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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

      Key Words

      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
      Former Task Force member; current member during the writing effort.
      Sana M. Al-Khatib, MD, MHS, FACC, FAHA
      Kim K. Birtcher, PharmD, MS, AACC
      Biykem Bozkurt, MD, PhD, FACC, FAHA
      Ralph G. Brindis, MD, MPH, MACC‡
      Former Task Force member; current member during the writing effort.
      Joaquin E. Cigarroa, MD, FACC
      Lesley H. Curtis, 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
      José Joglar, MD, FACC, FAHA
      Susan J. Pressler, PhD, RN, FAHA
      Duminda N. Wijeysundera, MD, PhD

      Table of Contents

      • Preamble 630
      • 1.
        Introduction 632
        • 1.1.
          Methodology and Evidence Review 632
        • 1.2.
          Organization of the Writing Group 632
        • 1.3.
          Document Review and Approval 632
      • 6.
        Initial and Serial Evaluation of the HF Patient 632
        • 6.3.
          Biomarkers 633
          • 6.3.1.
            Biomarkers for Prevention: Recommendation 634
          • 6.3.2.
            Biomarkers for Diagnosis: Recommendation 634
          • 6.3.3.
            Biomarkers for Prognosis or Added Risk Stratification: Recommendations 634
      • 7.
        Treatment of Stages A to D 635
        • 7.3.
          Stage C 635
          • 7.3.2.
            Pharmacological Treatment for Stage C HF With Reduced Ejection Fraction: Recommendations 635
            • 7.3.2.10.
              Renin-Angiotensin System Inhibition With Angiotensin-Converting Enzyme Inhibitor or Angiotensin Receptor Blocker or ARNI: Recommendations 635
            • 7.3.2.11.
              Ivabradine: Recommendation 635
          • 7.3.3.
            Pharmacological Treatment for Stage C HFpEF: Recommendations 639
      • 9.
        Important Comorbidities in HF 640
        • 9.2.
          Anemia: Recommendations 640
        • 9.5.
          Hypertension (New Section) 640
          • 9.5.1.
            Treating Hypertension to Reduce the Incidence of HF: Recommendation 640
          • 9.5.2.
            Treating Hypertension in Stage C HFrEF: Recommendation 641
          • 9.5.3.
            Treating Hypertension in Stage C HFpEF: Recommendation 641
        • 9.6.
          Sleep-Disordered Breathing: Recommendations 641
      • Appendix 1
        • Author Relationships With Industry and Other Entities (Relevant) 643
      • Appendix 2
        • Reviewer Relationships With Industry and Other Entities (Comprehensive) 644
      • Appendix 3
        • Abbreviations 645
      • References 646

      Preamble

      Since 1980, the American College of Cardiology (ACC) and American Heart Association (AHA) have translated scientific evidence into clinical practice guidelines (guidelines) with recommendations to improve cardiovascular 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 publication 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 applicable to patients with or at risk of developing cardiovascular disease. The focus is on medical practice in the United States, but guidelines developed in collaboration 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. Guidelines 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 modifies guideline methodology on the basis of published standards from organizations including the Institute of Medicine (
      Committee on Standards for Developing Trustworthy Clinical Practice GuidelinesInstitute of Medicine (U.S.)
      Clinical Practice Guidelines We Can Trust.
      ,
      Committee on Standards for Systematic Reviews of Comparative Effectiveness ResearchInstitute of Medicine (U.S.)
      Finding What Works in Health Care: Standards for Systematic Reviews.
      ) and on the basis of internal reevaluation. Similarly, the presentation and delivery of guidelines are reevaluated and modified on the basis of evolving technologies and other factors to facilitate optimal dissemination 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 supported by limited text (ideally, <250 words) and hyperlinks to supportive evidence summary tables. Ongoing efforts to further limit text are underway. Recognizing the importance 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 (
      • Anderson J.L.
      • Heidenreich P.A.
      • Barnett P.G.
      • 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 Practice Guidelines.
      ).
      To ensure that guideline recommendations remain current, new data are reviewed on an ongoing basis, with full guideline revisions commissioned in approximately 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 determine whether a focused update should be commissioned. For additional information and policies regarding guideline development, we encourage readers to consult the ACC/AHA guideline methodology manual (
      ACCF/AHA Task Force on Practice Guidelines
      Methodology Manual and Policies From the ACCF/AHA Task Force on Practice Guidelines.
      ) and other methodology articles (
      • Halperin J.L.
      • Levine G.N.
      • Al-Khatib S.M.
      • et al.
      Further evolution of the ACC/AHA clinical practice guideline recommendation classification system: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
      ,
      • Jacobs A.K.
      • Kushner F.G.
      • Ettinger S.M.
      • 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 Practice Guidelines.
      ,
      • Jacobs A.K.
      • Anderson J.L.
      • Halperin J.L.
      The evolution and future of ACC/AHA clinical practice guidelines: a 30-year journey: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
      ,
      • Arnett D.K.
      • Goodman R.A.
      • Halperin J.L.
      • et al.
      AHA/ACC/HHS strategies to enhance application of clinical practice guidelines in patients with cardiovascular disease and comorbid conditions: from the American Heart Association, American College of Cardiology, and U.S. Department of Health and Human Services.
      ).

       Selection of Writing Committee Members

      The Task Force strives to avoid bias by selecting experts from a broad array of backgrounds. Writing committee 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 related interests and expertise to participate as partners, collaborators, or endorsers.

       Relationships With Industry and Other Entities

      The ACC and AHA have rigorous policies and methods 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 members’ 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 committee uses evidence-based methodologies that are based on all available data (
      ACCF/AHA Task Force on Practice Guidelines
      Methodology Manual and Policies From the ACCF/AHA Task Force on Practice Guidelines.
      ,
      • Halperin J.L.
      • Levine G.N.
      • Al-Khatib S.M.
      • et al.
      Further evolution of the ACC/AHA clinical practice guideline recommendation classification system: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
      ,
      • Jacobs A.K.
      • Kushner F.G.
      • Ettinger S.M.
      • 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 Practice Guidelines.
      ,
      • Jacobs A.K.
      • Anderson J.L.
      • Halperin J.L.
      The evolution and future of ACC/AHA clinical practice guidelines: a 30-year journey: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
      ). 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 determine 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 benefit 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 recommendations 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 treatments. For these and all recommended drug treatment regimens, the reader should confirm the dosage by reviewing product insert material and evaluate the treatment regimen for contraindications and interactions. The recommendations are limited to drugs, devices, 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 proportion to risk. The Level of Evidence (LOE) rates the quality of scientific evidence that supports the intervention on the basis of the type, quantity, and consistency of data from clinical trials and other sources (Table 1) (
      ACCF/AHA Task Force on Practice Guidelines
      Methodology Manual and Policies From the ACCF/AHA Task Force on Practice Guidelines.
      ,
      • Halperin J.L.
      • Levine G.N.
      • Al-Khatib S.M.
      • et al.
      Further evolution of the ACC/AHA clinical practice guideline recommendation classification system: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
      ,
      • Jacobs A.K.
      • Kushner F.G.
      • Ettinger S.M.
      • 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 Practice Guidelines.
      ).
      Table 1Applying Class of Recommendation and Level of Evidence to Clinical Strategies, Interventions, Treatments, or Diagnostic Testing in Patient Care* (Updated August 2015)
      Glenn N. Levine, MD, FACC, FAHA
      Chair, ACC/AHA Task Force on Clinical Practice Guidelines

      1. Introduction

      The purpose of this focused update is to update the “2013 ACCF/AHA Guideline for the Management of Heart Failure” (
      • Yancy C.W.
      • Jessup M.
      • Bozkurt B.
      • et al.
      2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.
      ) (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 guidance 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 published as the “2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure” (
      • Yancy C.W.
      • 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.
      ), which introduced guidance on new therapies, specifically 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 for the Diagnosis and Treatment of Acute and Chronic Heart Failure” (
      • Ponikowski P.
      • Voors A.A.
      • Anker S.D.
      • 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 contribution of the Heart Failure Association (HFA) of the ESC.
      ).

      1.1 Methodology and Evidence Review

      To identify key data that influence guideline recommendations, 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 November 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 that have been deleted or superseded no longer appear. Please consult the full-text version of the 2013 HF guideline (
      • Yancy C.W.
      • Jessup M.
      • Bozkurt B.
      • et al.
      2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.
      ) for text and evidence tables supporting the unchanged recommendations and for clinical areas not addressed in this focused update. Individual recommendations in this focused update will be incorporated into the full-text guideline in the future. Recommendations 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 recommendations in this focused update reflect the latest COR/LOE system, in which LOE B and C are subcategorized for greater specificity (
      ACCF/AHA Task Force on Practice Guidelines
      Methodology Manual and Policies From the ACCF/AHA Task Force on Practice Guidelines.
      ,
      • Halperin J.L.
      • Levine G.N.
      • Al-Khatib S.M.
      • et al.
      Further evolution of the ACC/AHA clinical practice guideline recommendation classification system: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
      ,
      • Jacobs A.K.
      • Kushner F.G.
      • Ettinger S.M.
      • 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 Practice Guidelines.
      ). The section numbers correspond 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 invited to participate. They were joined by additional invited 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 relevant to the data under consideration. The group was composed of experts representing general cardiologists, HF and transplantation specialists, electrophysiologists, pharmacists, and general internists. The 2017 HF focused update writing group included representatives from the ACC, AHA, and HFSA, as well as the American Academy of Family Physicians, American College of Chest Physicians, American College of Physicians, 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 individual 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

      6.3 Biomarkers

      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 biomarker values track similarly, and either can be used in patient care settings as long as their respective absolute values and cutpoints are not used interchangeably. Notably, BNP, but not NT-proBNP, is a substrate for neprilysin. Therefore, ARNI increases BNP levels (
      • Packer M.
      • McMurray J.J.
      • Desai A.S.
      • et al.
      Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression in surviving patients with heart failure.
      ) but not NT-proBNP levels (
      • Zile M.R.
      • Claggett B.L.
      • Prescott M.F.
      • et al.
      Prognostic Implications of Changes in N-Terminal Pro-B-Type Natriuretic Peptide in Patients With Heart Failure.
      ). Note that the type of natriuretic 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 (
      • Packer M.
      • McMurray J.J.
      • Desai A.S.
      • et al.
      Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression in surviving patients with heart failure.
      ,
      • Solomon S.D.
      • Zile M.
      • Pieske B.
      • et al.
      The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled trial.
      ), with the reduction in 1 study being associated with improved clinical outcomes (
      • Packer M.
      • McMurray J.J.
      • Desai A.S.
      • et al.
      Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression in surviving patients with heart failure.
      ).
      A substantial evidence base exists that supports the use of natriuretic peptide biomarkers to assist in the diagnosis or exclusion of HF as a cause of symptoms (e.g., dyspnea, weight gain) in the setting of chronic ambulatory HF (
      • Richards A.M.
      • Doughty R.
      • Nicholls M.G.
      • et al.
      Plasma N-terminal pro-brain natriuretic peptide and adrenomedullin: prognostic utility and prediction of benefit from carvedilol in chronic ischemic left ventricular dysfunction. Australia-New Zealand Heart Failure Group.
      ,
      • Tang W.H.
      • Girod J.P.
      • Lee M.J.
      • et al.
      Plasma B-type natriuretic peptide levels in ambulatory patients with established chronic symptomatic systolic heart failure.
      ,
      • 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.
      ,
      • Son C.S.
      • Kim Y.N.
      • Kim H.S.
      • et al.
      Decision-making model for early diagnosis of congestive heart failure using rough set and decision tree approaches.
      ,
      • Kelder J.C.
      • Cramer M.J.
      • Van W.J.
      • et al.
      The diagnostic value of physical examination and additional testing in primary care patients with suspected heart failure.
      ,

      Balion C, Don-Wauchope A, Hill S, et al. Use of Natriuretic Peptide Measurement in the Management of Heart Failure [Internet]. 13(14)-EHC118-EF ed. Rockville, MD: 2013.

      ,
      • Booth R.A.
      • Hill S.A.
      • Don-Wauchope A.
      • et al.
      Performance of BNP and NT-proBNP for diagnosis of heart failure in primary care patients: a systematic review.
      ) or in the setting of acute care with decompensated HF (
      • Dao Q.
      • Krishnaswamy P.
      • Kazanegra R.
      • et al.
      Utility of B-type natriuretic peptide in the diagnosis of congestive heart failure in an urgent-care setting.
      ,
      • Davis M.
      • Espiner E.
      • Richards G.
      • et al.
      Plasma brain natriuretic peptide in assessment of acute dyspnoea.
      ,
      • Maisel A.S.
      • Krishnaswamy P.
      • Nowak R.M.
      • et al.
      Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure.
      ,
      • Moe G.W.
      • Howlett J.
      • Januzzi J.L.
      • et al.
      N-terminal pro-B-type natriuretic peptide testing improves the management of patients with suspected acute heart failure: primary results of the Canadian prospective randomized multicenter IMPROVE-CHF study.
      ,
      • Mueller C.
      • Scholer A.
      • Laule-Kilian K.
      • et al.
      Use of B-type natriuretic peptide in the evaluation and management of acute dyspnea.
      ,
      • van Kimmenade R.R.
      • Pinto Y.M.
      • Bayes-Genis A.
      • et al.
      Usefulness of intermediate amino-terminal pro-brain natriuretic peptide concentrations for diagnosis and prognosis of acute heart failure.
      ,
      • Januzzi Jr., J.L.
      • Chen-Tournoux A.A.
      • Moe G.
      Amino-terminal pro-B-type natriuretic peptide testing for the diagnosis or exclusion of heart failure in patients with acute symptoms.
      ,
      • Santaguida P.L.
      • Don-Wauchope A.C.
      • Ali U.
      • et al.
      Incremental value of natriuretic peptide measurement in acute decompensated heart failure (ADHF): a systematic review.
      ,
      • Hill S.A.
      • Booth R.A.
      • Santaguida P.L.
      • et al.
      Use of BNP and NT-proBNP for the diagnosis of heart failure in the emergency department: a systematic review of the evidence.
      ), especially when the cause of dyspnea is unclear. The role of natriuretic peptide biomarkers in population screening to detect incident HF is emerging (
      • Costello-Boerrigter L.C.
      • Boerrigter G.
      • Redfield M.M.
      • et al.
      Amino-terminal pro-B-type natriuretic peptide and B-type natriuretic peptide in the general community: determinants and detection of left ventricular dysfunction.
      ,
      • de Lemos J.A.
      • McGuire D.K.
      • Khera A.
      • et al.
      Screening the population for left ventricular hypertrophy and left ventricular systolic dysfunction using natriuretic peptides: results from the Dallas Heart Study.
      ,
      • Goetze J.P.
      • Mogelvang R.
      • Maage L.
      • et al.
      Plasma pro-B-type natriuretic peptide in the general population: screening for left ventricular hypertrophy and systolic dysfunction.
      ,
      • Ng L.L.
      • Loke I.W.
      • Davies J.E.
      • et al.
      Community screening for left ventricular systolic dysfunction using plasma and urinary natriuretic peptides.
      ,
      • Ho J.E.
      • Liu C.
      • Lyass A.
      • et al.
      Galectin-3, a marker of cardiac fibrosis, predicts incident heart failure in the community.
      ,
      • Wang T.J.
      • Wollert K.C.
      • Larson M.G.
      • et al.
      Prognostic utility of novel biomarkers of cardiovascular stress: the Framingham Heart Study.
      ,
      • Xanthakis V.
      • Larson M.G.
      • Wollert K.C.
      • et al.
      Association of novel biomarkers of cardiovascular stress with left ventricular hypertrophy and dysfunction: implications for screening.
      ). Elevated plasma levels of natriuretic peptide biomarkers are associated with a wide variety of cardiac and noncardiac causes (Table 2) (
      • Anwaruddin S.
      • Lloyd-Jones D.M.
      • Baggish A.
      • et al.
      Renal function, congestive heart failure, and amino-terminal pro-brain natriuretic peptide measurement: results from the ProBNP Investigation of Dyspnea in the Emergency Department (PRIDE) Study.
      ,
      • Redfield M.M.
      • Rodeheffer R.J.
      • Jacobsen S.J.
      • et al.
      Plasma brain natriuretic peptide concentration: impact of age and gender.
      ,
      • Wang T.J.
      • Larson M.G.
      • Levy D.
      • et al.
      Impact of age and sex on plasma natriuretic peptide levels in healthy adults.
      ,
      • Chang A.Y.
      • Abdullah S.M.
      • Jain T.
      • et al.
      Associations among androgens, estrogens, and natriuretic peptides in young women: observations from the Dallas Heart Study.
      ,
      • Clerico A.
      • Giannoni A.
      • Vittorini S.
      • et al.
      The paradox of low BNP levels in obesity.
      ). Obesity may be associated with lower natriuretic peptide concentrations, and this may modestly reduce diagnostic sensitivity in morbidly obese patients (
      • Clerico A.
      • Giannoni A.
      • Vittorini S.
      • et al.
      The paradox of low BNP levels in obesity.
      ).
      Table 2Selected Potential Causes of Elevated Natriuretic Peptide Levels
      • Anwaruddin S.
      • Lloyd-Jones D.M.
      • Baggish A.
      • et al.
      Renal function, congestive heart failure, and amino-terminal pro-brain natriuretic peptide measurement: results from the ProBNP Investigation of Dyspnea in the Emergency Department (PRIDE) Study.
      ,
      • Redfield M.M.
      • Rodeheffer R.J.
      • Jacobsen S.J.
      • et al.
      Plasma brain natriuretic peptide concentration: impact of age and gender.
      ,
      • Wang T.J.
      • Larson M.G.
      • Levy D.
      • et al.
      Impact of age and sex on plasma natriuretic peptide levels in healthy adults.
      ,
      • Chang A.Y.
      • Abdullah S.M.
      • Jain T.
      • et al.
      Associations among androgens, estrogens, and natriuretic peptides in young women: observations from the Dallas Heart Study.
      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
      • Yancy C.W.
      • Jessup M.
      • Bozkurt B.
      • et al.
      2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.
      .
      HF, indicates heart failure; LVH, left ventricular hypertrophy; and RV, right ventricular.
      Because of the absence of clear and consistent evidence for improvement in mortality and cardiovascular outcomes (
      • De Vecchis R.
      • Esposito C.
      • Di Biase G.
      • et al.
      B-type natriuretic peptide-guided versus symptom-guided therapy in outpatients with chronic heart failure: a systematic review with meta-analysis.
      ,
      • Felker G.M.
      • Hasselblad V.
      • Hernandez A.F.
      • et al.
      Biomarker-guided therapy in chronic heart failure: a meta-analysis of randomized controlled trials.
      ,
      • Li P.
      • Luo Y.
      • Chen Y.M.
      B-type natriuretic peptide-guided chronic heart failure therapy: a meta-analysis of 11 randomised controlled trials.
      ,
      • Porapakkham P.
      • Porapakkham P.
      • Zimmet H.
      • et al.
      B-type natriuretic peptide-guided heart failure therapy: a meta-analysis.
      ,
      • Savarese G.
      • Trimarco B.
      • Dellegrottaglie S.
      • et al.
      Natriuretic peptide-guided therapy in chronic heart failure: a meta-analysis of 2,686 patients in 12 randomized trials.
      ,
      • Troughton R.W.
      • Frampton C.M.
      • Brunner-La Rocca H.P.
      • et al.
      Effect of B-type natriuretic peptide-guided treatment of chronic heart failure on total mortality and hospitalization: an individual patient meta-analysis.
      ,
      • Xin W.
      • Lin Z.
      • Mi S.
      Does B-type natriuretic peptide-guided therapy improve outcomes in patients with chronic heart failure? A systematic review and meta-analysis of randomized controlled trials.
      ,
      • Berger R.
      • Moertl D.
      • Peter S.
      • et al.
      N-terminal pro-B-type natriuretic peptide-guided, intensive patient management in addition to multidisciplinary care in chronic heart failure: a 3-arm, prospective, randomized pilot study.
      ,
      • Eurlings L.W.
      • van Pol P.E.
      • Kok W.E.
      • et al.
      Management of chronic heart failure guided by individual N-terminal pro-B-type natriuretic peptide targets: results of the PRIMA (Can PRo-brain-natriuretic peptide guided therapy of chronic heart failure IMprove heart fAilure morbidity and mortality?) study.
      ,
      • Gaggin H.K.
      • Mohammed A.A.
      • Bhardwaj A.
      • et al.
      Heart failure outcomes and benefits of NT-proBNP-guided management in the elderly: results from the prospective, randomized ProBNP outpatient tailored chronic heart failure therapy (PROTECT) study.
      ,
      • Jourdain P.
      • Jondeau G.
      • Funck F.
      • et al.
      Plasma brain natriuretic peptide-guided therapy to improve outcome in heart failure: the STARS-BNP Multicenter Study.
      ,
      • Karlstrom P.
      • Alehagen U.
      • Boman K.
      • et al.
      Brain natriuretic peptide-guided treatment does not improve morbidity and mortality in extensively treated patients with chronic heart failure: responders to treatment have a significantly better outcome.
      ,
      • Lainchbury J.G.
      • Troughton R.W.
      • Strangman K.M.
      • et al.
      N-terminal pro-B-type natriuretic peptide-guided treatment for chronic heart failure: results from the BATTLESCARRED (NT-proBNP-Assisted Treatment To Lessen Serial Cardiac Readmissions and Death) trial.
      ,
      • Persson H.
      • Erntell H.
      • Eriksson B.
      • et al.
      Improved pharmacological therapy of chronic heart failure in primary care: a randomized Study of NT-proBNP Guided Management of Heart Failure–SIGNAL-HF (Swedish Intervention study–Guidelines and NT-proBNP AnaLysis in Heart Failure).
      ,
      • Pfisterer M.
      • Buser P.
      • Rickli H.
      • et al.
      BNP-guided vs symptom-guided heart failure therapy: the Trial of Intensified vs Standard Medical Therapy in Elderly Patients With Congestive Heart Failure (TIME-CHF) randomized trial.
      ,
      • Shah M.R.
      • Califf R.M.
      • Nohria A.
      • et al.
      The STARBRITE trial: a randomized, pilot study of B-type natriuretic peptide-guided therapy in patients with advanced heart failure.
      ,
      • Troughton R.W.
      • Frampton C.M.
      • Yandle T.G.
      • et al.
      Treatment of heart failure guided by plasma aminoterminal brain natriuretic peptide (N-BNP) concentrations.
      ,
      • Singer A.J.
      • Birkhahn R.H.
      • Guss D.
      • et al.
      Rapid Emergency Department Heart Failure Outpatients Trial (REDHOT II): a randomized controlled trial of the effect of serial B-type natriuretic peptide testing on patient management.
      ,
      • Stienen S.
      • Salah K.
      • Moons A.H.
      • et al.
      Rationale and design of PRIMA II: A multicenter, randomized clinical trial to study the impact of in-hospital guidance for acute decompensated heart failure treatment by a predefined NT-PRoBNP target on the reduction of readmIssion and Mortality rAtes.
      ,
      • Stienen S.
      PRIMA II: can NT-pro-brain-natriuretic peptide (NT-proBNP) guided therapy during admission for acute heart failure reduce mortality and readmissions?.
      ), there are insufficient data to inform specific guideline recommendations related to natriuretic peptide–guided therapy or serial measurements of BNP or NT-proBNP levels for the purpose of reducing hospitalization or deaths in the present document.
      Like natriuretic peptides, cardiac troponin levels may be elevated in the setting of chronic or acute decompensated HF, suggesting myocyte injury or necrosis (
      • Kociol R.D.
      • Pang P.S.
      • Gheorghiade M.
      • et al.
      Troponin elevation in heart failure prevalence, mechanisms, and clinical implications.
      ). 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 (
      • Amsterdam E.A.
      • Wenger N.K.
      • Brindis R.G.
      • et al.
      2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
      ).
      In addition to natriuretic peptides and troponins (
      • Masson S.
      • Anand I.
      • Favero C.
      • et al.
      Serial measurement of cardiac troponin T using a highly sensitive assay in patients with chronic heart failure: data from 2 large randomized clinical trials.
      ,
      • Savarese G.
      • Musella F.
      • D'Amore C.
      • et al.
      Changes of natriuretic peptides predict hospital admissions in patients with chronic heart failure: a meta-analysis.
      ,
      • de Lemos J.A.
      Increasingly sensitive assays for cardiac troponins: a review.
      ), multiple other biomarkers, including those of inflammation, oxidative stress, vascular dysfunction, and myocardial and matrix remodeling, have been implicated in HF (
      • de Boer R.A.
      • Daniels L.B.
      • Maisel A.S.
      • et al.
      State of the Art: Newer biomarkers in heart failure.
      ,
      • Gopal D.M.
      • Sam F.
      New and emerging biomarkers in left ventricular systolic dysfunction–insight into dilated cardiomyopathy.
      ,
      • O'Meara E.
      • de D.S.
      • Rouleau J.L.
      • et al.
      Circulating biomarkers in patients with heart failure and preserved ejection fraction.
      ,
      • Karayannis G.
      • Triposkiadis F.
      • Skoularigis J.
      • et al.
      The emerging role of Galectin-3 and ST2 in heart failure: practical considerations and pitfalls using novel biomarkers.
      ). Biomarkers of myocardial fibrosis, soluble ST2 receptor, and galectin-3 are predictive of hospitalization and death and may provide incremental prognostic value over natriuretic peptide levels in patients with HF (
      • Ahmad T.
      • Fiuzat M.
      • Neely B.
      • et al.
      Biomarkers of myocardial stress and fibrosis as predictors of mode of death in patients with chronic heart failure.
      ,
      • Bayes-Genis A.
      • de A.M.
      • Vila J.
      • et al.
      Head-to-head comparison of 2 myocardial fibrosis biomarkers for long-term heart failure risk stratification: ST2 versus galectin-3.
      ,
      • Gaggin H.K.
      • Szymonifka J.
      • Bhardwaj A.
      • et al.
      Head-to-head comparison of serial soluble ST2, growth differentiation factor-15, and highly-sensitive troponin T measurements in patients with chronic heart failure.
      ). Strategies that combine multiple biomarkers may ultimately prove beneficial in guiding HF therapy in the future, but multicenter studies with larger derivation and validation cohorts are needed (
      • Ky B.
      • French B.
      • Levy W.C.
      • et al.
      Multiple biomarkers for risk prediction in chronic heart failure.
      ,
      • Sabatine M.S.
      • Morrow D.A.
      • de Lemos J.A.
      • et al.
      Evaluation of multiple biomarkers of cardiovascular stress for risk prediction and guiding medical therapy in patients with stable coronary disease.
      ). Several emerging biomarkers await validation with well-defined outcome measures and prognostic accuracy before they can reach the clinical arena (
      • Ahmad T.
      • Fiuzat M.
      • Pencina M.J.
      • et al.
      Charting a roadmap for heart failure biomarker studies.
      ,
      • Miller W.L.
      • Hartman K.A.
      • Grill D.E.
      • et al.
      Serial measurements of midregion proANP and copeptin in ambulatory patients with heart failure: incremental prognostic value of novel biomarkers in heart failure.
      ,
      • Creemers E.E.
      • Tijsen A.J.
      • Pinto Y.M.
      Circulating microRNAs: novel biomarkers and extracellular communicators in cardiovascular disease?.
      ,
      • Wong L.L.
      • Armugam A.
      • Sepramaniam S.
      • et al.
      Circulating microRNAs in heart failure with reduced and preserved left ventricular ejection fraction.
      ,
      • Ovchinnikova E.S.
      • Schmitter D.
      • Vegter E.L.
      • et al.
      Signature of circulating microRNAs in patients with acute heart failure.
      ,
      • Shah S.H.
      • Kraus W.E.
      • Newgard C.B.
      Metabolomic profiling for the identification of novel biomarkers and mechanisms related to common cardiovascular diseases: form and function.
      ,
      • Cheng M.L.
      • Wang C.H.
      • Shiao M.S.
      • et al.
      Metabolic disturbances identified in plasma are associated with outcomes in patients with heart failure: diagnostic and prognostic value of metabolomics.
      ,
      • Zheng Y.
      • Yu B.
      • Alexander D.
      • et al.
      Associations between metabolomic compounds and incident heart failure among African Americans: the ARIC Study.
      ).
      This section categorizes the role of biomarkers into prevention, diagnosis, prognosis, and added risk stratification to clarify evidence-based objectives of their use in clinical practice.

      6.3.1 Biomarkers for Prevention: Recommendation

      Tabled 1Biomarkers: Recommendation for Prevention of HF
      CORLOERecommendationComment/Rationale
      IIaB-RFor 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-onset HF
      • Ledwidge M.
      • Gallagher J.
      • Conlon C.
      • et al.
      Natriuretic peptide-based screening and collaborative care for heart failure: the STOP-HF randomized trial.
      ,
      • Huelsmann M.
      • Neuhold S.
      • Resl M.
      • et al.
      PONTIAC (NT-proBNP selected prevention of cardiac events in a population of diabetic patients without a history of cardiac disease): a prospective randomized controlled trial.
      .
      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])
      • Ledwidge M.
      • Gallagher J.
      • Conlon C.
      • et al.
      Natriuretic peptide-based screening and collaborative care for heart failure: the STOP-HF randomized trial.
      , patients at risk of HF (identified by the presence of hypertension, diabetes mellitus, or known vascular disease [e.g., 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
      • Ledwidge M.
      • Gallagher J.
      • Conlon C.
      • et al.
      Natriuretic peptide-based screening and collaborative care for heart failure: the STOP-HF randomized trial.
      . 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 baseline
      • Huelsmann M.
      • Neuhold S.
      • Resl M.
      • et al.
      PONTIAC (NT-proBNP selected prevention of cardiac events in a population of diabetic patients without a history of cardiac disease): a prospective randomized controlled trial.
      . 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

      Tabled 1Biomarkers: Recommendation for Diagnosis
      CORLOERecommendationComment/Rationale
      IAIn patients presenting with dyspnea, measurement of natriuretic peptide biomarkers is useful to support a diagnosis or exclusion of HF
      • Richards A.M.
      • Doughty R.
      • Nicholls M.G.
      • et al.
      Plasma N-terminal pro-brain natriuretic peptide and adrenomedullin: prognostic utility and prediction of benefit from carvedilol in chronic ischemic left ventricular dysfunction. Australia-New Zealand Heart Failure Group.
      ,
      • Tang W.H.
      • Girod J.P.
      • Lee M.J.
      • et al.
      Plasma B-type natriuretic peptide levels in ambulatory patients with established chronic symptomatic systolic heart failure.
      ,
      • 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.
      ,
      • Son C.S.
      • Kim Y.N.
      • Kim H.S.
      • et al.
      Decision-making model for early diagnosis of congestive heart failure using rough set and decision tree approaches.
      ,
      • Kelder J.C.
      • Cramer M.J.
      • Van W.J.
      • et al.
      The diagnostic value of physical examination and additional testing in primary care patients with suspected heart failure.
      ,

      Balion C, Don-Wauchope A, Hill S, et al. Use of Natriuretic Peptide Measurement in the Management of Heart Failure [Internet]. 13(14)-EHC118-EF ed. Rockville, MD: 2013.

      ,
      • Booth R.A.
      • Hill S.A.
      • Don-Wauchope A.
      • et al.
      Performance of BNP and NT-proBNP for diagnosis of heart failure in primary care patients: a systematic review.
      ,
      • Dao Q.
      • Krishnaswamy P.
      • Kazanegra R.
      • et al.
      Utility of B-type natriuretic peptide in the diagnosis of congestive heart failure in an urgent-care setting.
      ,
      • Davis M.
      • Espiner E.
      • Richards G.
      • et al.
      Plasma brain natriuretic peptide in assessment of acute dyspnoea.
      ,
      • Maisel A.S.
      • Krishnaswamy P.
      • Nowak R.M.
      • et al.
      Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure.
      ,
      • Januzzi Jr., J.L.
      • Chen-Tournoux A.A.
      • Moe G.
      Amino-terminal pro-B-type natriuretic peptide testing for the diagnosis or exclusion of heart failure in patients with acute symptoms.
      ,
      • Santaguida P.L.
      • Don-Wauchope A.C.
      • Ali U.
      • et al.
      Incremental value of natriuretic peptide measurement in acute decompensated heart failure (ADHF): a systematic review.
      ,
      • Hill S.A.
      • Booth R.A.
      • Santaguida P.L.
      • et al.
      Use of BNP and NT-proBNP for the diagnosis of heart failure in the emergency department: a systematic review of the evidence.
      .
      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
      • Richards A.M.
      • Doughty R.
      • Nicholls M.G.
      • et al.
      Plasma N-terminal pro-brain natriuretic peptide and adrenomedullin: prognostic utility and prediction of benefit from carvedilol in chronic ischemic left ventricular dysfunction. Australia-New Zealand Heart Failure Group.
      ,
      • Tang W.H.
      • Girod J.P.
      • Lee M.J.
      • et al.
      Plasma B-type natriuretic peptide levels in ambulatory patients with established chronic symptomatic systolic heart failure.
      ,
      • 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.
      ,
      • Son C.S.
      • Kim Y.N.
      • Kim H.S.
      • et al.
      Decision-making model for early diagnosis of congestive heart failure using rough set and decision tree approaches.
      ,
      • Kelder J.C.
      • Cramer M.J.
      • Van W.J.
      • et al.
      The diagnostic value of physical examination and additional testing in primary care patients with suspected heart failure.
      ,

      Balion C, Don-Wauchope A, Hill S, et al. Use of Natriuretic Peptide Measurement in the Management of Heart Failure [Internet]. 13(14)-EHC118-EF ed. Rockville, MD: 2013.

      ,
      • Booth R.A.
      • Hill S.A.
      • Don-Wauchope A.
      • et al.
      Performance of BNP and NT-proBNP for diagnosis of heart failure in primary care patients: a systematic review.
      . 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

      Balion C, Don-Wauchope A, Hill S, et al. Use of Natriuretic Peptide Measurement in the Management of Heart Failure [Internet]. 13(14)-EHC118-EF ed. Rockville, MD: 2013.

      . 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)
      • Anwaruddin S.
      • Lloyd-Jones D.M.
      • Baggish A.
      • et al.
      Renal function, congestive heart failure, and amino-terminal pro-brain natriuretic peptide measurement: results from the ProBNP Investigation of Dyspnea in the Emergency Department (PRIDE) Study.
      ,
      • Redfield M.M.
      • Rodeheffer R.J.
      • Jacobsen S.J.
      • et al.
      Plasma brain natriuretic peptide concentration: impact of age and gender.
      ,
      • Wang T.J.
      • Larson M.G.
      • Levy D.
      • et al.
      Impact of age and sex on plasma natriuretic peptide levels in healthy adults.
      ,
      • Chang A.Y.
      • Abdullah S.M.
      • Jain T.
      • et al.
      Associations among androgens, estrogens, and natriuretic peptides in young women: observations from the Dallas Heart Study.
      .

      6.3.3 Biomarkers for Prognosis or Added Risk Stratification: Recommendations

      Tabled 1Biomarkers: Recommendations for Prognosis
      CORLOERecommendationsComment/Rationale
      IAMeasurement of BNP or NT-proBNP is useful for establishing prognosis or disease severity in chronic HF
      • Tang W.H.
      • Girod J.P.
      • Lee M.J.
      • et al.
      Plasma B-type natriuretic peptide levels in ambulatory patients with established chronic symptomatic systolic heart failure.
      ,
      • Anand I.S.
      • Fisher L.D.
      • Chiang Y.T.
      • et al.
      Changes in brain natriuretic peptide and norepinephrine over time and mortality and morbidity in the Valsartan Heart Failure Trial (Val-HeFT).
      ,
      • Berger R.
      • Huelsman M.
      • Strecker K.
      • et al.
      B-type natriuretic peptide predicts sudden death in patients with chronic heart failure.
      ,
      • Forfia P.R.
      • Watkins S.P.
      • Rame J.E.
      • et al.
      Relationship between B-type natriuretic peptides and pulmonary capillary wedge pressure in the intensive care unit.
      ,
      • Maeda K.
      • Tsutamoto T.
      • Wada A.
      • et al.
      High levels of plasma brain natriuretic peptide and interleukin-6 after optimized treatment for heart failure are independent risk factors for morbidity and mortality in patients with congestive heart failure.
      ,
      • Neuhold S.
      • Huelsmann M.
      • Strunk G.
      • et al.
      Comparison of copeptin, B-type natriuretic peptide, and amino-terminal pro-B-type natriuretic peptide in patients with chronic heart failure: prediction of death at different stages of the disease.
      ,
      • Taub P.R.
      • Daniels L.B.
      • Maisel A.S.
      Usefulness of B-type natriuretic peptide levels in predicting hemodynamic and clinical decompensation.
      .
      2013 recommendation remains current.
      IAMeasurement 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
      • van Kimmenade R.R.
      • Pinto Y.M.
      • Bayes-Genis A.
      • et al.
      Usefulness of intermediate amino-terminal pro-brain natriuretic peptide concentrations for diagnosis and prognosis of acute heart failure.
      ,
      • Bettencourt P.
      • Azevedo A.
      • Pimenta J.
      • et al.
      N-terminal-pro-brain natriuretic peptide predicts outcome after hospital discharge in heart failure patients.
      ,
      • Cheng V.
      • Kazanagra R.
      • Garcia A.
      • et al.
      A rapid bedside test for B-type peptide predicts treatment outcomes in patients admitted for decompensated heart failure: a pilot study.
      ,
      • Fonarow G.C.
      • Peacock W.F.
      • Horwich T.B.
      • et al.
      Usefulness of B-type natriuretic peptide and cardiac troponin levels to predict in-hospital mortality from ADHERE.
      ,
      • Logeart D.
      • Thabut G.
      • Jourdain P.
      • et al.
      Predischarge B-type natriuretic peptide assay for identifying patients at high risk of re-admission after decompensated heart failure.
      ,
      • Maisel A.
      • Hollander J.E.
      • Guss D.
      • et al.
      Primary results of the Rapid Emergency Department Heart Failure Outpatient Trial (REDHOT). A multicenter study of B-type natriuretic peptide levels, emergency department decision making, and outcomes in patients presenting with shortness of breath.
      ,
      • Zairis M.N.
      • Tsiaousis G.Z.
      • Georgilas A.T.
      • et al.
      Multimarker strategy for the prediction of 31 days cardiac death in patients with acutely decompensated chronic heart failure.
      ,
      • Peacock W.F.I.
      • De Marco T.
      • Fonarow G.C.
      • et al.
      Cardiac troponin and outcome in acute heart failure.
      ,
      • Lee D.S.
      • Stitt A.
      • Austin P.C.
      • et al.
      Prediction of heart failure mortality in emergent care: a cohort study.
      .
      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

      Balion C, Don-Wauchope A, Hill S, et al. Use of Natriuretic Peptide Measurement in the Management of Heart Failure [Internet]. 13(14)-EHC118-EF ed. Rockville, MD: 2013.

      ,
      • van Kimmenade R.R.
      • Pinto Y.M.
      • Bayes-Genis A.
      • et al.
      Usefulness of intermediate amino-terminal pro-brain natriuretic peptide concentrations for diagnosis and prognosis of acute heart failure.
      ,
      • Santaguida P.L.
      • Don-Wauchope A.C.
      • Ali U.
      • et al.
      Incremental value of natriuretic peptide measurement in acute decompensated heart failure (ADHF): a systematic review.
      ,
      • Bettencourt P.
      • Azevedo A.
      • Pimenta J.
      • et al.
      N-terminal-pro-brain natriuretic peptide predicts outcome after hospital discharge in heart failure patients.
      ,
      • Cheng V.
      • Kazanagra R.
      • Garcia A.
      • et al.
      A rapid bedside test for B-type peptide predicts treatment outcomes in patients admitted for decompensated heart failure: a pilot study.
      ,
      • Fonarow G.C.
      • Peacock W.F.
      • Horwich T.B.
      • et al.
      Usefulness of B-type natriuretic peptide and cardiac troponin levels to predict in-hospital mortality from ADHERE.
      ,
      • Logeart D.
      • Thabut G.
      • Jourdain P.
      • et al.
      Predischarge B-type natriuretic peptide assay for identifying patients at high risk of re-admission after decompensated heart failure.
      ,
      • Maisel A.
      • Hollander J.E.
      • Guss D.
      • et al.
      Primary results of the Rapid Emergency Department Heart Failure Outpatient Trial (REDHOT). A multicenter study of B-type natriuretic peptide levels, emergency department decision making, and outcomes in patients presenting with shortness of breath.
      ,
      • Zairis M.N.
      • Tsiaousis G.Z.
      • Georgilas A.T.
      • et al.
      Multimarker strategy for the prediction of 31 days cardiac death in patients with acutely decompensated chronic heart failure.
      ,
      • Peacock W.F.I.
      • De Marco T.
      • Fonarow G.C.
      • et al.
      Cardiac troponin and outcome in acute heart failure.
      ,
      • Lee D.S.
      • Stitt A.
      • Austin P.C.
      • et al.
      Prediction of heart failure mortality in emergent care: a cohort study.
      ,
      • Santaguida P.L.
      • Don-Wauchope A.C.
      • Oremus M.
      • et al.
      BNP and NT-proBNP as prognostic markers in persons with acute decompensated heart failure: a systematic review.
      . 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
      • Fonarow G.C.
      • Peacock W.F.
      • Horwich T.B.
      • et al.
      Usefulness of B-type natriuretic peptide and cardiac troponin levels to predict in-hospital mortality from ADHERE.
      ,
      • Peacock W.F.I.
      • De Marco T.
      • Fonarow G.C.
      • et al.
      Cardiac troponin and outcome in acute heart failure.
      ,
      • Horwich T.B.
      • Patel J.
      • MacLellan W.R.
      • et al.
      Cardiac troponin I is associated with impaired hemodynamics, progressive left ventricular dysfunction, and increased mortality rates in advanced heart failure.
      ,
      • Ilva T.
      • Lassus J.
      • Siirila-Waris K.
      • et al.
      Clinical significance of cardiac troponins I and T in acute heart failure.
      .

      Studies have demonstrated incremental prognostic value of these biomarkers to standard approaches of cardiovascular disease risk assessment
      • Santaguida P.L.
      • Don-Wauchope A.C.
      • Ali U.
      • et al.
      Incremental value of natriuretic peptide measurement in acute decompensated heart failure (ADHF): a systematic review.
      ,
      • Fonarow G.C.
      • Peacock W.F.
      • Horwich T.B.
      • et al.
      Usefulness of B-type natriuretic peptide and cardiac troponin levels to predict in-hospital mortality from ADHERE.
      . However, there were differences in the risk prediction models, assay cutpoints, and lengths of follow-up
      • Santaguida P.L.
      • Don-Wauchope A.C.
      • Ali U.
      • et al.
      Incremental value of natriuretic peptide measurement in acute decompensated heart failure (ADHF): a systematic review.
      . 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.
      IIaB-NRDuring a HF hospitalization, a predischarge natriuretic peptide level can be useful to establish a postdischarge prognosis
      • Bettencourt P.
      • Azevedo A.
      • Pimenta J.
      • et al.
      N-terminal-pro-brain natriuretic peptide predicts outcome after hospital discharge in heart failure patients.
      ,
      • Logeart D.
      • Thabut G.
      • Jourdain P.
      • et al.
      Predischarge B-type natriuretic peptide assay for identifying patients at high risk of re-admission after decompensated heart failure.
      ,
      • Dhaliwal A.S.
      • Deswal A.
      • Pritchett A.
      • et al.
      Reduction in BNP levels with treatment of decompensated heart failure and future clinical events.
      ,
      • O'Connor C.M.
      • Hasselblad V.
      • Mehta R.H.
      • et al.
      Triage after hospitalization with advanced heart failure: the ESCAPE (Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness) risk model and discharge score.
      ,
      • O'Brien R.J.
      • Squire I.B.
      • Demme B.
      • et al.
      Pre-discharge, but not admission, levels of NT-proBNP predict adverse prognosis following acute LVF.
      ,
      • Cohen-Solal A.
      • Logeart D.
      • Huang B.
      • et al.
      Lowered B-type natriuretic peptide in response to levosimendan or dobutamine treatment is associated with improved survival in patients with severe acutely decompensated heart failure.
      ,
      • Salah K.
      • Kok W.E.
      • Eurlings L.W.
      • et al.
      A novel discharge risk model for patients hospitalised for acute decompensated heart failure incorporating N-terminal pro-B-type natriuretic peptide levels: a European coLlaboration on Acute decompeNsated Heart Failure: ELAN-HF Score.
      ,
      • Flint K.M.
      • Allen L.A.
      • Pham M.
      • et al.
      B-type natriuretic peptide predicts 30-day readmission for heart failure but not readmission for other causes.
      ,
      • Kociol R.D.
      • Horton J.R.
      • Fonarow G.C.
      • et al.
      Admission, discharge, or change in B-type natriuretic peptide and long-term outcomes: data from Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) linked to Medicare claims.
      ,
      • Kociol R.D.
      • McNulty S.E.
      • Hernandez A.F.
      • et al.
      Markers of decongestion, dyspnea relief, and clinical outcomes among patients hospitalized with acute heart failure.
      ,
      • Verdiani V.
      • Ognibene A.
      • Rutili M.S.
      • et al.
      NT-ProBNP reduction percentage during hospital stay predicts long-term mortality and readmission in heart failure patients.
      ,
      • Bayes-Genis A.
      • Lopez L.
      • Zapico E.
      • et al.
      NT-ProBNP reduction percentage during admission for acutely decompensated heart failure predicts long-term cardiovascular mortality.
      .
      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
      • Bettencourt P.
      • Azevedo A.
      • Pimenta J.
      • et al.
      N-terminal-pro-brain natriuretic peptide predicts outcome after hospital discharge in heart failure patients.
      ,
      • Logeart D.
      • Thabut G.
      • Jourdain P.
      • et al.
      Predischarge B-type natriuretic peptide assay for identifying patients at high risk of re-admission after decompensated heart failure.
      ,
      • Dhaliwal A.S.
      • Deswal A.
      • Pritchett A.
      • et al.
      Reduction in BNP levels with treatment of decompensated heart failure and future clinical events.
      ,
      • O'Connor C.M.
      • Hasselblad V.
      • Mehta R.H.
      • et al.
      Triage after hospitalization with advanced heart failure: the ESCAPE (Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness) risk model and discharge score.
      ,
      • O'Brien R.J.
      • Squire I.B.
      • Demme B.
      • et al.
      Pre-discharge, but not admission, levels of NT-proBNP predict adverse prognosis following acute LVF.
      ,
      • Cohen-Solal A.
      • Logeart D.
      • Huang B.
      • et al.
      Lowered B-type natriuretic peptide in response to levosimendan or dobutamine treatment is associated with improved survival in patients with severe acutely decompensated heart failure.
      ,
      • Salah K.
      • Kok W.E.
      • Eurlings L.W.
      • et al.
      A novel discharge risk model for patients hospitalised for acute decompensated heart failure incorporating N-terminal pro-B-type natriuretic peptide levels: a European coLlaboration on Acute decompeNsated Heart Failure: ELAN-HF Score.
      ,
      • Flint K.M.
      • Allen L.A.
      • Pham M.
      • et al.
      B-type natriuretic peptide predicts 30-day readmission for heart failure but not readmission for other causes.
      ,
      • Kociol R.D.
      • Horton J.R.
      • Fonarow G.C.
      • et al.
      Admission, discharge, or change in B-type natriuretic peptide and long-term outcomes: data from Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) linked to Medicare claims.
      ,
      • Kociol R.D.
      • McNulty S.E.
      • Hernandez A.F.
      • et al.
      Markers of decongestion, dyspnea relief, and clinical outcomes among patients hospitalized with acute heart failure.
      ,
      • Verdiani V.
      • Ognibene A.
      • Rutili M.S.
      • et al.
      NT-ProBNP reduction percentage during hospital stay predicts long-term mortality and readmission in heart failure patients.
      ,
      • Bayes-Genis A.
      • Lopez L.
      • Zapico E.
      • et al.
      NT-ProBNP reduction percentage during admission for acutely decompensated heart failure predicts long-term cardiovascular mortality.
      . Several studies have suggested that predischarge natriuretic peptide biomarker levels had higher reclassification and discrimination value than clinical variables in predicting outcomes
      • Logeart D.
      • Thabut G.
      • Jourdain P.
      • et al.
      Predischarge B-type natriuretic peptide assay for identifying patients at high risk of re-admission after decompensated heart failure.
      ,
      • O'Brien R.J.
      • Squire I.B.
      • Demme B.
      • et al.
      Pre-discharge, but not admission, levels of NT-proBNP predict adverse prognosis following acute LVF.
      ,
      • Salah K.
      • Kok W.E.
      • Eurlings L.W.
      • et al.
      A novel discharge risk model for patients hospitalised for acute decompensated heart failure incorporating N-terminal pro-B-type natriuretic peptide levels: a European coLlaboration on Acute decompeNsated Heart Failure: ELAN-HF Score.
      ,
      • Flint K.M.
      • Allen L.A.
      • Pham M.
      • et al.
      B-type natriuretic peptide predicts 30-day readmission for heart failure but not readmission for other causes.
      ,
      • Kociol R.D.
      • Horton J.R.
      • Fonarow G.C.
      • et al.
      Admission, discharge, or change in B-type natriuretic peptide and long-term outcomes: data from Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) linked to Medicare claims.
      ,
      • Kociol R.D.
      • McNulty S.E.
      • Hernandez A.F.
      • et al.
      Markers of decongestion, dyspnea relief, and clinical outcomes among patients hospitalized with acute heart failure.
      . Patients with higher predischarge levels and patients who do not have a decrease in natriuretic peptide biomarker levels during hospitalization have worse outcomes
      • Logeart D.
      • Thabut G.
      • Jourdain P.
      • et al.
      Predischarge B-type natriuretic peptide assay for identifying patients at high risk of re-admission after decompensated heart failure.
      ,
      • O'Brien R.J.
      • Squire I.B.
      • Demme B.
      • et al.
      Pre-discharge, but not admission, levels of NT-proBNP predict adverse prognosis following acute LVF.
      ,
      • Salah K.
      • Kok W.E.
      • Eurlings L.W.
      • et al.
      A novel discharge risk model for patients hospitalised for acute decompensated heart failure incorporating N-terminal pro-B-type natriuretic peptide levels: a European coLlaboration on Acute decompeNsated Heart Failure: ELAN-HF Score.
      ,
      • Flint K.M.
      • Allen L.A.
      • Pham M.
      • et al.
      B-type natriuretic peptide predicts 30-day readmission for heart failure but not readmission for other causes.
      ,
      • Kociol R.D.
      • Horton J.R.
      • Fonarow G.C.
      • et al.
      Admission, discharge, or change in B-type natriuretic peptide and long-term outcomes: data from Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) linked to Medicare claims.
      ,
      • Kociol R.D.
      • McNulty S.E.
      • Hernandez A.F.
      • et al.
      Markers of decongestion, dyspnea relief, and clinical outcomes among patients hospitalized with acute heart failure.
      . 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
      • Bettencourt P.
      • Azevedo A.
      • Pimenta J.
      • et al.
      N-terminal-pro-brain natriuretic peptide predicts outcome after hospital discharge in heart failure patients.
      ,
      • Cohen-Solal A.
      • Logeart D.
      • Huang B.
      • et al.
      Lowered B-type natriuretic peptide in response to levosimendan or dobutamine treatment is associated with improved survival in patients with severe acutely decompensated heart failure.
      ,
      • Verdiani V.
      • Ognibene A.
      • Rutili M.S.
      • et al.
      NT-ProBNP reduction percentage during hospital stay predicts long-term mortality and readmission in heart failure patients.
      ,
      • Bayes-Genis A.
      • Lopez L.
      • Zapico E.
      • et al.
      NT-ProBNP reduction percentage during admission for acutely decompensated heart failure predicts long-term cardiovascular mortality.
      , 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.
      IIbB-NRIn 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
      • van Kimmenade R.R.
      • Pinto Y.M.
      • Bayes-Genis A.
      • et al.
      Usefulness of intermediate amino-terminal pro-brain natriuretic peptide concentrations for diagnosis and prognosis of acute heart failure.
      ,
      • Fonarow G.C.
      • Peacock W.F.
      • Horwich T.B.
      • et al.
      Usefulness of B-type natriuretic peptide and cardiac troponin levels to predict in-hospital mortality from ADHERE.
      ,
      • Zairis M.N.
      • Tsiaousis G.Z.
      • Georgilas A.T.
      • et al.
      Multimarker strategy for the prediction of 31 days cardiac death in patients with acutely decompensated chronic heart failure.
      ,
      • Peacock W.F.I.
      • De Marco T.
      • Fonarow G.C.
      • et al.
      Cardiac troponin and outcome in acute heart failure.
      ,
      • Ilva T.
      • Lassus J.
      • Siirila-Waris K.
      • et al.
      Clinical significance of cardiac troponins I and T in acute heart failure.
      ,
      • Alonso-Martinez J.L.
      • Llorente-Diez B.
      • Echegaray-Agara M.
      • et al.
      C-reactive protein as a predictor of improvement and readmission in heart failure.
      ,
      • Dieplinger B.
      • Gegenhuber A.
      • Kaar G.
      • et al.
      Prognostic value of established and novel biomarkers in patients with shortness of breath attending an emergency department.
      ,
      • Januzzi Jr., J.L.
      • Peacock W.F.
      • Maisel A.S.
      • et al.
      Measurement of the interleukin family member ST2 in patients with acute dyspnea: results from the PRIDE (Pro-Brain Natriuretic Peptide Investigation of Dyspnea in the Emergency Department) study.
      ,
      • Manzano-Fernandez S.
      • Mueller T.
      • Pascual-Figal D.
      • et al.
      Usefulness of soluble concentrations of interleukin family member ST2 as predictor of mortality in patients with acutely decompensated heart failure relative to left ventricular ejection fraction.
      ,
      • Rehman S.U.
      • Mueller T.
      • Januzzi Jr., J.L.
      Characteristics of the novel interleukin family biomarker ST2 in patients with acute heart failure.
      ,
      • Shah R.V.
      • Chen-Tournoux A.A.
      • Picard M.H.
      • et al.
      Galectin-3, cardiac structure and function, and long-term mortality in patients with acutely decompensated heart failure.
      .
      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 (e.g., 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
      • Manzano-Fernandez S.
      • Mueller T.
      • Pascual-Figal D.
      • et al.
      Usefulness of soluble concentrations of interleukin family member ST2 as predictor of mortality in patients with acutely decompensated heart failure relative to left ventricular ejection fraction.
      ,
      • Shah R.V.
      • Chen-Tournoux A.A.
      • Picard M.H.
      • et al.
      Galectin-3, cardiac structure and function, and long-term mortality in patients with acutely decompensated heart failure.
      ,
      • de Boer R.A.
      • Lok D.J.
      • Jaarsma T.
      • et al.
      Predictive value of plasma galectin-3 levels in heart failure with reduced and preserved ejection fraction.
      ,
      • Lok D.J.
      • van der Meer P.
      • de la Porte P.W.
      • et al.
      Prognostic value of galectin-3, a novel marker of fibrosis, in patients with chronic heart failure: data from the DEAL-HF study.
      ,
      • Tang W.H.
      • Shrestha K.
      • Shao Z.
      • et al.
      Usefulness of plasma galectin-3 levels in systolic heart failure to predict renal insufficiency and survival.
      ,
      • Tang W.H.
      • Wu Y.
      • Grodin J.L.
      • et al.
      Prognostic Value of Baseline and Changes in Circulating Soluble ST2 Levels and the Effects of Nesiritide in Acute Decompensated Heart Failure.
      ,
      • Januzzi J.L.
      • Mebazaa A.
      • Di S.S.
      ST2 and prognosis in acutely decompensated heart failure: the International ST2 Consensus Panel.
      ,
      • Mebazaa A.
      • Di S.S.
      • Maisel A.S.
      • et al.
      ST2 and multimarker testing in acute decompensated heart failure.
      ,
      • Fermann G.J.
      • Lindsell C.J.
      • Storrow A.B.
      • et al.
      Galectin 3 complements BNP in risk stratification in acute heart failure.
      . A combination of biomarkers may ultimately prove to be more informative than single biomarkers
      • Lassus J.
      • Gayat E.
      • Mueller C.
      • et al.
      Incremental value of biomarkers to clinical variables for mortality prediction in acutely decompensated heart failure: the Multinational Observational Cohort on Acute Heart Failure (MOCA) study.
      .

      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).
      Figure 1
      Figure 1Biomarkers Indications for Use
      Colors correspond to COR in .
      *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 decompensated 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.
      Figure 2
      Figure 2Treatment of HFrEF Stage C and D
      Colors correspond to COR in . 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
      (
      • Yancy C.W.
      • Jessup M.
      • Bozkurt B.
      • et al.
      2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.
      )
      .
      §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.
      Table 3Drugs Commonly Used for HFrEF (Stage C HF)
      DrugInitial Daily Dose(s)Maximum Doses(s)Mean Doses Achieved in Clinical TrialsReferences
      ACE inhibitors
      Captopril6.25 mg TID50 mg TID122.7 mg QD
      • Pitt B.
      • Segal R.
      • Martinez F.A.
      • et al.
      Randomised trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan in the Elderly Study, ELITE).
      Enalapril2.5 mg BID10–20 mg BID16.6 mg QD
      Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. The SOLVD Investigators.
      Fosinopril5–10 mg QD40 mg QDN/A
      Lisinopril2.5–5 mg QD20–40 mg QD32.5–35.0 mg QD
      • Packer M.
      • Poole-Wilson P.A.
      • Armstrong P.W.
      • et al.
      Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. ATLAS Study Group.
      Perindopril2 mg QD8–16 mg QDN/A
      Quinapril5 mg BID20 mg BIDN/A
      Ramipril1.25–2.5 mg QD10 mg QDN/A
      Trandolapril1 mg QD4 mg QDN/A
      ARBs
      Candesartan4–8 mg QD32 mg QD24 mg QD
      • Pfeffer M.A.
      • Swedberg K.
      • Granger C.B.
      • et al.
      Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme.
      Losartan25–50 mg QD50–150 mg QD129 mg QD
      • Konstam M.A.
      • Neaton J.D.
      • Dickstein K.
      • et al.
      Effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure (HEAAL study): a randomised, double-blind trial.
      Valsartan20–40 mg BID160 mg BID254 mg QD
      • Cohn J.N.
      • Tognoni G.
      • Investigators V.H.F.T.
      A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure.
      ARNI
      Sacubitril/valsartan49/51 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
      • McMurray J.J.V.
      • Packer M.
      • Desai A.S.
      • et al.
      Angiotensin-neprilysin inhibition versus enalapril in heart failure.
      If channel inhibitor
      Ivabradine5 mg BID7.5 mg BID6.4 mg BID (at 28 d)

      6.5 mg BID (at 1 y)
      • Swedberg K.
      • Komajda M.
      • Böhm M.
      • et al.
      Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study.
      ,
      • Fox K.
      • Ford I.
      • Steg P.G.
      • et al.
      Ivabradine in stable coronary artery disease without clinical heart failure.
      ,
      • Fox K.
      • Ford I.
      • Steg P.G.
      • et al.
      Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial.
      Aldosterone antagonists
      Spironolactone12.5–25 mg QD25 mg QD or BID26 mg QD
      • Pitt B.
      • Zannad F.
      • Remme W.J.
      • et al.
      The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators.
      Eplerenone25 mg QD50 mg QD42.6 mg QD
      • Pitt B.
      • Remme W.
      • Zannad F.
      • et al.
      Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction.
      Beta blockers
      Bisoprolol1.25 mg QD10 mg QD8.6 mg QD
      • Authors C.I.
      The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial.
      Carvedilol3.125 mg BID50 mg BID37 mg QD
      • Packer M.
      • Coats A.J.
      • Fowler M.B.
      • et al.
      Effect of carvedilol on survival in severe chronic heart failure.
      Carvedilol CR10 mg QD80 mg QDN/A
      Metoprolol succinate extended release (metoprolol CR/XL)12.5–25 mg QD200 mg QD159 mg QD
      Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF).
      Isosorbide dinitrate and hydralazine
      Fixed-dose combination20 mg isosorbide dinitrate/37.5 mg hydralazine TID40 mg isosorbide dinitrate/75 mg hydralazine TID90 mg isosorbide dinitrate/∼175 mg hydralazine QD
      • Taylor A.L.
      • Ziesche S.
      • Yancy C.
      • et al.
      Combination of isosorbide dinitrate and hydralazine in blacks with heart failure.
      Isosorbide dinitrate and hydralazine20–30 mg isosorbide dinitrate/25–50 mg hydralazine TID or QD40 mg isosorbide dinitrate TID with 100 mg hydralazine TIDN/A
      • Cohn J.N.
      • Archibald D.G.
      • Ziesche S.
      • et al.
      Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study.
      Modified (Table 15) from the 2013 HF guideline
      • Yancy C.W.
      • Jessup M.
      • Bozkurt B.
      • et al.
      2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.
      .
      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.

      7.3.2.10 Renin-Angiotensin System Inhibition With Angiotensin-Converting Enzyme Inhibitor or Angiotensin Receptor Blocker or ARNI: Recommendations

      Tabled 1Recommendations for Renin-Angiotensin System Inhibition With ACE Inhibitor or ARB or ARNI
      CORLOERecommendationsComment/Rationale
      IACE-I: AThe clinical strategy of inhibition of the renin-angiotensin system with ACE inhibitors (Level of Evidence: A)
      Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). The CONSENSUS Trial Study Group.
      ,
      Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. The SOLVD Investigators.
      ,
      • Packer M.
      • Poole-Wilson P.A.
      • Armstrong P.W.
      • et al.
      Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. ATLAS Study Group.
      ,
      • Pfeffer M.A.
      • Braunwald E.
      • Moyé L.A.
      • et al.
      Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: results of the Survival and Ventricular Enlargement Trial. The SAVE Investigators.
      ,
      Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators.
      ,
      • Kober L.
      • Torp-Pedersen C.
      • Carlsen J.E.
      • et al.
      A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. Trandolapril Cardiac Evaluation (TRACE) Study Group.
      , OR ARBs (Level of Evidence: A)
      • Cohn J.N.
      • Tognoni G.
      • Investigators V.H.F.T.
      A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure.
      ,
      • Pfeffer M.A.
      • McMurray J.J.V.
      • Velazquez E.J.
      • et al.
      Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both.
      ,
      • Konstam M.A.
      • Neaton J.D.
      • Dickstein K.
      • et al.
      Effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure (HEAAL study): a randomised, double-blind trial.
      ,
      • Pfeffer M.A.
      • Swedberg K.
      • Granger C.B.
      • et al.
      Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme.
      , OR ARNI (Level of Evidence: B-R)
      • McMurray J.J.V.
      • Packer M.
      • Desai A.S.
      • et al.
      Angiotensin-neprilysin inhibition versus enalapril in heart failure.
      in conjunction with evidence-based beta blockers
      • Yancy C.W.
      • Jessup M.
      • Bozkurt B.
      • et al.
      2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.
      ,
      Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF).
      ,
      • Packer M.
      • Fowler M.B.
      • Roecker E.B.
      • et al.
      Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the carvedilol prospective randomized cumulative survival (COPERNICUS) study.
      , and aldosterone antagonists in selected patients
      • Eschalier R.
      • McMurray J.J.V.
      • Swedberg K.
      • et al.
      Safety and efficacy of eplerenone in patients at high risk for hyperkalemia and/or worsening renal function: analyses of the EMPHASIS-HF study subgroups (Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure).
      ,
      • Pitt B.
      • Zannad F.
      • Remme W.J.
      • et al.
      The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators.
      , 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 Supplements 1, 2, 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
      Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). The CONSENSUS Trial Study Group.
      ,
      Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. The SOLVD Investigators.
      ,
      • Packer M.
      • Poole-Wilson P.A.
      • Armstrong P.W.
      • et al.
      Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. ATLAS Study Group.
      ,
      • Pfeffer M.A.
      • Braunwald E.
      • Moyé L.A.
      • et al.
      Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: results of the Survival and Ventricular Enlargement Trial. The SAVE Investigators.
      ,
      Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators.
      ,
      • Kober L.
      • Torp-Pedersen C.
      • Carlsen J.E.
      • et al.
      A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. Trandolapril Cardiac Evaluation (TRACE) Study Group.
      . 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 RCTs
      • Cohn J.N.
      • Tognoni G.
      • Investigators V.H.F.T.
      A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure.
      ,
      • Pfeffer M.A.
      • McMurray J.J.V.
      • Velazquez E.J.
      • et al.
      Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both.
      ,
      • Konstam M.A.
      • Neaton J.D.
      • Dickstein K.
      • et al.
      Effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure (HEAAL study): a randomised, double-blind trial.
      ,
      • Pfeffer M.A.
      • Swedberg K.
      • Granger C.B.
      • et al.
      Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme.
      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%
      • McMurray J.J.V.
      • Packer M.
      • Desai A.S.
      • et al.
      Angiotensin-neprilysin inhibition versus enalapril in heart failure.
      . 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.
      IACE-I: AThe use of ACE inhibitors is beneficial for patients with prior or current symptoms of chronic HFrEF to reduce morbidity and mortality
      Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). The CONSENSUS Trial Study Group.
      ,
      Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. The SOLVD Investigators.
      ,
      • Packer M.
      • Poole-Wilson P.A.
      • Armstrong P.W.
      • et al.
      Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. ATLAS Study Group.
      ,
      • Pfeffer M.A.
      • Braunwald E.
      • Moyé L.A.
      • et al.
      Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: results of the Survival and Ventricular Enlargement Trial. The SAVE Investigators.
      ,
      Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators.
      ,
      • Kober L.
      • Torp-Pedersen C.
      • Carlsen J.E.
      • et al.
      A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. Trandolapril Cardiac Evaluation (TRACE) Study Group.
      ,
      • Garg R.
      • Yusuf S.
      Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. Collaborative Group on ACE Inhibitor Trials.
      .
      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
      Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). The CONSENSUS Trial Study Group.
      ,
      Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. The SOLVD Investigators.
      ,
      • Packer M.
      • Poole-Wilson P.A.
      • Armstrong P.W.
      • et al.
      Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. ATLAS Study Group.
      ,
      • Pfeffer M.A.
      • Braunwald E.
      • Moyé L.A.
      • et al.
      Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: results of the Survival and Ventricular Enlargement Trial. The SAVE Investigators.
      ,
      Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators.
      ,
      • Kober L.
      • Torp-Pedersen C.
      • Carlsen J.E.
      • et al.
      A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. Trandolapril Cardiac Evaluation (TRACE) Study Group.
      . Data suggest that there are no differences among available ACE inhibitors in their effects on symptoms or survival
      • Garg R.
      • Yusuf S.
      Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. Collaborative Group on ACE Inhibitor Trials.
      . 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
      • Woodard-Grice A.V.
      • Lucisano A.C.
      • Byrd J.B.
      • et al.
      Sex-dependent and race-dependent association of XPNPEP2 C-2399A polymorphism with angiotensin-converting enzyme inhibitor-associated angioedema.
      . 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.
      IARB: AThe 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
      • Cohn J.N.
      • Tognoni G.
      • Investigators V.H.F.T.
      A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure.
      ,
      • Pfeffer M.A.
      • McMurray J.J.V.
      • Velazquez E.J.
      • et al.
      Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both.
      ,
      • Konstam M.A.
      • Neaton J.D.
      • Dickstein K.
      • et al.
      Effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure (HEAAL study): a randomised, double-blind trial.
      ,
      • Pfeffer M.A.
      • Swedberg K.
      • Granger C.B.
      • et al.
      Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme.
      ,
      • Yusuf S.
      • Teo K.K.
      • Pogue J.
      • et al.
      Telmisartan, ramipril, or both in patients at high risk for vascular events.
      ,
      • Yusuf S.
      • Teo K.
      • Anderson C.
      • et al.
      Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial.
      .
      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
      • Cohn J.N.
      • Tognoni G.
      • Investigators V.H.F.T.
      A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure.
      ,
      • Pfeffer M.A.
      • McMurray J.J.V.
      • Velazquez E.J.
      • et al.
      Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both.
      ,
      • Konstam M.A.
      • Neaton J.D.
      • Dickstein K.
      • et al.
      Effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure (HEAAL study): a randomised, double-blind trial.
      ,
      • Pfeffer M.A.
      • Swedberg K.
      • Granger C.B.
      • et al.
      Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme.
      . 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
      • Yusuf S.
      • Teo K.K.
      • Pogue J.
      • et al.
      Telmisartan, ramipril, or both in patients at high risk for vascular events.
      ,
      • Yusuf S.
      • Teo K.
      • Anderson C.
      • et al.
      Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial.
      . 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.
      IARNI: B-RIn 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
      • McMurray J.J.V.
      • Packer M.
      • Desai A.S.
      • et al.
      Angiotensin-neprilysin inhibition versus enalapril in heart failure.
      .
      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
      Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. The SOLVD Investigators.
      . 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
      . 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
      • Solomon S.D.
      • Zile M.
      • Pieske B.
      • et al.
      The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled trial.
      .
      III: HarmB-RARNI should not be administered concomitantly with ACE inhibitors or within 36 hours of the last dose of an ACE inhibitor
      • Packer M.
      • Califf R.M.
      • Konstam M.A.
      • et al.
      Comparison of omapatrilat and enalapril in patients with chronic heart failure: the Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE).
      ,
      • Kostis J.B.
      • Packer M.
      • Black H.R.
      • et al.
      Omapatrilat and enalapril in patients with hypertension: the Omapatrilat Cardiovascular Treatment vs. Enalapril (OCTAVE) trial.
      .
      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 angioedema
      • Packer M.
      • Califf R.M.
      • Konstam M.A.
      • et al.
      Comparison of omapatrilat and enalapril in patients with chronic heart failure: the Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE).
      ,
      • Kostis J.B.
      • Packer M.
      • Black H.R.
      • et al.
      Omapatrilat and enalapril in patients with hypertension: the Omapatrilat Cardiovascular Treatment vs. Enalapril (OCTAVE) trial.
      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
      • Kostis J.B.
      • Packer M.
      • Black H.R.
      • et al.
      Omapatrilat and enalapril in patients with hypertension: the Omapatrilat Cardiovascular Treatment vs. Enalapril (OCTAVE) trial.
      ,
      • Vardeny O.
      • Miller R.
      • Solomon S.D.
      Combined neprilysin and renin-angiotensin system inhibition for the treatment of heart failure.
      . An ARNI should not be administered within 36 hours of switching from or to an ACE inhibitor.
      III: HarmC-EOARNI should not be administered to patients with a history of angioedema.NEW: New clinical trial data.
      N/AOmapatrilat, 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
      • Packer M.
      • Califf R.M.
      • Konstam M.A.
      • et al.
      Comparison of omapatrilat and enalapril in patients with chronic heart failure: the Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE).
      . In a very large RCT of hypertensive patients, omapatrilat was associated with a 3-fold increased risk of angioedema as compared with enalapril
      • Kostis J.B.
      • Packer M.
      • Black H.R.
      • et al.
      Omapatrilat and enalapril in patients with hypertension: the Omapatrilat Cardiovascular Treatment vs. Enalapril (OCTAVE) trial.
      . Blacks and smokers were particularly at risk. The high incidence of angioedema ultimately led to cessation of the clinical development of omapatrilat
      • Messerli F.H.
      • Nussberger J.
      Vasopeptidase inhibition and angio-oedema.
      ,
      • Braunwald E.
      The path to an angiotensin receptor antagonist-neprilysin inhibitor in the treatment of heart failure.
      . In light of these observations, angioedema was an exclusion criterion in the first large trial assessing ARNI therapy in patients with hypertension
      • Ruilope L.M.
      • Dukat A.
      • Böhm M.
      • et al.
      Blood-pressure reduction with LCZ696, a novel dual-acting inhibitor of the angiotensin II receptor and neprilysin: a randomised, double-blind, placebo-controlled, active comparator study.
      and then in the large trial that demonstrated clinical benefit of ARNI therapy in HFrEF
      • McMurray J.J.V.
      • Packer M.
      • Desai A.S.
      • et al.
      Angiotensin-neprilysin inhibition versus enalapril in heart failure.
      . 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

      Tabled 1Recommendation for Ivabradine
      CORLOERecommendationComment/Rationale
      IIaB-RIvabradine can be beneficial to reduce HF hospitalization for patients with symptomatic (NYHA class II-III) stable chronic HFrEF (LVEF ≤35%) who are receiving GDEM
      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).
      , 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
      • Bohm M.
      • Robertson M.
      • Ford I.
      • et al.
      Influence of cardiovascular and noncardiovascular co-morbidities on outcomes and treatment effect of heart rate reduction with ivabradine in stable heart failure (from the SHIFT Trial).
      ,
      • Swedberg K.
      • Komajda M.
      • Böhm M.
      • et al.
      Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study.
      ,
      • Fox K.
      • Ford I.
      • Steg P.G.
      • et al.
      Ivabradine in stable coronary artery disease without clinical heart failure.
      ,
      • Fox K.
      • Ford I.
      • Steg P.G.
      • et al.
      Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial.
      .
      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 hospitalization
      • Swedberg K.
      • Komajda M.
      • Böhm M.
      • et al.
      Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study.
      . 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
      • Yancy C.W.
      • Jessup M.
      • Bozkurt B.
      • et al.
      2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.
      ,
      Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF).
      ,
      • Packer M.
      • Fowler M.B.
      • Roecker E.B.
      • et al.
      Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the carvedilol prospective randomized cumulative survival (COPERNICUS) study.