundle-branch block; LVAD, left ventricular assist device; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NSR, normal sinus rhythm; and NYHA, New York Heart Association. 2017 ACC/AHA/HFSA Heart Failure Focused Update CLINICAL STATEMENTS AND GUIDELINES IIb B-R In appropriately selected patients with HFpEF (with EF 45%, elevated BNP levels or HF admission within 1 year, estimated glomerular filtration rate >30 mL/min, creatinine <2.5 mg/dL, potassium <5.0 mEq/L), aldosterone receptor antagonists might be considered to decrease NEW: Current recommendation reflects new RCT data. See Online Data Supplement C. Mechanistic studies have suggested that mineralocorticoid receptor antagonists can improve measures of diastolic function in patients with HFpEF, possibly by a similar effect on remodeling.83,168 The TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial166 investigated the effects of spironolactone on a combined endpoint of death, aborted cardiac death, and HF hospitalization in patients with HFpEF. A small reduction (HR=0.89) in this composite endpoint did not reach statistical significance, although HF hospitalization was reduced (HR=0.83); known side effects of hyperkalemia and rising creatinine were seen more commonly in the treatment group.166 An unusual amount of regional variation was seen in this trial, prompting a post-hoc analysis167 that showed that rates of the primary endpoint were 4-fold lower in Russia/Georgia than in North America and South America (the Americas). Rates in the Americas were comparable to those in other HFpEF trials.169,170 The post-hoc analysis showed efficacy in the Americas (HR=0.83) but not in Russia/Georgia (HR=1.10). Moreover, a sample of the Russia/Georgia population, despite having been in the active treatment arm, had nondetectable levels of the metabolite of spironolactone. These post- hoc analyses have significant limitations, but they suggest that in appropriately selected patients with symptomatic HFpEF (with ejection fraction [EF] 45%, elevated BNP level or HF admission within 1 year, estimated glomerular filtration rate >30 mL/min creatinine <2.5 mg/dL, and potassium <5.0 mEq/L), particularly in those with elevated BNP levels, use of spironolactone might be considered with close monitoring of potassium and renal function. Confirmatory studies are required. With regard to the use of mineralocorticoid receptor antagonists, creatinine should be <2.5 mg/dL in men or <2.0 mg/dL in women (or estimated glomerular filtration rate >30 mL/min) and potassium should be <5.0 mEq/L. Careful monitoring of potassium, renal function, and diuretic dosing represents best practices at initiation and during follow-up thereafter to minimize risk of hyperkalemia and worsening renal function. IIb B The use of ARBs might be considered to decrease hospitalizations for patients with HFpEF.169 2013 recommendation remains current. III: No Benefit B-R Routine use of nitrates or phosphodiesterase-5 inhibitors to increase activity or QoL in patients with HFpEF is ineffective.171,172 NEW: Current recommendation reflects new data from RCTs. See Online Data Supplement C. Nitrate therapy can reduce pulmonary congestion and improve exercise tolerance in patients with HFrEF. However, the NEAT-HFpEF (Nitrate s Effect on Activity Tolerance in Heart Failure With Preserved Ejection Fraction) trial171 randomized 110 patients with EF 50% on stable HF therapy, not including nitrates, and with activity limited by dyspnea, fatigue, or chest pain, to either isosorbide mononitrate or placebo and found no beneficial effects on activity levels, QoL, exercise tolerance, or NT-proBNP levels. On the basis of this trial, routine use of nitrates in patients with HFpEF is not recommended. This recommendation does not apply to patients with HFpEF and symptomatic CAD for whom nitrates may provide symptomatic relief. Phosphodiesterase-5 inhibition augments the nitric oxide system by upregulating cGMP activity. The RELAX (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection randomized 216 patients with EF 50% on stable HF therapy and with reduced exercise tolerance (peak observed Vo2 <60% of predicted) to phosphodiesterase-5 inhibition with sildenafil or placebo. This study did not show improvement in oxygen consumption or exercise tolerance. III: No Benefit C Routine use of nutritional supplements is not recommended for patients with HFpEF. 2013 recommendation remains current. 9. IMPORTANT COMORBIDITIES IN HF 9.2. Anemia: Recommendations Recommendations for Anemia COR LOE Recommendations Comment/Rationale IIb B-R In patients with NYHA class II and III HF and iron deficiency (ferritin <100 ng/mL or 100 to 300 ng/mL if transferrin saturation is <20%), intravenous iron replacement might be reasonable to improve functional status and QoL.173,174 NEW: New evidence consistent with therapeutic benefit. See Online Data Supplement D. Routine baseline assessment of all patients with HF includes an evaluation for anemia in addition to other baseline laboratory measurements. Anemia is independently associated with HF disease severity, and iron deficiency appears to be uniquely associated with reduced exercise capacity. When iron deficiency is diagnosed and after full evaluation for cause, intravenous repletion of iron, especially in the setting of concomitant hepcidin deficiency in HF, may improve exercise capacity and QoL. Studies examining correction of iron deficiency in HF have demonstrated improvement in surrogate endpoints, such as QoL, NT- proBNP, and LVEF; however, controlled trials have been underpowered to detect reductions in hard clinical endpoints. The FAIR-HF (Ferric Carboxymaltose Assessment in Patients With Iron Deficiency and Chronic Heart Failure) trial173 demonstrated improvements in NYHA class and functional capacity over a short- term exposure. The CONFIRM-HF (Ferric Carboxymaltose Evaluation on Performance in Patients With Iron Deficiency in Combination with Chronic Heart Failure) included a larger cohort of patients (n=304) and demonstrated improvements in 6-minute walk test. A meta-analysis of 5 prospective controlled studies (631 patients) evaluated the effect of intravenous iron on deaths, hospitalizations, and other events in patients with HF and iron deficiency.175 Patients receiving intravenous iron experienced limited but statistically significant improvements in functional capacity and LVEF but no reduction in mortality rate. The FAIR-HF 2 trial is underway to further address the potential benefit of intravenous iron in HF associated with iron deficiency. Therefore, a strong recommendation for intravenous iron repletion must await the results of an appropriately powered trial on morbidity and mortality. There is an uncertain evidence base for oral iron repletion in the setting of anemia associated with HF. Recommendations for Stage C HFpEF (Continued) COR LOE Recommendations Comment/Rationale Yancy et al III: No Benefit B-R In patients with HF and anemia, erythropoietin-stimulating agents should not be used to improve morbidity and mortality.176 NEW: Current recommendation reflects new evidence demonstrating absence of therapeutic benefit. See Online Data Supplement D. Small studies evaluating the treatment of anemia in patients with HF have suggested a trend toward improvement in functional capacity and reduction in hospitalization with the use of erythropoietin-stimulating agents,177 182 but results have varied183 and have been limited because of sample size. Although a meta-analysis of 11 RCTs (n=794) comparing erythropoietin-stimulating agents to control in patients with HF demonstrated significant improvements in 6-minute walk, exercise duration, peak Vo2 , NYHA functional status, EF, BNP, HF-related hospitalizations, and QoL,184 in the STAMINA-HeFT (Study of Anemia in Heart Failure) trial,183 darbepoetin alfa was not associated with significant clinical benefits. In the largest RCT to date (n=2278), correction of anemia with darbopoetin alfa did not result in benefit and resulted in a significant increase in the risk of thromboembolic events and a nonsignificant increase in fatal and nonfatal strokes, supporting findings from other trials.176,185 188 In summary, the strongest evidence on erythropoietin-stimulating agent therapy in HF suggests lack of benefit and increased adverse events. Therefore, erythropoietin-stimulating agent therapy cannot be recommended in patients with HF and anemia. Table 3. Drugs Commonly Used for HFrEF (Stage C HF) Drug Initial Daily Dose(s) Maximum Doses(s) Mean Doses Achieved in Clinical Trials References ACE inhibitors Captopril 6.25 mg TID 50 mg TID 122.7 mg QD 158 Enalapril 2.5 mg BID 10 20 mg BID 16.6 mg QD 129 Fosinopril 5 10 mg QD 40 mg QD N/A Lisinopril 2.5 5 mg QD 20 40 mg QD 32.5 35.0 mg QD 130 Perindopril 2 mg QD 8 16 mg QD N/A Quinapril 5 mg BID 20 mg BID N/A Ramipril 1.25 2.5 mg QD 10 mg QD N/A Trandolapril 1 mg QD 4 mg QD N/A ARBs Candesartan 4 8 mg QD 32 mg QD 24 mg QD 137 Losartan 25 50 mg QD 50 150 mg QD 129 mg QD 136 Valsartan 20 40 mg BID 160 mg BID 254 mg QD 134 ARNI Sacubitril/valsartan 49/51 mg BID (sacubitril/valsartan) (therapy may be initiated at 24/26 mg BID) 97/103 mg BID (sacubitril/valsartan) 375 mg QD; target dose: 24/26 mg, 49/51 mg OR 97/103 mg BID If channel inhibitor Ivabradine 5 mg BID 7.5 mg BID 6.4 mg BID (at 28 d) 6.5 mg BID (at 1 y) Aldosterone antagonists Spironolactone 12.5 25 mg QD 25 mg QD or BID 26 mg QD 142 Eplerenone 25 mg QD 50 mg QD 42.6 mg QD 159 Beta blockers Bisoprolol 1.25 mg QD 10 mg QD 8.6 mg QD 160 Carvedilol 3.125 mg BID 50 mg BID 37 mg QD 161 Carvedilol CR 10 mg QD 80 mg QD N/A Metoprolol succinate extended release (metoprolol CR/XL) 12.5 25 mg QD 200 mg QD 159 mg QD 139 Isosorbide dinitrate and hydralazine Fixed-dose combination 20 mg isosorbide dinitrate/37.5 mg hydralazine TID mg hydralazine TID 90 mg isosorbide dinitrate/ ~175 mg hydralazine QD Isosorbide dinitrate and hydralazine mg hydralazine TID or QD 40 mg isosorbide dinitrate TID with 100 mg hydralazine TID Modified (Table 15) from the 2013 HF guideline.9 ACE indicates angiotensin-converting enzyme; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor-neprilysin inhibitor; BID, twice daily; CR, controlled release; CR/XL, controlled release/extended release; HF, heart failure; HFrEF, heart failure with reduced ejection fraction; N/A, not applicable; QD, once daily; and TID, 3 times daily. Recommendations for Anemia (Continued) COR LOE Recommendations Comment/Rationale 2017 ACC/AHA/HFSA Heart Failure Focused Update CLINICAL STATEMENTS AND GUIDELINES 9.5. Hypertension (New Section) 9.5.1. Treating Hypertension to Reduce the Incidence of HF: Recommendation Recommendation for Prevention COR LOE Recommendations Comment/Rationale I B-R In patients at increased risk, stage A HF, the optimal blood pressure in those with hypertension should be less than 130/80 mm Hg.189 193 NEW: Recommendation reflects new RCT data. See Online Data Supplements E and F. A large RCT demonstrated that in those with increased cardiovascular risk (defined as age >75 years, established vascular disease, chronic renal disease, or a Framingham Risk Score >15%), control of blood pressure to a goal systolic pressure of <120 mm Hg, as determined by blood pressure assessment as per research protocol, was associated with a significant reduction in the incidence of HF191 and an overall decrease in cardiovascular death. Blood pressure measurements as generally taken in the office setting are typically 5 to 10 mm Hg higher than research measurements; thus, the goal of <130/80 mm Hg is an approximation of the target blood pressure in conventional practice. Targeting a significant reduction in systolic blood pressure in those at increased risk for cardiovascular disease is a novel strategy to prevent HF. 9.5.2. Treating Hypertension in Stage C HFrEF: Recommendation Recommendation for Hypertension in Stage C HFrEF COR LOE Recommendation Comment/Rationale I C-EO Patients with HFrEF and hypertension should be prescribed GDMT titrated to attain systolic blood pressure less than 130 mm Hg.191 NEW: Recommendation has been adapted from recent clinical trial data but not specifically tested per se in a randomized trial of patients with HF. See Online Data Supplements E and F. Clinical trials evaluating goal blood pressure reduction and optimal blood pressure lowering agents in the setting of HFrEF and concomitant hypertension have not been done. However, it is apparent that in those patients at higher risk, blood pressure lowering is associated with fewer adverse cardiovascular events. GDMT for HFrEF with agents known to lower blood pressure should consider a goal blood pressure reduction consistent with a threshold now associated with improved clinical outcomes but not yet proven by RCTs in a population with HF. 9.5.3. Treating Hypertension in Stage C HFpEF: Recommendation Recommendation for Hypertension in Stage C HFpEF COR LOE Recommendation Comment/Rationale I C-LD Patients with HFpEF and persistent hypertension after management of volume overload should be prescribed GDMT titrated to attain systolic blood pressure less than 130 mm Hg.9,167,169,170,195 199 NEW: New target goal blood pressure based on updated interpretation of recent clinical trial data. See Online Data Supplements E and F. The use of nitrates in the setting of HFpEF is associated with a signal of harm and, in most situations, should be avoided. For many common antihypertensive agents, including alpha blockers, beta blockers, and calcium channel blockers, there are limited data to guide the choice of antihypertensive therapy in the setting of HFpEF.172 Nevertheless, RAAS inhibition with ACE inhibitor, ARB (especially mineralocorticoid receptor antagonists), and possibly ARNI would represent the preferred choice. A shared decision-making discussion with the patient influenced by physician judgment should drive the ultimate choice of antihypertensive agents. 9.6. Sleep-Disordered Breathing: Recommendations (Moved from Section 7.3.1.4, Treatment of Sleep Disorders in the 2013 HF guideline.) Recommendations for Treatment of Sleep Disorders COR LOE Recommendations Comment/Rationale IIa C-LD In patients with NYHA class II IV HF and suspicion of sleep-disordered breathing or excessive daytime sleepiness, a formal sleep assessment is NEW: Recommendation reflects clinical necessity to distinguish obstructive versus central sleep apnea. See Online Data Supplement G. Sleep disorders are common in patients with HF. A study of adults with chronic HF treated with evidence-based therapies found that 61% had either central or obstructive sleep apnea.202 It is clinically important to distinguish obstructive sleep apnea from central sleep apnea, given the different responses to treatment. Adaptive servo-ventilation for central sleep apnea is associated with harm.203 Continuous positive airway pressure (CPAP) for obstructive sleep apnea improves sleep quality, reduces the apnea-hypopnea index, and improves nocturnal oxygenation.200,201 IIb B-R In patients with cardiovascular disease and obstructive sleep apnea, CPAP may be reasonable to improve sleep quality and daytime NEW: New data demonstrate the limited scope of benefit expected from CPAP for obstructive sleep apnea. See Online Data Supplement G. In patients with sleep apnea, a trial evaluated the impact of CPAP with usual therapy versus usual therapy alone on subsequent cardiovascular events, including In this RCT of >2700 patients, there was no evidence of benefit on cardiovascular events at a mean follow-up of 3.7 years for CPAP plus usual care compared with usual care alone. Improvements in sleep quality were noteworthy and represented the primary indication for initiating CPAP treatment.204 However, in patients with atrial fibrillation (AF) (a frequent comorbidity noted with HF), the use of CPAP for obstructive sleep apnea was helpful. In a trial of 10132 patients with AF and obstructive sleep apnea, patients on CPAP treatment were less likely to progress to more permanent forms of AF than were patients without CPAP.205 Yancy et al ACC/AHA TASK FORCE MEMBERS Glenn N. Levine, MD, FACC, FAHA, Chair; Patrick T. O Gara, MD, FACC, FAHA, Chair-Elect; Jonathan L. Halperin, MD, FACC, FAHA, Immediate Past Chair*; Sana M. Al-Khatib, MD, MHS, FACC, FAHA; Kim K. Birtcher, PharmD, MS, AACC; Bi- ykem Bozkurt, MD, PhD, FACC, FAHA; Ralph G. Brindis, MD, MPH, MACC*; Joaquin E. Cigarroa, MD, FACC; Lesley H. Cur- tis, PhD, FAHA; Lee A. Fleisher, MD, FACC, FAHA; Federico Gentile, MD, FACC; Samuel Gidding, MD, FAHA; Mark A. Hlatky, MD, FACC; John Ikonomidis, MD, PhD, FAHA; Jos Joglar, MD, FACC, FAHA; Susan J. Pressler, PhD, RN, FAHA; Duminda N. Wijeysundera, MD, PhD PRESIDENTS AND STAFF American College of Cardiology Mary Norine Walsh, MD, FACC, President Shalom Jacobovitz, Chief Executive Officer William J. Oetgen, MD, MBA, FACC, Executive Vice President, Science, Education, Quality, and Publishing Amelia Scholtz, PhD, Publications Manager, Science, Education, Quality, and Publishing American College of Cardiology/ American Heart Association Katherine Sheehan, PhD, Director of Guideline Strategy and Operations Lisa Bradfield, CAE, Director, Guideline Methodology and Policy Abdul R. Abdullah, MD, Science and Medicine Advisor Morgane Cibotti-Sun, MPH, Project Manager, Clinical Practice Guidelines Sam Shahid, MBBS, MPH, Associate Science and Medicine Advisor American Heart Association Steven R. Houser, PhD, FAHA, President Nancy Brown, Chief Executive Officer Rose Marie Robertson, MD, FAHA, Chief Science and Medicine Officer Gayle R. Whitman, PhD, RN, FAHA, FAAN, Senior Vice Presi- dent, Office of Science Operations Jody Hundley, Production Manager, Scientific Publications, Office of Science Operations FOOTNOTES This document was approved by the American College of Cardiology Clinical Policy Approval Committee, the American Heart Association Science Advisory and Coordinating Com- mittee, the American Heart Association Executive Committee, and the Heart Failure Society of America Executive Committee in April 2017. The Comprehensive RWI Data Supplement table is avail- able with this article at http://circ.ahajournals.org/lookup/ suppl/doi:10.1161/CIR.0000000000000509/-/DC1. The Data Supplement is available with this article at CIR.0000000000000509/-/DC2. This article has been copublished in the Journal of the American College of Cardiology and the Journal of Cardiac Failure. Copies:ThisdocumentisavailableontheWorldWideWeb sites of the American College of Cardiology (www.acc.org), the American Heart Association (professional.heart.org), and the Heart Failure Society of America (www.hfsa.org). A copy of the document is available at http://professional. heart.org/statements by selecting either the By Topic link or the By Publication Date link. To purchase addi- tional reprints, call 843-216-2533 or e-mail kelle.ramsay@ wolterskluwer.com. Expert peer review of AHA Scientific Statements is con- ducted by the AHA Office of Science Operations. For more on AHA statements and guidelines development, visit http:// professional.heart.org/statements and select the Policies and Development link. Permissions: Multiple copies, modification, alteration, enhancement, and/or distribution of this document are not permitted without the express permission of the American Heart Association. Instructions for obtaining permission are located at http://www.heart.org/HEARTORG/General/Copyright- Permission-Guidelines_UCM_300404_Article.jsp. A link to the Copyright Permissions Request Form appears on the right side of the page. Circulation is available at http://circ.ahajournals.org. *Former Task Force member; current member during the writing effort. III: Harm B-R In patients with NYHA class II IV HFrEF and central sleep apnea, adaptive servo-ventilation causes harm.203 NEW: New data demonstrate a signal of harm when adaptive servo-ventilation is used for central sleep apnea. See Online Data Supplement G. Mortality rate (all cause and cardiovascular) was higher with adaptive servo-ventilation plus GDMT than with GDMT alone in a single RCT to test the addition of adaptive servo-ventilation ( 5 hours/night, 7 days/week) to GDMT in patients with HFrEF and central sleep apnea.203 A similar risk has been seen in another trial, and a third trial of adaptive servo-ventilation in central sleep apnea and HF was aborted because of ethical concerns. The weight of evidence does not support the use of adaptive servo-ventilation for central sleep apnea in HFrEF. Recommendations for Treatment of Sleep Disorders (Continued) COR LOE Recommendations Comment/Rationale 2017 ACC/AHA/HFSA Heart Failure Focused Update CLINICAL STATEMENTS AND GUIDELINES REFERENCES 1. Committee on Standards for Developing Trustworthy Clinical Practice Guidelines, Institute of Medicine (US). Clinical Practice Guidelines We Can Trust. Washington, DC: National Academies Press, 2011. 2. Committee on Standards for Systematic Reviews of Comparative Ef- fectiveness Research, Institute of Medicine (US). Finding What Works in Health Care: Standards for Systematic Reviews. Washington, DC: National Academies Press, 2011. 3. Anderson JL, Heidenreich PA, Barnett PG, et al. ACC/AHA statement on cost/value methodology in clinical practice guidelines and performance measures: a report of the American College of Cardiology/American Heart Association Task Force on Performance Measures and Task Force on Prac- tice Guidelines. Circulation. 2014;129:2329 45. 4. ACCF/AHA Task Force on Practice Guidelines. Methodology Manual and Policies From the ACCF/AHA Task Force on Practice Guidelines; 2010. American College of Cardiology and American Heart Association. Available at: http://my.americanheart.org/idc/groups/ahamah-public/@ wcm/@sop/documents/downloadable/ucm_319826.pdf Accessed May 5, 2017. 5. Halperin JL, Levine GN, Al-Khatib SM, et al. Further evolution of the ACC/AHA clinical practice guideline recommendation classification sys- tem: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2016;133:1426 8. 6. Jacobs AK, Kushner FG, Ettinger SM, et al. ACCF/AHA clinical practice guideline methodology summit report: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Prac- tice Guidelines. Circulation. 2013;127:268 310. 7. Jacobs AK, Anderson JL, Halperin JL. The evolution and future of ACC/ AHA clinical practice guidelines: a 30-year journey: a report of the Ameri- can College of Cardiology/American Heart Association Task Force on Prac- tice Guidelines. Circulation. 2014;130:1208 17. 8. Arnett DK, Goodman RA, Halperin JL, et al. AHA/ACC/HHS strategies to enhance application of clinical practice guidelines in patients with cardio- vascular disease and comorbid conditions: from the American Heart As- sociation, American College of Cardiology, and US Department of Health and Human Services. Circulation. 2014;130:1662 7. 9. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiol- ogy Foundation/American Heart Association Task Force on Practice Guide- lines. Circulation. 2013;128:e240 327. 10. Yancy CW, Jessup M, Bozkurt B, et al. 2016 ACC/AHA/HFSA focused update on new pharmacological therapy for heart failure: an update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation. 2016;134:e282 93. 11. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special con- tribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016;37:2129 200. 12. Packer M, McMurray JJ, Desai AS, et al. Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression in surviving patients with heart failure. Circulation. 2015;131:54 61. 13. Zile MR, Claggett BL, Prescott MF, et al. Prognostic Implications of Changes in N-Terminal Pro-B-Type Natriuretic Peptide in Patients With Heart Failure. J Am Coll Cardiol. 2016;68:2425 36. 14. Solomon SD, Zile M, Pieske B, et al. The angiotensin receptor nepri- lysin inhibitor LCZ696 in heart failure with preserved ejection frac- tion: a phase 2 double-blind randomised controlled trial. Lancet. 2012;380:1387 95. 15. Richards AM, Doughty R, Nicholls MG, et al. Plasma N-terminal pro-brain natriuretic peptide and adrenomedullin: prognostic utility and predic- tion of benefit from carvedilol in chronic ischemic left ventricular dys- function. Australia-New Zealand Heart Failure Group. J Am Coll Cardiol. 2001;37:1781 7. 16. Tang WH, Girod JP, Lee MJ, et al. Plasma B-type natriuretic peptide lev- els in ambulatory patients with established chronic symptomatic systolic heart failure. Circulation. 2003;108:2964 6. 17. Zaphiriou A, Robb S, Murray-Thomas T, et al. The diagnostic accuracy of plasma BNP and NTproBNP in patients referred from primary care with suspected heart failure: results of the UK natriuretic peptide study. Eur J Heart Fail. 2005;7:537 41. 18. Son CS, Kim YN, Kim HS, et al. Decision-making model for early diagnosis of congestive heart failure using rough set and decision tree approaches. J Biomed Inform. 2012;45:999 1008. 19. Kelder JC, Cramer MJ, Van WJ, et al. The diagnostic value of physical ex- amination and additional testing in primary care patients with suspected heart failure. Circulation. 2011;124:2865 73. 20. Balion C, Don-Wauchope A, Hill S, et al. 