ACC/AHA/HFSA Focused Update Developed in Collaboration With the American College of Chest Physi- cians and International Society for Heart and Lung Transplantation ACC/AHA Task Force Members, see page e287 WRITING COMMITTEE MEMBERS* Clyde W. Yancy, MD, MSc, MACC, FAHA, FHFSA, Chair Mariell Jessup, MD, FACC, FAHA, FESC, Vice Chair Biykem Bozkurt, MD, PhD, FACC, FAHA Javed Butler, MD, MBA, MPH, FACC, FAHA Donald E. Casey, Jr, MD, MPH, MBA, FACC Monica M. Colvin, MD, FAHA Mark H. Drazner, MD, MSc, FACC, FAHA Gerasimos Filippatos, MD, FESC Gregg C. Fonarow, MD, FACC, FAHA, FHFSA Michael M. Givertz, MD, FACC, FHFSA Steven M. Hollenberg, MD, FACC# JoAnn Lindenfeld, MD, FACC, FAHA, FHFSA Frederick A. Masoudi, MD, MSPH, FACC** Patrick E. McBride, MD, MPH, FACC Pamela N. Peterson, MD, FACC Lynne Warner Stevenson, MD, FACC Cheryl Westlake, PhD, RN, ACNS-BC, FHFSA 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 Key Words: AHA Scientific Statements angioedema angiotensin-converting enzyme inhibitors angiotensin receptor blockers angiotensin receptor- neprilysin inhibitor beta blockers focused update heart failure ivabradine natriuretic peptides 2016 by the American College of Cardiology Foundation, the American Heart Association, Inc., and the Heart Failure Society of America. The American Heart Association requests that this document be cited as follows: Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Colvin MM, Drazner MH, Filippatos G, Fonarow GC, Givertz MM, Hollenberg SM, Lindenfeld J, Masoudi FA, McBride PE, Peterson PN, Stevenson LW, Westlake C. 2016 ACC/AHA/HFSA focused update on new pharmacological therapy for heart failure: an update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation. 2016;134:e282 e293. DOI: 10.1161/CIR.0000000000000435. *Writing committee members are required to recuse themselves from voting on sections to which their specific relationships with industry may apply; see Appendix 1 for detailed information. ACC/AHA Task Force on Clinical Practice Guidelines Liaison. ACC/AHA Representative. ACP Representative. ISHLT Representative. HFSA Representative. #CHEST Representative. **ACC/AHA Task Force on Performance Measures Representative. AAFP Representative. Heart Failure Focused Update on Pharmacological Therapy CLINICAL STATEMENTS AND GUIDELINES Table of Contents Preamble . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e283 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e285 7.3. Stage C . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e285 Pharmacological Treatment for Stage C HF With Reduced Ejection Fraction: Recommendations e285 Renin-Angiotensin System Inhibition With Angiotensin-Converting Enzyme Inhibitor or Angiotensin Receptor Blocker or ARNI: Recommendations . . e285 Ivabradine: Recommendation . . . . . . . e287 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e288 Appendix 1. Author Relationships With Industry and Other Entities (Relevant) . . . . . . . . . . . e289 Appendix 2. Reviewer Relationships With Industry and Other Entities (Comprehensive) . . . . . . e291 Preamble Incorporation of new study results, medications, or de- vices that merit modification of existing clinical practice guideline recommendations, or the addition of new rec- ommendations, is critical to ensuring that guidelines re- flect current knowledge, available treatment options, and optimum medical care. To keep pace with evolving evi- dence, the American College of Cardiology (ACC)/Ameri- can Heart Association (AHA) Task Force on Clinical Prac- tice Guidelines ( Task Force ) has issued this focused update to reassess guideline recommendations on the basis of recently published study data. This update has been subject to rigorous, multilevel review and approval, similar to the full guidelines. For specific focused update criteria and additional methodological details, please see the ACC/AHA guideline methodology manual.1 Modernization Processes have evolved over time in response to pub- lished reports from the Institute of Medicine2,3 and ACC/ leading to adoption of a knowledge byte format. This process entails delineation of a rec- ommendation addressing a specific clinical question, followed by concise text (ideally <250 words) and hy- perlinked to supportive evidence. This approach better accommodates time constraints on busy clinicians, facil- itates easier access to recommendations via electronic search engines and other evolving technology, and sup- ports the evolution of guidelines as living documents that can be dynamically updated as needed. Guideline-Directed Evaluation and Management The term guideline-directed evaluation and management (GDEM) refers to care defined mainly by ACC/AHA Class I recommendations. For these and all recommended drug treatment regimens, the reader should confirm dosage with product insert material and carefully evaluate for contraindications and interactions. Recommendations are limited to treatments, drugs, and devices approved for clinical use in the United States. Class of Recommendation and Level of Evidence The Class of Recommendation (COR) and Level of Evi- dence (LOE) are derived independently of each other according to established criteria. The COR indicates the strength of recommendation, encompassing the es- timated magnitude and certainty of benefit of a clinical action in proportion to risk. The LOE rates the quality of scientific evidence supporting the intervention on the basis of the type, quantity, and consistency of data from clinical trials and other sources (Table 1). Recommenda- tions in this focused update reflect the new 2015 COR/ LOE system, in which LOE B and C are subcategorized for the purpose of increased granularity.1,5,8 Relationships With Industry and Other Entities The ACC and AHA exclusively sponsor the work of guide- line writing committees without commercial support, and members volunteer time for this activity. Selected orga- nizations and professional societies with related interests and expertise are invited to participate as partners or collaborators. The Task Force makes every effort to avoid actual, potential, or perceived conflicts of interest that might arise through relationships with industry or other entities (RWI). All writing committee members and reviewers are required to fully disclose current industry relationships or personal interests, beginning 12 months before initiation of the writing effort. Management of RWI involves selecting a balanced writing committee and re- quires that both the chair and a majority of writing com- mittee members have no relevant RWI (see Appendix 1 for the definition of relevance). Members are restricted with regard to writing or voting on sections to which RWI apply. Members of the writing committee who recused themselves from voting are indicated and specific section recusals are noted in Appendix 1. In addition, for transpar- ency, members comprehensive disclosure information is available as an Online Supplement, and reviewers RWI disclosures are included in Appendix 2. Comprehensive disclosure information for the Task Force is also avail- able at http://www.acc.org/guidelines/about-guidelines- and-clinical-documents/guidelines-and-documents-task- forces. The Task Force strives to avoid bias by selecting experts from a broad array of backgrounds representing different geographic regions, genders, ethnicities, intel- lectual perspectives, and scopes of clinical activities. Intended Use Guidelines provide recommendations applicable to pa- tients 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 organiza- tions may have a broader target. Although guidelines may Yancy et al be used to inform regulatory or payer decisions, the intent is to improve quality of care and align with patients inter- ests. The guidelines are reviewed annually by the Task Force and are official policy of the ACC and AHA. Each guideline is considered current unless and until it is up- dated, revised, or superseded by a published addendum. Related Issues For additional information pertaining to the methodology for grading evidence, assessment of benefit and harm, shared decision making between the patient and cli- nician, structure of evidence tables and summaries, standardized terminology for articulating recommen- dations, organizational involvement, peer review, and policies regarding periodic assessment and up- dating of guideline documents, we encourage read- ers to consult the ACC/AHA guideline methodology Jonathan L. Halperin, MD, FACC, FAHA Chair, ACC/AHA Task Force on Clinical Practice Guidelines Table 1. Applying Class of Recommendation and Level of Evidence to Clinical Strategies, Interventions, Treatments, or Diagnostic Testing in Patient Care* (Updated August 2015) Heart Failure Focused Update on Pharmacological Therapy CLINICAL STATEMENTS AND GUIDELINES Introduction The ACC, the AHA, and the Heart Failure Society of America (HFSA) recognize that the introduction of effec- tive new therapies that potentially affect a large number of patients presents both opportunities and challenges. The introduction of an angiotensin receptor neprilysin inhibitor (ARNI) (valsartan/sacubitril) and a sinoatrial node modulator (ivabradine), when applied judiciously, complements established pharmacological and device- based therapies and represents a milestone in the evolu- tion of care for patients with heart failure (HF). Accord- ingly, the writing committees of the 2016 ACC/AHA/ HFSA Focused Update on New Pharmacological Therapy for Heart Failure and the 2016 ESC Guideline on the Diagnosis and Treatment of Acute and Chronic Heart Failure concurrently developed recommendations for the incorporation of these therapies into clinical prac- tice. Working independently, each writing committee sur- veyed the evidence, arrived at similar conclusions, and constructed similar, but not identical, recommendations. Given the concordance, the respective organizations si- multaneously issued aligned recommendations on the use of these new treatments to minimize confusion and improve the care of patients with HF. Members of the ACC/AHA/HFSA writing committee without relevant RWI voted on the final recommendations. These were subjected to external peer review by 25 official, organizational, and content reviewers before ap- proval by the Task Force and the leadership of the ACC, AHA, and HFSA, as well as endorsement by the American College of Chest Physicians and the International Society for Heart and Lung Transplantation. The statements is- sued by the European Society of Cardiology writing com- mittee went through a similarly rigorous process of exter- nal review before endorsement by the societal leadership. No single clinical trial answers all pertinent questions, nor can trial results be perfectly replicated in clinical practice. Several critical questions remain unanswered, and further experience in both ongoing trials and clinical therapeutics may require modification of these initial rec- ommendations. On the basis of the currently available evidence, however, the recommendations that follow reflect our assessment of how best to proceed today. 7.3. Stage C 7.3.2. Pharmacological Treatment for Stage C HF With Reduced Ejection Fraction: Recommendations 7.3.2.10. Renin-Angiotensin System Inhibition With Angiotensin-Converting Enzyme Inhibitor or Angiotensin Receptor Blocker or ARNI: Recommendations See the Online Data Supplement for evidence supporting these recommendations. Recommendations for Renin-Angiotensin System Inhibition With ACE Inhibitor or ARB or ARNI COR LOE Recommendations I ACE: A The clinical strategy of inhibition of the renin-angiotensin system with ACE inhibitors (Level of Evidence: OR ARBs (Level of Evidence: A),15 18 OR ARNI (Level of Evidence: B-R)19 in conjunction with evidence- based beta blockers,20 22 and aldosterone antagonists in selected patients,23,24 is recommended for patients with chronic HFrEF to reduce morbidity and mortality. ARB: A ARNI: B-R See Online Data 18 20. Angiotensin-converting enzyme (ACE) inhibitors reduce morbidity and mortality in heart failure with reduced ejection fraction (HFrEF). Randomized controlled trials (RCTs) clearly establish the benefits of ACE inhibition in patients with mild, moderate, or severe symptoms of HF and in patients with or without coronary artery disease.9 14 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 RCTs15 18 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%.19 The benefit was seen to a similar extent for both death and HF hospitalization and was consistent across subgroups. The use of ARNI is associated with the risk of hypotension and renal insufficiency and may lead to angioedema, as well. I ACE: A The use of ACE inhibitors is beneficial for patients with prior or current symptoms of chronic HFr EF to reduce morbidity and mortality.9 14,25 (Continued) Yancy et al 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.9 14 Data suggest that there are no differences among available ACE inhibitors in their effects on symptoms or survival.25 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.26 Patients should not be given ACE inhibitors if they are pregnant or plan to become pregnant. ACE inhibitors also inhibit kininase and increase levels of bradykinin, which can induce cough in up to 20% of patients but also may contribute to beneficial vasodilation. If maximal doses are not tolerated, intermediate doses should be tried; abrupt withdrawal of ACE inhibition can lead to clinical deterioration and should be avoided. Although the use of an ARNI in lieu of an ACE inhibitor for HFrEF has been found to be superior, for those patients for whom ARNI is not appropriate, continued use of an ACE inhibitor for all classes of HFrEF remains strongly advised. I ARB: A The use of ARBs to reduce morbidity and mortality is recommended in patients with prior or current symptoms of chronic HFr EF who are intolerant to ACE inhibitors because of cough or angioedema.15 18,27,28 See Online Data and 19. ARBs have been shown to reduce mortality and HF hospitalizations in patients with HFrEF in large RCTs.15 18 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.27,28 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. I ARNI: B-R In patients with chronic symptomatic HFr EF NYHA class II or III who tolerate an ACE inhibitor or ARB, replacement by an ARNI is recommended to further reduce morbidity and mortality.19 See Online Data 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.10 This ARNI has recently 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.29 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.30 III: Harm B-R ARNI should not be administered concomitantly with ACE inhibitors or within 36 hours of the last dose of an 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 angioedema31,32 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.32,33 An ARNI should not be administered within 36 hours of switching from or to an ACE inhibitor. Recommendations for Renin-Angiotensin System Inhibition With ACE Inhibitor or ARB or ARNI (Continued) COR LOE Recommendations (Continued) CLINICAL STATEMENTS AND GUIDELINES Heart Failure Focused Update on Pharmacological Therapy 7.3.2.11. Ivabradine: Recommendation See the Online Data Supplement for evidence supporting this recommendation. The remainder of the 2016 ACC/AHA/HFSA Focused Update on the Management of Heart Failure: An Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure will be forthcoming. ACC/AHA TASK FORCE MEMBERS Jonathan L. Halperin, MD, FACC, FAHA, Chair Glenn N. Levine, MD, FACC, FAHA, Chair-Elect 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 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 Jos Joglar, MD, FACC, FAHA Susan J. Pressler, PhD, RN, FAHA Duminda N. Wijeysundera, MD, PhD Presidents and Staff American College of Cardiology Richard A. Chazal, MD, FACC, President Shalom Jacobovitz, Chief Executive Officer William J. Oetgen, MD, MBA, FACC, Executive Vice President, Science, Education, Quality, and Publications Amelia Scholtz, PhD, Publications Manager, Science, Educa- tion, Quality, and Publishing American College of Cardiology/American Heart Association Melanie Stephens-Lyman, MSc, Director, Guideline Operations and Strategy Lisa Bradfield, CAE, Director, Guideline Methodology and Policy Abdul R. Abdullah, MD, Associate Science and Medicine Advisor Recommendation for Ivabradine COR LOE Recommendation IIa B-R Ivabradine can be beneficial to reduce HF hospitalization for patients with symptomatic (NYHA class II-III) stable chronic HFr EF (LVEF 35%) who are receiving GDEM, including a beta blocker at maximum tolerated dose, and who are in sinus rhythm with a heart rate of 70 bpm or greater at rest.37 40 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.38 The benefit of ivabradine was driven by a reduction in HF hospitalization. The study included patients with HFrEF (New York Heart Association [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 bpm. 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.20 22,38 Given the well-proven mortality benefits of beta-blocker therapy, it is important to initiate and up titrate these agents to target doses, as tolerated, before assessing the resting heart rate for consideration of ivabradine initiation.38 III: Harm C-EO ARNI should not be administered to patients with a history of angioedema. N/A Omapatrilat, a neprilysin inhibitor (as well as an ACE inhibitor and aminopeptidase P inhibitor), was associated with a higher frequency of angioedema than that seen with enalapril in an RCT of patients with HFrEF.31 In a very large RCT of hypertensive patients, ompatrilat was associated with a 3-fold increased risk of angioedema as compared with Blacks and smokers were particularly at risk. The high incidence of angioedema ultimately led to cessation of the clinical development of omapatrilat.34,35 In light of these observations, angioedema was an exclusion criterion in the first large trial assessing ARNI therapy in patients with hypertension36 and then in the large trial that demonstrated clinical benefit of ARNI therapy in HFrEF.19 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. Recommendations for Renin-Angiotensin System Inhibition With ACE Inhibitor or ARB or ARNI (Continued) COR LOE Recommendations Yancy et al Morgane Cibotti-Sun, MPH, Project Manager, Clinical Practice Guidelines American Heart Association Mark A. Creager, MD, FACC, FAHA, President Nancy Brown, Chief Executive Officer Rose Marie Robertson, MD, FAHA, Chief Science and Medical Officer Gayle R. Whitman, PhD, RN, FAHA, FAAN, Senior Vice Presi- dent, Office of Science Operations Comilla Sasson, MD, PhD, FACEP, Vice President, Science and Medicine Jody Hundley, Production Manager, Scientific Publications, Office of Science Operations FOOTNOTES This document was approved by the American College of Cardiology Board of Trustees and Executive Committee, the American Heart Association Science Advisory and Coordinating Committee and Executive Committee, and the Heart Failure Society of America Executive Committee in April 2016. The Comprehensive RWI Data Supplement table is available with this article at http://circ.ahajournals.org/lookup/suppl/ doi:10.1161/CIR.0000000000000435/-/DC1. The Data Supplement is available with this article at CIR.0000000000000435/-/DC2. This article has been copublished in the Journal of the American College of Cardiology and the Journal of Cardiac Failure. Copies: This document is available on the World Wide Web sites of the American College of Cardiology (www.acc.org), the American Heart Association (professional.heart.org), and the Heart Failure Society of America (www.hfsa.org). A copy of the document is available at http://professional.heart. org/statements by using either Search for Guidelines & Statements or the Browse by Topic area. To purchase addi- tional reprints, call 843-216-2533 or e-mail kelle.ramsay@ wolterskluwer.com. Expert peer review of AHA Scientific Statements is conducted by the AHA Office of Science Operations. For more on AHA state- ments and guidelines development, visit http://professional. heart.org/statements. Select the Guidelines & Statements drop-down menu, then click Publication Development. Permissions: Multiple copies, modification, alteration, enhancement, and/or distribution of this document are not permitted without the express permission of the American Heart Association. Instructions for obtaining permission are located at http://www.heart.org/HEARTORG/General/ Copyright-Permission-Guidelines_UCM_300404_Article.jsp. A link to the Copyright Permissions Request Form appears on the right side of the page. Circulation is available at http://circ.ahajournals.org. References 1. ACCF/AHA Task Force on Practice Guidelines. Methodology Manual and Policies From the ACCF/AHA Task Force on Practice Guidelines. Available at: http://assets.cardiosource.com/Method- ology_Manual_for_ACC_AHA_Writing_Committees.pdf and http:// my.americanheart.org/idc/groups/ahamah-public/@wcm/@sop/ College of Cardiology and American Heart Association. Accessed April 7, 2016. 2. Committee on Standards for Developing Trustworthy Clinical Practice Guidelines, Institute of Medicine (US). Clinical Practice Guidelines We Can Trust. Washington, DC: National Academies Press; 2011. 3. 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Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial. Lancet. 2008;372:807 16. Appendix 1. Author Relationships With Industry and Other Entities (Relevant) 2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure (December 2015) Committee Member Employment Consultant Speakers Bureau Ownership/ Partnership/ Principal Personal Research Institutional, Organizational, or Other Financial Benefit Expert Witness Voting Recusals By Section* Clyde W. Yancy, Chair Northwestern University Feinberg School of Medicine, Division of Cardiology Professor of Medicine and Chief; Diversity and Inclusion Vice Dean None None None None None None None Mariell Jessup, Vice Chair University of Pennsylvania Professor of Medicine None None None None None None None Biykem Bozkurt Michael E. DeBakey VA Medical Center The Mary and Gordon Cain Chair and Professor of Medicine None None None Novartis None None 7.3.2.10 and 7.3.2.11. (Continued) Yancy et al Javed Butler Stony Brook University Division Chief of Cardiology Bayer CardioCell Medtronic Merck Novartis Relypsa Takeda Trevena Z Pharma Zensun Novartis None Amgen (DSMB) None None 7.3.2.10 and 7.3.2.11. Donald E. Casey, Jr Thomas Jefferson College of Population Health Adjunct Faculty; Alvarez & Marsal IPO4Health Principal and Founder None None None None None None None Monica M. Colvin University of Michigan Associate Professor of Medicine, Cardiology None None None None None None None Mark H. Drazner University of Texas Southwestern Medical Center Professor, Internal Medicine None None Trevena None DCRI/Otsuka UptoDate None None Gerasimos S. Filippatos National and Kapodistrian University of Athens; Attikon University Hospital, Department of Cardiology, Heart Failure Unit Professor of Cardiology None None None Bayer Bayer (DSMB) Novartis Servier Pharmaceuticals Vifor None None 7.3.2.10 and 7.3.2.11. Gregg C. Fonarow Ahmanson-UCLA Cardiomyopathy Center Director; UCLA Division of Cardiology Co-Chief Amgen Janssen Pharmaceuticals Novartis None None Novartis None None 7.3.2.10 and 7.3.2.11. Michael M. Givertz Brigham and Women s Hospital Professor of Medicine Merck Novartis None None None None None 7.3.2.10 and 7.3.2.11. Steven M. Hollenberg Cooper University Hospital Director, Coronary Care Unit, Professor of Medicine None None None None None None None JoAnn Lindenfeld Vanderbilt Heart and Vascular Institute Director, Advanced Heart Failure and Transplant Section Professor of Medicine Abbott Janssen Pharmaceuticals Novartis Relypsa ResMed None None AstraZeneca Novartis None None 7.3.2.10 and 7.3.2.11. Frederick A. Masoudi University of Colorado, Denver Associate Professor of Medicine, Division of Cardiology None None None None None None None Patrick E. McBride University of Wisconsin School of Medicine and Public Health Professor of Medicine and Family Medicine; Associate Director, Preventive Cardiology None None None None None None None Pamela N. Peterson University of Colorado, Denver Health Medical Center Associate Professor of Medicine, Division of Cardiology None None None None None None None Lynne W. Stevenson Brigham and Women s Hospital Cardiovascular Division Director, Cardiomyopathy and Heart Failure Program None None None Novartis PARENT trial (PI) NHLBI INTERMACS (Co PI) None None 7.3.2.10 and 7.3.2.11. Appendix 1. Continued Committee Member Employment Consultant Speakers Bureau Ownership/ Partnership/ Principal Personal Research Institutional, Organizational, or Other Financial Benefit Expert Witness Voting Recusals By Section* (Continued) CLINICAL STATEMENTS AND GUIDELINES Heart Failure Focused Update on Pharmacological Therapy Appendix 2. Reviewer Relationships With Industry and Other Entities (Comprehensive) 2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure (March 2016) Reviewer Representation Employment Consultant Speakers Bureau Ownership/ Partnership/ Principal Personal Research Institutional, Organizational, or Other Financial Benefit Expert Witness Kim K. Birtcher Official Reviewer ACC/AHA Task Force on Clinical Practice Guidelines University of Houston College of Pharmacy Clinical Professor Jones & Bartlett Learning None None None None None Akshay S. Desai Official Reviewer HFSA Brigham and Women s Hospital Director, Heart Failure Disease Management, Advanced Heart Disease Section, Cardiovascular Division; Harvard Medical School, Associate Professor of Medicine Medscape Cardiology* Merck Novartis* Relypsa* St. Jude Medical* None None None Novartis* Thoratec None Anita Deswal Official Reviewer AHA Michael E. DeBakey VA Medical Center Associate Chief of Cardiology; Director, Heart Failure Program; Baylor College of Medicine Professor of Medicine None None None NIH* AHA AHA (GWTG Steering Committee) HFSA None Dipti Itchhaporia Official Reviewer ACC Board of Trustees Newport Coast Cardiology Robert and Georgia Roth Endowed Chair for Excellence in Cardiac Care; Director of Disease Management None None None None St. Jude Medical None Ileana L. Pi a Official Reviewer AHA Montefiore Medical Center Associate Chief for Academic Affairs, Cardiology Relypsa None None None None None Geetha Raghuveer Official Reviewer ACC Board of Governors University of Missouri-Kansas City School of Medicine Professor of Pediatrics; Children s Mercy Hospital Pediatric Cardiology None None None None None None (Continued) Cheryl Westlake Azusa Pacific University Professor and Associate Dean, International and Community Programs None None None None None None None This table represents the relationships of committee members with industry and other entities that were determined to be relevant to this document. These relationships were reviewed and updated in conjunction with all meetings and/or conference calls of the writing committee during the document development process. The table does not necessarily reflect relationships with industry at the time of publication. A person is deemed to have a significant interest in a business if the interest represents ownership of 5% of the voting stock or share of the business entity, or ownership of $5000 of the fair market value of the business entity, or if funds received by the person from the business entity exceed 5% of the person s gross income for the previous year. Relationships that exist with no financial benefit are also included for the purpose of transparency. Relationships in this table are modest unless otherwise noted. According to the ACC/AHA, a person has a relevant relationship IF: a) The relationship or interest relates to the same or similar subject matter, intellectual property or asset, topic, or issue addressed in the document; or b) the company/entity (with whom the relationship exists) makes a drug, drug class, or device addressed in the document, or makes a competing drug or device addressed in the document; or c) the person or a member of the person s household has a reasonable potential for financial, professional, or other personal gain or loss as a result of the issues/content addressed in the document. *Writing committee members are required to recuse themselves from voting on sections to which their specific relationships with industry and other entities may apply. Significant relationship. ACC indicates American College of Cardiology; AHA, American Heart Association; DCRI, Duke Clinical Research Institute; DSMB, data safety monitoring board; HFSA, Heart Failure Society of America; INTERMACS, The Interagency Registry for Mechanically Assisted Circulatory Support; NHLBI, National Heart, Lung, and Blood Institute; PARENT, pulmonary artery pressure reduction with Entresto; and VA, Veterans Affairs. Appendix 1. Continued Committee Member Employment Consultant Speakers Bureau Ownership/ Partnership/ Principal Personal Research Institutional, Organizational, or Other Financial Benefit Expert Witness Voting Recusals By Section* Yancy et al James E. Udelson Official Reviewer HFSA Tufts Medical Center Chief, Division of Cardiology Lantheus Medical Imaging None None Gilead (DSMB) GlaxoSmithKline (DSMB) NHLBI Otsuka Abbott Laboratories (Eligibility Committee) AHA* Circulation/Circulation: Heart Failure HFSA (Executive Council) Pfizer/ GlaxoSmithKline (Clinical Events Committee) Sunshine Heart (Eligibility Committee) None Mary Norine Walsh Official Reviewer ACC Board of Trustees St Vincent Heart Center of Indiana Medical Director, Heart Failure and Cardiac Transplantation None None None None Corvia Medical Otsuka PCORI Thoratec None David A. Baran Organizational Reviewer ISHLT Newark Beth Israel Medical Center Director of Heart Failure and Transplant Research Maquet Otsuka* Novartis None CareDx IMAGE trial (Steering Committee)* NIH* None None Kenneth Casey Organizational Reviewer CHEST Wm. S. Middleton Memorial Veterans Hospital Director, Sleep Medicine None None None None CHEST None M. Fuad Jan Organizational Reviewer CHEST Aurora Advanced Healthcare Cardiologist None None None None None None Kenneth W. Lin Organizational Reviewer AAFP Georgetown University School of Medicine Clinician Educator Track, Associate Professor None None None None None None Joaquin E. Cigarroa Content Reviewer ACC/ AHA Task Force on Clinical Practice Guidelines Oregon Health & Science University Clinical Professor of Medicine None None None None ACC/AHA AHA ASA Catheterization and Cardiovascular Intervention NIH Portland Metro Area AHA (President) SCAI Quality Interventional Council None Lee A. Fleisher Content Reviewer ACC/ AHA Task Force on Clinical Practice Guidelines University of Pennsylvania Health System Robert Dunning Dripps Professor of Anesthesiology and Critical Care; Chair, Department of Anesthesiology & Critical Care Blue Cross/ Blue Shield* NQF Yale University None None Johns Hopkins (DSMB) Association of University Anesthesiologists NIH None Samuel S. Gidding Content Reviewer ACC/AHA Task Force on Clinical Practice Guidelines Nemours/Alfred I. duPont Hospital for Children Chief, Division of Pediatric Cardiology FH Foundation International FH Foundation None None FH Foundation NIH* None None James L. Januzzi Content Reviewer Massachusetts General Hospital Hutter Family Professor of Medicine in the Field of Cardiology Critical Diagnostics* Novartis* Phillips Roche Diagnostics* Sphingotec* None None Amgen (DSMB) Boeringer Ingelheim (DSMB)* Janssen Pharmaceuticals (DSMB) Prevencio* None None (Continued) Appendix 2. Continued Reviewer Representation Employment Consultant Speakers Bureau Ownership/ Partnership/ Principal Personal Research Institutional, Organizational, or Other Financial Benefit Expert Witness CLINICAL STATEMENTS AND GUIDELINES Heart Failure Focused Update on Pharmacological Therapy Jos A. Joglar Content Reviewer ACC/ AHA Task Force on Clinical Practice Guidelines UT Southwestern Medical Center Professor of Internal Medicine; Clinical Cardiac Electrophysiology Program Director None None None None None None Edward K. Kasper Content Reviewer Johns Hopkins Cardiology E. Cowles Andrus Professor in Cardiology None None None None None None Wayne C. Levy Content Reviewer University of Washington Professor of Medicine Abbott Laboratories Biotronik GE Healthcare HeartWare PharminIN None None NIH Novartis* St. Jude Medical* Amgen* AHA HeartWare* Novartis* Resmed* Thoratec None Judith E. Mitchell Content Reviewer SUNY Downstate Medical Center Director/Heart Failure Center; SUNY Downstate College of Medicine Associate Professor of Medicine None None None None Association of Black Cardiologists None Sean P. Pinney Content Reviewer ACC Heart Failure and Transplant Council Mount Sinai School of Medicine Associate Professor of Medicine, Cardiology Acorda Therapeutics Thoratec CareDX None None Thoratec NIH None None Randall C. Starling Content Reviewer ACC Heart Failure and Transplant Council Cleveland Clinic Department of Cardiovascular Medicine Vice Chairman,Department of Cardiovascular Medicine; Section Head,Heart Failure & CardiacTransplant BioControl Medtronic Novartis None None Medtronic NIH* Novartis St. Jude Medical St. Jude Medical None W. H. Wilson Tang Content Reviewer Cleveland Clinic Foundation Assistant Professor of Medicine None None None NIH* Alnylam Pharmaceuticals NIH NHLBI Roche Novartis Thoratec None Emily J. Tsai Content Reviewer Columbia University College of Physicians & Surgeons Assistant Professor, Section of Cardiology None None None Bayer Bristol-Myers Squib NHLBI* None None Duminda N. Wijeysundera Content Reviewer ACC/ AHA Task Force on Clinical Practice Guidelines Li Ka Shing Knowledge Institute of St. Michael s Hospital Scientist; University of Toronto Assistant Professor, Department of Anesthesia and Institute of Health Policy Management and Evaluation None None None CIHR (DSMB) CIHR* Heart and Stroke Foundation of Canada* Ministry of Health & Long-term Care of Ontario* PCORI (DSMB) None None This table represents the relationships of reviewers with industry and other entities that were disclosed at the time of peer review, including those not deemed to be relevant to this document.The table does not necessarily reflect relationships with industry at the time of publication.A person is deemed to have a significant interest in a business if the interest represents ownership of 5% of the voting stock or share of the business entity, or ownership of $5000 of the fair market value of the business entity, or if funds received by the person from the business entity exceed 5% of the person s gross income for the previous year.A relationship is considered to be modest if it is less than significant under the preceding definition. Relationships that exist with no financial benefit are also included for the purpose of transparency. Relationships in this table are modest unless otherwise noted. Names are listed in alphabetical order within each category of review. American College of Physicians did not provide a peer reviewer for this document. *Significant relationship. No financial benefit. AAFP indicates American Academy of Family Physicians; ACC,American College of Cardiology; AHA,American Heart Association; ASA,American Stroke Association; CHEST,American College of Chest Physicians; CIHR, Canadian Institutes of Health Research; DSMB, data safety monitoring board; FH, familial hypercholesterolemia; GWTG, Get With The Guidelines; HFSA, Heart Failure Society of America; IMAGE, Invasive Monitoring Attenuation through Gene Expression; ISHLT, International Society for Heart and Lung Transplantation; NIH, National Institutes of Health; NHLBI, National Heart, Lung, and Blood Institute; NQF, National Quality Forum; PCORI, Patient-Centered Outcomes Research Institute; SCAI, Society for Cardiovascular Angiography and Interventions; SUNY, State University of New York; UT, University of Texas; and VA, Veterans Affairs. Appendix 2. Continued Reviewer Representation Employment Consultant Speakers Bureau Ownership/ Partnership/ Principal Personal Research Institutional, Organizational, or Other Financial Benefit Expert Witness