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Yancy et al 

2017 ACC/AHA/HFSA Heart Failure Focused Update 

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

Developed in Collaboration With the American Academy of Family Physicians, American
College of Chest Physicians, and International Society for Heart and Lung Transplantation

WRITING GROUP MEMBERS*

Clyde W. Yancy, MD, MSc, MACC, FAHA, FHFSA, Chair
Mariell Jessup, MD, FACC, FAHA, Vice Chair
Biykem Bozkurt, MD, PhD, FACC, FAHA*† Steven M. Hollenberg, MD, FACC#
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Javed Butler, MD, MBA, MPH, FACC, FAHA*‡ JoAnn Lindenfeld, MD, FACC, FAHA, FHFSA*¶
Donald E. Casey, Jr, MD, MPH, MBA, FACC§ Frederick A. Masoudi, MD, MSPH, FACC**
Monica M. Colvin, MD, FAHA║ Patrick E. McBride, MD, MPH, FACC††
Mark H. Drazner, MD, MSc, FACC, FAHA, FHFSA‡ Pamela N. Peterson, MD, FACC, FAHA‡
Gerasimos S. Filippatos, MD* Lynne Warner Stevenson, MD, FACC*‡
Gregg C. Fonarow, MD, FACC, FAHA, FHFSA*‡ Cheryl Westlake, PhD, RN, ACNS-BC, FAHA, FHFSA¶
Michael M. Givertz, MD, FACC, FHFSA*¶

ACC/AHA TASK FORCE MEMBERS

Glenn N. Levine, MD, FACC, FAHA, Chair
Patrick T. O’Gara, MD, FACC, FAHA, Chair-Elect
Jonathan L. Halperin, MD, FACC, FAHA, Immediate Past Chair‡‡
Sana M. Al-Khatib, MD, MHS, FACC, FAHA Federico Gentile, MD, FACC
Kim K. Birtcher, PharmD, MS, AACC Samuel Gidding, MD, FAHA
Biykem Bozkurt, MD, PhD, FACC, FAHA Mark A. Hlatky, MD, FACC
Ralph G. Brindis, MD, MPH, MACC‡‡ John Ikonomidis, MD, PhD, FAHA
Joaquin E. Cigarroa, MD, FACC José Joglar, MD, FACC, FAHA
Lesley H. Curtis, PhD, FAHA Susan J. Pressler, PhD, RN, FAHA
Lee A. Fleisher, MD, FACC, FAHA Duminda N. Wijeysundera, MD, PhD

*Writing group members are required to recuse themselves from voting on sections to which their specific
relationships with industry may apply; see Appendix 1 for detailed information. †ACC/AHA Task Force on Clinical
Practice Guidelines Liaison. ‡ACC/AHA Representative. §ACP Representative. ║ISHLT Representative. ¶HFSA
Representative. #CHEST Representative. **ACC/AHA Task Force on Performance Measures Representative.
††AAFP Representative. ‡‡Former Task Force member; current member during the writing effort.

This document was approved by the American College of Cardiology Clinical Policy Approval Committee, the
American Heart Association Science Advisory and Coordinating Committee, the American Heart Association
Executive Committee, and the Heart Failure Society of America Executive Committee in April 2017.

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Yancy et al 
2017 ACC/AHA/HFSA Heart Failure Focused Update 

The Comprehensive RWI Data Supplement table is available with this article at
http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIR.0000000000000509/-/DC1.

The Data Supplement is available with this article at
http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIR.0000000000000509/-/DC2.

The American Heart Association requests that this document be cited as follows: Yancy CW, Jessup M, Bozkurt B,
Butler J, Casey DE Jr, Colvin MM, Drazner MH, Filippatos GS, Fonarow GC, Givertz MM, Hollenberg SM,
Lindenfeld J, Masoudi FA, McBride PE, Peterson PN, Stevenson LW, Westlake C. 2017 ACC/AHA/HFSA focused
update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of
Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of
America. Circulation. 2017;:e–e. DOI: 10.1161/CIR.0000000000000509.

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
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(Circulation. 2017;000:e000–e000. DOI: 10.1161/CIR.0000000000000509.)

© 2017 by the American College of Cardiology Foundation, the American Heart Association, Inc., and the Heart
Failure Society of America.

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Yancy et al 
2017 ACC/AHA/HFSA Heart Failure Focused Update 

Table of Contents

Preamble ....................................................................................................................................................... 4 
1. Introduction ............................................................................................................................................... 7 
1.1. Methodology and Evidence Review .................................................................................................. 7
1.2. Organization of the Writing Group .................................................................................................... 8
1.3. Document Review and Approval ....................................................................................................... 8
6. Initial and Serial Evaluation of the HF Patient ....................................................................................... 10 
6.3. Biomarkers ....................................................................................................................................... 10 
6.3.1. Biomarkers for Prevention: Recommendation .......................................................................... 11 
6.3.2. Biomarkers for Diagnosis: Recommendation ........................................................................... 12 
6.3.3. Biomarkers for Prognosis or Added Risk Stratification: Recommendations ............................ 12 
7. Treatment of Stages A to D .................................................................................................................... 14 
7.3. Stage C ............................................................................................................................................. 14 
7.3.2. Pharmacological Treatment for Stage C HF With Reduced Ejection Fraction:
Recommendations ............................................................................................................................... 14 
7.3.2.10. Renin-Angiotensin System Inhibition With Angiotensin-Converting Enzyme Inhibitor or
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Angiotensin Receptor Blocker or ARNI: Recommendations ......................................................... 15
7.3.2.11. Ivabradine: Recommendation .......................................................................................... 18
7.3.3. Pharmacological Treatment for Stage C HFpEF: Recommendations ....................................... 22 
9. Important Comorbidities in HF ............................................................................................................... 23 
9.2. Anemia: Recommendations ............................................................................................................. 23 
9.5. Hypertension (New Section) ............................................................................................................ 24 
9.5.1. Treating Hypertension to Reduce the Incidence of HF: Recommendation............................... 24 
9.5.2. Treating Hypertension in Stage C HFrEF: Recommendation................................................... 25 
9.5.3. Treating Hypertension in Stage C HFpEF: Recommendation .................................................. 25 
9.6. Sleep Disordered Breathing: Recommendations ............................................................................. 26 
References ................................................................................................................................................... 28
Appendix 1. Author Relationships With Industry and Other Entities (Relevant)....................................... 37 
Appendix 2. Reviewer Relationships With Industry and Other Entities (Comprehensive) ........................ 40 
Appendix 3. Abbreviations ......................................................................................................................... 45 
 

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but not all. 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. Methodology and Modernization The ACC/AHA Task Force on Clinical Practice Guidelines (Task Force) continuously reviews.ahajournals. Recognizing the importance of cost-value considerations in certain guidelines. The focus is on medical practice in the United States. <250 words) and hyperlinks to supportive evidence summary tables. 4 . new data are reviewed on an ongoing basis. Ongoing efforts to further limit text are underway. updates. or intervention may be performed in accordance with the ACC/AHA methodology (3). device. and associated conditions and comorbidities. These guidelines. an analysis of the value of a drug. Adherence to recommendations can be enhanced by shared decision making between healthcare providers and patients. we encourage readers to consult the ACC/AHA guideline methodology manual (4) and other methodology articles (5-8). Guidelines are intended to define practices meeting the needs of patients in most. potentially practice-changing study results that are relevant to an existing or new drug. when appropriate and feasible. provide a cornerstone for quality cardiovascular care. Yancy et al  2017 ACC/AHA/HFSA Heart Failure Focused Update  Preamble Since 1980. to determine whether a focused update should be commissioned. Although guidelines may be used to inform regulatory or payer decisions. For additional information and policies regarding guideline development. which are based on systematic methods to evaluate and classify evidence. To ensure that guideline recommendations remain current. circumstances and should not replace clinical judgment. in consultation with the relevant guideline writing committee. 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.org/ by guest on March 28. their intent is to improve patients’ quality of care and align with Downloaded from http://circ. Clinical Implementation Guideline recommended management is effective only when followed by healthcare providers and patients. 2) and on the basis of internal reevaluation. Intended Use Practice guidelines provide recommendations applicable to patients with or at risk of developing cardiovascular disease. preferences. and members of each organization volunteer their time to the writing and review efforts. Guidelines are official policy of the ACC and AHA. Similarly. Publication of new. with patient engagement in selecting interventions based on individual values. 2018 patients’ interests. device. Given time constraints of busy healthcare providers and the need to limit text. or management strategy will prompt evaluation by the Task Force. with full guideline revisions commissioned in approximately 6-year cycles. the current guideline format delineates that each recommendation be supported by limited text (ideally. and modifies guideline methodology on the basis of published standards from organizations including the Institute of Medicine (1. The ACC and AHA sponsor the development and publication of guidelines without commercial support. but guidelines developed in collaboration with other organizations may have a global impact.

or treatment strategy and to what degree. 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. Criteria for commissioning an ERC and formal systematic review include: a) the absence of a current authoritative systematic review.ahajournals. the recommendations developed by the writing committee on the basis of the systematic review are marked with “SR”. Only key references are cited. and pharmacological and procedural treatments. systematic reviews. and expert opinion. or endorsers. collaborators. Class of Recommendation and Level of Evidence The Class of Recommendation (COR) indicates the strength of the recommendation. and treatments approved for clinical use in the United States. For these and all recommended drug treatment regimens. ethnicities. sexes. encompassing the estimated magnitude and certainty of benefit in proportion to risk. intellectual perspectives/biases. Evidence Review and Evidence Review Committees When developing recommendations. nonrandomized comparative and descriptive studies. and scopes of clinical practice. This systematic review will strive to determine which patients are most likely to benefit from a drug. Literature searches focus on randomized controlled trials (RCTs) but also include registries. b) the feasibility of defining the benefit and risk in a time frame consistent with the writing of a guideline. case series. ERC members may include methodologists. Comprehensive disclosure information for the Task Force is available at Downloaded from http://circ. 2018 http://www. 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.0000000000000509/-/DC1. the writing committee uses evidence-based methodologies that are based on all available data (4-7). devices. c) the relevance to a substantial number of patients. Writing committee members represent different geographic regions. epidemiologists. Appendix 1 of the current document lists writing committee members’ relevant RWI. The Task Force may also invite organizations and professional societies with related interests and expertise to participate as partners. The recommendations are limited to drugs. the reader should confirm the dosage by reviewing product insert material and evaluate the treatment regimen for contraindications and interactions. Guideline-Directed Management and Therapy The term guideline-directed management and therapy (GDMT) encompasses clinical evaluation. writing committee members’ comprehensive disclosure information is available online at http://circ.org/lookup/suppl/doi:10.acc. cohort studies. When a formal systematic review has been commissioned. and biostatisticians.acc.org/guidelines/about-guidelines-and-clinical-documents/relationships-with- industry-policy. The complete relationships with industry and other entities (RWI) policy can be found at http://www.ahajournals. Yancy et al  2017 ACC/AHA/HFSA Heart Failure Focused Update  Selection of Writing Committee Members The Task Force strives to avoid bias by selecting experts from a broad array of backgrounds.org/ by guest on March 28. diagnostic testing. For the purposes of full transparency. and d) the likelihood that the findings can be translated into actionable recommendations.org/guidelines/about-guidelines-and-clinical-documents/guidelines-and-documents-task- forces.1161/CIR. The Level of Evidence (LOE) rates the 5 . device. races. healthcare providers.

MD. and consistency of data from clinical trials and other sources (Table 1) (4-6).org/ by guest on March 28. Levine. FAHA Chair. 2018 6 . ACC/AHA Task Force on Clinical Practice Guidelines Downloaded from http://circ.ahajournals. Glenn N. quantity. Yancy et al  2017 ACC/AHA/HFSA Heart Failure Focused Update  quality of scientific evidence that supports the intervention on the basis of the type. FACC.

but the LOE reflects the COR/LOE system used when the recommendations were initially developed. For this update and future heart failure (HF) guidelines. Introduction The purpose of this focused update is to update the “2013 ACCF/AHA Guideline for the Management of Heart Failure” (9) (2013 HF guideline) in areas in which new evidence has emerged since its publication. modified. Individual recommendations in this focused update will be incorporated into the full-text guideline in the future.ahajournals. specifically for the use of an angiotensin receptor–neprilysin inhibitor (ARNI) (valsartan/sacubitril) and a sinoatrial node modulator (ivabradine).1161/CIR. in which LOE 7 . and hypertension. The scope of the focused update includes revision to the sections on biomarkers. All recommendations (new. anemia. updates on HF with preserved ejection fraction (HFpEF). Recommendations from the prior guideline that remain current have been included for completeness. 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. with the first part having been published as the “2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Downloaded from http://circ. new data on important comorbidities. 1. 2018 Heart Failure” (10). new therapies indicated for stage C HF with reduced ejection fraction (HFrEF). The text explains new and modified recommendations. Methodology and Evidence Review To identify key data that influence guideline recommendations.org/ by guest on March 28.ahajournals.org/lookup/suppl/doi:10. whereas recommendations from the previous guideline that have been deleted or superseded no longer appear. That focused update was published concurrently with the European Society of Cardiology’s complete guideline. Please consult the full-text version of the 2013 HF guideline (9) for text and evidence tables supporting the unchanged recommendations and for clinical areas not addressed in this focused update. the Heart Failure Society of America (HFSA) has partnered with the ACC and AHA to provide coordinated guidance on the management of HF. Yancy et al  2017 ACC/AHA/HFSA Heart Failure Focused Update  1. New and modified recommendations in this focused update reflect the latest COR/LOE system. including sleep apnea.0000000000000509/-/DC2). The evidence is summarized in tables in the Online Data Supplement (http://circ. AHA.1. which introduced guidance on new therapies. and unchanged) for each clinical section are included to provide a comprehensive assessment. and European Society of Cardiology and other scientific meetings and that were published in peer-reviewed format from April 2013 through November 2016. This focused update represents the second part of a 2-stage publication. “2016 ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure” (11). and new insights into the prevention of HF.

Yancy et al  2017 ACC/AHA/HFSA Heart Failure Focused Update  B and C are subcategorized for greater specificity (4-6). AHA. HF and transplantation specialists. Reviewers’ RWI information is published in this document (Appendix 2). which is referred to as the 2017 HF focused update writing group.2. AHA. American Downloaded from http://circ. as well as the American Academy of Family Physicians. The section numbers correspond to the full-text guideline sections. representative members of the 2013 HF guideline writing committee were invited to participate. The group was composed of experts representing general cardiologists. This document was approved for publication by the governing bodies of the ACC. American College of Chest Physicians. Members were required to disclose all RWI relevant to the data under consideration. electrophysiologists. 2018 College of Physicians. 1. and International Society for Heart and Lung Transplantation. 1.3. AHA. 8 . They were joined by additional invited members to form a new writing group. Organization of the Writing Group For this focused update. and HFSA.org/ by guest on March 28. The 2017 HF focused update writing group included representatives from the ACC. and International Society for Heart and Lung Transplantation. and general internists. Document Review and Approval The focused update was reviewed by 2 official reviewers each nominated by the ACC. pharmacists. and 19 individual content reviewers. American College of Chest Physicians.ahajournals. 1 reviewer each from the American Academy of Family Physicians. and HFSA. and HFSA.

Treatments. Applying Class of Recommendation and Level of Evidence to Clinical Strategies.ahajournals. or Diagnostic Testing in Patient Care* (Updated August 2015) Downloaded from http://circ. Yancy et al  2017 ACC/AHA/HFSA Heart Failure Focused Update  Table 1. Interventions.org/ by guest on March 28. 2018 9 .

and this may modestly reduce diagnostic sensitivity in morbidly obese patients (42). Biomarkers Assays for BNP (B-type natriuretic peptide) and NT-proBNP (N-terminal pro-B-type natriuretic peptide). weight gain) in the setting of chronic ambulatory HF (15-21) or in the setting of acute care with decompensated HF (22-30). especially when the cause of dyspnea is unclear. Elevations in either troponin I or T levels in the setting of acute HF are of prognostic significance and must be interpreted in the clinical context (64). and myocardial and matrix remodeling. Troponins I and T respond similarly for acute coronary syndromes and acute decompensated HF. Obesity may be associated with lower natriuretic peptide concentrations. In addition to natriuretic peptides and troponins (65-67). have been used increasingly to establish the presence and severity of HF. Strategies that combine multiple biomarkers may 10 .. both natriuretic peptide biomarker values track similarly. Biomarkers of myocardial fibrosis.3. Elevated plasma levels of natriuretic peptide biomarkers are associated with a wide variety of cardiac and noncardiac causes (Table 2) (38-42). 2018 reduction in 1 study being associated with improved clinical outcomes (12).org/ by guest on March 28. with the Downloaded from http://circ. 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. have been implicated in HF (68-71). Yancy et al  2017 ACC/AHA/HFSA Heart Failure Focused Update  6. Because of the absence of clear and consistent evidence for improvement in mortality and cardiovascular outcomes (43-62). In 2 studies with ARNI. soluble ST2 receptor. 14). Initial and Serial Evaluation of the HF Patient 6. oxidative stress. cardiac troponin levels may be elevated in the setting of chronic or acute decompensated HF. Notably.ahajournals. multiple other biomarkers.g. and either can be used in patient care settings as long as their respective absolute values and cutpoints are not used interchangeably. Like natriuretic peptides. Therefore. BNP. but not NT-proBNP. which are both natriuretic peptide biomarkers. including those of inflammation. ARNI increases BNP levels (12) but not NT-proBNP levels (13). and galectin-3 are predictive of hospitalization and death and may provide incremental prognostic value over natriuretic peptide levels in patients with HF (72-74). In general. The role of natriuretic peptide biomarkers in population screening to detect incident HF is emerging (31-37). NT-proBNP levels were reduced (12. 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. suggesting myocyte injury or necrosis (63). vascular dysfunction. is a substrate for neprilysin. dyspnea. 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.

diabetes mellitus. Table 2. natriuretic NEW: New data suggest peptide biomarker–based screening followed by that natriuretic peptide team-based 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. Biomarkers for Prevention: Recommendation Biomarkers: Recommendation for Prevention of HF COR LOE Recommendation Comment/Rationale IIa B-R For patients at risk of developing HF. including a cardiovascular biomarker screening and See Online Data specialist optimizing GDMT. Several emerging biomarkers await validation with well-defined outcome measures and prognostic accuracy before they can reach the clinical arena (77-84). This section categorizes the role of biomarkers into prevention. including LVH Valvular heart disease Pericardial disease Atrial fibrillation Myocarditis Downloaded from http://circ. including RV syndromes Acute coronary syndromes Heart muscle disease.3. Selected Potential Causes of Elevated Natriuretic Peptide Levels (38-41) Cardiac HF. 2018 Cardiac surgery Cardioversion Toxic-metabolic myocardial insults. can be useful to early intervention may Supplements A and B. stage A HF])..1. including cancer chemotherapy Noncardiac Advancing age Anemia Renal failure Pulmonary: obstructive sleep apnea. 6. but multicenter studies with larger derivation and validation cohorts are needed (75. dysfunction (systolic or diastolic) or new-onset HF (85. right ventricular. All patients received further coaching by a specialist nurse who emphasized individual risk and the importance of adherence to medication 11 .g. severe pneumonia Pulmonary hypertension Critical illness Bacterial sepsis Severe burns  HF indicates heart failure. left ventricular hypertrophy.ahajournals. and RV. or known vascular disease [e. diagnosis. but without established left ventricular systolic dysfunction or symptomatic HF at baseline. 86). and added risk stratification to clarify evidence-based objectives of their use in clinical practice. Yancy et al  2017 ACC/AHA/HFSA Heart Failure Focused Update  ultimately prove beneficial in guiding HF therapy in the future.org/ by guest on March 28. Modified from Table 8 of the 2013 HF guideline (9). were randomly assigned to receive screening with BNP testing or usual primary care. 76). In a large-scale unblinded single-center study (STOP-HF [The St Vincent’s Screening to Prevent Heart Failure]) (85). prevent the development of left ventricular prevent HF. patients at risk of HF (identified by the presence of hypertension. LVH. prognosis.

6. measurement MODIFIED: 2013 acute I A of natriuretic peptide biomarkers is useful to and chronic support a diagnosis or exclusion of HF (15-24. abnormal levels of circulating cardiac troponin are commonly found in patients with acute decompensated HF. Similarly.org/ by guest on March 28. 93-101).3. Although lower values of natriuretic peptide biomarkers exclude the presence of HF. and composite outcomes. especially when the etiology of dyspnea is unclear (15-21). 29. 87-92). 6. In emergency settings. 27. across different time intervals in patients with decompensated HF (20. admission levels of Supplements A and B. Natriuretic peptide biomarker testing in the setting of chronic ambulatory HF provides incremental diagnostic value to clinical judgment. natriuretic peptide biomarkers that are useful. in another small.3.3. Further studies are needed to determine cost-effectiveness and risk of such screening. HF (16. Higher levels of natriuretic peptide biomarkers on admission are usually associated with greater risk for clinical outcomes. heterogeneity of prevalence in different populations. 28. clinicians should be aware that elevated plasma levels for both natriuretic peptides have been associated with a wide variety of cardiac and noncardiac causes (Table 2) (38-41). often without obvious 12 . 93-100). natriuretic peptide biomarker levels usually have higher sensitivity than specificity and may be more useful for ruling out than ruling in HF (20). 2018 In patients presenting with dyspnea. Yancy et al  2017 ACC/AHA/HFSA Heart Failure Focused Update  and healthy lifestyle behaviors. variable duration until clinical HF or left ventricular dysfunction develops. been combined into a Supplements A and B. and variable interventions for risk factor modification or treatment. Biomarkers for Prognosis or Added Risk Stratification: Recommendations Biomarkers: Recommendations for Prognosis COR LOE Recommendations Comment/Rationale Measurement of BNP or NT-proBNP is useful for 2013 recommendation I A establishing prognosis or disease severity in chronic remains current. 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 (86). morbidity. Developing a standardized strategy to screen and intervene in patients at risk of HF can be difficult because of different definitions of HF risk. Biomarkers for Diagnosis: Recommendation Biomarkers: Recommendation for Diagnosis COR LOE Recommendation Comment/Rationale Downloaded from http://circ. Measurement of baseline levels of natriuretic MODIFIED: Current I A peptide biomarkers and/or cardiac troponin on recommendation admission to the hospital is useful to establish a emphasizes that it is See Online Data prognosis in acutely decompensated HF (27.2. including all-cause and cardiovascular mortality. recommendations have See Online Data 30).ahajournals. single-center RCT. and higher values have reasonably high positive predictive value to diagnose HF. Similarly. BNP-based screening reduced the composite endpoint of asymptomatic left ventricular dysfunction (systolic or diastolic) with or without newly diagnosed HF (85). as well as its impact on quality of life (QoL) and mortality rate. diagnosis section.

104-113). and others) are predictive of hospitalization and death in patients with HF and also are additive to natriuretic peptide biomarker levels in their prognostic value (117. 103). 108-111). In patients with chronic HF. 113). soluble ST2 receptor. 112.g. assay cutpoints. Although observational or retrospective studies have suggested that patients with natriuretic peptide biomarker reduction had better outcomes than those without any changes or with a biomarker rise (93. 102. 13 . prognosis section. resulting in LOE change from A to B-NR. and lengths of follow-up (29). 106. and this is associated with worse clinical outcomes and higher risk of death (95. A combination of biomarkers may ultimately prove to be more informative than single biomarkers (127).. especially if they already have advanced HF with established poor prognosis or persistently elevated levels of biomarkers in former settings. a predischarge NEW: Current IIa B-NR natriuretic peptide level can be useful to establish a recommendation reflects postdischarge prognosis (93. new observational studies. 96. Therefore. and the prognostic value of a predischarge value or relative changes does not imply the necessity for serial and repeated biomarker measurements during hospitalization. See Online Data Supplements A and B. Yancy et al  2017 ACC/AHA/HFSA Heart Failure Focused Update  myocardial ischemia or underlying coronary artery disease (CAD). 119). 96. high-sensitivity cardiac troponin. However. 107. 98. 108-111). 99. measurement of other MODIFIED: 2013 IIb B-NR clinically available tests. 104-113). Furthermore. may be considered for been combined into See Online Data additive risk stratification (27. targeting a certain threshold. Several studies have suggested that predischarge natriuretic peptide biomarker levels had higher reclassification and discrimination value than clinical variables in predicting outcomes (96. 2018 strong predictors of the risk of death or hospital readmission for HF (93. such as biomarkers of recommendations have myocardial injury or fibrosis. 95). value. assays of natriuretic peptide biomarkers for incremental prognostication should not preclude good clinical judgment. During a HF hospitalization. not all patients may need biomarker measurement for prognostication. 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. 106. Clinical assessment and adherence to GDMT should be the emphasis. Supplements A and B. an individualized approach to each patient is paramount. 99. Patients with higher predischarge levels and patients who do not have a decrease in natriuretic peptide biomarker levels during hospitalization have worse outcomes (96. 114. Predischarge natriuretic peptide biomarker levels and the relative change in levels during hospital treatment are Downloaded from http://circ.org/ by guest on March 28. Biomarkers of myocardial fibrosis (e. 119-126). 103. there were differences in the risk prediction models.ahajournals. 95. galectin-3. Studies have demonstrated incremental prognostic value of these biomarkers to standard approaches of cardiovascular disease risk assessment (29.

ED. acute decompensated heart failure. B-type natriuretic peptide. Stage C 7. 2018 Predischarge Prognosis or BNP or added risk NT-proBNP stratification (COR IIa) Other biomarkers Other biomarkers of myocardial of myocardial injury or fibrosis* injury or fibrosis* (COR IIb) (COR IIb) Colors correspond to COR in Table 1. HF. Treatment of Stages A to D 7. Pharmacological Treatment for Stage C HF With Reduced Ejection Fraction: Recommendations (See Figure 2 and Table 3). AHA.3.org/ by guest on March 28. galectin-3. and high-sensitivity troponin. 14 . 7.2. NT-proBNP and cardiac troponin (COR I) (COR I) Downloaded from http://circ. ACC indicates American College of Cardiology. ADHF. BNP. heart failure. and pts. patients. N-terminal pro-B-type natriuretic peptide. New York Heart Association. Yancy et al  2017 ACC/AHA/HFSA Heart Failure Focused Update  Figure 1.ahajournals. Biomarkers Indications for Use ACC/AHA ACC/AHA Stage C/D HF ACC/AHA Acute/Hospitalized HF Stage A/B HF Ambulatory pts Acute dyspnea Hospitalized At risk for HF with new-onset NYHA class II-IV to ED for ADHF dyspnea BNP or Prevention NT-proBNP (COR IIa) BNP or BNP or Diagnosis NT-proBNP NT-proBNP (COR I) (COR I) BNP or BNP or NT-proBNP. American Heart Association. *Other biomarkers of injury or fibrosis include soluble ST2 receptor. NT-proBNP. emergency department.3. COR. NYHA. Class of Recommendation.

an ARB is combined with an inhibitor of neprilysin. the ARNI reduced the composite endpoint of cardiovascular death or HF hospitalization significantly. The benefit was seen to a similar extent for both death and HF hospitalization and was consistent across subgroups. Renin‐Angiotensin System Inhibition With Angiotensin‐Converting Enzyme Inhibitor or Angiotensin Receptor Blocker or ARNI: Recommendations Recommendations for Renin-Angiotensin System Inhibition With ACE Inhibitor or ARB or ARNI COR LOE Recommendations Comment/Rationale The clinical strategy of inhibition of the renin. ACE inhibitors can produce angioedema and should be given with caution to patients with low systemic blood pressures. is ARNI: B-R recommended for patients with chronic HFrEF to reduce morbidity and mortality. 15 . and clinical effects consistent with those expected after interference with the renin-angiotensin system and have been shown in RCTs (134-137) to reduce morbidity and mortality. In an RCT that compared the first approved ARNI. but like ACE inhibitors. or elevated 18-20. as well. neurohormonal. with enalapril in symptomatic patients with HFrEF tolerating an adequate dose of either ACE inhibitor or ARB. I ARB: A Evidence: B-R) (138) in conjunction with evidence- based beta blockers (9. valsartan/sacubitril. patients with low systemic blood pressure. ARBs should be given with caution to Supplements 1.2. by 20% (138). ARBs do not inhibit kininase and are associated with a much lower incidence of cough and angioedema than ACE See Online Data inhibitors. which can induce cough but also may contribute to their beneficial effect through vasodilation. renal insufficiency. NEW: New clinical ACE-I: A angiotensin system with ACE inhibitors (Level of trial data prompted Evidence: A) (128-133). The use of ARNI is associated with the risk of hypotension and renal insufficiency and may lead to angioedema. 2.ahajournals. 140). Angiotensin-converting enzyme (ACE) inhibitors reduce morbidity and Downloaded from http://circ. bradykinin.org/ by guest on March 28. 142). OR ARNI (Level of important updates. Randomized controlled trials (RCTs) clearly establish the benefits of ACE inhibition in patients with mild. Long-term therapy with ARBs produces hemodynamic. Angiotensin receptor blockers (ARBs) were developed with the rationale that angiotensin II production continues in the presence of ACE inhibition. ACE inhibitors also inhibit kininase and increase levels of bradykinin. adrenomedullin. serum potassium. moderate. an enzyme that degrades natriuretic peptides.10. especially in ACE inhibitor– intolerant patients. Yancy et al  2017 ACC/AHA/HFSA Heart Failure Focused Update  7. 2018 mortality in heart failure with reduced ejection fraction (HFrEF). renal insufficiency. driven through alternative enzyme pathways. or elevated serum potassium. or severe symptoms of HF and in patients with or without coronary artery disease (128-133). OR ARBs (Level of clarification and Evidence: A) (134-137). and other vasoactive peptides.3. 139. and aldosterone antagonists in selected patients (141. In ARNI.

moderate. continued use of an ACE inhibitor for all classes of HFrEF remains strongly advised. ARBs have been shown to reduce mortality and HF hospitalizations in patients with HFrEF in large RCTs (134-137). Patients intolerant to ACE inhibitors because of cough or angioedema should be started on ARBs. or elevated serum potassium (>5. (128-133. 146). ARBs do not inhibit kininase and are associated with a much lower incidence of cough and angioedema. neurohormonal. Data suggest that there are no differences among available ACE inhibitors in their effects on symptoms or survival (143). for those patients for whom ARNI is not appropriate. ACE inhibitors also inhibit kininase and increase levels of bradykinin. ARBs should be given with caution to patients with low systemic blood pressure. Angioedema occurs in <1% of See Online Data patients who take an ACE inhibitor. and clinical effects consistent with those expected after interference with the renin-angiotensin system (145. 145. but it occurs more frequently in blacks and Supplement 18. women (144).ahajournals. Although ARBs are 16 . or severe symptoms of HF. Patients should not be given ACE inhibitors if they are pregnant Downloaded from http://circ. Yancy et al  2017 ACC/AHA/HFSA Heart Failure Focused Update  The use of ACE inhibitors is beneficial for 2013 recommendation patients with prior or current symptoms of repeated for clarity in I ACE-I: A chronic HFrEF to reduce morbidity and mortality this section. 19. ACE inhibitors have been shown in large RCTs to reduce morbidity and mortality in patients with HFrEF with mild.org/ by guest on March 28. renal insufficiency. The use of ARBs to reduce morbidity and mortality 2013 is recommended in patients with prior or current recommendation I ARB: A symptoms of chronic HFrEF who are intolerant to repeated for clarity ACE inhibitors because of cough or angioedema in this section. ARBs should be started at low doses and titrated upward. Long-term therapy with ARBs in patients with HFrEF produces hemodynamic. 143). Although the use of an ARNI in lieu of an ACE inhibitor for HFrEF has been found to be superior. Unlike ACE inhibitors. If maximal doses are not tolerated. although See Online Data kininase inhibition by ACE inhibitors may produce beneficial vasodilatory Supplements 2 and effects. with or without coronary artery disease (128-133). intermediate doses should be tried.0 mEq/L). patients already tolerating ARBs for other indications may be continued on ARBs if they subsequently develop HF. abrupt withdrawal of ACE inhibition can lead to clinical deterioration and should be avoided. renal insufficiency. with an attempt to use doses shown to reduce the risk of cardiovascular events in clinical trials. which can induce cough in up to 20% of patients but also may contribute to beneficial vasodilation. 146). 2018 or plan to become pregnant. ACE inhibitors can produce angioedema and should be given with caution to patients with low systemic blood pressures. ACE inhibitors should be started at low doses and titrated upward to doses shown to reduce the risk of cardiovascular events in clinical trials.0 mEq/L). or elevated serum potassium (>5. (134-137.

hospitalizations and See Online Data mortality were significantly decreased with the valsartan/sacubitril compound Supplements 1 and compared with enalapril. 200 mg twice daily. Similar benefits have been shown for ARBs in populations with mild-to- moderate HF who are unable to tolerate ACE inhibitors. adjustment of concomitant HF medications. ARNI should not be administered concomitantly NEW: Available with ACE inhibitors or within 36 hours of the last evidence dose of an ACE inhibitor (148. HF effects and potential off-target effects may be complex with inhibition of the neprilysin enzyme. the target dose used in the trial was 97/103 mg twice daily (147). the approved ARNI is available in 3 doses that include a dose that was not tested in the HF trial. particularly with regard to blood pressure. BNP [B-type natriuretic peptide] >150 pg/mL or NT-proBNP [N- terminal pro-B-type natriuretic peptide] ≥600 pg/mL. 2018 levels. Yancy et al  2017 ACC/AHA/HFSA Heart Failure Focused Update  alternatives for patients with ACE inhibitor–induced angioedema. 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.ahajournals. This ARNI has been approved for patients with symptomatic HFrEF and is intended to be substituted for ACE inhibitors or ARBs. In patients with chronic symptomatic HFrEF NEW: New clinical NYHA class II or III who tolerate an ACE inhibitor trial data necessitated I ARNI: B-R or ARB. In patients with mild- to-moderate HF (characterized by either 1) mildly elevated natriuretic peptide Downloaded from http://circ. from asymptomatic to severely symptomatic HF. to further reduce morbidity and mortality (138). Use of an ARNI is associated with hypotension and a low-frequency incidence of angioedema. hospitalizations. replacement by an ARNI is recommended this recommendation. caution is advised because some patients have also developed angioedema with ARBs. use of an ARB remains advised. For those patients for whom an ACE inhibitor or ARNI is inappropriate. and mortality rate have been shown consistently for patients across the clinical spectrum. 149). with the ARB component equivalent to valsartan 160 mg). To facilitate initiation and titration.org/ by guest on March 28. 17 . Clinical experience will provide further information about the optimal titration and tolerability of ARNI. with that known to improve outcomes in previous landmark clinical trials (129). Benefits of ACE inhibitors with regard to decreasing HF progression. The target dose of the ACE inhibitor was consistent 18. Head-to-head comparisons of an ARB versus ARNI for HF do not exist. and the rare complication of angioedema (14). which has multiple biological targets. demonstrates a III: potential signal of B-R Harm harm for a concomitant use of ACE inhibitors and ARNI.

omapatrilat was associated Downloaded from http://circ. (NYHA class II-III) stable chronic HFrEF IIa B-R (LVEF ≤35%) who are receiving GDEM*. III: ARNI should not be administered to patients with a NEW: New clinical C-EO Harm history of angioedema. An ARNI should not be administered within 36 hours of switching from or to an ACE inhibitor. The study included patients with HFrEF (NYHA class II-IV. 2018 with a 3-fold increased risk of angioedema as compared with enalapril (149). trial data. in sinus rhythm with a resting heart rate of ≥70 beats per minute. which directly or indirectly can cause angioedema (149. Patients enrolled included a small number with paroxysmal atrial fibrillation (<40% of the time) but otherwise in 18 . One RCT demonstrated the efficacy of ivabradine in reducing the composite endpoint of cardiovascular See Online Data death or HF hospitalization (155).org/ by guest on March 28. omapatrilat. and who are in sinus rhythm with a heart rate of 70 bpm or greater at rest (154-157).11. used in combination with ACE inhibitors can lead to angioedema and concomitant use is contraindicated and should be avoided. but its development was See Online Data terminated because of an unacceptable incidence of angioedema (148. In a very large RCT of hypertensive patients. The benefit of ivabradine was driven by a Supplement 4. 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. reduction in HF hospitalization.3. including a beta blocker at maximum tolerated dose.2. Omapatrilat. 152).ahajournals. A medication that represented both a neprilysin inhibitor and an ACE inhibitor. 149) and Supplement 3. providing heart rate reduction. Blacks and smokers were particularly at risk. was studied in both hypertension and HF. Ivabradine is a new therapeutic agent that selectively inhibits the If current in the sinoatrial node. albeit with only a modest representation of NYHA class IV HF) and left ventricular ejection fraction (LVEF) ≤35%. 150). was associated with a higher frequency of angioedema than that seen with enalapril in an RCT of patients with HFrEF (148). This adverse effect was thought to occur because both ACE and neprilysin break down bradykinin. angioedema was an exclusion criterion in the first large trial assessing ARNI therapy in patients with hypertension (153) and then in the large trial that demonstrated clinical benefit of ARNI therapy in HFrEF (138). associated significant morbidity. Yancy et al  2017 ACC/AHA/HFSA Heart Failure Focused Update  Oral neprilysin inhibitors. The high incidence of angioedema N/A ultimately led to cessation of the clinical development of omapatrilat (151. In light of these observations. Ivabradine: Recommendation Recommendation for Ivabradine COR LOE Recommendation Comment/Rationale Ivabradine can be beneficial to reduce HF NEW: New clinical trial hospitalization for patients with symptomatic data. a neprilysin inhibitor (as well as an ACE inhibitor and aminopeptidase P inhibitor).

140. 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. however. as tolerated. 2018 19 . 155). it is important to initiate and up titrate these agents to target doses.ahajournals. Given the well-proven mortality benefits of beta-blocker therapy.org/ by guest on March 28. the term “GDMT” has been used to denote guideline-directed management and therapy. Downloaded from http://circ. before assessing the resting heart rate for consideration of ivabradine initiation (155). *In other parts of the document. In this recommendation. Yancy et al  2017 ACC/AHA/HFSA Heart Failure Focused Update  sinus rhythm and a small number experiencing ventricular pacing but with a predominant sinus rhythm. 139. but only 25% of patients studied were on optimal doses of beta-blocker therapy (9. Those with a myocardial infarction within the preceding 2 months were excluded. The target of ivabradine is heart rate slowing (the presumed benefit of action). 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).

HF. BP. heart rate ≥70 bpm on Ivabradine maximally tolerated dose (COR IIa) beta blocker Continue GDMT with serial reassessment & optimized dosing/adherence Colors correspond to COR in Table 1. 20 . ARNI. LVEF LVAD‡ ICD‡ Symptoms (COR IIa) ≤35%. LVEF. HFrEF. †Hydral-Nitrates green box: The combination of ISDN/HYD with ARNI has not been robustly tested. heart failure with reduced ejection fraction. CRT-D. K+. Class of Recommendation. Yancy et al  2017 ACC/AHA/HFSA Heart Failure Focused Update  Figure 2. beats per minute. Aldosterone antagonist provided est. For all medical therapies. 2018 diuretics as needed (COR I) NYHA class II–III. diagnosis. COR. angiotensin receptor-neprilysin inhibitor. MI. NYHA class II and III HF. left ventricular assist device. Dx. myocardial infarction. >40 d post MI) NYHA class II–IV. bpm. guideline-directed management and therapy.0 mEq/L Palliative care‡ NYHA class II–III HF (COR I) Discontinue ACEI or Adequate BP on ARB.org/ by guest on March 28. Hydral-Nitrates†‡ Refractory in black patients (COR I) NYHA class III-IV ACEI or ARB AND (Stage D) GDMT beta blocker. NSR. ISDN/HYD. left bundle-branch block. isosorbide dinitrate hydral-nitrates. C/I. Step 4 Establish Dx of HFrEF. Consider Consider the following Choices are not mutually Reassess assess volume. NSR. NSR & QRS CRT or CRT-D‡ studies§ ≥150 ms with LBBB (COR I) pattern NYHA class II–III. CrCl >30 (COR I) mL/min & K+<5. and no order is symptoms initiate GDMT therapy inferred NYHA class II–IV. LBBB. GDMT. initiate ARNI* ACEI or ARB*. §Participation in investigational studies is also appropriate for stage C. ACEI indicates angiotensin-converting enzyme inhibitor. contraindication. and NYHA. heart failure. creatinine clearance. additional patient scenarios exclusive. Treatment of HFrEF Stage C and D Step 1 Step 3 Step 5 Step 2 Implement indicated GDMT. New York Heart Association. CrCl. dosing should be optimized and serial assessment exercised.ahajournals. cardiac resynchronization therapy–device. *See text for important treatment directions. normal sinus rhythm. blood pressure. left ventricular ejection fraction. ARB. ICD. potassium. ‡See 2013 HF guideline (9). BP response should be carefully monitored. LVAD. (caveat: >1 y (COR I) improved survival. angiotensin receptor-blocker. Downloaded from http://circ. No C/I to HFrEF (COR I) ARB or sacubitril NYHA class I–IV (Stage C) Transplant‡  (COR I) NYHA class III–IV. implantable cardioverter-defibrillator. LVEF Investigational ≤35%.

5–25 mg QD 25 mg QD or BID 26 mg QD (142) Eplerenone 25 mg QD 50 mg QD 42.5–35.5–5 mg QD 20–40 mg QD 32. 21 .25 mg QD 10 mg QD 8. (therapy may be (sacubitril/valsartan) valsartan 49/51 mg OR initiated at 97/103 mg BID 24/26 mg BID) If channel inhibitor 6.5 mg BID 10–20 mg BID 16.5–25 mg QD 200 mg QD 159 mg QD (metoprolol CR/XL) Isosorbide dinitrate and hydralazine 20 mg isosorbide 40 mg isosorbide (162) Fixed-dose 90 mg isosorbide dinitrate / dinitrate / 37. 2018 Losartan 25–50 mg QD 50–150 mg QD 129 mg QD (136) Valsartan 20–40 mg BID 160 mg BID 254 mg QD (134) ARNI 49/51 mg BID (138) 375 mg QD.5 mg BID 6.5 mg BID (at 1 y) Aldosterone antagonists Spironolactone 12. (sacubitril/valsartan) 97/103 mg BID Sacubitril/ target dose: 24/26 mg.125 mg BID 50 mg BID 37 mg QD (161) Carvedilol CR 10 mg QD 80 mg QD N/A --- Metoprolol (139) succinate extended release 12. Drugs Commonly Used for HFrEF (Stage C HF) Mean Doses Achieved in References Drug Initial Daily Dose(s) Maximum Doses(s) Clinical Trials ACE inhibitors Captopril 6.6 mg QD (129) Fosinopril 5–10 mg QD 40 mg QD N/A --- Lisinopril 2.25 mg TID 50 mg TID 122.5 mg dinitrate / 75 mg combination ~175 mg hydralazine QD hydralazine TID hydralazine TID Isosorbide 20–30 mg 40 mg isosorbide (163) dinitrate and isosorbide dinitrate / dinitrate TID with N/A hydralazine 25–50 mg hydralazine 100 mg hydralazine TID TID or QD Modified (Table 15) from the 2013 HF guideline (9).7 mg QD (158) Enalapril 2.6 mg QD (160) Carvedilol 3.6 mg QD (159) Beta blockers Bisoprolol 1.5 mg QD 10 mg QD N/A --- Trandolapril 1 mg QD 4 mg QD N/A --- ARBs Candesartan 4–8 mg QD 32 mg QD 24 mg QD (137) Downloaded from http://circ.ahajournals. Yancy et al  2017 ACC/AHA/HFSA Heart Failure Focused Update  Table 3.0 mg QD (130) Perindopril 2 mg QD 8–16 mg QD N/A --- Quinapril 5 mg BID 20 mg BID N/A --- Ramipril 1.25–2.4 mg BID (at 28 d) (155-157) Ivabradine 5 mg BID 7.org/ by guest on March 28.

angiotensin receptor- neprilysin inhibitor. Coronary revascularization is reasonable in patients 2013 recommendation Downloaded from http://circ. not applicable. The post-hoc analysis showed efficacy in the Americas (HR=0. QD. considered to decrease hospitalizations (83. >30 mL/min. aldosterone receptor antagonists might be Supplement C. Management of AF according to published clinical 2013 recommendation practice guidelines in patients with HFpEF is remains current IIa C reasonable to improve symptomatic HF. twice daily. had nondetectable levels of 22 .89) in this composite endpoint did not reach statistical significance. possibly by a similar effect on remodeling (83. and TID. IIa C demonstrable myocardial ischemia is judged to be having an adverse effect on symptomatic HFpEF despite GDMT. 7. ARB. 170). HFrEF. aborted cardiac death.org/ by guest on March 28. ARNI. BID. CR. prompting a post-hoc analysis (167) that showed that rates of the primary endpoint were 4-fold lower in Russia/Georgia than in North America and South America (the Americas). and HF hospitalization in patients with HFpEF. In appropriately selected patients with HFpEF (with NEW: Current IIb B-R EF ≥45%.3.10). heart failure. known side effects of hyperkalemia and rising creatinine were seen more commonly in the treatment group (166). I B with published clinical practice guidelines to prevent morbidity (164. 165). estimated glomerular filtration rate new RCT data. 2013 recommendation and ARBs in patients with hypertension is remains current. Yancy et al  2017 ACC/AHA/HFSA Heart Failure Focused Update  ACE indicates angiotensin-converting enzyme. controlled release/extended release. The TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial (166) investigated the effects of spironolactone on a combined endpoint of death. Rates in the Americas were comparable to those in other HFpEF trials (169. creatinine <2.ahajournals.5 mg/dL. ACE inhibitors. potassium <5. Mechanistic studies have suggested that mineralocorticoid receptor antagonists can improve measures of diastolic function in patients with HFpEF. heart failure with reduced ejection fraction. N/A. controlled release. elevated BNP levels or HF admission recommendation reflects within 1 year. HF. 2018 with CAD in whom symptoms (angina) or remains current. CR/XL. 168). 3 times daily. Diuretics should be used for relief of symptoms due 2013 recommendation I C to volume overload in patients with HFpEF. The use of beta-blocking agents. 166. A small reduction (HR=0.3. Moreover.83) but not in Russia/Georgia (HR=1. remains current.1 in the 2013 HF guideline). despite having been in the active treatment arm.83). An unusual amount of regional variation was seen in this trial. a sample of the Russia/Georgia population. once daily. IIa C reasonable to control blood pressure in patients with HFpEF. Pharmacological Treatment for Stage C HFpEF: Recommendations Recommendations for Stage C HFpEF COR LOE Recommendations Comment/Rationale Systolic and diastolic blood pressure should be 2013 recommendation controlled in patients with HFpEF in accordance remains current. 167). angiotensin receptor blocker. (Section 9.0 See Online Data mEq/L). although HF hospitalization was reduced (HR=0.

III: No Routine use of nutritional supplements is not 2013 recommendation C recommended for patients with HFpEF. The use of ARBs might be considered to decrease 2013 recommendation IIb B hospitalizations for patients with HFpEF (169). particularly in those with elevated BNP levels. and iron 23 . III: No Routine use of nitrates or phosphodiesterase-5 NEW: Current B-R inhibitors to increase activity or QoL in patients recommendation reflects Benefit with HFpEF is ineffective (171. However. Careful monitoring of potassium. See Online Data Downloaded from http://circ. QoL. 172). Routine baseline assessment of all patients with HF includes an evaluation for anemia in addition to other baseline laboratory measurements. On the basis of this trial. exercise tolerance. Yancy et al  2017 ACC/AHA/HFSA Heart Failure Focused Update  the metabolite of spironolactone. remains current. and potassium <5.2. fatigue.5 mg/dL in men or <2. 174). remains current. Anemia is independently associated with HF disease severity. and with activity limited by dyspnea. or chest pain.0 mEq/L. estimated glomerular filtration rate >30 mL/min creatinine <2. intravenous iron therapeutic benefit.ahajournals. routine use of nitrates in patients with HFpEF is not recommended. Nitrate therapy can reduce pulmonary congestion and improve exercise tolerance in patients with HFrEF. The RELAX (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction) trial (172) randomized 216 patients with EF ≥50% on stable HF therapy and with reduced exercise tolerance (peak observed VO2 <60% of predicted) to phosphodiesterase-5 inhibition with sildenafil or placebo. Benefit 9. renal function. use of spironolactone might be considered with close monitoring of potassium and renal function. replacement might be reasonable to improve functional status and QoL(173. This study did not show improvement in oxygen consumption or exercise tolerance. elevated BNP level or HF admission within 1 year. 2018 Supplement C. or NT-proBNP levels. Phosphodiesterase-5 inhibition augments the nitric oxide system by upregulating cGMP activity. Anemia: Recommendations Recommendations for Anemia COR LOE Recommendations Comment/Rationale IIb B-R In patients with NYHA class II and III HF and iron NEW: New evidence deficiency (ferritin <100 ng/mL or 100 to 300 ng/mL consistent with See Online Data if transferrin saturation is <20%). Supplement D. These post-hoc analyses have significant limitations. new data from RCTs. the NEAT-HFpEF (Nitrate’s Effect on Activity Tolerance in Heart Failure With Preserved Ejection Fraction) trial (171) randomized 110 patients with EF ≥50% on stable HF therapy.0 mEq/L). creatinine should be <2. This recommendation does not apply to patients with HFpEF and symptomatic CAD for whom nitrates may provide symptomatic relief.5 mg/dL. Important Comorbidities in HF 9. and diuretic dosing represents best practices at initiation and during follow-up thereafter to minimize risk of hyperkalemia and worsening renal function. but they suggest that in appropriately selected patients with symptomatic HFpEF (with ejection fraction [EF] ≥45%. With regard to the use of mineralocorticoid receptor antagonists. to either isosorbide mononitrate or placebo and found no beneficial effects on activity levels.0 mg/dL in women (or estimated glomerular filtration rate >30 mL/min) and potassium should be <5. Confirmatory studies are required. not including nitrates.org/ by guest on March 28.

may improve exercise capacity and QoL. When iron deficiency is diagnosed and after full evaluation for cause. Small studies evaluating the treatment of anemia in patients with HF have suggested a trend toward improvement in functional capacity and reduction in hospitalization with the use of erythropoietin-stimulating agents (177- 182).org/ by guest on March 28.5.278). Therefore. and other events in patients with HF and iron deficiency (175). A meta-analysis of 5 prospective controlled studies (631 patients) evaluated the effect of intravenous iron on deaths. erythropoietin. 9. Studies examining correction of iron deficiency in HF have demonstrated improvement in surrogate endpoints. and LVEF. Therefore. exercise duration. the optimal NEW: Recommendation I B-R blood pressure in those with hypertension should be reflects new RCT data. 24 . The FAIR-HF (Ferric Carboxymaltose Assessment in Patients With Iron Deficiency and Chronic Heart Failure) trial (173) demonstrated improvements in NYHA class and functional capacity over a short-term exposure.5. 2018 powered trial on morbidity and mortality. EF. Yancy et al  2017 ACC/AHA/HFSA Heart Failure Focused Update  deficiency appears to be uniquely associated with reduced exercise capacity. Treating Hypertension to Reduce the Incidence of HF: Recommendation Recommendation for Prevention COR LOE Recommendations Comment/Rationale In patients at increased risk. however. NEW: Current B-R stimulating agents should not be used to improve recommendation reflects Benefit morbidity and mortality (176). hospitalizations. HF- related hospitalizations. such as QoL. In the largest RCT to date (n=2. BNP. The FAIR-HF 2 trial is underway to further address the potential benefit of intravenous iron in HF associated with iron deficiency. NT-proBNP. and QoL (184). The CONFIRM-HF (Ferric Carboxymaltose Evaluation on Performance in Patients With Iron Deficiency in Combination with Chronic Heart Failure) trial (174) included a larger cohort of patients (n=304) and demonstrated improvements in 6-minute walk test. therapeutic benefit. but results have varied (183) and have been limited because of sample size. Hypertension (New Section) 9. controlled trials have been underpowered to detect reductions in hard clinical endpoints. Although a meta-analysis of 11 RCTs (n=794) comparing erythropoietin-stimulating agents to control in patients with HF demonstrated significant improvements in 6-minute walk. stage A HF. There is an uncertain evidence base for oral iron repletion in the setting of anemia associated with HF. III: No In patients with HF and anemia. Patients receiving intravenous iron experienced limited but statistically significant improvements in functional capacity and LVEF but no reduction in mortality rate. a strong recommendation for intravenous iron repletion must await the results of an appropriately Downloaded from http://circ. intravenous repletion of iron. 185-188). peak VO2.1. the strongest evidence on erythropoietin-stimulating agent therapy in HF suggests lack of benefit and increased adverse events. NYHA functional status. In summary. erythropoietin-stimulating agent therapy cannot be recommended in patients with HF and anemia. supporting findings from other trials (176.ahajournals. correction of anemia with darbopoetin alfa did not result in benefit and resulted in a significant increase in the risk of thromboembolic events and a nonsignificant increase in fatal and nonfatal strokes. new evidence See Online Data demonstrating absence of Supplement D. darbepoetin alfa was not associated with significant clinical benefits. in the STAMINA-HeFT (Study of Anemia in Heart Failure) trial (183). especially in the setting of concomitant hepcidin deficiency in HF.

Treating Hypertension in Stage C HFpEF: Recommendation Recommendation for Hypertension in Stage C HFpEF COR LOE Recommendation Comment/Rationale Patients with HFpEF and persistent hypertension NEW: New target goal I C-LD after management of volume overload should be blood pressure based on prescribed GDMT titrated to attain systolic blood updated interpretation of See Online Data pressure less than 130 mm Hg (167. or a Framingham Risk Score >15%). per se in a randomized trial of patients with HF. Yancy et al  2017 ACC/AHA/HFSA Heart Failure Focused Update  See Online Data less than 130/80 mm Hg (189-193). it is apparent that in those patients at higher risk. should be avoided.5. Targeting a significant reduction in systolic blood pressure in those at increased risk for cardiovascular disease is a novel strategy to prevent HF. Clinical trials evaluating goal blood pressure reduction and optimal blood pressure–lowering agents in the setting of HFrEF and concomitant hypertension have not been done. was associated with a significant reduction in the incidence of HF (191) and an overall decrease in cardiovascular death. blood pressure lowering is associated with fewer adverse cardiovascular events. recent clinical trial data See Online Data but not specifically tested Supplements E and F. A large RCT demonstrated that in those with increased cardiovascular risk (defined as age >75 years. The use of nitrates in the setting of HFpEF is associated with a signal of harm and. 9. established vascular disease. the goal of <130/80 mm Hg is an approximation of the target blood pressure in conventional practice. A shared decision-making discussion with the patient influenced by physician judgment should drive the ultimate choice of antihypertensive agents.ahajournals. GDMT for HFrEF with agents known to lower blood pressure should consider a goal blood pressure reduction consistent with a threshold now associated with improved clinical outcomes but not yet proven by RCTs in a population with HF.org/ by guest on March 28. 9. Nevertheless. control of blood pressure to a goal systolic pressure of <120 mm Hg. including alpha blockers. Treating Hypertension in Stage C HFrEF: Recommendation Recommendation for Hypertension in Stage C HFrEF Downloaded from http://circ. Blood pressure measurements as generally taken in the office setting are typically 5 to 10 mm Hg higher than research measurements. and possibly ARNI would represent the preferred choice. 199). thus. 170. For many common antihypertensive agents.3. 25 . 194. chronic renal disease. as determined by blood pressure assessment as per research protocol. RAAS inhibition with ACE inhibitor. recent clinical trial data. 169. beta blockers. 2018 COR LOE Recommendation Comment/Rationale Patients with HFrEF and hypertension should be NEW: Recommendation I C-EO prescribed GDMT titrated to attain systolic blood has been adapted from pressure less than 130 mm Hg (191). Supplements E and F. in most situations. Supplements E and F.2. ARB (especially mineralocorticoid receptor antagonists). However.5. there are limited data to guide the choice of antihypertensive therapy in the setting of HFpEF (172). and calcium channel blockers.

patients on CPAP treatment were less likely to progress to more permanent forms of AF than were patients without CPAP (205).3. and a third trial of adaptive servo-ventilation in central sleep apnea and HF was aborted because of ethical concerns. including HF (204). CPAP may be reasonable to demonstrate the limited improve sleep quality and daytime sleepiness (204). Continuous positive airway pressure (CPAP) for obstructive sleep apnea improves sleep quality. harm when adaptive See Online Data servo-ventilation is used Supplement G. 201). a formal sleep assessment is reasonable to distinguish obstructive See Online Data (200. Treatment of Sleep Disorders in the 2013 HF guideline. Sleep disorders are common in patients with HF.org/ by guest on March 28. obstructive sleep apnea. The weight of evidence does not support the use of adaptive servo-ventilation for central sleep apnea in HFrEF.ahajournals. In patients with sleep apnea. A study of adults with chronic HF treated with evidence-based therapies found that 61% had either central or obstructive sleep apnea (202). Mortality rate (all cause and cardiovascular) was higher with adaptive servo-ventilation plus GDMT than with GDMT alone in a single RCT to test the addition of adaptive servo-ventilation (≥5 hours/night. and improves Downloaded from http://circ. 26 . In patients with cardiovascular disease and NEW: New data IIb B-R obstructive sleep apnea. there was no evidence of benefit on cardiovascular events at a mean follow-up of 3. the use of CPAP for obstructive sleep apnea was helpful. In this RCT of >2. Improvements in sleep quality were noteworthy and represented the primary indication for initiating CPAP treatment (204).1. for central sleep apnea. given the different responses to treatment. In patients with NYHA class II–IV HFrEF and NEW: New data III: Harm B-R central sleep apnea. scope of benefit expected See Online Data from CPAP for Supplement G. adaptive servo-ventilation demonstrate a signal of causes harm (203).700 patients. Yancy et al  2017 ACC/AHA/HFSA Heart Failure Focused Update  9. Sleep Disordered Breathing: Recommendations (Moved from Section 7. Supplement G. A similar risk has been seen in another trial. in patients with atrial fibrillation (AF) (a frequent comorbidity noted with HF). 2018 nocturnal oxygenation (200. It is clinically important to distinguish obstructive sleep apnea from central sleep apnea.4. versus central sleep apnea. reduces the apnea-hypopnea index. In a trial of 10.7 years for CPAP plus usual care compared with usual care alone.) Recommendations for Treatment of Sleep Disorders COR LOE Recommendations Comment/Rationale In patients with NYHA class II–IV HF and suspicion NEW: Recommendation IIa C-LD of sleep disordered breathing or excessive daytime reflects clinical necessity sleepiness.6. 201). However. a trial evaluated the impact of CPAP with usual therapy versus usual therapy alone on subsequent cardiovascular events. Adaptive servo-ventilation for central sleep apnea is associated with harm (203). 7 days/week) to GDMT in patients with HFrEF and central sleep apnea (203).132 patients with AF and obstructive sleep apnea.

PhD. Director. PhD. MD. Clinical Practice Guidelines Sam Shahid. Guideline Methodology and Policy Abdul R. and Publishing Amelia Scholtz. Abdullah. 2018 American Heart Association Steven R. Associate Science and Medicine Advisor Downloaded from http://circ. Education. FACC. and Publishing American College of Cardiology/American Heart Association Katherine Sheehan. MD. MPH. Executive Vice President. RN. MD. Chief Executive Officer Rose Marie Robertson. President Nancy Brown. Chief Science and Medicine Officer Gayle R. MBBS. Oetgen. FAHA. Director of Guideline Strategy and Operations Lisa Bradfield. Publications Manager. Office of Science Operations Key Words: AHA Scientific Statements ■ heart failure ■ focused update ■ angiotensin receptor- neprilysin inhibitor ■ ivabradine ■ angiotensin receptor blockers ■ angiotensin-converting enzyme inhibitors ■ beta blockers ■ angioedema ■ natriuretic peptides ■ ferric carboxymaltose ■ iron deficiency ■ hypertension ■ sleep apnea ■ natriuretic peptide biomarker 27 . Science. Project Manager. Chief Executive Officer William J. Education. Science. Houser. Science and Medicine Advisor Morgane Cibotti-Sun. Scientific Publications. FAHA. FAHA. PhD. MBA. President Shalom Jacobovitz. Whitman. Quality. Production Manager. CAE. FACC. MPH. Office of Science Operations Jody Hundley. PhD.org/ by guest on March 28. MD. Senior Vice President. Yancy et al  2017 ACC/AHA/HFSA Heart Failure Focused Update  Presidents and Staff American College of Cardiology Mary Norine Walsh. Quality.ahajournals. FAAN.

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American Society of Nephrology. 2016. J Med. van Veldhuisen DJ. et al. Pittman SD. Aronow WS. MacDonald M. 202. Engl. Adaptive Servo-Ventilation for Central Sleep Apnea in Systolic Heart Failure. 375:919-31. et al. 201. Floras JS. J. 2008. BMJ. 169:647-54. 2015. Yancy C. Suppression of central sleep apnea by continuous positive airway pressure and transplant-free survival in heart failure: a post hoc analysis of the Canadian Continuous Positive Airway Pressure for Patients with Central Sleep Apnea and Heart Failure Trial (CANPAP). 2015. 194. Pepine CJ. Woehrle H. a Downloaded from http://circ. Bradley TD. congestive heart failure. CMAJ. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. Effects of intensive blood pressure lowering on cardiovascular and renal outcomes: updated systematic review and meta-analysis. et al. 315:2673-82.123:2434 –506. J. 191. Engl. Atkins E. Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies. Chen CY. 4:38-42. Am Heart J. 2011.ahajournals. 373:1095-105. et al. et al. et al. Secondary analysis of the CHOIR trial epoetin-alpha dose and achieved hemoglobin outcomes. 2016. 124:1811- 8. Wegscheider K. Burdmann EA. 2007. Whelton PK. 361:2019-32. ACCF/AHA 2011 expert consensus document on hypertension in the elderly: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus documents. Xie X. Circulation. Long-term follow-up of participants with heart failure in the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). Williamson JD. 2016. Kimoff RJ. 2016. et al. A Randomized Trial of Intensive versus Standard Blood- Pressure Control. Guan N. 189. 2009. et al. Morris JK. Am J Cardiol. et al. less intensive blood pressure lowering and different achieved blood pressure levels . 387:435-43. McEvoy RD. 353:2025-33. J Hypertens. and left ventricular ejection fraction > or = 40% treated with diuretics plus angiotensin-converting enzyme inhibitors. N. 2006. Developed in collaboration with the American Academy of Neurology. Intensive vs standard blood pressure control and cardiovascular disease outcomes in adults aged >/=75 years: A randomized clinical trial. Engl. Bohlius J. Wright JT Jr. J Am Coll Cardiol. et al.updated overview and meta-analyses of randomized trials. J Natl. 203. Kronzon I. Inrig JK. et al. Circulation. Barnhart HX. Parati G. 2008. Law MR. Effect of propranolol versus no propranolol on total mortality plus nonfatal myocardial infarction in older patients with prior myocardial infarction. Fleg JL. Fang J. Ehteshami P. Med. and European Society of Hypertension. Williamson JD. 115:3173-80. Seidenfeld J. Association of Black Cardiologists. J. 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ahajournals.3. Yancy Northwestern University Feinberg None None None None None None None (Chair) School of Medicine. Department of Medicine — 7.5. Division of Cardiology—Professor of Medicine and Chief. Diversity and Inclusion—Vice Dean Mariell Jessup Fondation Leducq—Chief None None None None None None None (Vice Chair) Scientific Officer Biykem Bozkurt Baylor College of Medicine. The Mary and Gordon Cain Chair & W. None None None  Novartis None None 7. Author Relationships With Industry and Other Entities (Relevant)—2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure (December 2015) Committee Employment Consultant Speakers Ownership/ Personal Research Institutional. — Chair.3.2.3. Division Chief of Cardiology  Boehringer 7. 7.A. Jr. “Tex” and Deborah Moncrief. Downloaded from http://circ.org/ by guest on March 28.5. Professor of Medicine. 2018 Yancy et al  2017 ACC/AHA/HFSA Heart Failure Focused Update  Appendix 1.3. Ingelheim and 9.10. Cardiovascular Research Institute — Associate Director Javed Butler Stony Brook University—  Bayer†  Novartis† None  Amgen (DSMB)† None None 7.3. Witness Recusals By Principal or Other Section* Financial Benefit Clyde W.  CardioCell†  Luitpold  Medtronic  Merck†  Novartis†  Relypsa†  Takeda  Trevena†  Z Pharma 37 .11.10.2.11.2. 7. DeBakey VA Medical Center — Chief.2. Cardiology Section. Winters Center for Heart Failure Research — Director.3.3. Expert Voting Member Bureau Partnership/ Organizational. and 9.3.

11. 7. Coronary Care Unit. University of Colorado.10. Casey. and 9.2.2.10.3.ahajournals. UCLA Division of Pharmaceuticals and 9.10.3. Section—Professor of Medicine  Novartis  Relypsa†  ResMed† Frederick A. Cooper University Hospital— None None None None None None None Hollenberg Director. 7.3. Internal Medicine Gerasimos S.3. 7. and 9.10.3.2. 2018 Yancy et al  2017 ACC/AHA/HFSA Heart Failure Focused Update   Zensun Donald E. and 9.11. Professor of Medicine JoAnn Vanderbilt Heart and Vascular  Abbott None None  AstraZeneca None None 6. Downloaded from http://circ. Steven M.3.2. Lindenfeld Institute—Director.2.3.2. Fonarow Cardiomyopathy Center—  Janssen 7. 7. Division of Cardiology Patrick E.3.5. University Hospital. University of Wisconsin School None None None None None None None McBride of Medicine and Public Health— Professor of Medicine and Family 38 .2. Drazner University of Texas Southwestern None None None None None None None Medical Center—Professor. Cardiology—Co-Chief  Novartis† Michael M.6.3. Director.5. National and Kapodistrian None None None  Bayer† None None 7.5.3.3. Attikon  Bayer (DSMB) 7. Heart Failure and Transplant Pharmaceuticals 9. Alvarez & Marsal IPO4Health— Principal and Founder Monica M. 7. University of Michigan— None None None None None None None Colvin Associate Professor of Medicine.3.11. of Cardiology.3.3. Advanced  Janssen  Novartis† 7. Thomas Jefferson College of None None None None None None None Jr Population Health— Faculty.3. Brigham and Women's  Merck None None None None None 7.3. Anschutz None None None None None None None Masoudi Medical Campus—Professor of Medicine. Cardiology Mark H.5. Heart Failure  Servier Unit—Professor of Cardiology Pharmaceuticals†  Vifor Gregg C. Department  Novartis† 9. Givertz Hospital—Professor of Medicine  Novartis 7.org/ by guest on March 28.2.2.3. Ahmanson-UCLA  Amgen None None Novartis† None None 7. Filippatos University of Athens.11.

American College of Cardiology Foundation. or if funds received by the person from the business entity exceed 5% of the person’s gross income for the previous year. 2018 Yancy et al  2017 ACC/AHA/HFSA Heart Failure Focused Update  Medicine. drug class.3.2. ACCF.3. Associate Director. Downloaded from http://circ. *Writing committee members are required to recuse themselves from voting on sections to which their specific relationships with industry and other entities may apply. Duke Clinical Research Institute. These relationships were reviewed and updated in conjunction with all meetings and/or conference calls of the writing committee during the document development process. or b) the company/entity (with whom the relationship exists) makes a drug. Doctoral Programs— Professor This table represents the relationships of committee members with industry and other entities that were determined to be relevant to this document. DCRI. 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. HFSA. †Significant relationship. 39 . Los Angeles. Cardiomyopathy and (PI) and 9. According to the ACC/AHA. or ownership of ≥$5.5. and VA. data safety monitoring board. AHA.2. Preventive Cardiology Pamela N.10. Veterans Affairs. Director. PARENT. Denver None None None None None None None Peterson Health Medical Center— Associate Professor of Medicine. or issue addressed in the document.3. National Heart.3. Pulmonary artery pressure reduction with entresto. University of Colorado. Division of Cardiology Lynne Warner Brigham and Women’s Hospital None None None  Novartis— None None 7. School None None None None None None None of Nursing. American Heart Association. 7. a person has a relevant relationship IF: a) The relationship or interest relates to the same or similar subject matter. Relationships in this table are modest unless otherwise noted. UCLA. Relationships that exist with no financial benefit are also included for the purpose of transparency. or other personal gain or loss as a result of the issues/content addressed in the document. University of California.ahajournals. INTERMACS. or makes a competing drug or device addressed in the document.000 of the fair market value of the business entity. or c) the person or a member of the person’s household has a reasonable potential for financial. Lung. DSMB. Heart Failure Society of America. Heart Failure Program  NHLBI— INTERMACS (Co–PI) Cheryl Westlake Azusa Pacific University. and Blood Institute. Stevenson Cardiovascular Division— PARENT trial 7. ACC indicates American College of Cardiology. or device addressed in the document. intellectual property or asset. professional. NHLBI. Interagency Registry for Mechanically Assisted Circulatory Support. topic.org/ by guest on March 28.11.

2018 Yancy et al  2017 ACC/AHA/HFSA Heart Failure Focused Update  Appendix 2. DeBakey VA None None None  NIH*  AHA None Reviewer—AHA Medical Center—Chief of  AHA (GWTG Cardiology. Harvard Medical Medical* School Anita Deswal Official Michael E. Cardiovascular  Relypsa* Division.org/ by guest on March 28. or Witness / Principal Other Financial Benefit Kim K. Reviewer Relationships With Industry and Other Entities (Comprehensive)—2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure (October 2016) Reviewer Representation Employment Consultant Speakers Ownership/ Personal Research Institutional. Heart Cardiology*  Thoratec Failure Disease Management. Baylor Committee)† College of Medicine—  HFSA† Professor of Medicine Dipti Official Newport Coast Cardiology— None None None None  St. Expert Bureau Partnership Organizational. Official University of Houston College  Jones & None None None None None Birtcher Reviewer— of Pharmacy—Clinical Bartlett ACC/AHA Task Professor Learning Force on Clinical Practice Guidelines Akshay S.  Merck Advanced Heart Disease  Novartis* Section. Heart Steering Failure Program. Professor of Medicine & Epidemiology and Population Health— Albert Einstein College of Medicine Geetha Official University of Missouri-Kansas None None None None None None 40 . Official Brigham and Women’s  Medscape None None None  Novartis* None Desai Reviewer—HFSA Hospital—Director. Cardiology.ahajournals. Associate Professor  St. Jude of Medicine. Downloaded from http://circ. Director of Disease Management Ileana L. Piña Official Montefiore Medical Center—  Relypsa None None None None None Reviewer—AHA Associate Chief for Academic Affairs. Jude Medical None Itchhaporia Reviewer—ACC Robert and Georgia Roth Board of Trustees Endowed Chair for Excellence in Cardiac Care. Director.

2018 Yancy et al  2017 ACC/AHA/HFSA Heart Failure Focused Update  Raghuveer Reviewer—ACC City School of Medicine— Board of Professor of Pediatrics. Organizational Georgetown University None None None None None None Lin Reviewer—AAFP School of Medicine— Clinician Educator Track.  Otsuka Board of Trustees Heart Failure and Cardiac  PCORI Transplantation  Thoratec David A. Content Oregon Health & Science None None None None  ACC/AHA† None Cigarroa Reviewer— University—Clinical Professor  AHA† ACC/AHA Task of Medicine  ASA† Force on Clinical  Catheterization Practice and Guidelines Cardiovascular 41 . S. Associate Professor Joaquin E. Middleton Memorial None None None None  CHEST None Casey Reviewer— Veterans Hospital—Director. Official Tufts Medical Center—Chief. Organizational Newark Beth Israel Medical  Maquet  Novartis None  XDx* None None Baran Reviewer—ISHLT Center—Director of Heart  Otsuka*  NIH* Failure and Transplant Research Kenneth Organizational Wm.ahajournals. CHEST Sleep Medicine M. Downloaded from http://circ. Fuad Jan Organizational Aurora Advanced None None None None None None Reviewer— Healthcare—Cardiologist CHEST Kenneth W.  Lantheus None None  Gilead (DSMB)  Abbott None Udelson Reviewer—HFSA Division of Cardiology Medical  GlaxoSmithKline Laboratories Imaging (DSMB)  AHA*  NHLBI  Circulation /  Otsuka Circulation: Heart Failure†  HFSA (Executive Council)†  Pfizer/ GlaxoSmithKline  Sunshine Heart Mary Norine Official St Vincent Heart Center of None None None None  Corvia Medical None Walsh Reviewer—ACC Indiana—Medical Director. Governors Children's Mercy Hospital— Pediatric Cardiology James E.org/ by guest on March 28.

Content Nemours/Alfred I. Clinical Cardiac Force on Clinical Electrophysiology—Program Practice Director Guidelines Edward K. Joglar Content UT Southwestern Medical None None None None None None Reviewer— Center—Professor of Internal ACC/AHA Task Medicine. Chair. 2018 Yancy et al  2017 ACC/AHA/HFSA Heart Failure Focused Update  Intervention†  NIH  Portland Metro Area AHA (President)† SCAI Quality Interventional Council† Lee A. Content Reviewer Johns Hopkins Cardiology— None None None None None None Kasper E.org/ by guest on March 28. duPont  FH None None  FH Foundation† None None Gidding Reviewer— Hospital for Children—Chief. Cowles Andrus Professor in Cardiology Wayne C. Content Reviewer Massachusetts General  Critical None None  Amgen (DSMB) None None Januzzi Hospital—Hutter Family Diagnostics*  Boeringer Professor of Medicine in the  Novartis* Ingelheim Field of Cardiology  Phillips (DSMB)*  Roche  Janssen Diagnostics* Pharmaceuticals  Sphingotec* (DSMB)  Prevencio* José A. Department of University Guidelines Anesthesiology & Critical Care Samuel S. Foundation†  NIH* ACC/AHA Task Division of Pediatric  International Force on Clinical Cardiology FH Practice Foundation† Guidelines James L.ahajournals. Downloaded from http://circ. Content Reviewer University of Washington—  Abbott None None  NIH  Amgen* None 42 . Content University of Pennsylvania  Blue Cross/ None None  Johns Hopkins  Association of None Fleisher Reviewer— Health System—Robert Blue Shield* (DSMB) University ACC/AHA Task Dunning Dripps Professor of  NQF† Anesthesiologists† Force on Clinical Anesthesiology and Critical  Yale  NIH Practice Care.

Jude Medical*  HeartWare*  GE  Novartis* Healthcare  Resmed*  HeartWare  Thoratec  PharminIN Judith E. 2018 Yancy et al  2017 ACC/AHA/HFSA Heart Failure Focused Update  Levy Professor of Medicine Laboratories  Novartis*  AHA  Biotronik  St. Content Reviewer SUNY Downstate Medical None None None None  Association of None Mitchell Center—Director/Heart Black Failure Center. Downloaded from http://circ. Heart Failure & Cardiac Transplant W. Content Cleveland Clinic Department  BioControl None None  Medtronic  St. Jude Medical None Starling Reviewer—ACC of Cardiovascular Medicine—  Medtronic  NIH* Heart Failure and Vice Chairman. SUNY Cardiologists† Downstate College of Medicine—Associate Professor of Medicine Sean P. H.ahajournals. Michael’s  CIHR* ACC/AHA Task Hospital—Scientist. Content Mount Sinai School of  Acorda None None  Thoratec† None None Pinney Reviewer—ACC Medicine—Associate Therapeutics  NIH† Heart Failure and Professor of Medicine.org/ by guest on March 28.  Thoratec Transplant Council Cardiology  XDx Randall C. Tsai Content Reviewer Columbia University College None None None  Bayer† None None of Physicians & Surgeons—  Bristol-Myers Assistant Professor of Squib† Medicine. Division of  NHLBI* Cardiology Duminda N.  Heart and Stroke Force on Clinical University of Toronto— Foundation of Practice Assistant Professor. Jude Medical† Section Head. Wilson Content Reviewer Cleveland Clinic None None None  NIH*  Alnylam None Tang Foundation—Assistant Pharmaceuticals Professor of Medicine  NIH  NHLBI  Roche  Novartis  Thoratec Emily J. Canada* 43 .  St. Department of  Novartis  Novartis† Transplant Council Cardiovascular Medicine. Content Li Ka Shing Knowledge None None None  CIHR (DSMB)† None None Wijeysundera Reviewer— Institute of St.

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Yancy et al 
2017 ACC/AHA/HFSA Heart Failure Focused Update 

Guidelines Department of Anesthesia and  Ministry of Health
Institute of Health Policy & Long-term Care
Management and Evaluation of Ontario*
 PCORI DSMB)†
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 ≥$5,000 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; ACCF, American College of Cardiology Foundation; 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; 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 Cardiac Angiography and Interventions; SUNY, State University of New York; UT, University of Texas; and VA, Veterans
Affairs.

44

Yancy et al 
2017 ACC/AHA/HFSA Heart Failure Focused Update 

Appendix 3. Abbreviations
ACE = angiotensin-converting enzyme
ARB = angiotensin-receptor blocker
ARNI = angiotensin receptor–neprilysin inhibitor
BNP = B-type natriuretic peptide
BP = blood pressure
COR = Class of Recommendation
CPAP = continuous positive airway pressure
EF = ejection fraction
Downloaded from http://circ.ahajournals.org/ by guest on March 28, 2018

GDMT = guideline-directed management and therapy
HFpEF = heart failure with preserved ejection fraction
HFrEF = heart failure with reduced ejection fraction
LOE = Level of Evidence
LVEF = left ventricular ejection fraction
NT-proBNP = N-terminal pro-B-type natriuretic peptide
QoL = quality of life
RCT = randomized controlled trial

45

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
Clyde W. Yancy, Mariell Jessup, Biykem Bozkurt, Javed Butler, Donald E. Casey, Jr, Monica M.
Colvin, Mark H. Drazner, Gerasimos S. Filippatos, Gregg C. Fonarow, Michael M. Givertz, Steven
M. Hollenberg, JoAnn Lindenfeld, Frederick A. Masoudi, Patrick E. McBride, Pamela N. Peterson,
Lynne Warner Stevenson and Cheryl Westlake
Downloaded from http://circ.ahajournals.org/ by guest on March 28, 2018

Circulation. published online April 28, 2017;
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2017 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539

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Diversity and Inclusion—Vice Dean Mariell Jessup Fondation Leducq—Chief None None None None  ABIM† None (Vice Chair) Scientific Officer  AHA†  Up to Date Biykem Bozkurt Baylor College of None None None  Novartis†  ABIM None Medicine.  Circulation Editorial The Mary and Gordon Board Membership Cain Chair & W. Cardiovascular Research Institute — Associate Director Javed Butler Stony Brook University—  Bayer*  Novartis* None  Amgen (DSMB)*  AHA (Deputy Chief None Division Chief of  Boehringer Ingelheim*  Bristol-Myers Science Officer)* Cardiology  CardioCell* Squibb (DSMB)  American Heart Journal  CVRx  Corvia Medical (Editorial Board)†  Gilead Sciences (DSMB)  European Journal of  Janssen  European Union* Heart Failure (Associate Pharmaceuticals  NIH* Editor)†  HFSA (Executive © 2017 American College of Cardiology Foundation.. Division of Cardiology—Professor of Medicine and Chief.A. — Chair. Inc. . the American Heart Association. Winters Center for Heart Failure Research — Director. Jr. and the Heart Failure Society of America. Expert Member Bureau Partnership/ Organizational or Other Witness Principal Financial Benefit Clyde W. Cardiology  Circulation Heart Failure Section. Yancy Northwestern University None None None  PCORI†  JAMA Cardiology None (Chair) Feinberg School of (Deputy Editor)* Medicine. Department of  ACC Heart Failure Medicine — Professor of Council Chair Medicine.Author Relationships With Industry and Other Entities (Comprehensive)—2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure Committee Employment Consultant Speakers Ownership/ Personal Research Institutional. DeBakey VA Associate Editor Medical Center — Chief. “Tex” and Deborah Moncrief.

of Population Health— Adjunct Faculty. Department of  Cardiorentis Cardiology. and the Heart Failure Society of America. Jude Medical  PharmaIn  Relypsa*  Stealth Peptide  Takeda†  Trevena*  Z Pharma  Zensun Donald E. . Heart Failure (Steering Unit—Professor of Committee)† Cardiology  European Union*  Medtronic © 2017 American College of Cardiology Foundation. Thomas Jefferson College None None None None None None Jr.. University of Michigan— None None None  Scientific Registry  CareDX None Colvin Associate Professor of of Transplant  Thoratec Medicine. Drazner University of Texas None None  Trevena*  AHA*  Alnylam None Southwestern Medical  DCRI/Otsuka Center—Professor. Alvarez & Marsal IPO4Health— Principal and Founder Monica M. National and Kapodistrian None None None  Bayer (Steering  European Heart Journal None Filippatos University of Athens. Committee)* (Associate Editor) Attikon University  Bayer (DSMB) Hospital. Casey. Inc. the American Heart Association. Jude Medical (HF Fellowship)*  Up to Date Gerasimos S. Cardiology Recipients/HRSA* Mark H.  AHA Circulation (Senior Internal Medicine Associate Editor)†  NHLBI (Co-PI for GUIDE-IT)  St.  Luitpold Council Member)† Pharmaceuticals  JACC†  Medscape  JACC: Heart Failure†  Medtronic  Medscape  Merck*  NIH  Novartis*  St.

UCLA Pharmaceuticals (Steering  ACC/AHA Task Force Division of Cardiology—  Medtronic Committee)† on Performance Co-Chief  Novartis*  NHLBI* Measures (Chair-Elect)†  NIH/NIAID*  ACTION Registry  Novartis* GWTG Steering Committee (Chair)†  AHA Consumer Health Quality Coordinating Committee†  AHA Manuscript Oversight Committee†  GWTG Steering Committee (PRT)†  JAMA Cardiology (Associate Editor)† Michael M. (Steering Committee)†  Novartis (Steering Committee)*  Servier Pharmaceuticals (Steering Committee)*  Vifor (Endpoint Adjudication Committee) Gregg C. Jude Medical* Failure and Transplant  CVRx © 2017 American College of Cardiology Foundation. and the Heart Failure Society of America. Inc. Coronary Care Unit.. . Advanced Heart  Cardiomems*  St. the American Heart Association. Brigham and Women's  Cardioxyl None None  BioControl (CEC) None None Givertz Hospital—Professor of  Merck Medicine  Novartis Steven M. Ahmanson-UCLA  Amgen None None  Medtronic–  ACC/AHA Task Force None Fonarow Cardiomyopathy  Janssen IMPROVE-HF on Data Standards† Center—Director. Professor of Medicine JoAnn Vanderbilt Heart and  Abbott None None  AstraZeneca†  JACC HF (Deputy None Lindenfeld Vascular Institute—  Boston Scientific  Novartis* Editor) Director. Cooper University None None None None None None Hollenberg Hospital—Director.

 AHRQ*  JournalWatch Cardiology Division of Cardiology (Associate Editor) Patrick E..  ABIM None None  ACC*  Circulation (Associate None Masoudi Denver—Associate  ACC-NCDR* Editor) Professor of Medicine. 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. Editor)† Cardiomyopathy and (HF Network and  Medtronic† Heart Failure Program Skills Training)†  NHLBI— INTERMACS (Co–PI)†  St. . Inc.  NHLBI (Co–PI). University of Wisconsin None None None  NIH-NIDDK None None McBride School of Medicine and (DSMB) Public Health—Professor of Medicine and Family Medicine. Jude Medical Cheryl Westlake Azusa Pacific None None None None None None University—Professor and Associate Dean. Associate Director. Section— Professor of  Janssen Medicine Pharmaceuticals  Novartis  Relypsa*  RESMED* Frederick A. International and Community Programs This table represents all relationships of committee members with industry and other entities that were reported by authors. the American Heart Association. or ownership of ≥$5. University of Colorado. Preventive Cardiology Pamela N. including those not deemed to be relevant to this document. University of Colorado. and the Heart Failure Society of America. 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 © 2017 American College of Cardiology Foundation. Jude Medical None None  Novartis (PI for  Circulation Heart Failure None Stevenson Hospital Cardiovascular  NHLBI Parent Trial)† (Senior Associate Division—Director. Brigham and Women’s  St. Division of Cardiology Lynne W. The table does not necessarily reflect relationships with industry at the time of publication.  ACC* None None None  JAHA (Associate None Peterson Denver Health Medical Editor)* Center—Associate Professor of Medicine.000 of the fair market value of the business entity. at the time this document was under development.

Gordon Cain Chair and 7. AHRQ. DCRI. Interagency Registry for Mechanically Assisted Circulatory Support. Medical Center—The Mary and 7. National Institute of Allergy and Infectious Diseases.3. Please refer to http://www. DSMB.2. HF.10.2.3.3. Get With The Guidelines. NIH. UCLA. heart failure. HSAG. Lung.11. Heath Resources and Services Administration. and 9. Inc. NIAID.financial benefit are also included for the purpose of transparency. †No financial benefit. Registry to Improve the use of Evidence-Based Heart Failure Therapies in the Outpatient Setting. National Heart.5. PI.3. American Board of Internal Medicine. INTERMACS.2. NHLBI. Health Services Advisory Group.11. ACC indicates American College of Cardiology. DeBakey VA None None None  Novartis None None 7. Division Chief of Cardiology  Boehringer (DSMB)† 7. Los Angeles. GWTG. AHA. NIDDK. Agency for Healthcare Research and Quality. Author Relationships With Industry and Other Entities (Relevant)—2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure (December 2015) Committee Employment Consultant Speakers Ownership/ Personal Institutional.3. JAHA.3. principal investigator. Division of Cardiology— Professor of Medicine and Chief. Diversity and Inclusion—Vice Dean Mariell Jessup Fondation Leducq—Chief None None None None None None None Scientific Officer (Vice Chair) Biykem Bozkurt Michael E. National Institutes of Health. Patient Centered Outcomes Research Institute.3. PRT. data safety monitoring board.10.. ABIM. . the American Heart Association. Professor of Medicine Javed Butler Stony Brook University—  Bayer†  Novartis† None  Amgen None None 7. and 9.  CardioCell† © 2017 American College of Cardiology Foundation. Appendix 1. Expert Voting Member Bureau Partnership/ Research Organizational. and the Heart Failure Society of America. IMPROVE-HF. Heart Failure Society of America. and VA. HRSA. and Blood Institute. PCORI. HFSA.org/guidelines/about- guidelines-and-clinical-documents/relationships-with-industry-policy for definitions of disclosure categories or additional information about the ACC/AHA Disclosure Policy for Writing Committees. National Institute of Diabetes and Digestive and Kidney Diseases. University of California. Duke Clinical Research Institute. pharmaceutical round table. Witness Recusals By Principal or Other Section* Financial Benefit Clyde W. Veterans Affairs.5. Ingelheim 7.3. Relationships in this table are modest unless otherwise noted. Yancy Northwestern University None None None None None None None (Chair) Feinberg School of Medicine. American Heart Association. *Significant relationship.2.acc. Journal of the American Heart Association.

Fonarow Ahmanson-UCLA  Amgen None None Novartis† None None 7.3.10.3.  Luitpold  Medtronic  Merck†  Novartis†  Relypsa†  Takeda  Trevena†  Z Pharma  Zensun Donald E.5. Medicine 7. Cardiology—Co-Chief Novartis† Michael M.11. Casey.3. Cardiology Mark H.3.3.10.2.3.3.11. Drazner University of Texas None None None None None None None Southwestern Medical Center—Professor. Steven M. Internal Medicine Gerasimos S. Alvarez & Marsal IPO4Health—Principal and Founder Monica M.5.11.2.2.2.  Novartis† 9.2. Filippatos University of Athens. Jr Thomas Jefferson College of None None None None None None None Population Health— Faculty. Director.2. Heart Failure Unit—Professor  Servier of Cardiology  Pharmaceutic als†  Vifor Gregg C. Givertz Brigham and Women's  Merck None None None None None 7. Colvin University of Michigan— None None None None None None None Associate Professor of Medicine. Inc.10. and the Heart Failure Society of America. and Department of Cardiology. (DSMB) 7.3.3. Attikon  Bayer 7. UCLA Division of Pharmaceuticals 7. and 9. Cooper University Hospital— None None None None None None None © 2017 American College of Cardiology Foundation.3.3. . University Hospital.2.3. and 9. Hospital—Professor of  Novartis 7. 9. National and Kapodistrian None None None  Bayer† None None 7. Cardiomyopathy Center—  Janssen 7. the American Heart Association..5.

The table does not necessarily reflect relationships with industry at the time of publication. None None None None None None None Masoudi Denver—Associate Professor of Medicine. Division of Cardiology Lynne W.3. Professor of Medicine JoAnn Lindenfeld Vanderbilt Heart and Vascular  Abbott None None  AstraZeneca None None 6. or ownership of ≥$5. International and Community Programs This table represents the relationships of committee members with industry and other entities that were determined to be relevant to this document.5 and Section—Professor of  Novartis 9. Heart Failure and Transplant Pharmaceuticals 7.3. University of Colorado. Stevenson Hospital Cardiovascular PARENT trial 7. Inc. 7. Cardiomyopathy and Heart  NHLBI— Failure Program INTERMACS (Co–PI) Cheryl Westlake Azusa Pacific University— None None None None None None None Professor and Associate Dean. . Medicine  Relypsa†  ResMed† Frederick A. and the Heart Failure Society of America. McBride University of Wisconsin School None None None None None None None of Medicine and Public Health—Professor of Medicine and Family Medicine. Coronary Care Unit.3.6.2. or if funds received by the person from the business entity exceed 5% of the © 2017 American College of Cardiology Foundation.2. 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. Associate Director. the American Heart Association.. Hollenberg Director. 9. Division of Cardiology Patrick E.5.000 of the fair market value of the business entity. (PI) 7. Denver None None None None None None None Health Medical Center— Associate Professor of Medicine.3. Institute—Director. These relationships were reviewed and updated in conjunction with all meetings and/or conference calls of the writing committee during the document development process.3.3.3. Preventive Cardiology Pamela N. Brigham and Women’s None None None  Novartis— None None 7.2. Peterson University of Colorado. Advanced  Janssen  Novartis† 7.2.10.3.10. Division—Director.11.3. and 9.11.

PARENT. a person has a relevant relationship IF: a) The relationship or interest relates to the same or similar subject matter. or other personal gain or loss as a result of the issues/content addressed in the document. ACC indicates American College of Cardiology. University of California. American Heart Association. Inc. topic. HFSA. © 2017 American College of Cardiology Foundation. UCLA. *Writing committee members are required to recuse themselves from voting on sections to which their specific relationships with industry and other entities may apply. or makes a competing drug or device addressed in the document. According to the ACC/AHA. Los Angeles. drug class. the American Heart Association. or issue addressed in the document. or c) the person or a member of the person’s household has a reasonable potential for financial. Relationships in this table are modest unless otherwise noted. INTERMACS. professional. Veterans Affairs. and VA. . intellectual property or asset. or device addressed in the document. or b) the company/entity (with whom the relationship exists) makes a drug. Relationships that exist with no financial benefit are also included for the purpose of transparency. DSMB. Heart Failure Society of America. data safety monitoring board. and the Heart Failure Society of America.person’s gross income for the previous year. DCRI. Pulmonary Artery Pressure Reduction With Entresto.. AHA. Interagency Registry for Mechanically Assisted Circulatory Support. †Significant relationship. Duke Clinical Research Institute.

3.... aspartate transaminase....... Nonrandomized Trials for Hypertension (Section 9........................................... acute decompensated heart failure... APE......... 33 Data Supplement C. Angiotensin Receptor-Neprilysin Inhibitor...... ALLHAT...............5) .. 66    Key Search Terms: Heart Failure. ACE... 15 Data Supplement 1........5) .10) .... 6 min walk test. AIRE..... area under the curve........................  Master Abbreviation List: 1 indicates primary... AKI/ARF.......................................................... Angiotensin-Converting Enzyme Inhibitors........................................... 41 Data Supplement E.............................. ARB..... secondary. ALT.............. AV.. 36 Data Supplement D.............. AMI... ACS.... acute kidney injury/acute renal failure.... Iron deficiency.. acute myocardial infarction..... AST.....3........................... Acute Infarction Ramipril Efficacy.... apnea- hypopnea index...........................) Table of Contents   Data Supplement A......................... ASA.2..... 29 Data Supplement 3.2) .................................................3) ........ Nonrandomized Trials/ Observational Studies/ Registries for Changes in or Discharge NP Levels in ADHF – Biomarkers (Section 6...........4) ........ Ivabradine..............................2................. angiotensin receptor-neprilysin inhibitor................ ARBs (Section 7... ADHERE...2............................ approximately. atrioventricular..........................3... 51 2013 HF Guideline Data Supplement 18........3) ................... Inc............. angiotensin-receptor blocker...... RCTs Comparing Pharmacological Treatment for of ARNI With ACE (Section 7................3......................2.............10) .......... 44 Data Supplement F.. RCTs Comparing RAAS Inhibition (Section 7........... BEAUTIFUL................................................................ acute pulmonary embolism..... 50 Data Supplement G....................6) .... 31 Data Supplement 4.. 2..... ARNI.......3.................... Assessment of Treatment with Lisinopril and Survival.... RCTs Comparing Treatment of Sleep Disorders (CPAP makers) (Section 9.............................2................... RCTs Comparing Anemia (Section 9.....................2..............................................3... alanine aminotransaminase....................... AHRQ.. acute coronary syndrome........2.......... 65 2013 HF Guideline Data Supplement 20. AF................ ACEI indicates angiotensin-converting-enzyme inhibitor.................................. Angioedema....2). AUC............... ACE Inhibitors (Section 7...... Agency for Healthcare Research and Quality...... 6MWT.................... Morbidity-Mortality Evaluation of the If Inhibitor Ivabradine in Patients With Coronary Disease and © 2017 American College of Cardiology Foundation... ATLAS............................... ADHF.............................. hypertension........... RCTs Comparing Pharmacological Treatment for Stage C HFrEF (Section 7.. and the Heart Failure Society of America...................3) ...............................3) ........ AHI.11)....... RCTs Comparing HTN (Section 9............... RCTs Comparing Pharmacologic Treatment for HFpEF: Recommendations (Section 7.............. angiotensin-converting enzyme......... 2017 Heart Failure Focused Update Data Supplement (Section numbers correspond to the 2013 full-text guideline.... Beta Blockers (Section 7....... 27 Data Supplement 2... Acute Decompensated Heart Failure National Registry....... aspirin................................................. atrial fibrillation......................... Angiotensin Receptor Blockers. ~.......................................... natriuretic peptide biomarker.......... 62 2013 HF Guideline Data Supplement 19............. Natriuretic Peptides... RCTs Comparing ARNI (Section 7. 3 Data Supplement B...............3..... Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial......................... RCTs and Meta-analyses With Biomarkers (Section 6.. .....3..........................3) ........... Beta Blockers............   ............. the American Heart Association.................. Ferric Carboxymaltose................... sleep apnea.....

RCT. European Collaboration on Acute Decompensated Heart Failure. cardiac troponin I. cardiovascular disease. neutral endopeptidase. twice a day. MI. TSAT. diabetes mellitus. plasma B-type natriuretic peptide. HR. PVD. patients. Continuous positive airway pressure. intent to treat. and the Heart Failure Society of America. positive airway pressure. Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure. natriuretic peptide. quality of life. ischemic heart disease. systematic review. SCr. IQR. hazard ratio. Study Assessing the Morbidity–Mortality Benefits of the If Inhibitor Ivabradine in Patients with Coronary Artery Disease. EuroQoL five dimensions questionnaire. SBP. RR. intravenous. Vincent’s Screening to Prevent Heart Failure. STARBRITE. PCP. ProBNP Outpatient Tailored Chronic Heart Failure Therapy. FCM. EMPHASIS. renin-angiotensin system. LVEF. the Strategies for Tailoring Advanced Heart Failure Regimens in the Outpatient Setting. CI. mitral valve. SOB. odds ratio. high sensitivity C- reactive protein. maximal tolerated dose. HTN. interquartile range. emergency department. percutaneous coronary intervention. . Prospective Comparison of ARNI With ACE to Determine Impact on Global Mortality and Morbidity in Heart Failure. NT-proBNP Guided Primary Prevention of CV Events in Diabetic Patients. bpm. . valvular heart disease VT. FU. ROC. ejection fraction. STEMI. obstructive sleep apnea. myocardial infarction. minute walk test. DM. implantable cardioverter defibrillator. chronic heart disease. phosphodiesterase. MR-proANP. OSA. coronary artery bypass graft. . SPRINT. hypertension. CABG. relative risk. CRT. NT-proBNP. number needed to treat. QoL. Comparison of Vasopeptidase Inhibitor.. ST–elevation myocardial infarction. end-stage renal disease. LV. PAD. Systolic Blood Pressure Intervention Trial. Heart failure with reduced ejection fraction. Reduction of events by darbepoetin alfa in heart failure. UL. Hypertension in the Very Elderly Trial. DBP. Heart failure with preserved ejection fraction. PDE. chronic obstructive pulmonary disease. UPSTEP. Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure. VHD. diastolic blood pressure. diastolic blood pressure. GP. Systolic Heart Failure Treatment with the If Inhibitor Ivabradine Trial. . the Telmisartan Randomised Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease. Ferric carboxymaltose evaluation on performance in patients with iron deficiency in combination with chronic heart failure. LCZ. N-terminal pro-B-type natriuretic peptide. CKD. left ventricular end-diastolic dimension. and w/o. RAS. PEP-CHF. compared with. HDL. Survival of Patients with Acute Heart Failure in Need of Intravenous Inotropic Support. EF. OR. LVEDD. cardiovascular. body surface area. shortness of breath. cardiothoracic ratio . STOP-HF. . IV. left ventricular hypertrophy. Kansas City Cardiomyopathy Questionnaire. not available. contrast media. CM. peripheral artery disease. BNP. CVD. . LVD. OCTAVE. heart failure. transient ischemic attack. IHD. Diuretic Optimization Strategy Evaluation in Acute HF. CHARM. major adverse cardiac event. Omapatrilat. RAAS. guideline-directed evaluation and management. effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure. HFpEF. Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure With Preserved Ejection Fraction. TIME-CHF. cTnl. TOPCAT. HCM. MWT. ELAN-HF. Use of Peptides in Tailoring Heart Failure Project. creatinine. IDI. HEAAL study. VF. SSS. HF. MR-proADM. PARAMOUNT. C/W. CPAP. chronic kidney disease. integrated discrimination improvement. Systolic Heart Failure Treatment Supported by BNP. NNH. ferric carboxymaltose. history. NSTEMI. NYHA. CONFIRM-HF. PARADIGM-HF. ventricular fibrillation. renin-angiotensin- aldosterone system. 2 © 2017 American College of Cardiology Foundation. ED. BP. estimated glomerular filtration rate. patient global assessment. CHD. NNT. net reclassification improvement. left ventricular. ventricular tachycardia. left ventricular ejection fraction. The Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial. SR. baseline. PSG. PAP. Canadian Continuous Positive Airway Pressure for Patients with Central Sleep Apnea and Heart Failure Trial. Nitrate's Effect on Activity Tolerance in Heart Failure With Preserved Ejection Fraction. ITT. NEAT-HFpEF. systolic blood pressure. guideline-directed management and therapy. N/A. The Omapatrilat Cardiovascular Treatment vs. CV. Systolic Hypertension in the Elderly Program. non-ST-elevation myocardial infarction. KCCQ. SHIFT. and Lisinopril on Exercise Tolerance and Morbidity. PGA. ID. CTR. CVA. . receiver-operating characteristic. FAIR-HF. cGMP. CCB. BL. SUPPORT. . MRA. ECG. blood pressure. SURVIVE. Inc. SHEP. NS. TRANSCEND. high density lipoprotein. eGFR. beats per minute. PPM. h/o. permanent pacemaker. Adaptive Servo-Ventilation for Central Sleep Apnea in Systolic Heart Failure. MV. RELAX. ESRD. LVH. cerebrovascular accident. follow-up. CSA. SERVE-HF. Perindopril in Elderly People With Chronic Heart Failure. ONTARGET. BID. peripheral vascular disease. Hx. cardiac resynchronization therapy. HFrEF.2017 Heart Failure Focused Update Data Supplement    Left-Ventricular Dysfunction. PTCA. transferrin saturation. history of. IMPRESS. iron deficiency. NEP. NP. Prospective Comparison of ARNI With ARB on Management of Heart Failure With Preserved Ejection Fraction. NRI. DPB. GDEM. Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist. PONTIAC. OPTIMIZE-HF. Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity. ET. electrocardiography. DOSE-AHF. ICD. CAD. Irbesartan in Heart Failure with Preserved Ejection Fraction Study. Cr. BSA. TIA. Can Pro-Brain-Natriuretic Peptide Guided Therapy of Chronic Heart Failure Improve Heart Failure Morbidity and Mortality?. randomized controlled trial. PRIMA. the American Heart Association. Supplemental Benefit of ARB in Hypertensive Patients With Stable Heart Failure Using Olmesartan. Left ventricular dysfunction. hs-CRP. STARS-BNP. PROTECT. MACE. CONSENSUS Cooperative North Scandinavian Enalapril Survival Study. Ferinject Assessment in Patients with Iron Deficiency and Chronic Heart Failure. cyclic guanosine monophosphate. central sleep apnea. number needed to harm. RED-HF. nonsignificant. Enalapril. MTD. . I- PRESERVE. polysomnography. CANPAP. COPD. unstable angina. SIGNIFY. Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events. confidence interval. Primary Care Physician. pts. PCI. percutaneous transluminal coronary angioplasty. GDMT. OVERTURE. without. St. serum creatinine. EQ-5D. New York Heart Association. UA. calcium channel blockers. HYVET. mineralocorticoid receptor antagonists. coronary artery disease. sick sinus syndrome.

2013 To assess the Pts with type 2 DM. & Adverse Events (# patients) 95% CI) Biomarker Studies Pertinent to Stage A / B HF Patients PONTIAC Aim: Inclusion criteria: Intervention: 1 endpoint:  All-cause hospitalizations. infections or diabetes. Patient Population Study Intervention Endpoint Results Relevant 2 Endpoint (if any).127–0.60 OR. diabetes care units 1 Safety endpoint: antagonist/beta-blocker and the systemic cortisone  BP was significantly reduced dosage reached higher in Study type: RCT treatment. (150). Year Published Study Size (N) Study Comparator P values. Study Type.05). and the Heart Failure Society of America.81. population mainly Caucasian. Individualized up-titration of  Hospitalization or death due hospitalizations and unplanned CV (1) effectiveness of age ≥18 y. statistical analysis done without of Vienna with increased disease. pt cardiac events in Exclusion criteria: intervention group (HR: 0. heart rate  No difference in NT-proBNP levels Size: 300 therapy.2017 Heart Failure Focused Update Data Supplement      Data Supplement A. 22 (0. referral for BNP ≥50 pg/mL E/E′ ratio >15) with or CV investigations more likely to be care in at-risk hypercholesterolemi for echocardiography and without newly diagnosed done in the intervention group with ● Heartbeat Trust.3) Study Acronym. OR or RR. and history BNP screening at BL and  LV dysfunction (systolic: major MACE [40 vs.044) adjustment of co-variates ● Roche Pharma AG biomarker NT. elevated RAS antagonists and beta to cardiac disease following hospitalizations or death (p<0. RCTs and Meta-analyses With Biomarkers (Section 6. HF Huelsmann et al. Inc.45-0. renal in both intervention and intensified group (p<0. chronic “Control” group treated for p=0. (697) HF(with symptoms of HF BNP levels ≥50 pg/mL Health Research reducing newly disease including requiring admission to Increase in RAAS agents in the 3 © 2017 American College of Cardiology Foundation. 2013 To establish efficacy Pts ≥40 y. the American Heart Association.002)]] 23821090 and collaborative ≥1 mo). Aim of Study.. was only reduced in the nondiabetic intensified group (p=0. Author. vascular collaborative care. (# patients) / (Absolute Event Rates.0001) replacement control (p<0.  Results: Significant  Study limitations: Absence of pt prevention of treated at cardiology clinic reduction of 1 endpoint in randomization for treatment. (2) of BNP screening of HTN (on meds annually and protocol LVEF <50% or diastolic: 95% CI: . p=. . obesity. ● Medical University pts with type 2 DM Free of heart Comparator: 95% CI: 0.351.004) conditions that lowered life expectancy to <1 y and absence of reliable contraception in women of childbearing age STOP-HF Aim: Inclusion criteria: Intervention: 1 endpoint: Emergency hospitalizations for Ledwidge et al. population in a. Study Limitations.05 23810874 neurohumoral NT-proBNP (≥125 blockers in addition to 24 mo reduction) therapy for the pg/mL) diabetes treatment (150).975. treated at  Pts treated with a RAS proBNP malignancies.

Takeda. 95% CI: unaddressed and statistical tests proBNP trials aggregated data 0.55 OR. Size: study.78.02) are not powerful Don-Wauchope et al. hospital.2017 Heart Failure Focused Update Data Supplement    Board of the Irish diagnosed HF and CAD. 4 © 2017 American College of Cardiology Foundation.97.  The results might not be applicable Heartbeat Trust or moderate to to general population (single received unrestricted Study type: severe valvular center).67–0. Menarini.  Lesser HF admissions in treatment management aspects 2. Incremental value of and Abbott.7 %) vs. 95% CI: 0.” clinical practice. and prevalence of cerebrovascular Comparator: summary)  In the subgroup with BNP levels European significant LV disease or Usual 1 care (677)  59 (8. symptomatic HF. sample size for pts with HFpEF. Lack of specific guided therapy and  Lower mortality in HFrEF testing for diagnosis of Study type: Exclusion criteria: HFpEF (301) with guided treatment (HR: comorbidities.3%) ≥50 pg/mL. 2015 To assess which HF Studies that (NT-pro)BNP-guided therapy  All-cause mortality and harmful in HFpEF without HTN and (3) pts benefit from included individual and HFrEF (1.80.137 pts from 8 NT. 37 (5. STARBRITE p=0. arrhythmia therapy. 1° meta. Alere. absence of Meta-Analysis Pts with unknown 0. Cost-effectiveness Roche. Aim: Inclusion criteria: Intervention: 1 endpoint  Underlying SRs largely comprised 2015 Review evidence of SRs that authors NP-guided therapy  8 SRs assessed all-cause analysis of the same RCTs. EF ≤45% Comparator: (NT-pro)BNP. Event rate was lower than A.. Results: of aggregate data.003) of that in the control group Programme. diagnosis compromising survival Meta-Analyses or SRs of RCTs of NP Guided Therapy in Stage C HF Brunner-La Rocca et Aim: Inclusion criteria: Intervention: 1 endpoint:  NT pro BNP-guided treatment al. 0. the American Heart Association. . Size: Exclusion criteria: unclear. 95% CI: 0. p=0. 25448029 utility of NPs in through their Comparator: found there was a benefit. comorbidity index. p=0. RCT (unblinded) disease bias. participation in an Clinically-guided care  4 SRs examined all cause- AHRQ comparative hospitalization and did not Study type: effectiveness find decrease with NP- Review of SRs review. population studied.374 Established LV cut-off of BNP may change in and Servier. insufficient LVEF. Covidien.731) admission for HF in pts with renal failure 26419999 NT-pro BNP pt data HFpEF and  Limitations: Bias due to exclusion therapy HFrEF.82. expected. The dysfunction. (4) SRs regarding were aware of mortality and “generally  Results were qualitative. confirmed by d/c intervention group Government. systolic dysfunction.62–0. DM.03).. 1. analyses that HFrEF (HR: 0.97. non-blinding introduces grants from Pfizer. Inc.37– in the intervention group was ~1/2 Framework diastolic disease. and the Heart Failure Society of America. increase in BNP levels Commission systolic and /or peripheral vascular (0.

79.39) or all-cause hospitalization (RR: 0.63–0. BNP-guided therapy (1. guided treatment of comparing the effects hospitalization.03).90–4. risk of HF-related 3. p=0. the American Heart Association.94. all-cause weighted mean difference=2.69%. 95% CI: 0.80 24603309 guided treatment of comparing BNP.01). although did not significantly affect the risk of all-cause mortality (RR: 0. p=0.004 pts hospitalization (RR: 0.81–1. cause mortality and with clinically guided pts [HR: 0.004]  Each of the included RCTs was Meta-analysis trial) that did not relatively small and 2 trials did not 5 © 2017 American College of Cardiology Foundation.67–0. p=0.82 (0..89–1. Inc.99). p=0. p=0.86).80%.009] as were CV chronic HF on guided treatment of guided therapy (994)  All-cause mortality was admissions [HR: 0.94).97. et al. outcomes HF with clinically significantly reduced by NP. 95% CI: 0.2017 Heart Failure Focused Update Data Supplement    guided therapy Size: Exclusion criteria:  4 SRs assessed HF 9 reviews N/A hospitalization and “consistently” found a significant reduction with NP-guided therapy Xin W. 2015 Aim: Inclusion criteria: Intervention: 1 endpoints:  BNP-guided therapy improved (5) To assess the Prospective RCTs BNP or NT-proBNP-guided  All-cause mortality. chronic HF on of BNP or NT. 1 Safety endpoint:  NP-guided therapy was not associated with increased risk for serious adverse events. BNP-guided treatment significantly decreased the Size: 14 studies. p=0. compared (6) effects of NP. p=0.07.048] guided treatment and guided treatment [HR: 0. Troughton RW et al.501) NYHA class or QoLs (p=ns) therapy with clinically Results: Study type: guided therapy  Compared with clinical Meta-analysis group. and the Heart Failure Society of America.67–0. Comparator: Clinically (adverse events)  But did not significantly affect outcomes proBNP-guided guided therapy (1. 95% CI: 0.503) hospitalization.62 Study type: 1 study (PROTECT (0. . with adult HF pts therapy (1.006)  All-cause mortality in the NP-guided group. Comparator: Clinically Results: (0.56).98. Aim: Inclusion criteria: Intervention: 1 endpoint:  HF hospitalizations were reduced 2014 To assess the RCTs reporting all.08.45–0. safety 95% CI: 0. HF LV systolic function in HF pts (LVEF: 24888383 effects of NP.

data in pts <75 y [HR: 0. BNP/NT- Study type: proBNP cutpoint.503) wide variation in study guided treatment of heterogeneity. p=0. .026) 1. was found to be low due to inconsistency and 6 © 2017 American College of Cardiology Foundation. Inc. the American Heart Association.95.000 pts individual pt data) efficacy (p=0..028).45– from the 3rd (‘usual 0. p = 0. 2014 Aim: Inclusion criteria Intervention: 1 endpoint: Limitations: (7) To assess the  RCT to a strategy BNP or NT-proBNP-guided  Combined endpoint of all. design and how parameters chronic HF on Comparator: Clinically were reported including pt outcomes guided therapy (1. and SR outcome types. not included.3). and they HF hospitalizations (OR: 0.98 (0. 2014 Aim: Meta-analysis was Intervention: 1 Outcome: N/A (8) To assess the not done due to BNP or NT-proBNP-guided  Review: Overall. Size: 6 studies. and the Heart Failure Society of America. pts reported in 7 studies. study therapy (1. BL characteristics. of titrating drug therapy cause mortality and HF relatively small guided treatment of therapy based on hospitalization  Benefit was not seen in some of chronic HF on the level of a Comparator: Clinically the studies outcomes circulating NP (BNP guided therapy Results: NP-guided therapy or NT-proBNP) for outpatients with HF was Study type: compared to clinical shown to be associated with a Meta-analysis conventional decreased risk of death and criteria.75–1.43–0. 9 with between age and treatment 2. with a survival benefit for BNP- Exclusion criteria: guided vs. Should have included >60 pts and its follow-up should have been longer than 90 d. Balion et al. 2. studies. reported all-cause 95% CI: 0.64.  The strength of evidence for Size: 9 RCTs. therapy goals.  Each of the included RCTs was 24522083 effects of NP.62 (0. clinical treatment For 2 studies.85).104 the outcome of mortality.501) selection. p=ns] De Vecchis et al. Size: 11 studies.2017 Heart Failure Focused Update Data Supplement    report mortality (11  Significant interaction provide individual pt data.004] but not in pts care’) groups were ≥75 y [HR: 0.775 pts mortality. there was a 25074674 effects of NP.

2013 Aim: Inclusion criteria: Intervention: 1 endpoints  When separately assessed.084 cause mortality (OR: 0. 0. p=0. Meta-analysis guided therapy vs.53. Comparator: Clinically hospitalization 0.399–0.599. p=0.000.035. clinically guided hospitalization guided therapy NP-guided therapy (either but not all-cause hospitalization therapy.  All-cause mortality. 95% CI: 0. and HF drug therapy of the decreased risk of all-cause p=0.000) hospitalization pts with chronic HF mortality (RR: 0.5).003). and involved cause mortality and HF decreased in the pts <70 y (RR: guided treatment of comparison of BNP.69–0.465. p=0.913. 1.738.563–0.717. 95% CI: 0. therapy did not significantly reduce Study type: or NT-proBNP 95% CI: 0.99. all-cause proBNP-guided therapy reduced 23472172 whether NP-guided reporting clinical guided: 373 hospitalization.779. Li et al.077) in NT-proBNP p=0. Savarese et al.45.043).914. p=0. all-cause mortality (OR: 0. but not in older pts (>75 y) (OR: 0.554. 95% CI: 0.629–1.303–1.39–0.811.449.371).686 participants hospitalization (OR: 0. p=0.33–0.279.207– 0. Size: chronic HF pts reported in 3 trials.83.007) and proBNP) therapy. p=0.509 – 1.024. 95% CI:0. Inc. p=0.513.800. 2013 Aim: Inclusion criteria Intervention: 1 endpoint: In the subgroup analysis. endpoints (all. 95% CI: 0. HF all-cause mortality (OR: 0.956 95% CI: 0.973.769. (730 in BNP.531.14) or 12 trials enrolling p=0. HF a control group in ≤ or >75 y using data hospitalization (OR: 0. and HF 7 © 2017 American College of Cardiology Foundation. NT- (9) To determine All randomized trials  BNP-guided therapy: BNP.596–0. (BNP or NT. the American Heart Association. or chronic HF on all. cause mortality HF hospitalization (OR: 0. and the Heart Failure Society of America. improves and/or all-cause  BNP group control 357 BNP or NT-proBNP) (OR: 0.187. whereas BNP-guided comparison of BNP 1. p=0.000). but not all-cause all-cause hospitalization (OR: 2.  NT-proBNP guided: 872 hospitalization 95% CI:0. 95% CI: 0.61.077)  Analysis from 3 trials showed the related trials) composite outcome of all-cause mortality and HF hospitalization was significantly reduced by NP- guided therapy in younger pts (≤75 y) (OR: 0.803. compared to and/or HF related Comparator: Clinically Results: 95% CI: 0.518–1.414–1. HF (10) To assess the Studies with >40 pts BNP-guided therapy  Combined end point of all.726.035.423–1.438). rehospitalization was significantly 23602555 effects of NP. guided therapy with BL higher BNP (≥2114 pg/mL) cause mortality guideline-guided Results: Significantly (RR: 0. outcomes hospitalization) with  NT-proBNP group control significantly reduced all. . 95% CI: 0. related hospitalization (OR: 0.  Separate analyses on pts p=0.814.2017 Heart Failure Focused Update Data Supplement    imprecision. guided vs. 95% CI: in the outpatient 0.347–0. 0. CI:0. p=0. p=0.72.005) and HF related CI:0..

 Additional % pts achieving target doses of ACE-inhibitors and beta blockers 21% and 22% in the BNP group and 11.85–1.52.25.12 and RR: 1.64–1. and the Heart Failure Society of America. usual clinical care 95% CI: 0.33–0. guided therapy in pts ≥75 y (RR: vs.003) 0. CV outcomes in comparison of BNP.5% in the control group. 95% CI: 0. respectively).55–0. respectively. 2009 Aim: Inclusion criteria Intervention: 1 endpoint: N/A (11) To determine Prospective RCTs of BNP-guided therapy  All-cause mortality 19699866 whether titration of pts with chronic HF therapy based on NP randomized pts to a Comparator: Clinically Results: Significant mortality measurements strategy of titrating guided therapy advantage for biomarker- improves mortality in medical therapy guided therapy (HR: 0.07.05. in the BNP-guided therapy Size: 11 studies.58.627 pts Porapakkham et al. 95% CI: 0. Inc. chronic HF based on the level of 95% CI: 0. Study type: of the pt with chronic in the BNP-guided therapy  All-cause hospitalization and Meta-analysis HF in an outpatient group compared with the survival free of any hospitalization setting control group was not significantly different Size: 8 studies. cause mortality 1.726 pts CI: 0.2017 Heart Failure Focused Update Data Supplement    Study type: setting rehospitalization (RR: 0.63–0. guided therapy Significantly lower risk of all. between groups (RR: 0.70). Aim: Inclusion criteria Intervention: 1 endpoint:  In pts <75 y.7% and 12.82. RCTs of NP Guided Therapy in HF 8 © 2017 American College of Cardiology Foundation.62–0.75. . 95% 1.414 pts Felker et al. Meta-analysis 95% CI: 0.71–1. group.. 2.005). p=0.94. p=0. the American Heart Association.76.  No reduction in mortality with BNP- chronic HF guided drug therapy cause mortality (RR: 0. p=0. 95% CI: 20308637 therapy improves >20 pts and involved Comparator: Clinically Results: 0.004. p=0.91.34. all-cause mortality 2010 To determine Eligible RCTs were BNP-guided therapy  All-cause mortality was significantly lower in the BNP- (12) whether BNP guided those that enrolled guided group (RR: 0.91.69.82.86) a circulating compared to control Study type: biomarker compared Meta-analysis to a parallel control group. reporting all- Size: 6 studies. p=0. p=0.

50–0. class of II or greater.01). guided treatment. delayed time to first event outcomes Exclusion criteria: hospitals.92]. 2000 Aim: Inclusion criteria: Intervention: 1 endpoints:  Changes in LVEF. p=0.001). CV hospitalization function. 54. 62%. QoL. and the Heart Failure Society of America..034). y with systolic HF based treatments to BNP cause hospitalizations N-terminal BNP-guided group 19176440 terminal BNP.68 [95% CI: 0.02) Minimum 6 mo  At 6 mo. 2009 To compare 18-mo Ambulatory HF pts 60 Uptitration of guideline.05). LVEF <40% and with a target of NT-proBNP and outpatient HF event similar in both groups. and adverse events were 10791374 effects of NT. HF was higher among those in the (15) outcomes of N. NP guidance changed therapy Size: 69 pts Follow up : p=0. proBNP-guided symptomatic HF level  N-BNP-guided treatment of HF treatment of (NYHA II-IV) <200 pmol Results: reduced total CV events.2017 Heart Failure Focused Update Data Supplement    Troughton et al. renal (13) To assess the Ambulatory pts with (NT-pro)BNP-guided therapy  Death. TIME-CHF Aim: Inclusion criteria: Intervention: 1 endpoints:  Survival free of hospitalization for Pfisterer et al. or HF compared with intensive clinically Pts with unknown Comparator: Standardized decompensation) in the NT. (BNP-guided therapy) Results: 0. and chronic HF on  Fewer CV events (death. 2007 To evaluate the Ambulatory NYHA BNP-guided therapy  HF-related death or hospital  Unknown whether BNP-guided (14) prognostic impact class II to III pts Target : BNP <100 pg/mL stay for HF therapy resulted in reduction in 17448376 of a therapeutic considered Comparator: BNP levels strategy using optimally treated Medical treatment according Results: plasma BNP to either current guidelines  Mean dosages of ACE Exclusion criteria: (clinical group) inhibitors and beta blockers Study type: N/A significantly higher in the RCT BNP group (p<0. mainly obtained through an increase in ACE inhibitor and beta blocker dosages. symptom guided prior HF  N-terminal BNP and  N-terminal BNP-guided therapy HF therapy hospitalization within Targets: 9 © 2017 American College of Cardiology Foundation.5 mo) BNP group and 53% in the clinical group had experienced a first CV event (p=0. 52%. (LVEF ≤45%). Inc. STARS-BNP Aim: Inclusion criteria: Intervention: 1 endpoint  NP guidance changed therapy Jourdain et al. the American Heart Association. Study type: RCT LVEF clinical assessment proBNP group than in the  NP was reduced significantly and (clinical group) clinical group (19 vs. 27% of pts in the (median 9. .  18 mo survival free of all. Follow up : median  BNP-guided strategy Size: 15 mo reduced the risk of HF 220 pts related death or hospital stay for HF (24% vs. respectively. HR: guided vs. NYHA level of ≤2 times of UL (72% vs. p<0.

NT-proBNP levels Results: compared with either clinically therapy with those >50 pmoL/l or 400 Target: NT-proBNP 1-y mortality was less in both managed treatment (30.048) or usual care (31. admission. 2009 to compare the Pts admitted to a Outpatient post d/c therapy Mortality reduced in pts ≤75 y receiving (16) effects of NT.9%. Results: highest proportion of RAAS proBNP-guided.2017 Heart Failure Focused Update Data Supplement    1 y. and the Heart Failure Society of America.1%) p=0.0001) with the usual care group (39%.9%. HR: 0..72–1. p=0.  QoL improvements were similar in Size: Comparator: 40%. but was lower compared outcome in pts groups (p<0. intensive up-titration of  Pt management reduced HF inhibition triple-therapy intensive pt Cardiothoracic medication by HF hospitalization (488 D)  Death rate was similar between management to Index>0. following Comparators  Combined end point of pt management: p<0. and N-terminal NT-proBNP <400 pg/mL if symptom-guided therapy improved outcomes in pts 60 to 75 Study type: BNP level of ≥2 times age <75 y. 2010 Aim: Inclusion criteria: Intervention: 1 endpoints:  NT-ProBNP levels were not (17) To investigate Pts admitted to a Outpatient post discharge Hospitalization different between groups: Pt 20170790 whether the hospital with HF. hospitalization due  Multidisciplinary care: 2 death or HF multidisciplinary care: p<0.03)  NT-ProBNP levels were not Study Type: clinical management. p=0.(included <150 pmoL/l (1. or different between groups RCT (Australia according to usual care hospitals) Size: 364 pts Berger et al.5%) 20117364 proBNP)-guided HF. of intensive clinical pg/mL.02) to HF consultations from an HF rehospitalization was lower 10 © 2017 American College of Cardiology Foundation. [95% CI: 0.200 pg/mL) D) and usual care (1. ARB.91 both the N-terminal BNP-guided 499 pts Uptitration of guideline. Beta guided therapy) blockers and higher use of spironolactone)  NT-ProBNP levels were not different between groups BATTLESCARRED Aim: Inclusion criteria: Intervention: 1 endpoints:  3 y mortality was selectively Lainchbury et al.02 for interaction). management and HFpEF) clinically-guided (9. hospitalizations (41% vs. the American Heart Association.02.021). Inc. vs. respectively.39) and symptom guided strategies based treatments to reduce  BNP guidance changed symptoms to NYHA class therapy (higher doses of of II or less (symptom ACE inhibitors.588 d) (22%).1%) and p=0. single hospital with guided by NT-proBNP hormone guided treatment (15. normal.270 pg/mL) the hormone (9. NYHA III or IV on  BM: NT-proBNP-guided. NT-proBNP resulted in similar rates of y of age but not in those ≥75 y of RCT the upper limit of <800 pg/mL if 75 y survival free of all-cause age (p<0. vs.14]. .5 or LVEF specialists in high-risk pts. compared with the the pt management (22%) and multidisciplinary <40%  Target: NT-proBNP multidisciplinary care (1254 multidisciplinary care groups care improves (<2.3%. with usual care Comparators: groups compared with usual  NP guidance changed therapy Therapy guided by intensive care (18. discontinue management group had the addition of NT.

by an individually set NT. or symptom score. as 46 pts died (18) management by an with for out pt management guided hospital after index (26.28) or its components (CV) death. 2010 To investigate if NT. 2010 To assess whether Hospitalized HF pts After discharge discontinue Number of d alive outside the mortality was lower. Study Type: p=0.2017 Heart Failure Focused Update Data Supplement    specialist-therapeutic in the BM (37%) than in the Study Type: RCT (8 recommendations and multidisciplinary care group Viennese home care by a HF nurse (50%.05) and in the hospitals)  Usual care multidisciplinary care than in the usual care group (65%.49) medication (p=0.04)  NT-ProBNP levels were lowered in guided pt management arm PRIMA Aim: Inclusion criteria: Intervention: 1 endpoints:  In the NT-proBNP-guided group Eurlings et al.5%) vs.88. and RAS blockers were markedly (19) proBNP-guided NYHA class II-IV. significantly improve the 1 increased the use of HF management (included HFpEF) endpoint p=0. .. RCT (Sweden 1 p=0. the American Heart Association.700 pg/mL discharge or 2 wk proBNP target did not  Individualized NT-proBNP target compared with HF at admission thereafter.006) guided by clinical Comparators: assessment alone Clinically-guided outpatient management (n=171) Study Type: RCT Size: 345 pts SIGNAL HF Trial Aim: Inclusion criteria: Intervention: 1 endpoints:  Treatment doses of beta blockers Persson et al. p<0. decompensated. but this proBNP target symptomatic HF proBNP (n=174) defined by Results: was not statistically significant would lead to with NT-proBNP the lowest level at Management guided by NT. according to guidelines d out of hospital and increased towards target doses a 20876734 therapy in HF pts LVEF <50% and with or without NT-proBNP symptom score similar degree in both groups in 1 care would NT-proBNP levels monitoring improve clinical males >800. Size: 278 pts p=0.93. Results: outcomes over and females >1. and the Heart Failure Society of America. clinically guided group. care centers) p=0.3%) in the 21144969 individualized NT. CV hospitalization. Inc. 57 (33.000 ng/  Target: At least a 50% There were no differences above treatment reduction from BL NT.21) improved outcome levels >1.28 11 © 2017 American College of Cardiology Foundation. (p=0. between the groups according to proBNP concerning either the 1 guidelines endpoint (p=0. Ambulatory HF pts Structured treatment of HF Composite endpoint of d alive.

LVEF goal <150 or 300 ng/L for worsening/hosp for HF  Subgroup analysis: improved 21715446 guided HF <40% and elevated elderly survival (p<0. Inc. and the Heart Failure Society of America. Total CV events in 2 age indices of LV volume with guided (21) benefit from NP. . LV systolic proBNP with a goal to categories 75 and ≥75 y approach 22858078 guided HF care dysfunction lower NT-proBNP ≤1000  NP guidance changed therapy: pg/mL over 10 mo Results: greater use of aldosterone Study Type: Pts ≥75 y with NT-proBNP antagonists and lesser use of loop Single center RCT Comparator: management had lowest diuretics in the guided therapy Standard of care rate of CV events (1.18) vs. the American Heart Association.  BNP strategy pts received 21807321 management assessment guided significantly more ACE inhibitors.71 events per pt with NT-proBNP guide. 95% CI: 0. guided by BNP and Exclusion criteria: therapy Results: beta blockers clinical assessment Serum creatinine No significant difference HR: better compared >3..27. treatment 12 © 2017 American College of Cardiology Foundation.76 group (no difference in ACE Size: events per pt with standard inhibitors or beta blockers) 151 of care vs.41–1. nonresponders. 2011 To determine Ambulatory HF BNP-guided (BNP) with a Combined death and and younger vs. NYHA II-IV. p=0. 0. LVEF. or Shah et al. (22) whether BNP.2017 Heart Failure Focused Update Data Supplement    Size: 252 pts STARBRITE Trial Aim: Inclusion criteria Intervention: 1 endpoints:  Change in serum creatinine. with clinical Clinical assessment alone.25 assessment alone Study Type: Multicenter (3) RCT Size: 130 PROTECT Study Aim: Inclusion criteria Intervention: 1 endpoints:  Improvement in QoL. 2011 Whether outpatient Hospitalized HF pts Outpatient post discharge Composite endpoint of d alive change in SBP not different (20) diuretic with LEVF ≤35% BNP and clinical and d out of hospital. and Gaggin et al. Karlstrom et al.0001 for the 1 treatment improves BNP levels Results: outcome) among responders with morbidity and/or Comparator: No significant differences 1 >30% decrease in BL BNP value mortality Conventional (CTR) HF outcome (p=0. p=0.72. 2012 Whether elders Chronic HF pts with Management guided by NT. elderly.03) UPSTEP-study group Aim: Inclusion criteria Intervention: 1 endpoints:  No differences for d out of hospital.5 mg/dL and ACS Comparator: 0.

Aim: Inclusion criteria: Intervention: 1 endpoint: Adding specific clinical information 2006 To analyze the role Acutely dyspneic pts Comparisons of NT-pro. and subjects with gray. measurements of blinded. unstable angina. Subjects with HF and to NT-pro-BNP improves (24) of NT-pro-BNP in BNP among diagnostic diagnostically elevated NT.4%. . myocardial disease.. NT-pro-BNP concentrations less characteristics. angina. the so. and irrespective of their final than the gray zone 60-d mortality were diagnoses. those with power to other clinical Size: 1. concentrations diagnostic for HF concentrations. and the Heart Failure Society of America. Inc. rapid 12124404 characterize the emergency among diagnostic groups a cutoff of 100 pg/mL was measurement of BNP is useful in use of BNP in the department with including HF and non HF 83. studied in acutely dyspneic pts from an international 13 © 2017 American College of Cardiology Foundation. unstable rates. 2002 Aim: Inclusion criteria: Intervention: 1 endpoint: Used in conjunction with other (23) To validate and Pts who came to the Comparisons of BNP values Diagnostic accuracy of BNP at clinical information. with acute dyspnea Age <18 y and Non-HF pts such as Secondary endpoint : Study type: those whose pulmonary disease. Mortality rates in dyspnea.2017 Heart Failure Focused Update Data Supplement    Study Type: Multicenter RCT- probe design Size: 279 Maisel et al. The negative establishing or excluding the diagnosis of HF in acute dyspnea pts predictive value of BNP <50 diagnosis of acute HF failure in pts pts with dyspnea Exclusion criteria:  Comparator: pg/mL was 96%.. diagnostic accuracy in subjects 16860029 diagnosis of HF in Exclusion criteria: groups including HF and pro-BNP concentrations had with intermediate NT-pro-BNP pts presenting with With trauma or non-HF pts the highest mortality rates. concentrations. acute such as pulmonary pro-BNP concentrations < 300 BNP concentrations are lower than peptide gray zone. dyspnea was pulmonale analysis. diagnostic clearly not BNP added significant accuracy study secondary to HF independent predictive (i. subjects with intermediate NT-pro- called natriuretic tamponade). cor In multiple logistic-regression Prospective. or renal zone NT-pro-BNP had but are higher than in subjects with clinical failure intermediate outcomes. acute predicting which pts had HF myocardial infarction.e. or renal failure van Kimmenade et al. cardiac Comparator: Non-HF pts subjects without HF and NT. cor pulmonale ng/L had the lowest mortality in those with NT-pro-BNP NT-pro-BNP infarction.856 trauma or cardiac variables in models tamponade). the American Heart Association.

per advanced symptoms (not the during inotrope use 20 mg/dL increase (HR: general population of acute HF) hospitalization in 1. and the Heart Failure Society of America. Current MI or ACS outcomes admitted with BNP <200 data will help further refine prospective. BUN.2017 Heart Failure Focused Update Data Supplement    multicenter study Study type: Prospective. or Size: 464 pts with a baseline BNP concentration of ≤100 pg/mL were excluded O'Connor et al. with ST-segment pg/mL and >200 pg/mL was biomarker-guided outpatient blinded. cardiac arrest or Limitations: ESCAPE represented modeling using creatinine >3. LVEF rehospitalization rates (64%) 5% (score=0) to 94% (score=8). SBP 125 Validation cohort: FIRST Multivariate discharge  Bootstrap validation demonstrated mmHg. the American Heart Association. . Inc. Emerging clinical Multicenter. per unit managed at experienced centers.006). requiring dialysis. The 90-d outcomes and thus may aid outcomes admission for HF Comparison between combined event rate (HF physicians in making triage were included. 9% and 29%. diagnostic deviation of ≥1 mm. pts with severe LV dysfunction and variables obtained mg/dL. discharge 30%. there is a disconnect between 15364340 relationships y presenting to the the actual BNP level and or discharge a pt had no the perceived severity of HF by ED among BNP levels ED with HF and subsequent BNP influence on 90-d outcomes. 2010 Aim: Inclusion criteria: Derivation cohort: 1 endpoint:  A simplified discharge score (26) To identify high-risk hospitalized with ESCPAPE trial.5 mechanical ventilation. the ESCAPE trial mEq/L increase (HR: 0. The clinical decision treatment in the ED strong predictor of 90-d BNP levels can predict future making. diagnostic accuracy study Size: 1. 2004 Aim: Inclusion criteria: Intervention: 1 endpoint:  In pts presenting to the ED with (25) To examine the Pts over the age of 18 Physicians were blinded to ED doctor's intention to admit HF. n=471 predictors of death included: good internal validation for the Study type: BNP. strategies involving BNP. n=423 6-mo mortality and death or discriminated mortality risk from 20185037 HF pts at hospital severe HF. per doubling (HR: model (c-index 0. physicians and severity as and HF severity. while the BNP level was a determined by BNP levels. trial.93) exclusion of pts with characteristics 14 © 2017 American College of Cardiology Foundation..42). prior yes/no (HR: 2. and or hospital Comparator: outcome.22) and sodium. who received measurements.256 Maisel et al. severity of HF determined visits or admissions and decisions about whether to admit Study type: Exclusion criteria: by physicians or BNP and mortality) in the group of pts or discharge pts. blinded. respectively therapeutic and monitoring accuracy study renal failure (p=0.54).78) Predictive Exclusion criteria: 1.

04) for the composite endpoint (death or readmission). 15 © 2017 American College of Cardiology Foundation. p=0. the American Heart Association.12–17.4. OR or RR & 95 % CI) Study Size (N) Bayés-Genís et al. creatinine >3. Summary / Conclusion / Comments Year Published Study Type.63 (95% CI: 0. 2008 Aim: Inclusion criteria: 1 endpoint  NT-ProBNP reduction percentage (28) To evaluate the Pts consecutively admitted  Percent reduction in NT-proBNP and its <30% was the best cut off for the 18545069 prognostic significance with ADHF association with CV mortality identification of pts of NT-proBNP % reduction during ADHF Follow up: 6 mo Results:  Study relatively old and small  In ROC. last 5 years. and the Heart Failure Society of America. Nonrandomized Trials/ Observational Studies/ Registries for Changes in or Discharge NP Levels in ADHF – Biomarkers (Section 6.51–0. Patient Population Primary Endpoint and Results (P values.81 (95% CI: 0. Aim of Study. Study type: NR Follow up :12 mo 0. Prospective cohort p=0. Last search done on April 18. human. 2005 Aim: Inclusion criteria: 1 endpoints:  30% NT-proBNP reduction (27) Percentage of NT.75.3) Study Acronym.90. CV death in multivariate analysis proBNP reduction to predict CV death was (OR: 4.01) for CV mortality at risk of 120 pts events.. requiring inotropes) Search Terms and Date: natriuretic peptides.5 mg/dL. heart failure.2017 Heart Failure Focused Update Data Supplement    known to be associated with worse Size: 423 outcomes (e.002) p=0. and 0.65– Size: 0. Author. 95% CI: 1.03). 2016. Inc.4. Data Supplement B.66–0. the mean AUC for NT-ProBNP % Study type: reduction was 0.97. Prospective cohort  Study relatively old and small Size: 74 pts Verdiani et al. p=0.. . Pts diagnosed with acute HF  Percent reduction in NT-proBNP and its percentage cutoff value had 75% 15948093 proBNP reduction in emergency department association with CV mortality accuracy for the identification of during admission and and who had follow-up high-risk pts and was the only its prognostic evaluation for 6 & 12 mo Results: variable that was associated with significance after admission  The area under the ROC curve for % NT.78 (95% CI: 0.g.

2004 Aim: Inclusion criteria: 1 endpoints:  Pts demonstrating a ≥30% increase (29) To compare 18 mo Consecutive ADHF pts  Death or readmission in NT-proBNP levels during the 15451800 outcomes of NT-BNP.18 for change <30%.04). p<0. 2013 Aim: Inclusion criteria: 1 endpoints:  Favorable changes in each of (30) Examine relationship Pts enrolled in DOSE-AHF  Time to death. only % reduction in NT- Study type: proBNP was significantly associated with retrospective analysis symptom relief (r=0. symptom Framingham criteria Results: most adverse prognosis guided HF therapy  Pts were classified into 3 groups: (1) Follow up: 6 mo decreasing NT-proBNP levels by at least 30%  Study relatively old and small Study type: Prospective (n=82).2017 Heart Failure Focused Update Data Supplement    Bettencourt et al.04. 95% CI: 0.99 per Size: 308 pts 10% reduction).5%.34. Size: 182 pts  Among the 64 pts discharged without volume overload.95. 95% CI: 0. a positive association between change in NT-proBNP and outcome was observed (HR: 2.49 – 52.77–9. 95% CI: 1.40) and 1 y death or mortality: NRI: 5. (2) no significant modifications on NT- cohort single center proBNP levels (n=49).66.. first rehospitalization or the 3 markers of decongestion 23250981 between markers of emergency department visit were associated with decongestion and improvement in time to death. hospitals in OPTIMIZE-HF characteristic for predicting 1 y mortality reclassification and discrimination in or change from to Medicare claims (HR for log transformation: 1.28–1. 1-y mortality or measure is the most 1. p=0. and the Heart Failure Society of America. and (3) increasing NT- study proBNP levels by at least 30% (n=25). IDI: discharge BNP Follow up: 1 y rehospitalization (HR: 1. department visit at 60 d proBNP reduction.15.023. or emergency clinical outcomes  Of the weight loss.12– 0.0001.  Reduction in NT-proBNP AHF Associated with better outcome (NT- proBNP HR: 0.2%. p<0. discharge. p<0. Inc. (31) To examine if Linked pts ≥65 y of age from performance and was the most important discharge BNP model improved risk 21743005 admission. the American Heart Association. important predictor of p<0.02 for increase ≥30% compared with those with decreasing NT-proBNP by at least 30% Kociol et al.0001) long-term outcomes 16 © 2017 American College of Cardiology Foundation.18).0001. 95% CI: predicting each outcome (1 y admission to 1.0001. fluid loss. .13. defined by ESC or course of their admission had the guided vs. 95% CI: 9. rehospitalization: NRI: 4. of the RCT. IDI: 0.010. HR: 16. DOSE. Kociol et al.91–0. symptom relief and Follow up: 60 d Results: rehospitalization. and NT. 2011 Aim: Inclusion criteria:  The discharge BNP had the best  Compared with a clinical variables.

generates a relatively discharge BNP alive. and smaller percent important predictor of Follow up: change in BNP from admission to outcomes 30 d discharge. 0. discharge.039 pts Flint KM et al. and the Heart Failure Society of America. discharge. 1 diagnosis of HF in the [p<0.. 95% CI: 0. cohorts with pts admitted cause mortality and/or first readmission for proBNP values as well as the 24179162 or change from because of clinically CV reason within 180 d after discharge change in NT-proBNP to known risk admission to validated ADHF. and NT-proBNP Results: simple yet robust discharge risk measure is the most measurements available at  NT-proBNP levels at discharge and the score that importantly improves the important predictor of admission and at discharge changes in NT-proBNP during prediction of adverse events outcomes hospitalization yielded the best C-statistic Follow up: 180 d (AUC: 0. 2014 To examine if Pts from 7 prospective All-cause mortality and a composite of all. the American Heart Association. 9% [p<0. NRI.000 ng/L had Retrospective analysis an unadjusted 30 d HF readmission rate from VA database over 3 times as high as pts whose discharge BNP was ≤200 ng/L (15% vs. Size: 109. discharged markers.875 pts 4.639–0. Study type: Individual pt data meta- analyses of prospective cohort studies Size: 1.2017 Heart Failure Focused Update Data Supplement    Study type: Retrospective analysis –from OPTIMIZE HF Trial Size: 7.1%). 2014 Aim: Inclusion criteria: 1 endpoints:  Discharge BNP had the greatest (32) To examine if All hospital discharges with a  30 d readmission rate for HF effect (C-statistic.82).78.74–0. addition of the discharge NT- (33) admission. elevated measure is the most discharge BNP.0001]. ELAN-HF Score Aim: Inclusion criteria: 1 endpoints:  In pts hospitalized for ADHF. or change from Veterans Affairs Health Results: admission to Care System from 2006 to 30 d HF readmission was associated with  Large sample size discharge BNP 2009.664 24922626 admission. . Study type:  Pts with a discharge BNP ≥1. elevated admission BNP. the Salah et al.301 pts 17 © 2017 American College of Cardiology Foundation. Inc.0001]).

whereas long-term (180-d) all-cause mortality risk reduction was 47% Size: 1. Inc. the American Heart Association. p=0.027  Study relatively old and small Size: 105 pts O'Brien et al.80) echocardiographic parameters and and remained the lone significant variable in more relevant than changes in BNP Study type: multivariate analysis (HR: 1.2017 Heart Failure Focused Update Data Supplement    Cohen-Solal et al. p=0.71 18 © 2017 American College of Cardiology Foundation. independent marker of 14975475 of BNP predicting were performed from death or readmission after post-discharge admission to discharge in 2 Results: decompensated HF. and the Heart Failure Society of America.30. for ADHF had reduced mortality 19539144 decreases in BNP analysis included 1. ..4–168.038 who cause mortality and/or first readmission for risks (31. 2003 Aim: Inclusion criteria: 1 endpoints:  Plasma NT-proBNP measured pre- (36) To determine the value NT-proBNP was measured at Combined death or HF discharge provides useful 12921811 of BNP predicting admission in 96 pts prognostic information following post-discharge hospitalized with acute LVF Results: hospitalization with acute LVF.79 cf 0. 95% CI: levels during acute cares Prospective cohort 1.14.327 SURVIVE pts.02–1.70) or HF as an outpatient (0. The AUC ROC curve for pre- Prospective cohort discharge NT-proBNP was superior to that for admission NT-proBNP for prediction of Size: death or HF (AUC ROC 0.66).9].and 180-d) compared to levels during the first had BNP samples at both CV reason within 180 d after discharge those with little or no BNP decrease few d of hospitalization BL and d 5 were associated with Results: greater survival in pts  A pt was classified as a "responder" if the with ADHF Follow up: 180 d follow-up BNP level was ≥30% lower than BL BNP Study type:  Short-term 30 d mortality risk reduction was Retrospective analysis 67% in d 5 BNP responders compared with of SURVIVE nonresponders. more relevant outcome of pts samples of consecutive pts The predischarge BNP assay had the best than common clinical or admitted for ADHF discriminative power (AUC for ROC=0.78 cf 0. LVF hospitalization (0.026) was  Study relatively old and small independently predictive of the composite Study type: endpoint. 95% CI: 1. 2009 Aim: Inclusion criteria: 1 endpoints:  Pts with lowered BNP on treatment (34) Examine whether Of 1. this All-cause mortality and a composite of all. outcome of pts Only pre-discharge plasma NT-proBNP (OR: admitted for ADHF Follow up: 180 d 15. for 96 pts death (0. 2004 Aim: Inclusion criteria: 1 endpoints:  High predischarge BNP assay is a (35) To determine the value Serial BNP measurements Combined death or first re-admission for HF strong.70).87 cf 0.327 pts Logeart et al.28.

primary preserved cardiac and renal function. NYHA clinic population  This phenotype (HF with non- Size: 558  class I-III.7) and HF sinus syndrome. nonischemic etiology. CKD..2017 Heart Failure Focused Update Data Supplement    cf 0. . 2003 Study type: Inclusion criteria: 1 endpoint:  A sizeable minority (21%) of (38) Retrospective. EF<45%.  Associations persist in multivariable treatment with beta-blocker. the American Heart Association. CI 2–10.5) degree heart block. BP<90 or >160/100. CI 1. Inc. 2001 Study type: Inclusion criteria: 1 endpoint:  NT-proBNP and adrenomedullin (37) Observational study Ischemic CM. 2008 Study type: Inclusion criteria: 1 endpoint:  NT-proBNP testing can help with (39) Review paper regarding Studies using NT-proBNP N/A the diagnosis and triage of the 18243855 utility of NT-proBNP assays used commercially patients with acute dyspnea. gender. stable medical characteristics of a BNP<100 pg/mL in a HF have a BNP <100 pg/mL therapy. mortality (HR: 4.CI 1.7.7. sick risk of mortality (HR 3. Chronic systolic HF >3 mo Prevalence. female Congenital heart disease. followed in diagnostic BNP) is associated with outpatient HF clinic at a Results: identifiable clinical characteristics single center who had BNP  21% of symptomatic HF pts had BNP <100 obtained at clinic visit pg/mL  Characteristics associated with this Exclusion criteria: phenotype include younger age. less valvular disease.9. and ambulatory pts with chronic HF 14662703  observational duration. clinical characteristics.  Above median adrenomedullin increased hepatic/renal disease. IDDM. NYHA adrenomdeullin with mortality and HF with outcome in pts with heart trial II-III or prior II--IV events at 18 mo failure from an ischemic cardiomyopathy Size: Exclusion criteria: Results: 297   Current NYHA IV. active have atrial fibrillation ischemia requiring urgent revascularization Januzzi et al. LVEF<50%.” testing for diagnosis or Results: exclusion of HF in pts Exclusion criteria:  NT-proBNP had comparable with acute HF N/A sensitivity/specificity to BNP for diagnosis of acute HF in dyspneic pts Size:  NT-proBNP testing may be superior to N/A 19 © 2017 American College of Cardiology Foundation. HR<50  Above median proBNP increased risk of bpm.3-4. modeling  beta-agonist or verapamil Tang et al. 2nd or 3rd admission (HR 2.8-8. Association of plasma N-BNP and levels are independently associated 11401111 within a randomized chronic stable CHF.61 Richards et al.9) and HF coronary event/procedure admission (HR: 4. and the Heart Failure Society of America. CI: 2–10) last 4 weeks.4. better cardiac transplant.

specificity 67% (50–80%)  Both BNP and NT-proBNP performed well to rule out. 2005 Study type: Inclusion criteria: 1 endpoint:  2 of 5 sites withdrew after recruiting (42) Diagnostic accuracy Pts with new symptoms Sensitivity. for the diagnosis of  Studies with pts who had heart failure among patients conditions that may impact presenting to the ED or urgent care NP levels (transplant. 25 NT. PPV.  English language articles 97%). specificity 67% (58–75%) of evidence for specificity rated as proBNP alone. 2014 Study type: Inclusion criteria: 1 endpoint:  Both BNP and NT-proBNP had high (41) Systematic review  Age >18 y presenting to ED Test performance characteristics sensitivity but low specificity 24957908 or urgent care center with  Overall strength of evidence for Size: signs/symptoms suggestive Results: sensitivity and all decision cutpoints 76 publications included acute HF BNP pooled sensitivity=95%. HCM.. centers. . AUC 18 and 14 pts 15921792 study (observational) suggestive of HF referred for diagnosis of HF  Both BNP and NT-proBNP are by GP to rapid access HF useful for ruling out HF in pts Size: clinics at 5 centers in UK Results: presenting to PCP with possible HF 306 pts between 201 and 2003  104 (34%) of pts had HF symptoms 20 © 2017 American College of Cardiology Foundation. valvular) Zaphiriou et al. but less Exclusion criteria: well to rule in. LR. Inc. the American Heart Association. both)  FDA-approved assays CI: 88–93). strength (37 BNP alone. 95% CI: 93– for both peptides was high. 2014 Study type: Inclusion criteria: 1 endpoint:  Clinical heterogeneity precluded (40) Systematic review Study assessing incremental BNP or NT-proBNP improved prognostic formal meta-analysis 25052418 value of BNP or NT-proBNP model performance for mortality as Size: for predicting morbidity and assessed by discrimination and or likelihood 7 publications included mortality in acute statistics decompensated HF Results: Exclusion criteria:  5 BNP publications consistently predicted Studies of stable HF. all-cause mortality in short (3–6 mo) and natriuretic peptide could not long (9. and the Heart Failure Society of America.12 mo) beyond base model but not be included in base model all statistically significant to allow assessment of  Two NT-proBNP publications both showed incremental value incremental value at 22 mo and 6.8 y with 1 being statistically significant Hill et al. specificity. NPV. 14 from 1989-2012  NT-proBNP pooled sensitivity 91% (95% moderate.2017 Heart Failure Focused Update Data Supplement    clinical assessment in diagnosing HF Santaguida et al.

2012 Study type: Inclusion criteria: 1 endpoint: HF diagnosis  NT-proBNP identified as a critical (43) Observational.79–0.97. respectively)  Tests have better sensitivity than Exclusion criteria:  NT-proBNP pooled sensitivity (lowest specificity Studies with subjects with: cutpoint 0. PPV: 0.44 Son et al.84 (95% CI: 0.85 (0. Inc.83  C-statistic with proBNP =0. Nt- None listed proBNP 0.86. optimal 0.89).5. 0.8. 0.2017 Heart Failure Focused Update Data Supplement    Exclusion criteria:  AUC BNP 0. optimal 0.. manufacturer  Authors felt that it was unlikely that  Age <18 y 0. PPV: 0. established HF Acute HF requiring immediate therapeutic intervention Booth et al.59  NT-proBNP NPV: 0.9)  BNP: NPV: 0. and the Heart Failure Society of America. the American Heart Association. Results: in pts with dyspnea presenting to using rough set and Noncardiac control) NT-proBNP was one of 6 variables identified ED decision tree  Complete medical records in decision-tree rough set and one of 4 approaches variables in logistic regression model Exclusion criteria: Size:  HF excluded if other 159 subjects (71 HF. manufacturer 0.81–0. 20 presentation  BNP pooled sensitivity (lowest cutpoint signs/symptoms of HF or at risk of NT-proBNP  Primary care setting 0. 88 diagnosis made control) Kelder et al.87.58.85.54. 2014 Study type: Inclusion criteria: 1 endpoint:  Both BNP and NT-proBNP have (45) Systematic review  Pts presenting with signs or Diagnostic accuracy of BNP or NT-proBNP good diagnostic utility for 24969534 symptoms of HF or were at diagnosing HF in the primary care Size: risk of HF a time of Results: setting in those with 12 BNP publications. further studies will change these  Acute HF respectively) conclusions  Known exacerbation of chronic stable HF 21 © 2017 American College of Cardiology Foundation. .58.90.82) and specificity (0.58. 0. Pts presenting with Diagnosis of HF history and physical for diagnosing 22104551 diagnostic accuracy signs/symptoms of HF who HF among primary care outpatients (observational) were referred to 1 of 8 rapid Results: presenting with signs/symptoms of access clinics in the  207/721 (29%) had HF HF Size: 721 subjects Netherlands  C-statistic without proBNP =0.74) and developing HF publications specificity (0. 0.86 Exclusion criteria: NRI 69% Known. 2011 Study type: Inclusion criteria: 1 endpoint:  NT-proBNP had utility beyond the (44) Cross-sectional.5.  ED presentation for variable for decision making of HF 22564550 decision making model dyspnea (HF vs.

2017 Heart Failure Focused Update Data Supplement     Conditions that may interfere with NP levels (heart transplant. BNP pts admitted for decompensated HF Observational discharge concentrations were strong predictors of subsequent readmission (area Size: 72 under the receiver operator curve of 0.73). p<0. Cheng et al. ECG Davis et al. measurement and subsequent death and strong predictors for mortality and admitted with measuring daily BNP levels 30-d readmission early readmission. and the Heart Failure Society of America. independent 18178412 prognostic value of April 2003 to December were associated with significantly increased predictors of in-hospital mortality in 22 © 2017 American College of Cardiology Foundation. valvular lesion) Dao et al.7. 2001 Aim: Inclusion criteria: 1 endpoint:  In pts admitted with (48) To determine if BNP Pts admitted with Association between initial BNP and the decompensated HF.88 presentation was HF  BNP remained independently associated with HF diagnosis in multivariable model beyond H+P. changes in 11216951 levels predict decompensated NYHA predischarge or premoribund BNP BNP levels during treatment are outcomes of pts class III to IV HF. SOB as prominent complaint Diagnostic utility of point-of-care BNP for diagnosis in the urgent care setting 11216950 convenience sample diagnosis of HF at 1 VA urgent care Exclusion criteria: center  Dyspnea clearly not from Results: HF  BNP C-statistic =0.98 Size: 250  ACS (unless predominant  Treating physician C statistic =0. Fonarow et al.59. p<0.. Inc. 1994 Aim: Inclusion criteria: 1 endpoint:  One of the original studies that (47) Assessed value of ANP Suspected HF among Strong negative correlations between LVEF showed that plasma BNP was 7905953 and BNP in pts elderly pts presenting with and log BNP (r=-0. HCM. 2001 Study type: Inclusion criteria: 1 endpoint:  BNP had diagnostic utility for HF (46) Observational. xray. decompensated HF  BNP levels might be used Exclusion criteria: Results: successfully to guide treatment of Study type: Lack of levels In pts surviving hospitalization. or sensitivity and 90% specificity when BNP   Size: pneumothorax ≥22 pmol/L) than LVEF or plasma ANP 52 concentration.  But not in acutely breathless pts dyspnea admission with lung disease Results  Rapid BNP assays may assist in Study type: Exclusion criteria:  Admission plasma BNP more accurately the diagnosis of pts with acute Observational Pneumonia. 2008 Aim: Inclusion criteria: 1 endpoint:  Admission BNP and cardiac Tn (49) To determine additive Hospitalizations for HF from BNP above the median and increased Tn levels are significant.001) and log ANP raised in dyspneic pts with HF presenting with acute dyspnea requiring (r=-0. obesity. . pulmonary reflected the final diagnosis of HF (93% dyspnea thromboembolism. the American Heart Association.001).

Study type: Multicenter Prospective cohort Size: 577 Peacock et al. 2. MI cTnI (p<0.24–2.467 Registry analysis hospitalization episodes Size: Exclusion criteria: 48.001) and hs-CRP (p=0. p<0.0001).09 and acutely decompensated HF.. and higher HF time of hospitalization in-hospital mortality (8. is associated with higher in-hospital cardiac troponin levels between 2001 and 2004 in mortality. hospitalized pts with included a troponin level Pts who were positive for troponin had lower acute decompensated that was obtained at the SBP on admission. Tn levels in acutely were analyzed. recruited in the 5 There was a significant gradual increased risk enhanced early risk stratification. in participating centers of 31-d cardiac death with increasing in the pts hospitalized number of elevated biomarkers (p<0.240 pts (6.001) 23 © 2017 American College of Cardiology Foundation. decompensated Competing diagnoses of elevated serum levels of BNP (p=0. 2008 Aim: Inclusion criteria: 1 endpoint:  In pts with acute decompensated (51) Describe the association Hospitalizations for acute Overall. each p<0. point.002).55 (95% CI: 2. and the Heart Failure Society of America.0 mg per deciliter test was 2. the American Heart Association. p<0.629 Absence of BNP levels Zairis et al. .7%. independently of other and adverse events in ADHERE. 2010 Aim: Inclusion criteria: 1 endpoint:  In pts hospitalized for acute (50) To investigate the Consecutive hospitalized Cardiac mortality by 31 d decompensation of severe (NYHA 19157603 combined prognostic acute decompensated HF III/IV) low-output HF. The adjusted odds ratio for death Registry analysis Pts with a serum creatinine in the group of pts with a positive troponin level ≥ 2. because of acutely Exclusion criteria: By multivariate Cox regression analysis. cTnI and hs-CRP. cTnI and value of admission pts with NYHA class III/IV Results: hs-CRP upon admission offers serum levels of BNP.2017 Heart Failure Focused Update Data Supplement    admission BNP and 2004 entered into ADHERE risk of in-hospital mortality (OR: 2.001) than those who were negative for Study type: Exclusion criteria: troponin.41 respectively. 4. Inc. BNP 2.02) were III/IV) low-output independent predictors of the study end chronic HF. BNP.001). Entry criteria Results: predictive variables. a lower EF. decompensated HF assessment on admission was performed in 48. severe (NYHA class renal failure. a positive cardiac troponin test 18480204 between elevated decompensated HF troponin.2%) were positive for HF.629 Study type: (63%) of 77.89.0% vs.

6–0.9.52 [CI: 1.30] ED. single-center 24 © 2017 American College of Cardiology Foundation.33] per 5%). Study type: Exclusion criteria: per 10 beats/min) and creatinine Multicenter Registry No lab availability concentration (OR: 1.. 12034159 of CRP in predicting admission with HF. discharge in HF syncope p<0. .924 (177 micromol per liter).01) and increasing tertiles of be possible given that high BNP add prognostic percent reduction in BNP. decompensated HF readmission for HF  More BNP measurements do not  Follow-up BNP performed better than did add prognostic information beyond Study type: baseline BNP or percent reduction in BNP. Lee et al. [CI: 1.14–1.77] per 20 Size: 12. 2004 to 2007 Mortality risk increased with higher triage pts with acute HF presenting to the heart rate (OR: 1.7. had a HR:0.005).2017 Heart Failure Focused Update Data Supplement    Size: 67.03–1.1– which pts should be treated may not BNP measurements acute coronary syndrome 1.01–1.84. and the Heart Failure Society of America.16 [CI: 1.35. severe lung disease. future clinical events. Size: 203 Alonso-Martinez et al. [95% CI: 1. p<0.591 mm Hg) and initial oxygen saturation (OR.94 vs. treatment had a hazard ratio of 1.60] per analysis 1 mg/dL [88. 0. 2009 Aim: Inclusion criteria: 1 endpoint:  Both lower absolute BNP levels and (53) Compare the Pts hospitalized for acute For the combined end point of total mortality greater percentage reduction in 19398076 relationship between decompesated HF by or readmission for HF BNP with treatment of absolute and relative Framingham criteria decompensated HF are associated changes in BNP with Results: with better event-free survival. respectively. 2012 Aim: Inclusion criteria: 1 endpoint:  A multivariate index comprising (52) To derive and validate a Population-based random Death within 7 d of presentation routinely collected variables 22665814 model for acute HF sample of 12.15. Inc. 1.4 (1.591 pts stratified mortality risk with high mortality applicable in presenting to the ED from Results:   discrimination in a broad group of the ED. for the associated with better outcomes treated for combined end point of total mortality or during the short period of treatment. the American Heart Association. 2002 Aim: Inclusion criteria: 1 endpoint:  Multivariate predictors of (54) To determine usefulness Intervention group: 18-mo HF readmission readmission were CRP levels.7 levels tend not to decrease to levels information in pts (0. p=0.4 micro mol/L]).0007)  Limitation: small.31–1. control  CRP levels were higher in pts with HF NYHA class and plasma K on need for readmission group: admission with compared to syncope (3. Exclusion criteria: Renal  Increasing tertiles of BNP levels after  Advocating a threshold BNP to and whether serial failure. Dhaliwal et al. that provided by a single BNP level Retrospective registry  More BNP measurements other than the after treatment analysis follow-up BNP did not improve the fit of the model further. and lower triage SBP (OR: 1.

cystatin C. troponin release proBNP  Limitations: exclusion of pts with Size: 364 ACS was based on clinician judgment. 2007 Aim: Inclusion criteria: 1 endpoint:  ST2 levels were higher in pts with (57) To examine the value of Pts presenting to ED with death at 1 y HFrEF (0. MR- Size: 251 proADM. OR: 0. 18599345 and prognostic  51% of pts had +cTnI and 30% had +cTnT logNT-proBNP (OR: 1.0–1.5) and (/10 mm Hg increase.9) were independent risk associated with adverse outcome in pts with predictors. and the Heart Failure Society of America.. inflammation.g. .9. soluble ST2.. IQR 0. 95% CI: 3. but no de novo HF not Observational and 48 hours:  Mortality was proportional to substudy cTnT.50) 17692745 measuring ST2 in pts acute dyspnea  ST2 levels were significantly higher in pts vs. adiponectin.6. cTnI. 2010 Aim: Inclusion criteria: 1 endpoint:  Low systolic BP and advanced age (55) To evaluate the Pts presenting to ED with All-cause mortality at 1 y were also independent predictors of 20153308 prognostic value of acute dyspnea  25% died within 1 y 1-y mortality established and novel  At baseline. cystatin (56) To evaluate prevalence Hospitalized with acute HF -mo mortality C (OR: 6.42 ng/ml. proguanylin. only MR-proANP majority men (94%) Study type: (RR: 1. chromogranin A (CgA).6). missing sample for  Both cTnI (OR: 2. the American Heart Association. cut-off values for troponins was based on 2000 ESC/ACC guidelines Januzzi et al. ST2 (RR: 1.67 ng/ml. increased risk of HF Observational Clear cause for elevated CRP readmission. IQR 0. copeptin.22– 25 © 2017 American College of Cardiology Foundation. decedents (n=62) had higher  Limitations: post-hoc analysis.3.2–13). HFpEF (0. MR-proANP. troponin pos. and increased mortality Size: infection) 76 Safety endpoint: NYHA class on discharge and death Dieplinger et al.0. sub- biomarkers in pts with Exclusion criteria: median plasma concentrations of all 10 group (87 of 251) had dyspnea due acute dyspnea STEMI. single-center. Inc.8) and SBP on admission elevated cTnI and ACS pts. prouroguanylin Ilva et al. NSTEMI or ACS biomarkers than survivors (n=189) to acute HF alone. 95% CI: 1.2017 Heart Failure Focused Update Data Supplement     Higher CRP levels were associated with observational study Study type: Exclusion criteria: higher NYHA class.7% 1.5) Observational Biomarkers: were independent predictors of death BNP.31–1.4) were CI: 0.8–0. C- terminal pro-ET-1. (e.7) and CgA (RR: 1. 95% CI: 1.  In multivariate model.4. shorter time to readmission. 95% CI: significance of Exclusion criteria:  6-mo all-cause mortality was 18.2–3.5–4. 2008 Aim: Inclusion criteria: 1 endpoint: 6  On multivariable analysis. NT. whereas troponins were Study type: Biomarkers on admission previous. 95% cTnT in acute HF cardiac TnI/TnT cTnT (OR: 2.

1.27–1.001) biologic role of ST2 in acute HF 209. no Murcia. 1.7% identified subjects with the highest  ST2 levels were significantly higher in risk for death Size: decedents than survivors (1. 0. other causes of  In multivariable analysis.38 improved C statistic and both net HFpEF vs. NT.2017 Heart Failure Focused Update Data Supplement    with acute dyspnea with acute HF (0. regardless of LVEF Observational study CRP levels were associated with greater risk of  Limitations: pooled multinational combining 3 1-y mortality for HFpEF (HR: 1.20. Austria. troponin T. 2008 Aim: Inclusion criteria: 1 endpoint:  Pts with HFpEF had lower ST2 (59) To examine patient.50 ng/ml. Spain) pre-discharge ST2 levels Size: 447 Rehman et al.24) of ST2.80 ng/ml vs. p<0.0. 0.10–1. BNP.  On multivariate analysis.32) echocardiographic measures. 593 (pts with acute HF ng/ml. Austria) HF poorly understood Size: 346 26 © 2017 American College of Cardiology Foundation.. those without (0.55 (58) risk of mortality  During 1-y follow-up. CRP  In a multivariable model. p<0. 95% CI: analysis that lacked predefined databases (Boston. the American Heart Association.03 vs.18  Limitations: single-center study.22) 0. 117 pts (26%) died ng/ml vs. Study type: Biomarkers: proBNP and CRP BNP/NT-proBNP did not predict Observational study ST2.42) ST2 and NT-proBNP levels Observational  1-y mortality was 15. LVEF and creatinine clearance BNP/NT-proBNP  ST2 levels correlated with BNP. Acute HF ROC curves and multivariable Cox levels compared to HFrEF 19017513 specific characteristic proportional hazards analyses 1-y mortality was 42% among 116 of ST2 in pts with Exclusion criteria:  ST2 levels correlated with severity of HF pts with elevation in both ST2 and acute HF N/A (p<0. Aim: Inclusion criteria: 1 endpoint:  Pts with HFrEF had higher ST2 2011 To determine whether Acute HF 1 y vital status levels than HFpEF (median 0.30–3.001). Inc.20 ng/ml poorly understood acute dyspnea 384) strongly predicted death at 1 y Manzano-Fernandez et al. elevated ST2 improvement.15 ng/ml. Linz. IQR 0.06–  A multi-marker approach with both Study type: Not reported 0. NT-proBNP. IQR 0. 95% CI: endpoints and complete MA. 95% CI:  Limitations: lack of serial measures databases (Boston. 1.001) 21211603 associated with ST2 Exclusion criteria:  ST2 levels were higher among deceased  Addition of ST2 to NT-proBNP differs in pts with acute N/A than survivors (median 0.76) than HFrEF (HR: 1. ST2 remained a mortality combining 2 predictor of mortality (HR: 2.  In the presence of a low ST2 level. . biologic role of ST2 in acute MA. NT-proBNP.41.04. HFrEF ng/ml. and the Heart Failure Society of America. and this pattern was true reclassification improvement and Biomarkers: for HFrEF and HFpEF integrated discrimination Study type: ST2. ST2 0.001).38 ng/ml. p<0.14–1. Linz.90) Exclusion criteria: vs.

OR or RR. detailed and clinical indices In multivariate analysis.  No difference in KCCQ scores  Serious adverse events:  Trial not powered to ascertain clinical 15% in LCZ696 vs. 2012 To address safety Pts ≥40 y of age. galectin-3 galectin-3 and cardiac echo exams during Higher levels of galectin-3 associated with remained a significant predictor of structure and function admission older age.77.2.09 for DBP) Exclusion criteria: valsartan (ratio of change  Change in BP correlated poorly with the Study type: Right HF due to pulmonary disease. single- Observational Biomarkers: center cohort galectin-3. human.8 (95% CI: 0. IV. Patient Population Study Intervention Endpoint Results Relevant 2 Endpoint (if any).2017 Heart Failure Focused Update Data Supplement    Shah et al. NYHA class II. 2010 Aim: Inclusion criteria: 1 endpoint: Galectin-3 levels higher in pts who (60) To determine the PT presenting to ED with Association between galectin-3 and echo died at 1 and 4 y 20525986 relationship between acute dyspnea. Valsartan (152) target 0. To compare survival ≥18 y of age. III.005)  No difference in improvement in NYHA valvular/myocardial disease. small. NT-pro BNP >400 200 mg BID achieved in for NT-proBNP  BP reduced in the LCZ696 group vs. Further studies needed to valsartan group assess safety and efficacy in HFpEF pts. and higher 4-y mortality independent to in pts with acute NT-proBNP echocardiographic markers of risk dyspnea Exclusion criteria: Significant relationship between galectin-3 Limitations: delay between collection N/A and poorer RV function. 95% CI: change in pro-BNP RCT dyspnea due to noncardiac causes. 81%  Results: Reduction in valsartan at 12 wk (p=0. 2016. Data Supplement 1. p=0. LVEF ≥45%. Author. .71–0. p=0.11) and 36 wk Size: or CVD needing revascularization achieved in 78% 1 Safety endpoint: (p=0. McMurray et al. NT-proBNP Size: 115 Search Terms and Date: natriuretic peptides. 308 within 3 mo of screening.. and the Heart Failure Society of America. higher RV systolic of biomarkers and Study type: pressure and more severe MR and TR echocardiograms. (# patients) / (Absolute Event Rates. Study Limitations. Comparator: from BL: 0. & Adverse Events (# patients) 95% CI) PARAMOUNT Aim: Inclusion criteria: Intervention: 1 endpoint:  No difference in change in NT-proBNP Solomon et al. the American Heart Association.92.3. Inc.001 for SBP and pts with HFpEF LCZ696 group vs. PARADIGM-HF Aim: Inclusion criteria: Intervention: 1 endpoint:  Less CV death in LCZ696 arm (558 vs.89. last 5 years. heart failure. LCZ696 (4.187) target  Composite of death (CV 693) HR: 0.05). Study Type.10) Study Acronym.  LCZ-696 well tolerated. BNP of at least 150 dose 200 mg BID (mean causes) or a first p<0. RCTs Comparing ARNI (Section 7. 22932717 LCZ696 (ARNI) in pg/mL. Last search done on April 18. NYHA LCZ696 (149) target dose  Change from BL at 12 wk from BL at 36 wk (61) and efficacy of class II-III HF. 2014 rates with the use of EF ≤35%. CAD dose 160 mg BID class at 12 wk (p=0. 20% in outcomes.64–0.001) 27 © 2017 American College of Cardiology Foundation. poorer renal function. Aim of Study. Year Published Study Size (N) Study Comparator P values.

p=0. Exclusion criteria: 83. SBP <95  No difference in protocol defined decline mm Hg. p=0.2 mmol/L.001) Study type: screening. (26.4 enalapril. 658) HR: 0.87. 28 © 2017 American College of Cardiology Foundation.76–0.001) Size: enalapril. p<0.  Less death from any cause in LCZ696 RCT dose of beta blockers and an ACE mg BID (mean 18. 1. and the Heart Failure Society of America. angioedema history.001) side effects of ACE inhibitors or  No difference in angioedema. the American Heart Association. 835).212) target 10 LCZ696 group vs.86 (95% CI: mL/min/min/1.8%) vs. 4.2%.13) Search Terms and Date: 3 trials identified by chairs in December 2015.13. HR: LCZ 100 BID. p=0.9+3. HR: 0.  The change from baseline to 8 mo in the 8. p<0.2017 Heart Failure Focused Update Data Supplement    (62) LCZ696 with pg/mL.442 were required to complete 2 wk p<0. .001) score on the KCCQ in LCZ696 arm (2. eGFR <30 in renal function.001)  No difference in new onset of AF (84 vs.65–1.80 0.84 (95% CI: inhibitor (or ARB) equal to 10mg of mg daily) 1. on ACE (537 vs.89.5%) HR: 0.28).64 (95% CI: 0.63–2.63 points). Prior to randomization pts (95% CI: 0.79 (95% CI: 0.99 each of enalapril 10 mg BID and points reduction vs. arm (711 vs.. p<0.71– inhibitors or ARBs ≥4 wk before Comparator:  Results: Composite less in 0. 19 vs.10 ARBs (p=0. 914 (21. HR: 0.117. serum K level >5.73–0. unacceptable 9. area. hospitalized for HF <12 mo 375+71 mg daily) hospitalization for HF  Less HF hospitalizations in LCZ696 arm 25176015 enalapril in HF (≥BNP100 pg/mL).73m2 of body surface 0.93. Inc.65.84) Symptomatic hypotension. required to take stable Enalapril (4.  More symptomatic hypotension (14% vs.

25637937 ACE and beta II-IV. or HF hospitalization at 4. Inc.926 SUPPORT Aim: Inclusion Criteria: Intervention: 1 endpoint:  Pts on triple therapy with Sakata et al. the American Heart Association. HR: 1. NYHA class olmesartan (578) titrated stroke.47 (95% CI: 1. stroke. stable on ACE ± beta up to 40 mg as tolerated 28. Yusuf et al. MI.4 y of 1° composite outcome. Author. then  Composite of CV death. Aim of Study. Run in. or  Telmisartan had more Investigators et al. 17.11 19.001).954) Results: CVD or high-risk No significant difference RR: 0. and the Heart Failure Society of America.3. ARB previous stroke. or randomization to HF hospitalization at 5 y population . and DM with end-organ damage (8.4/9. Study Limitations.05).502). HR: 1. and Study Type: <3 mo renal dysfunction (p<0.50 (95% CI: 29 © 2017 American College of Cardiology Foundation.18 (95% CI: 0. MI. then  Composite of CV death.006). p=0. .94–1. PVD.2%. CI: ARB  Combination arm had more risk DM intolerance. Study Type. (# patients) / (Absolute Event Rates. Titration of other Study Type: revascularization planned or mediations as needed to RCT <3 mo control BP (2. titrated to BP RR: 1. 16.01).46). previous stroke. OR or RR.944) Size: 5. HF at trial entry.5%. CAD.5% ACE.. MI.3) Study Acronym.9 1. p=0. with CVD or high. Year Published Study Size (N) Study Comparator P values. telmisartan Results: and angioedema (p=0. & Adverse Events (# patients) 95% CI) ONTARGET Aim: Inclusion Criteria: Intervention: 1 endpoint:  Compared to the ramipril arm: ONTARGET Compare ACE Pts >55 y of age. 2008 To assess the ACE-intolerant pts with CAD. ACE/ARB/Beta blocker had more (65) addition of ARB to hypertension.81–1.3% combination.4/7.11– blockers in pts with blockers (578) (mean dose Results: No significant difference RR: 1.1 vs.576) target dose 10 (p<0. syncope. syncope (p=0. p=0. stroke.4 vs.542) target dose 80 No difference in outcome (16.95.001) RCT  BP fell by 6. all-cause death.7% ARB.620 TRANSCEND Aim: Inclusion Criteria: Intervention: 1 endpoint:  No difference in 2° outcomes.01 (95% CI: 0.92 (95% DM Exclusion Criteria: Comparator: CI: 0.001) (63) combination mg daily.2.001).2017 Heart Failure Focused Update Data Supplement    Data Supplement 2.216 HF at trial entry. 38. high-risk DM with end-organ telmisartan titrated to 80 intolerant pts with damage mg as tolerated (2. chronic HF will achieved at 5 y. less cough (p<0. Patient Population Study Intervention Endpoint Results Relevant 2 Endpoint (if any). RCTs Comparing RAAS Inhibition (Section 7. ACE or ARB mg daily or combination 16. or high-risk randomization to ramipril HF hospitalization at 5 y hypotensive symptoms 2008 (telmisartan). or ARB was safe in this pt (64) effectiveness of PVD. (8. 2015 Discover whether Pts 20–79 y of age with Randomization to  Composite of all-cause death.no angioedema 18757085 ARB in ACE.96–1. Run in. same 18378520 ACE/ARB in pts Exclusion Criteria: (8. (ramipril).8 mm Hg  Less angioedema with Size: telmisartan 25. 13.03).09) hypotensive symptoms revascularization planned or (p<0.

 No clinically important safety with severe HF.85 (95% CI: 1. DM. Inc. <3. subgroup analysis Safety: increased risk of K+ >5.046).001) concerns for electrolytes.5. p=0. p<0. Results:  Improvement in NYHA class   mortality and Digitalis and vasodilators Comparator:  Placebo vs.001) morbidity in pts allowed. 12. No differences from the main trial results in the high-risk subgroups. clinically significant hyperkalemia.147 Mineralocorticoids Antagonist Trials EMPHASIS subgroup Aim: Inclusion Criteria: Intervention: 1 endpoint:  The beneficial effects of analysis Investigate the safety Pts enrolled in EMPHASIS at Randomization to  Efficacy: Hospitalization for HF or eplerenone were maintained in Eschalier et al.24–2. On ACE (822) cardiac causes (p<0.70. Spironolactone group (46% (p<0.5%. RR: 0. or SBP Comparator: Placebo hyperkalemia.5. RALES Aim: Inclusion Criteria: Intervention: 1 endpoint:  Reduction in death from cardiac Pitt et al. Spironolactone 25 mg daily  Death from all causes causes and Hospitalization for (67) effect of Left EF≤35%. hospitalization for hyperkalemia <123) worsening renal function Study Type: Exclusion Criteria: eGFR<30 Results: Prespecified Efficacy: reduced composite endpoint.737 study medication due to adverse events. frequent in the spironolactone 30 © 2017 American College of Cardiology Foundation. HF≤6 mo. Study Type: Open mo Titration to control BP label blinded without use of an ARB endpoint (568) Size: 1. K >5. 35%.82. loop diuretic. dysfunction (21. 2013 and efficacy of high risk for hyperkalemia of eplerenone worsening renal failure. Safety: K >5.0. MI or.5 was increased in the whole cohort and the subgroups. and the Heart Failure Society of America. 95% CI: 0. Exclusion Criteria:  Trial stopped early due to favorable Gynecomastia/breast pain more Study Type: 1° operable VHD (other than results at 24 mo. IV.2017 Heart Failure Focused Update Data Supplement    improve clinical Exclusion Criteria: mg/d) 1. the high-risk subgroups. p=0.001) 10471456 spironolactone on inhibitors. (66) eplerenone in pts worsening renal function (>75 >6. but K >6.01–2.60–0. hospitalization for hyperkalemia or discontinuation of Size: 2. Placebo (841) vs.23.0.1 vs. 1999 To investigate the NYHA class III.0. hospitalization for significant 23810881 at high risk for y. HR: revascularization within 6 Comparator: 1..76. eGFR <60. . and change in eGFR were not substantially higher.5 of RCT mmol/L. and renal outcomes Creatinine >3.003). the American Heart Association.

001) unstable angina. Inc.2.5 mg/dL.0x109/L. The ACE inhibitor evidence table from the 2013 Heart Failure Guideline is also included at the end of this document.96. 1 taking  Uncontrolled hypertension enalapril Study type:  Acute coronary events within 3 mo Double blind RCT Comments: Vasopeptidase inhibitor  Revascularization within 3 mo  Serum potassium <3. Study Type..52) 10968433 ACE with the II–IV HF) Comparator: Results:  Combined endpoint of death and vasopeptidase  Decreased LVEF <40 Lisinopril (284) target Similar exercise duration comorbidity for worsening HF was inhibitor omapatrilat  ≥4 wk dose of ACE inhibitors dose 20 mg daily at 12 wk (p=0. Author. 5x109/L. OR or RR. active cancer.10) Study Acronym. Determine if inhibition  Informed consent Omapatrilat (289) target exercise duration from  No difference in combined 2000 of neutral  Age ≥18 dose 40 mg daily baseline to wk 12 endpoint of death and admission for (68) endopeptidase and  Stable (>3 mo) symptomatic HF (NYHA class worsening HF (p=0.52 (95% is better than ACE  Seated SBP ≥90 mm Hg CI: 0.035) inhibition alone with  Angioedema occurred in no pts lisinopril Exclusion criteria: taking omapatrilat vs. RCTs Comparing Pharmacological Treatment for of ARNI With ACE (Section 7. group (p<0.663 threatening disease. life 1.28–0. & Adverse Events (# patients) 95% CI) IMPRESS Aim: Inclusion criteria: Intervention: 1 endpoint: Change in 2 endpoint: Rouleau et al. or platelets <120x109/L 31 © 2017 American College of Cardiology Foundation. . heart transplant.5 or >5. Data Supplement 3. and the Heart Failure Society of America. Year Published Study Size (N) Study Comparator P values.3 mmol/L omapatrilat did not improve exercise Size: tolerance compared with ACE 573 pts  Creatinine >221 mcmol/L inhibitor lisinopril  Transaminases >2 upper limit of normal  Leucocytes <3. The Beta Blocker evidence table from the 2013 Heart Failure Guideline is included at the end of this document. p=0. 1° heaptic Size: failure.45) better for omapatrilat HR: 0. serum K ≥5.2017 Heart Failure Focused Update Data Supplement    RCT mitral or tricuspid).0 mmoL/L The ARB evidence table from the 2013 Heart Failure Guideline is included at the end of this document. serum Cr ≥2. Study Limitations. Aim of Study.3. neutrophils <1. (# patients) / (Absolute Event Rates. the American Heart Association. ACHD. Patient Population Study Intervention Endpoint Results Relevant 2 Endpoint.

the American Heart Association. Comments: 32 © 2017 American College of Cardiology Foundation. alone Exclusion criteria: (2. renal. p=0.770 pts  Hx of intolerance to ACE inhibitors  ACS within 1 mo  Coronary revascularization or an acute cerebral ischemic event within 3 mo  Hx of ventricular tachycardia. or hepatic disease 5.5% requiring IV treatment p=0. 2002 Determine dual ACE  NYHA class II–IV HF due to non/ischemic Omapatrilat (2. For this analysis.5%) Double blind RCT  Likely to receive cardiac transplant or left ventricular assist device Size:  Severe 1° pulmonary. and the Heart Failure Society of America. Inc.94 (95%  Surgically correctable or reversible cause of mg BID achieved 86. or trough by wk 24 Double blind RCT DBP 90–99 mm Hg and SBP <160 mm Hg).2 mmol/L OCTAVE Aim: Inclusion criteria: Intervention: 1 endpoints: 2 endpoints: Kostis et al. pts were benefit in pts with HF mo treated with intensification of oral than ACE inhibitors Comparator: Enalapril Results: No significant medications.82–0. risk of death or and hospitalization for chronic HF (69) and NEP inhibitors cardiomyopathy for ≥2 mo.86–1. Group 2 hypertension and Comparator: Enalapril adjunctive  BP control (SBP <140 mm Hg and persistent mild hypertension (trough SBP 140– target dose 40 mg daily antihypertensive therapy DBP <90 mm Hg) at wk 8 and 24 Study type: 159 mm Hg and DBP <100 mm Hg.4% CI: 0.886). or target dose 40 mg daily hospitalization for HF HR: 0.012).03. or sudden death who did not have an ICD placed and had not fired within 2 mo  Hx or hospitalization or intravenous therapy for HF within 48 h  IV positive inotropic agent within 2 wk  SBP >180 or <90 mm Hg  Heart rate >130 bpm  Serum creatinine >2.98. .89 (95% CI: 0.8% vs.2017 Heart Failure Focused Update Data Supplement     Use of beta blockers <6 mo  Calcium channel blockers for use other than AF  Pts included in previous RCTs of omapatrilat OVERTURE Aim: Inclusion criteria: Intervention: 1 endpoint: Combined  Omapatrilat reduced risk of death Packer et al. 12186794 provides greater  LVEF ≤30% and hospitalized for HF within 12 achieved 82.884) target dose 10 difference HR: 0..5 mg/dL  Serum potassium <3.5 or >5. 2004 Compare safety and  Age ≥18 Omapatrilat target dose  Reduction in SBP at wk  Reduction in DBP at wk 8 (70) efficacy of dual ACE  3 separate BP criteria for 3 groups: Group 1 80 mg daily 8  Reduction in SBP and DBP at wk 14751650 and NEP inhibitors to untreated hypertension (SBP ≥140 mm Hg or  Need for new 24 ACE inhibitors alone DBP ≥90 mm Hg). ventricular fibrillation. 0.187)  More frequent angioedema with Study type: HF omapatrilat (0.

anaphylaxis. Study type:  Hospitalization rate lower Post hoc analysis of for comorbidity loads of RCT ivabradine 33 © 2017 American College of Cardiology Foundation. TIA or COPD events. Year Published Study Size (N) Study Comparator P values. heart rate at rest hospitalization rate all comorbidity loads 26508709 on outcomes and ≥70 bpm. (# patients) / (Absolute Event Rates. the American Heart Association.. chronic renal for omapatrilat and enalapril disease 2° to autoimmune disease.81%) Search Terms and Date: March 2016. and deaths were the same  Recent treatment for malignancy. omapatrilat. Author. 1. or multiple drug sensitivities subgroups. and the Heart Failure Society of America.62%) and current smokers (3.68%)  Hypertensive pts treated with ACE inhibitors  More angioedema in blacks with whose BP placed them in study group 3 omapatrilat (5. or end-stage  More angioedema with omapatrilat renal disease of any etiology (2. 0. and placebo. angioedema. or trough DBP (p<0.3. Data Supplement 4.54% vs. drug-induced smaller with both drugs than in other or chronic urticarial. . Inc. OR or RR.2017 Heart Failure Focused Update Data Supplement    Group 3 hypertension with persistent moderate  Greater reductions in BP in Size: to severe hypertension (trough SBP 160–179 omapatrilat within each study 25. neprilysin inhibitors. But overall reduction  Hx of angioedema.93% vs.0001) with most heart rate N/A events in pts with >3 reduction in stable comorbidities for both drug HF. Aim of Study.6 mm Hg Exclusion criteria:  Larger reductions in BP in black  Contraindication to therapy with ACE inhibitors pts with omapatrilat than with or angiotensin II receptor antagonists enalapril. Study Type.001) 100–109 mm Hg and SBP <180 mm Hg)  Overall mean reduction in SBP ≥3. RCTs Comparing Pharmacological Treatment for Stage C HFrEF (Section 7.2. MTD for HF meds Comparator: increased with the ivabradine Placebo comorbidity load treatment effect of Exclusion criteria: (p<0.  Recent hospitalization for MI. & Adverse Events (# patients) 95% CI) SHIFT HF Aim: Inclusion criteria: Intervention: 1 endpoint:  Number of comorbidities was related to outcomes Böhm et al. Study Limitations.11) Study Acronym. serious adverse stroke. 2015 To assess influence Pts ≥18 y of age in sinus Ivabradine  CV death or HF  Heart rate reduction with Ivabradine is conserved at (71) of comorbidities rhythm.  Adverse events. 0. unstable angina.302 pts mm Hg and DBP <110 mm Hg.17% vs. Patient Population Study Intervention Endpoint Results Relevant 2 Endpoint (if any).

MI within 2 0. placebo 8% (p=0. HF double-blind HF due to congenital heart worsening HF: ivabradine hospitalization.505 SHIFT Aim: Inclusion criteria: O Intervention: 1 endpoint:  Composite of CV death or hospital admission for Swedberg K et al.012) SIGNIFY Aim: Inclusion criteria: Intervention: 1 endpoint:  Adverse Events: Increased bradycardia. 2014 Assess the Stable CAD without clinical Ivabradine (n=9.014 higher baseline heart rate (≥77 bpm) 6. previous admission to ivabradine better.241 ivabradine  diltiazem and verapamil 3. Fox et al. HF hospitalization.001)  Phosphenes 3% (p<0. any CV death. HF:  In subgroup analysis. p<0. symptomatic  Death from HF: ivabradine Size: hypotension better. Event nonfatal MI.505 analyzed The following treatments not allowed during study:  Use of devices was low (CRT in 1% and ICD in 4%) 3. valvular disease.75–0. AF. outcomes in outcomes in HF the hospital for HF within 12 rate 24% vs. any CV hospitalization. 3% vs. 677 centers mo. CV hospitalization. in sinus Ivabradine  Composite of CV death or worsening HF among those receiving at least 50% of 2010 of heart rate rhythm. (73) mortality-morbidity HF and heart rate of ≥70 and nonfatal MI 34 © 2017 American College of Cardiology Foundation.66–0. ventricular or AV pacing p<0. symptomatic chronic HF Placebo cause hospitalization. All (72) reduction by the ≥70 bpm. Inc. 29%.74 (0.94). 5%. Exclusion criteria:  Hospitalization for  Ivabradine better for all-cause hospitalization.90). including beta blocker at 3A4 optimal dose. AF or Median follow-up of 22. composite of CV death HF hospitalization.001)  Comparable across age groups  AF . resting heart rate of hospital admission for target beta blocker dose at time of randomization. all- 20801500 selective sinus. driven largely by HF mortality or HF hospitalization Adverse Effects:  1% withdrew due to bradycardia (p<0. . effect limited to those with 6.264 placebo (nondihydropyridine CCB)  Mean age 61 y  class I antiarrhythmics  strong inhibitors of CYP450  When added to GDEM.001)  Analyzed as time to first event.74 (95% CI: 0. To assess the effect ver 18 y of age. HR: endpoint trial. the American Heart Association. HR 0. stable Comparator: worsening HF cause death. Ivabradine and ivabradine on wk. 37 countries for ≥40% of the d.ivabradine 9% vs.550)  Composite of CV death phosphenes and cardiac disorders.558 0. LVEF ≤35% (0. death node inhibitor (NYHA class II-IV) for ≥4  Primary endpoint: from HF. 16% vs 21%.. and the Heart Failure Society of America. ivabradine reduced adverse events. p=0. and composite 2° placebo-controlled disease or 1° severe better.83.9 mo flutter.58–0.0001  No difference in all-cause mortality or CV mortality (SHIFT) Study type: randomized.2017 Heart Failure Focused Update Data Supplement    Size: 6.82 chronic HF mo.

25).97. Inc.479 ivabradine Exclusion criteria:  In subgroup with heart rate of ≥70. unstable CV rate of death (HR: 1. LVEF ≤40%. 2) composite of admission for AMI or UA (HR 0. Comparator:  Results: No significant  Significant interaction between ivabradine and Ivabradine in pts persistence and Placebo (n=9.00. ALT nonfatal MI (HR: 1. stroke death. the American Heart Association. p=0.02).10.06.479 admission for MI and 2) Cardiac death (death from MI or HF or related to a 18757088 benefits of MI.5% vs. p=0.04. /L.001) BEAUTIFUL Aim: Inclusion criteria: Intervention: 1 endpoint: 2 endpoints: Fox et al. valvular disease likely to 0.917 CV medication for 1 mo.552) difference in incidence of presence of angina in a subgroup analysis (p=0.49–0. . p=0. prespecified subgroup.21. condition. death from CV Study type: Exclusion criteria: causes (HR: 1.91–1.62–0.94) 4) Composite of admission for fatal and nonfatal MI or Study type: dimension of >56 mm.21. with stable CAD confirmation of ≥1 CV risk 1° endpoint (HR: 1. with CAD and LV surgery). stroke or TIA 0.90–1. PPM or ICD. 2008 Assess the  Pts ≥55 y of age with stable Ivabradine  Composite of CV death. p=0.102 normal value.438 p=0. Sinus UA Randomized.84. p=0. other systolic evidence of ≥1 stenosis of to appropriate CV 1° endpoint (22. rhythm with resting heart  No differences in any 5) Coronary revascularization double-blind.20. 0. without clinical HF factors 95% CI: 0. and the Heart Failure Society of America. previous admission for HF cardiac procedure) Ivabradine in pts revascularization (PCI or Comparator: 3) CV death (death from a vascular procedure. 95% CI: RCT Serum creatinine >200 mcmol 0.  No differences in 2° endpoints in overall population. 95% CI: 0.8%. 95% Size: or AST >3 times upper CI: 0.60) and 19.94–1.2017 Heart Failure Focused Update Data Supplement    25176136 benefits of bpm and in sinus rhythm. rate of ≥60 bpm.35) stroke <3 mo.1.023) 35 © 2017 American College of Cardiology Foundation. 1) All-cause mortality (74) mortality-morbidity CAD defined as: previous n=5.64.96–1. 5. 1 Safety endpoint:  Incidence of bradycardia higher in Ivabradine group (p=0. and end diastolic internal n=5.78.20). HR: 1. or angiographic  Placebo in addition  No difference in composite presumed arrhythmic death.001) within 3 mo.28. 6) CV death placebo-controlled  Angina and HF symptoms 7) Admission for HF stable for 3 mo 8) Admission for MI  Appropriate conventional Size: 10. p=0. significant anemia.08. admission for HF. MI. coronary revascularization. previous 6 mo.94–1. ivabradine 5438 placebo MI or coronary reduced revascularization within the 1) admission for AMI (fatal and nonfatal) (HR 0. vascular death or sudden death of unknown cause) or dysfunction ≤50%) AND LVEF <40% medication 22..

RCTs Comparing Pharmacologic Treatment for HFpEF: Recommendations (Section 7. low 2. 0.933) treatment 51 strokes p<0. largely due to bradycardia (13% vs. diabetes. Author. Aim of Study. 3. Study Limitations. persistent Indapamide + perindopril if  Fatal or nonfatal stroke.06 for both) Study type: μmol/L (1.3. 95% CI: 0. Study Type.16) congenital long QT. & Adverse Events (# patients) 95% CI) HYVET Aim: Inclusion criteria: Intervention: 1 endpoint:  Significantly reduced all-cause Beckett et al.046) ALLHAT Long-term Aim: Inclusion criteria: Intervention: 1 endpoint:  Increased HF mortality with Follow-up To compare diuretic. p=0. severe  28% in Ivabradine group discontinued medication or uncontrolled (vs.  Trend for improved 0. p=0. 95% CI: with incident HF by drug treatment Study type: Chlorthalidone (15. 3) coronary revascularization (HR 0.42 (95% CI: 95% CI: 4. stroke.001) and  No difference in mortality in pts HDL.7 mg/dL). Age >55. PVD) Comparator: HFrEF: HR: 3.904). 23%. DBP≥90).99.62.000 pt. at with in-trial HF. HTN (SBP Amlodipine (8.38–0.. p<0. sinoatrial block. OR or RR. 16%). p=0.79 (95% CI: 0.18–6.49–1.58.36–10. both HFpEF: HR: Piller et al. p=0.22–0.001) with active treatment elderly.7/1000 pt-y).001) RCT Exclusion criteria: 720 with in-trial HF 36 © 2017 American College of Cardiology Foundation.912) y). HF HFpEF: HR: 2.52–0.001) HTN LVH.08–2.7/1. Inc. Trend for decreased CV and HF creatinine >150 Comparator: placebo 69 (17.80. one study added by Jan 2016.51.000 pt-y) vs. death (p=0. beneficial in the Exclusion criteria: (1. (# patients) / (Absolute Event Rates. p<0. complete AV block.845 vs. least 1 CV risk (8. 21969009 based treatment of factor (MI. SSS. p=0. and the Heart Failure Society of America. p<0. .36 (95% CI: 0.4/1.06) and significantly reduced fatal Size: stroke 27 (6.002).02) and HF incidence 18378519 of HTN is Target 150/80 mm Hg outcome with active HR: 0.93. Patient Population Study Intervention Endpoint Results Relevant 2 Endpoint (if any). Year Published Study Size (N) Study Comparator P values.61.67. ≥140.70. the American Heart Association.01.95. HR: 0. (76) inhibitor or CCB.06.898) 572  Adjusted mortality risk incident HF. death HR: 0.3) Study Acronym. 2.65– (75) whether treatment HTN (SBP >160) needed for BP control.81. Lisinopril  Increased mortality with in. Placebo (1. (12. 95% CI: RCT CVA <6 mo 0.001) and HFrEF: HR: 6.67–3. both p<0. HR: 0.81 (95% CI: 2. 2011 based to ACE.2017 Heart Failure Focused Update Data Supplement    need surgery within 3 y. 469 with in-trial trial incident HF. Known HF. 2008 To determine Age >80. NYHA class IV HF  No significant difference in adverse effects (23% vs. Data Supplement C. placebo 42 (10.5/1000 pt-y) 3.70) Search Terms and Date: studies identified by chairs in December 2015. 2%) hypertension.7.

4%. p=0. DBP<90 step 1. SBP 160– Antihypertensive therapy:  Incident HF decreased stroke risk with active (77) of antihypertensive 219. stroke.21.4%) with placebo to  LV function was not measured Study type: stroke. and the Heart Failure Society of America.5. p=0.023 mmol/L.4 vs.71.5 y Size: 4. μmol/L (3.12) covariate  Adverse effects requiring Size: potassium >5.003) at HTN Recent MI or CABG. placebo 53 (12. Comparator: decreased HF events from 4.736 CHARM-Preserved Aim: Inclusion criteria: Intervention: 1 endpoint:  No differences for 2 endpoints Yusuf et al.37–0. p<0.514)  CV death or admission for except for covariate adjusted (78) of candesartan in class II-IV with EF HF. 2003 To ascertain efficacy Age ≥70.70–1.00. risk of HF admission HR: 0.89. p=0.77– p=0. echo criteria for Placebo (426) 107 (25. >40% Comparator:  No difference for (95% CI: 0.5 0. Inc.. placebo p=0.4%). Comparator:  No difference for perinopril HR: 0.92.047). (8.82.365) decreased BP from mean placebo to 96 (5. MI. Rx with Perindopril (424)  All-cause mortality or with perindopril: 34 events (79) of perindopril in pts diuretics for clinical admission for HF.918).029)  Limitations: Some pts may have had previous EF <40%. 37 © 2017 American College of Cardiology Foundation. 1. p=0.804 SHEP HF Results Aim: Inclusion criteria: Intervention: 1 endpoint:  1 results of SHEP showed Kostis et al.2017 Heart Failure Focused Update Data Supplement    Symptomatic HF. 1997 To assess the effect Age > 60. open-label ACE inhibitors (36% Size: Exclusion criteria: .005. 1.0 mg/dL). 2003 To ascertain efficacy HF pts in NYHA Candesartan (1. p=0. diagnosis of HF. the American Heart Association. hyperkalemia previous 4 wk 1.51 (95% RCT CI: 0. HR: 0.03. chlorthalidone.371) 105 (4. HR: Limitations: Many pts withdrew RCT dysfunction 0.2 vs.509) candesartan 333 (22%) vs. by study end). 95% CI: 0.009. p=0.80–1.5 vs.051) (2.41–0. 95% CI: 0. p=0.5 adjusted HR: 0.4%) RR: 0. 95% CI: 0. surgery in the 2.  Active treatment treatment 149 (8.1%) vs.63. atenolol (2. or open-heart increased creatinine.1%.84 13678871 pts with HFpEF.2%) with 9218667 treatment in step 2.6%) at 3 y. (40% by 18 mo). 0. Placebo (2.6%. AF 55 (2.86 (95% discontinuation: hypotension 3.0%) vs.70– 1.3%) RR: 0.033). EF Size: <35% at trial entry 32. 4. 11. often to take p=0.22.3% HR: Study type: Exclusion criteria: placebo 366 (24%) at 3. 16963472 with HFpEF.74–1. .99 (95% CI: 0.97. CI: 0.49–0.00).5 y pts with DM. PEP-CHF Aim: Inclusion criteria: Intervention: 1 endpoint:  HF hospitalization lower at 1 y Cleland et al. Study type: diastolic 131 (23.001) at 4.8 vs. CV death 11. RCT Creatinine >265 y.64 isolated systolic Exclusion criteria: of 170/77 to mean of and (95% CI: 0. Placebo (1.

. peak VO2 Comparator:  No difference between were not increased in sildenafil in pts with HFpEF. stroke. activity accelerometer units during unfavorable for nitrates) daily activity in pts limited by dyspnea.05. raising questions about either nt-proBNP 1. 2008 To ascertain efficacy Age > 60. 2%. High prevalence of Study type: >400 or elevated 38 © 2017 American College of Cardiology Foundation. pain lower daily activity in the Study type: treatment group. HR: 0.128 ACS.  No difference in BNP levels RCT Previous EF <40%.067)  CV death or hospitalization any other 2° endpoints (80) of irbesartan on in NYHA class II-IV for CV cause.5 mg/dL) doubling of creatinine. 763 (37%). dosing. 2013 To ascertain effects Age ≥18 on stable Sildenafil (113)  Change in peak VO2 from score or 6-min walk (82) of sildenafil on HF therapy.0 3% vs.01) the previous 3 mo Limitations: Study drug discontinuation in 34% of pts by end of study.20. 6MWT (81) of isosorbide HF therapy. fatigue.061) irbesartan vs. 95% crossover SBP <110mm Hg CI: -780–17. or 4%. K >6.3 mg/dL).30 h. revascularization in p=0. 95% CI: PDE-5 inhibitors -0.2017 Heart Failure Focused Update Data Supplement    850 Creatinine >200 μmol/L (2. or chest Placebo (110)  Nonsignificant trend for escalation of study drug. HF pts in Irbesartan (2.95.20. (-381 Double-blind Exclusion criteria: accelerometer units. Inc.  Limitations: Rapid dose with HFpEF. significant decrease in h of Size: 110 current nitrates or activity/d (-0. p<0. High rate of concomitant ACE-I (40%) NEAT-HFpEF Aim: Inclusion criteria: Intervention: 1 endpoint:  No differences for any of the 3 Redfield et al. 95% CI: 0. placebo same Study type: Exclusion criteria: (742 (36%) vs.  Minnesota living with HF scale 19001508 pts with HFpEF. p=0. the American Heart Association..7– group. 6% vs. and the Heart Failure Society of America. EF (110) assessed by and levels of NT-proBNP (trend 26549714 mononitrate on ≥50%. EF BL at 24 wk Limitations: Urinary cGMP levels 23478662 exercise capacity ≥50%. groups to the Placebo (2.35) requiring discontinuation: Size: μmol/L (2.4 mmol/L I-PRESERVE Aim: Inclusion criteria: Intervention: 1 endpoint:  No differences for mortality or Massie et al.05. Comparator: 120 mg phase. p=0.001. 4. IQR -1.11) and placebo (-0.86 –  No difference in adverse effects creatinine >222 1. p=0. with EF >45% Comparator:  No difference for improved in both.06) and and >180 mm Hg. 2015 To ascertain efficacy Age ≥50 y on stable Isosorbide mononitrate  Average daily activity doses on QoL scores. potassium > 5. <60% normal and Placebo (103) sildenafil (-0.02) RELAX Aim: Inclusion criteria: Intervention: 1 endpoint:  No differences in clinical rank Redfield et al.55– -0.

. 2014 To assess the Symptomatic HF.99.1%). 0. Inc.0) chronotropic incompetence in  More worsening of renal study population. the American Heart Association. 95% CI: 0.HF Hospitalization spironolactone vs.2% vs.04) ● New England . 22.2017 Heart Failure Focused Update Data Supplement    Double-blind PCWP IQR -0.04. or (12.722)  Composite of CV mortality.70–1.89. Specific co- existing conditions.2% vs.047) Hg and >180 mm Hg..83. pts with HFpEF. HR: 24716680 spironolactone in ≥45% stratified Comparator: aborted cardiac arrest. and acute events 39 © 2017 American College of Cardiology Foundation. placebo  Increased hyperkalemia (18.69–0. MMI or revascularization within 60 d. reduced with spironolactone 206 (83) effects of Age ≥50y. eGFR <20 mL/min TOPCAT Aim: Inclusion criteria: Intervention: 1 endpoint and results:  HF hospitalization was Pitt et al.7% Research Institutes Study type: within past y 320 (18.723)  No difference with p=0. according to Placebo (1.6%) vs. 7.0%) with outcomes by 3. and the Heart Failure Society of America. 351 vs. p=0.Elevated NPs (20. 245 (14.5 mg/dL).77–1. Size: Exclusion criteria: function in sildenafil group 216 Systolic BP <110mm (p=0. 9. systemic illness with life expectancy <3 y.138) and more doubling of creatinine differences in Size: Exclusion criteria: (10.0%) vs. 95% hypokalemia (16. decreased Post-hoc analysis RCT .for (eGFR <30 or reference list only creatinine >22 μmol/L (2. meds. LVEF HF hospitalization.2%).445 Renal disease spironolactone geography .4%). HR: 0. Spironolactone (1.9%) that captures CI: 0.

Study type: post-MI and those Or standard therapy (301) placebo 0.10 vs. p=0. 95% CI: deceleration time. 95% CI:  Gynecomastia in 2. relative to placebo (0.6 mm Hg.2017 Heart Failure Focused Update Data Supplement    TOPCAT Regional Aim: Inclusion criteria: Intervention: 1 endpoint and results:  Spironolactone had markedly Analysis To assess regional Symptomatic HF.2. and increase within past y (29.12) in Russia/Georgia.04. 0. p=0.3).026) in the Americas events and 1.03) 0. outcomes and their assessment.08 mmol/L).249)  All-cause mortality and HF mean difference −5. greater effects on BP (4.001) that captures RCT in Russia/Georgia. HR <3 y.  HF Hospitalization  1 outcome events in 522 vs.4/100 pt y and creatinine >22 12. placebo existing conditions.17) interventricular relaxation time or asymptomatic  Reduced risk of HF  Renal failure in 1.02 Post-hoc analysis Study type:  Elevated NPs Americas and 149 (8. heterogeneity of trial MRAs (12. pts that assessed at 0. the American Heart Association. 2015 differences in the Age ≥50y. Spironolactone (1. 0. Specific co.5%) pts in the in creatinine (0.5 mg/dL). pts with LVEF Comparator:  No difference in all-cause  MRA’s improved echo indices of ≥40% (including Placebo (2.. LVEF HF hospitalization. meds.861) mortality (RR: MRAs vs. placebo 0. Meta-analysis with symptomatic Or active comparator (31) 0.98. Chen et al.82.722)  Composite of CV mortality.19% of pts with Size: HF) with a study hospitalization (RR: MRA MRAs vs. and acute p=0.3% least 1 clinical  Limitations: discrepancies in outcome of 1 Safety endpoint : definitions of HFpEF in different interest.98. p<0.3/100 pt y in with life expectancy Russia/Georgia. p<0.001. 95% CI: 25598008 MRAs in pts with that enrolled adult hospitalization −8. HFpEF. 0. 95% CI: 0. 0.428 duration of ≥4 mo vs.445 (eGFR <30 or placebo 10.83.51. LV function: E/e’. or Hg drop vs.69–0. E/A ratio.10 95% CI: 0. (84) effects of ≥45% stratified Comparator: aborted cardiac arrest p<0.81%R vs. spironolactone vs. 2015 Aim: Inclusion criteria: Intervention: 1 endpoint and results:  MRAs improved QOL (weighted (85) To assess effects of Prospective.39% 14 RCTs with 6.9%) mg/dL.70–0. .2%.90.26 mmol/L pts with HFpEF. p=0. 1  Limitations: post-hoc analysis differences in Exclusion criteria: outcome event rates with outcomes by Size: Renal disease spironolactone and geography 3. and the Heart Failure Society of America.723) across regions.0– −2. RCTs MRAs (3.79– 1. Americas and 2. Inc. potassium change 25406305 spironolactone in according to Placebo (1.2% vs. 0.5/100 pt y systemic illness and 2.2 mm Pfeffer et al.6/100 pt y in the μmol/L (2. 6.78–1.  More hyperkalemia with trials. 1 outcome results driven by 40 © 2017 American College of Cardiology Foundation.001) including follow-up duration.

dyspnea due to noncardiac causes.64–0.77. NT-pro BNP Valsartan (152) compared to valsartan 36 wk in LCZ676 group compared >400 pg/mL 0. perhaps because CVD needed 20% in valsartan group this was an entry criterion. & Adverse Events (# patients) 95% CI) 41 © 2017 American College of Cardiology Foundation.001)  Reduction of LA size at 36 wk in RCT Previous EF <45%. 2012 To address safety Pts ≥40 y of age..2017 Heart Failure Focused Update Data Supplement    TOPCAT PARAMOUNT Aim: Inclusion criteria: Intervention: 1 endpoint:  Effect persisted after adjustment Solomon et al. 95% CI: 0. Study Type. OR or RR. LCZ676 group compared to isolated right HF. Author.   Data Supplement D. . HF. Patient Population Study Intervention Endpoint Results Relevant 2 Endpoint (if any). Size: noncardiac Serious adverse events  BNP levels higher than in other 308 dyspnea. LCZ696 (149)  Change in BNP at 12 wk for more lowering of BP in LCZ676 (61) and efficacy of LVEF ≥45%. the American Heart Association. Study Limitations.92.  Greater reduction with group 22932717 LCZ696 in pts with NYHA class II-III Comparator: LCZ696 (ratio of change  Improvement in NYHA class at HFpEF. revascularization (p=NS) <3 mo Right HF due to pulmonary disease. Study type: Exclusion criteria: p=0. Date: Some studies added by chairs in December 2015. others added by the writing committee. CAD or CVD needing revascularization within 3 mo of screening. RCTs Comparing Anemia (Section 9. Aim of Study. Inc. CAD or 15% in LCZ676 group and HFpEF trials. (# patients) / (Absolute Event Rates. Year Published Study Size (N) Study Comparator P values.2) Study Acronym. to valsartan. 1 Safety endpoint: valsartan. and the Heart Failure Society of America. valvular/myocardial disease.

PGA. Inc. Study type: ferritin 100–  Assessed at wk 6. 12. time to first hospitalization transfusion.. LVEF≤45%. ID Placebo (152) distance FCM vs. HTN. to death for any CV reason. Hb <15 hospitalization for any CV reason.19–0. .002)  KCCQ <100 ng/mL. from BL to wk 24  PGA 25176939 term FCM in iron. infection. the American Heart Association. placebo of  Fatigue score HF defined as ferritin 33±11 m (p=0. 2015 To assess benefits Pts at least 18 y. rate of Research <20%. FCM (152)  Change in 6MWT distance  Changes in NYHA class (86) and safety of long NYHA class II or III. Size: mg/dL and rate of hospitalization due to 304 worsening HF. 6 MWD up to 52 wk  Significant reduction in the risk of hospitalizations for deteriorating HF. or  EQ-5D ● Vifor Inc. and the Heart Failure Society of America.2017 Heart Failure Focused Update Data Supplement    CONFIRM-HF Aim: Inclusion criteria: Intervention: 1 endpoint: 2°Endpoints: Ponikowski et al.82) (p=0. QoL and Fatigue scores. uncontrolled HF. Exclusion criteria:  Time to first hospitalization for any Pts in need of reason. 36. and time impaired liver or to death due to worsening HF. 52 ● ICON Clinical RCT (1:1) 300 ng/mL if TSAT  Rate of any hospitalization. renal function Results:  Significant improvements in NYHA class. time malignancy.  Time to death for any reason.39 (95% CI: 0. Comparator:  Results: Change in 6MWT  6MWT distance deficient pts with elevated NPs. HR: 0. 24.009)  Preserved treatment effect across subgroups  No differences in adverse events when compared to placebo  Study was not designed to test morbidity and mortality outcomes of the ID therapy with FCM 42 © 2017 American College of Cardiology Foundation. if not for any CVCV reason and time to able to complete first hospitalization due to worsening 6MWT.

001) Study type:  NYHA class at 24 wk RCT (2:1) Exclusion criteria:   Results: improvement in the  Uncontrolled HTN FCM arm compared to Size: placebo  Other clinically 459  47% with NYHA I or II vs.001) 19920054  intravenous iron  LVEF ≤40% (for pts was corrected (n=304) FCM group compared to Mean improvement in 6MWT of (FCM) on HF in NYHA class II) or placebo 35±8m at 24 wk (p<0. Comparator: for worsening HF and anemia. Significant improvement in the EQ- without anemia. and the Heart Failure Society of America. 28% (OR for 12 wk and ID.13. 2009 To evaluate the  Chronic HF Ferric carboymaltose 200 mg  PGA at 24 wk PGA and NYHA at wk 4 and 12 (87) effects of  NYHA class II or III. 1 Safety endpoint: Trend towards fewer HF hospitalizations in the FCM group (p=0.001) impaired liver or   renal function.90– Size: Transferrin saturation 1.0–12.87) 2. 5D and in KCCQ   ID p<0. 95% CI: 1. darbepoeitin alfa group vs. LVEF≤40%. weekly until hemoglobin  Results: improvement in the (p<0.75–3.51. on guideline. BP treatment group (p=0. 2013 To assess effects of NYHA class II. 2. bleeding or other causes of 1 Safety endpoint : anemia.40. III.01.278 <15%. serum  Increased thromboembolic creatinine >3 adverse events in the mg/dL.. the American Heart Association.08) RED-HF Aim: Inclusion criteria: Intervention: 1 endpoint:  Limitation: pts with severe anemia Swedberg et al. . or Darbepoetin alfa (1. p<0.001). Placebo (1.55– significantly 3.01).61. RCT 562 in the placebo group Exclusion criteria: (HR: 1. Placebo (n=155) improved vs. 2. p=0.71. significant heart   disease 30% in the placebo arm  Inflammation (OR for improvement by 1  Clinically class.0 g/dL. 95–135 g/L 95% CI: 1. 43 © 2017 American College of Cardiology Foundation. Inc. with and  Hemoglobin level being in a better rank.142)  Results: 1 outcome ● Amgen recommended HF occurred in 576 pts in the Study type: treatment.136)  Composite of death from were excluded (88) darbepoetin alfa on IV HF. also symptoms in pts ≤45% (for pts in Comparator:  50% much or moderately significant improvements at 4 and with systolic HF NYHA class III).2017 Heart Failure Focused Update Data Supplement    FAIR-HF Aim: Inclusion criteria: Intervention: 1 endpoint:  Improvement in the FCM group in Anker et al. any cause or hospitalization 23473338 pts with systolic HF Hgb: 9. 95% CI: 0.

960 pts) enrolled 1 Outcomes: Study Limitations: (89) To assess the RCTs with different only pts with DM and 6 Major CV events. albuminuria: 10% (95% CI: 3.to enrolled pts had vascular analysis macroalbuminuria and disease. 22).2017 Heart Failure Focused Update Data Supplement    >160/100 mm Hg. RCTs Comparing HTN (Section 9.. however.989 19 trials with 44. 3. & Adverse Events (# patients) 95% CI) Xie et al. Exclusion Criteria: retinopathy in pts with DM. Data Supplement E. No significant increase in fatal/nonfatal strokes in treatment group and similar cancer-related adverse events between groups Date: Chairs selected trials in December 2015.960 pts with DM were 26559744 efficacy and safety BP targets or trials (2. 2016 Aim: Inclusion Criteria: 5 RCTs (6. Year Published Study Size (N) Study Comparator P values.960 of the 44. and the Heart Failure Society of America.989 pts. renal disease or DM. 44. follow-up. CKD and/or vascular the less intensive group. included in the total study size of of intensive BP different BP specifically recruited pts separately and combined. One trial added by writing committee. ESRD. stroke: 22% (95% CI: 10. OR or RR. However. more 44 © 2017 American College of Cardiology Foundation. . ria or change from micro. Author. (# patients) / (Absolute Event Rates. only 6. 16). Only 6.8 y of follow. 32). Study Limitations. outcome. for DM was provided. lowering treatment group had the outcome benefits were mean BP 133/76 mm Hg qualitatively most striking for pts compared with 140/81 mm Hg in with DM.989 assess a different Results: pts had DM and no subanalysis pts. the American Heart Association. defined as MI. MI: 13% (95% CI: 0. Patient Population Study Intervention Endpoint Results Relevant 2 Endpoint (if any). target or relevant Pts in the more intensive BP. Size: Trials that did not However. up. Intensive BP-lowering treatment achieved RR reductions for major CV events: 14% (95% CI: 4. Inc. and retinopathy progression: 19% (95% CI: 0–34). more vs. nonvascular and all-cause strategies.809 pts) stroke. disease. less mortality. lowering changes between with CKD. 24). new onset The absolute CV benefits were Study Type: with at least 6 mo microalbuminuria/macroalbuminu greatest in trials in which all SR and meta. Study Type.5) Study Acronym. HF or CV death. and adverse Conclusions: intense therapy events. Aim of Study.

2017 Heart Failure Focused Update Data Supplement 
 

intensive treatment had no clear
effects on HF: RR: 15% (95% CI:
-11, 34), CV death: 9% (-11, 26),
total mortality: 9% (95% CI: -3,
19), or ESRD: 10% (95% CI: -6,
23). The reduction in major CV
events was consistent across pt
groups, and additional BP
lowering had a clear benefit even
in pts with SBP <140 mm Hg. The
absolute benefits were greatest in
trials in which all enrolled pts had
vascular disease, renal disease,
or DM. Serious adverse events
associated with BP lowering were
only reported by 6 trials and had
an event rate of 1·2% per y in
intensive BP lowering group pts,
compared with 0.9% in the less
intensive treatment group (RR:
1.35 (95% CI: 0.93, 1.97)).
Severe hypotension was more
frequent in the more intensive
treatment regimen (RR: 2.68
(95% CI: 1.21, 5.89), p=0·015),
but the absolute excess was
small (0.3% vs. 0.1% per pt-y for
the duration of follow-up).
SPRINT Aim: Inclusion criteria: Intervention: 1 Endpoint: Summary:
Wright et al. 2015 To test the SBP ≥130 mm Hg, Intensive BP lowering  Composite of MI, non-MI ACS,  More intensive SBP lowering to
(90) effectiveness of a with upper limit treatment to goal SBP stroke, ADHF, CV death; HR: a goal of <120 mm Hg with
26551272 goal SBP <120 varying as number <120 mm Hg (4,678) 0.75 (95% CI: 0.64, 0.89) achieved mean of ~121 mm Hg
mm Hg vs. a goal of pre-trial BP- resulted in less CVD and lower
SBP <140 mm Hg lowering meds Comparison:  Lower BP target reduced total mortality over 3.26 y in
for the prevention increased.  Standard BP lowering composite outcome 243 pts comparison with a goal SBP
of CVD in pts with Age ≥50 y treatment to goal SBP (1.65%/y) vs. higher target 319 <140 mm Hg and achieved SBP
SBP ≥130 mm Hg Presence of at least <140 mm Hg (4,678) (2.19%/y), HR: 0.75; 95% CI: of ~135 mm Hg.
at BL. 1:  Net treatment difference 0.64–0.89; p<.001) and death:  There were small increases in
 Clinical or ~3 drugs (2.8) on average lower target 155 vs. 201, HR: some expected SAEs. Perhaps
Study type: subclinical CVD vs. 2 drugs (1.8) on 0.73; 95% CI: 0.60–0.90; unexpected, a sizable increase

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© 2017 American College of Cardiology Foundation, the American Heart Association, Inc., and the Heart Failure Society of America.

2017 Heart Failure Focused Update Data Supplement 
 

RCT  CKD stage 3 or average p=0.003) in reduced eGFR in the non-CKD
greater  During the trial, mean group and AKI/ARF overall was
Size:  Age ≥75 SBP was 121.5 vs. 134.6. observed in the intensive group.
9361 pts followed  Framingham Other endpoints: While of uncertain etiology and
median of 3.26 y. General CVD risk  Total deaths HR: 0.73 (95% CI: significance, there is speculation
≥15% in 10 y 0.60–0.90) this could be an acute
 1 or death HR: 0.78 (95% CI: hemodynamic effect, especially
Exclusion criteria: 0.67–0.90) given the findings regarding
DM, history of  Components of 1 composite albuminuria.
stroke, ESRD mostly consistent in direction  Low target significantly reduced
(eGFR <20 other than ACS – no difference. HF: HR: 0.62 (95% CI: 0.45–
mL/min), 0.84; p=0.002)
anticipated survival CKD outcomes:  No difference in composite or
<3 y  1 in CKD pts: reduction in GFR individual renal outcomes with
of ≥50% or ESRD HR: 0.89 (95% lowering of BP
CI: 0.42, 1.87)
 Incident albuminuria HR: 0.72
(95% 0.48, 1.07) Limitations:
 In pts without CKD: reduction in Few pts were untreated at BL
GFR ≥30% and to <60 ~9%, so SPRINT provides little if
 HR: 3.49 (95% CI: 2.44–5.10) any insight at present regarding
 Incident albuminuria HR: 0.81 BP lowering medication initiation
(95% CI: 0.63–1.04) for untreated people with SBP
130–139.
Adverse events:
 SAEs: 1.04, p=0.25
 Significant absolute increases
seen in intensive group for
hypotension (1%), syncope
(0.6%), electrolyte abnormality
(0.8%), AKI/ARF (1.6%) over the
study period.
 1.7% fewer pts had orthostatic
hypotension in intensive group,
p=0.01.

46

© 2017 American College of Cardiology Foundation, the American Heart Association, Inc., and the Heart Failure Society of America.

2017 Heart Failure Focused Update Data Supplement 
 

SPRINT Senior Aim: Inclusion: Intervention: 1 endpoint: Limitations:
Williamson et al. Intensive SBP goal Men and women age Medications and dietary Composite CVD outcome (AMI, Does not apply to nursing home
2016 <120mmHg) vs 75+; mean age advice to achieve SBP of non-MI ACS, Stroke, HF, CVD patients or those with dementia
(91) standard (SBP 79.8 y; 38% <120 mm Hg death.
27195814 goal <140) women; 17% Conclusions:
black, 74% Comparator: Results: 102 events in the Intensive SBP is safe and effective
Study Type: Caucasian; Medications and dietary intensive treatment group vs 148 for lowering CVD events and
RCT Exclusions: advice to achieve SBP of events in the standard treatment total mortality in persons age 75
Nursing home <140 mm Hg group; HR: 0.66; and older
Size: residents; 95%CI: 0.51–0.85 and all-cause
2,636 diabetes, Stroke, Achieved SBP: mortality (73 deaths vs. 107
symptomatic HF in Intensive= 123.4 mm Hg deaths, respectively; HR: 0.67;
30% met criteria for past 6 mo or EF Standard= 134.8 mm Hg 95%CI: 0.49–0.91. No significant
being classified as <35%, dx or difference in falls, orthostatic
ambulatory frail treatment of hypotension, or overall SAEs.
dementia, NNT for primary outcome=27 and
Mean follow-up: unintentional wt NNT for all-cause mortality=41
3.1 y loss >10% in past
5 mo. SBP<110
after standing 1
min, expected
survival <3y
TOPCAT Regional Aim: Inclusion criteria: Intervention: 1 endpoint and results:  Spironolactone had markedly
Analysis To assess regional Symptomatic HF, Spironolactone (1,722)  Composite of CV mortality, HF greater effects on BP (4.2 mm
Pfeffer et al. 2015 differences in the Age ≥50y, LVEF hospitalization, or aborted cardiac Hg drop vs. 0.6 mm Hg; p<0.001,
(84) effects of ≥45% stratified Comparator: arrest across regions. potassium change relative to
25406305 spironolactone in according to Placebo (1,723)  1 outcome events in 522 placebo (0.26 mmol/L vs. 0.08
pts with HFpEF.  HF Hospitalization (29.5%) pts in the Americas and mmol/L), and increase in
within past y 149 (8.9%) in Russia/Georgia. 1 creatinine (0.10 vs. 0.02 mg/dL;
Post-hoc analysis that Study type:  Elevated NPs outcome event rates with p<0.001)
captures RCT spironolactone and placebo  Limitations: post-hoc analysis
differences in Exclusion criteria: 10.4/100 pt y and 12.6/100 pt y in
outcomes by Size: Renal disease the Americas and 2.5/100 pt y
geography 3,445 (eGFR <30 or and 2.3/100 pt y in
creatinine >22 Russia/Georgia. HR
μmol/L (2.5 spironolactone vs. placebo 0.82;
mg/dL), systemic 95% CI: 0.69–0.98; p=0.026) in
illness with life the Americas and 1.10 95% CI:
expectancy <3 y. 0.79–1.51; p=0.12) in
Specific co-existing Russia/Georgia.
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© 2017 American College of Cardiology Foundation, the American Heart Association, Inc., and the Heart Failure Society of America.

892 pts. 2009 Study type: Inclusion criteria: 1 endpoint:  With the exception of the extra (92) Meta-analysis of use The database CAD events. In 27 trials in reduction in BP. and 37 included the trials in which beta trials of other Cochrane blockers were used after antihypertensive Collaboration and long term CAD. Results: minor additional effect of CCBs in prevention of CVD Dec..000 CAD events or used after acute MI. and mo. beta and previous meta. meds. beta of BP lowering drugs have a randomized trials identify blockers reduced CAD similar effect in reducing CAD randomized trials events 29% (95% CI: events and stroke for a given Size: of BP lowering 22%–34%).395 databases and the reduced CAD events pts citations in trials 13%. 37 trials of strokes were blockers reduced CAD beta blockers in recorded. Stroke was reduced 38% (95% CI: 28%–47%) in 10 48 © 2017 American College of Cardiology Foundation. review articles. all the classes from 147 language) to history of CAD.. blockers reduced stroke analyses and 17% (95% CI: 1%–30%). Inc. In 7 trials. CAD events were reduced 14% (95% CI: 2%–25%) Exclusion criteria: in 11 trials of thiazide Trials were diuretics. 2007 in any In 37 trials of pts with a preventing stroke. and acute events Law et al. events and strokes insignificantly 14% in 4 or if treatment trials of angiotensin duration was <6 receptor blockers.2017 Heart Failure Focused Update Data Supplement    conditions. 17% (95% CI: excluded if there 11%–22%) in 21 trials of were <5 CAD ACE inhibitors. . The events 31% (95% CI: CAD included search also 24%–38%). the American Heart Association. Of 147 randomized drugs in which which beta blockers were trials of 464. 15% (95% CI: 8%–22%) in 22 trials of CCBs. and in 11 38. beta pts. stroke protective effect of beta blockers 19454737 of BP lowering search used given shortly after a MI and the drugs in Medline (1966. beta drugs in CAD Web of Science blockers insignificantly included 85. and the Heart Failure Society of America.

and LVEF ≥40% treatment with propranolol multivariate Cox regression increased by propranolol from no propranolol on and HF NYHA analysis showed that compared 57% to 63% (p<0.63. the American Heart Association.66–1.6 m follow-up.5-mo follow-up. a CV cause in pts and quality of life with HFpEF 49 © 2017 American College of Cardiology Foundation. and 34% (95% CI: 25%–42%) in 9 trials of CCBs.047) by candesartan placebo in pts with HFpEF and NYHA candesartan or placebo hospitalization for HF was HFpEF class II-IV HF reduced 11% (p=0.018) was stopped because of adverse All pts continued diuretic effects in 11 of 79 pts (14%) and ACE inhibitor therapy. or placebo hospitalization for CV cause was of death from HF or cause mortality or or IV HF reduced 5% by irbesartan hospitalization for HF.62–1.023 pts were At 36.2017 Heart Failure Focused Update Data Supplement    trials of thiazide diuretics.33) for or to placebo 1.001) and LV mortality plus class II or III Comparator: with no propranolol..84 (95% 19497441 placebo in pts with HFpEF history of HFpEF were CV hospitalization was reduced CI: 0. 1997 Aim: Inclusion criteria: Intervention: 1 endpoint: Relevant 2 Endpoint: (93) To determine effect Pts ≥62 y with MI 79 pts were randomized to At 32-mo mean follow-up.35) any cause and from CV causes. propranolol mass was decreased by nonfatal MI in pts treated with 79 pts were randomized to reduced mortality 35% (p=0. Van Veldhuisen et al. 2008 Aim: To determine Inclusion criteria: Intervention/Comparator 1 endpoint: Relevant 2 Endpoint: (80) the effect of Pts 60 y and older 4. the primary Irbesartan did not significantly 19001508 irbesartan vs.91 (95% CI: 0. .04) in pts with HFrEF and 19% HFpEF (95% CI: 0. 2003 Aim: To determine Inclusion criteria: Intervention/Comparator: 1 endpoint: Relevant 2 Endpoint: (78) the effects of 3. Aronow et al. HF and HFrEF or HFrEF and 752 pts with a endpoint of all-cause mortality or mortality by nebivolol: 0. death from hospitalization for (p=0. At 1-y follow-up. age 67 y. with randomized to outcome of CV death or (p=0. mean 3.08) for HFrEF and HFrEF and HFpEF randomized to nebivolol by nebivolol 14% (95% CI: 0.023 pts. and the Heart Failure Society of America.001) Propranolol HFpEF inhibitors for 2 mo 37% (p=0.72– 0. and mortality plus nonfatal MI 278 grams (p=0. Inc. the primary HR for reduction of all-cause (94) nebivolol vs.128 pts were At 49. 1. Aim: To determine Inclusion criteria: Intervention/Comparator: 1 endpoint: Relevant 2 Endpoint: 2009 the effect of Pts ≥70 y history of 1. 22% (95% CI: 8%–34%) in 13 trials of angiotensin- converting enzyme inhibitors. III.118) by candesartan Massie et al. LVEF was 9230162 of propranolol vs. the primary Hospitalization was reduced 16% 13678871 candesartan vs. with HFpEF and randomized to irbesartan outcome of all-cause mortality or reduce the secondary outcomes placebo on all.04) in pts with HFpEF Yusuf et al.359 pts with a history of At 21-mo follow-up. NYHA class II.03) propranolol from 312 grams to with prior MI and diuretics and ACE no propranolol.

. mean At 8. less  Stroke RR: 0. .5/4.127 pts) active vs.051 Date: Chairs selected trials in October 2016. 95% CI: 0. amlodipine.5) Study Acronym. Meta-analysis of 16 trials (52.  Data Supplement F.79. 2011 Aim: Inclusion criteria: Intervention/Comparator 1 endpoint: Relevant 2 Endpoint: (76) To determine 1.68–0. 95% CI: 0. difference. and (84%) and for those with HFpEF HF in ALLHAT during ALLHAT lisiopril.97 Stratification of SBP cutoffs (150.9-y mean follow-up.5 mm Hg BP More intensive strategy for BP (95) randomly assigned total of 37. Intensive BP control reduced cardio-renal end 23798459 individuals to lowering achieved. placebo  Major CV events RR: 0. 1. 95% CI: 0. 95% CI: 0%–34% p=0. 2013 MA of RTC that 15 trials including a 7. 95% CI: 3%–18%  Albuminuria: 10%. and the Heart Failure Society of America.71.80. the American Heart Association. 10-y adjusted rates for (81%) with no significant mortality were 86% for differences by randomized amlodipine.761 pts.84) outcomes compared to less intense (96) versus less intense treatment 34  Coronary heart disease RR: 0. Post-HF all-cause mortality was All-cause mortality rates were 21969009 mortality rates in age 70 y.95) be associated with CV benefit.348 of 1.60–0. and treatment arm 83% for chlorthalidone Lv et al.68–  Achieved BP of <130/80 mm Hg may 26848994 intense BP control (138. 95% CI: 8%–37%  ESRD: 11%.85  CV mortality RR: 0. Inc. or RR & 95 % CI) Year Published Study Size (N) Thomopoulos et al. point different target BP RR for levels  Major CV events: 11%. 0. Patient Population Primary Endpoint and Results (P values. OR Summary / Conclusion / Comments Author. Aim of Study. 95% CI: 0%– 25%  Stroke: 24%.761 pts (77%) similar for pts treated with similar for those with HFrEF pts who developed developed HF with HF died chlorthalidone. 87% for lisinopril.. Nonrandomized Trials for Hypertension (Section 9.348 pts.63–0. 95% CI: 0.2017 Heart Failure Focused Update Data Supplement    Piller LB. et al. 140 and 130 50 © 2017 American College of Cardiology Foundation.75. Study Type.235 pts) More intense BP  Intensive BP reduction improves CV 2016 RCT’s of more compared more vs. 95% CI: 1%–21%)  MI: 13%. 95% CI: 4%–16%  Retinopathy 19%.

2016 To whether  Adults 45 .717 15.0–3. .6) Study Intervention Endpoint Results Study Acronym. HR: 1.2017 Heart Failure Focused Update Data Supplement    mmHg) showed that a SBP/DBP difference of _10/_5mmHg across each cutoff reduced risk of all outcomes Date: Chairs selected trials in October 2016.75 y of age CPAP treatment Composite of death from CVD. and the Heart Failure Society of America. Patient Population Study Limitations. (# patients) / (Absolute Event Rates. n=207.91–1.  CPAP significantly reduced snoring and daytime sleepiness and improved health-related quality of life and mood.  Other CV outcomes (97) treatment with  Moderate-to-severe OSA plus usual care stroke. Aim of Study.32. 29. 17. MI. 95% CI: 0.0% vs..7  Primarily men with run-in on sham y. p=0. & Year Published Study Size (N) Adverse Events (# patients) 95% CI) SAVE Aim: Inclusion criteria: Intervention: 1 endpoint: Secondary end points: McEvoy et al. 25965712 diagnosed AF • Composite of first event of CV Study Limitations: 51 © 2017 American College of Cardiology Foundation. Author.34). N/A (98) frequency of • Electrocardiographic evidence of Comparator: N/A • First all-cause hospitalization. the American Heart Association.3 h/night.  Data Supplement G. RCTs Comparing Treatment of Sleep Disorders (CPAP makers) (Section 9.  No significant difference in any individual or other composite CV end point. 2015 1) Define • >18 years of age • All-cause mortality.10 with CPAP.7 events/h moderate-to-severe OSA CPAP  Primary endpoint – no significant and minimal sleepiness difference in CPAP vs usual-care Size: group (n=229. Inc. Relevant 2 Endpoint. or TIA  Snoring symptoms major CV disease  Daytime sleepiness events. Study type: (usual-care AHI events/h decreased from Study Limitations: RCT with 1 wk group) baseline to end of follow up at 3. or hospitalization for UA. Study Type.4%. Comparator: Results:  Mood Exclusion criteria: Usual care alone  Duration of CPAP=3. ORBIT-AF Aim: Inclusion criteria: Intervention: N/A 1 endpoint: Secondary end points: Holmqvist et al. Adverse Events: n=2. Study Comparator P values. OR or RR.  Health-related quality of life 27571048 CPAP prevents  Coronary or cerebrovascular (CPAP group) HF.

p=. p=. accounted for in data CPAP 1.12. Inc. descriptive. and the Heart Failure Society of America. death. 0.46-0.77-1. representative 95% CI. correlational / o First major bleeding (HR.18. 95% CI. 95% CI.22.selection & AF • Life expectancy of <6 months or registry or MI. & events/100 patient-years • Maturation – changes in 3) Determine among patients without OSA subjects over 2 years not whether [adjusted hazard ratio (HR).03-1. 1.51). p=. b) Arrhythmic OSA associations w/ outcomes • No data on average AF • Higher risk of: duration of CPAP use per progressi o Hospitalization (43 vs 35 night on. • 18% (n =1.34. stroke/non–central • Voluntary.06.15. 6-month CPAP treatment association w/ intervals for outcomes in patients w/ AF & minimum of 2 OSA years Less likely to progress to more permanent forms of AF versus Size: Nationally patients w/out CPAP (HR.selection & is associated Results: reporting biases w/: Frequency of diagnosed OSA o OSA diagnosis made on a) Worse among nationwide AF population basis of physician report outcomes. 52 © 2017 American College of Cardiology Foundation. the American Heart Association. 1.2017 Heart Failure Focused Update Data Supplement    OSA among Multicenter.07. 1.94.57). study .96-1.54). observational nationwide Exclusion criteria: ambulatory-based nervous system embolism. TIA. or MI • Prospective (HR. . p=. o Composite of CV death.28.66. p=. 95% confidence interval treatment is (CI). 0. 95% enrollment & CI. stroke/non–central nervous Study type: system embolism.0078] Adverse Events: associated w/ • No higher risk of: N/A outcomes in o Death (HR. AF secondary to reversible • First major bleed within 2 years o No randomization - 2) Determine conditions of baseline enrollment in registry Voluntary. reporting biases population.. patients w/ 0.89-1. TIA. 0.46. comparative.11) time-series OSA associations w/ AF design progression • Data • Not associated w/ higher risk of collection at AF progression (HR. p=.841) & medical records. 1. 0. observational whether OSA study . 0.94.021). 95% CI.85-1. 0. AF & OSA.

2017 Heart Failure Focused Update Data Supplement 
 

sample enrolled
consecutively
• n=10,132 w/
AF
o n=1,841 w/
AF & OSA
o n=1,837
patients w/
OSA &
complete
CPAP data
o n =1,763
patients w/
OSA & 2-
year
outcomes
data
o n=937
patients w/
AF, OSA, &
CPAP
treatment

Sites: 176
national sites
that w/ provider
& geographic
heterogeneity
SERVE-HF Aim: Inclusion criteria: Intervention: 1 endpoint: 2 Endpoint
Cowie et al. 2015 Effects of  Chronic HF (defined as ≥12 wk Adaptive servo  Death from any cause  CV death
(99) adaptive servo- since diagnosis) according to ventilation use  Lifesaving CV intervention  Unplanned hospitalization
26323938 ventilation in current ESC guidelines ≥5h/night, 7d/wk. (cardiac transplantation, from any cause
HF pts with  LVEF ≤45% (n=666) implantation of a ventricular assist  Time to death from CV
 ResMed reduced EF  Hypopnea index of ≥10/h device, resuscitation after sudden causes
 The Clinical and CSA  Stable, GDMT Comparator: cardiac arrest, or appropriate  Change in NYHA class
Research Institute  NYHA class III or IV, or NYHA GDMT (n=659) lifesaving shock) or  Change in 6-MWT (both at
GmbH Study type: class II with ≥1 hospitalization for  Unplanned hospitalization for HF follow-up visits).
RCT HF in the last 24 mo Significant Results  General QoL (EuroQOL)
 No hospitalization for HF in 4 wk  All-cause mortality was higher  HF-specific QoL (MLWHF)
Size: prior to enrolment with the intervention (34.8%) than  Daytime sleepiness
53

© 2017 American College of Cardiology Foundation, the American Heart Association, Inc., and the Heart Failure Society of America.

2017 Heart Failure Focused Update Data Supplement 
 

1,325  Optimized GDMT control (29.3%; HR: 1.28; 95% CI: (Epworth Sleepiness Scale)
 No new class of disease- 1.06–1.55; p=0.01).
modifying drug for prior ≥4 wk  CV mortality was higher with the Limitations:
 AHI >15/h with ≥50% central intervention (29.9%) than control  Unblinded study - more
events and a central AHI ≥10/h (24.0%; HR: 1.34; 95% CI: 1.09– likely to favor treatment
1.65; p=0.006). group, particularly for QOL,
Exclusion criteria:  6MWT decreased over time and but no QOL improvement
 Significant COPD with a forced were significantly lower with the seen
expiratory volume in 1 s in 4 wk intervention than with the control  HF pts with reduced EF only
before randomization (p=0.02).  HF pts with predominantly
 O2 saturation ≤90% at rest during  Daytime sleepiness decreased CSA not obstructive sleep
d over time and was significantly apnea.
 Currently receiving PAP therapy lower with the intervention than  Sample had very limited # of
 Cardiac surgery, PCI, MI or UA with the control (p<0.001). women but reflects
within the previous 6 mo epidemiology of CSA with
 Cardiac resynchronization Non-Significant Results HFrEF
therapy implantation scheduled or  Unplanned hospitalization for HF
performed within 6 mo prior to was not significantly higher with
randomization the intervention (43.1%) than
 TIA or stroke within the previous control (41.3%; HR: 1.13; 95% CI:
3 mo 0.95–1.33; p=0.16)
 1 hemodynamically-significant  Of the lifesaving CV interventions,
uncorrected VHD (obstructive or none were significantly higher with
regurgitant) or any valvular the intervention than control
disease expected to require (p=0.08–0.61)
surgery during the trial;  Unplanned hospitalization for any
 Acute myocarditis/pericarditis cause was not significantly lower
within the previous 6 mo with the intervention (67.9%) than
 Untreated or therapy-refractory control (68.0%; HR: 1.05; 95% CI:
restless legs syndrome .92–1.20; p=0.47)
 Contraindication to the use of  The NYHA class change was not
AutoSet CS2 because of significantly different with the
symptomatic hypotension or intervention than with the control
significant intravascular volume (p=0.46)
depletion or pneumothorax or  General QoL trends were not
pneumomediastinum significantly higher with the
 Pregnancy intervention than with the control
(p=0.09).
 HF-specific QoL trends were not
significantly higher with the
54

© 2017 American College of Cardiology Foundation, the American Heart Association, Inc., and the Heart Failure Society of America.

2017 Heart Failure Focused Update Data Supplement 
 

intervention than with the control
(p=0.92).
CANPAP Aim: Inclusion criteria: Intervention: 1 endpoint: 2 endpoint:
Arzt et al. 2007 Investigate  Age 18 to 79 y  CPAP=CSA  Transplant free survival -  AHI
(100) whether  NYHA II-IV suppressed, n=57 Combined rate of all-cause  Mean nocturnal SaO2
17562959 suppression of  HF due to ischemic, hypertensive,  CPAP=CSA mortality & ht tx  LVEF
CSA below or idiopathic DCM suppressed, n=43
threshold by  Stabilized w/ optimal medical Significant Results Limitations:
CPAP would therapy for ≥1 mo Comparator: 1 endpoint:  Post hoc analysis
LVEF & ht tx–  LVEF <40% Control, n=110: Transplant free survival  Stratification of CPAP-
free survival.  CSA  Significantly different between 3 treated pts based on
groups (p=0.016) polysomnogram performed
Study type: Post Exclusion criteria:  Significantly higher in CPAP- 3 mo after randomization.
hoc analysis of  Pregnancy suppressed vs. control group  Because suppressed and
RCT (p<0.043)
 MI unsuppressed status could
 Unstable angina  No difference between CPAP- not be ascertained until
Size:100 unsuppressed vs. control group
 Cardiac surgery w/in 3 mo of completion of PSG, events
enrollment (p<0.26) that occurred during the first
 OSA 3 mo could not be included
2 endpoint:  The CPAP-CSA–
AHI suppressed group was
 AHI significantly > reduction in younger, had a lower AHI,
both CPAP-suppressed (p<0.001) and had a slightly lower
and CPAP-unsuppressed proportion of central events
(p<0.001) groups than the CPAP CSA–
 AHI significantly > reduction in unsuppressed group
CPAP-suppressed (p<0.001) and
CPAP-unsuppressed (p<0.002)
than control groups

Mean nocturnal SaO2
 Mean nocturnal SaO2 significantly
> increased in CPAP-suppressed
vs. control group (p<0.001)
 No significant difference between
CPAP-unsuppressed and control
group

LVEF

55

© 2017 American College of Cardiology Foundation, the American Heart Association, Inc., and the Heart Failure Society of America.

control groups (p≤0. 2005 treatment of  NYHA II-IV  No significant difference in  EF (101) CSA w/ CPAP  HF due to ischemia Comparator: No transplant free survival between  Frequency of apnea and 16282177 in HF pts  HTN.45) Study type: 11  EF: Significant increase in EF Exclusion criteria: Limitations: center RCT between CPAP vs. the American Heart Association. control groups  Pregnancy  Underpowered because trial  MI (p=0. difference between CPAP and  CSA w/ ≥15 AHI norepinephrine and atrial NP >50% of AHI had to be central. control (p<0.  No significant difference between CPAP-unsuppressed and control group (p=0.984) CPAP for CSA & HF Aim: Inclusion criteria: Intervention: 1 endpoint: 2 endpoints: (CANPAP) Test long-term  18-79 y CPAP n=128 Transplant free survival  Hospitalizations Bradley et al.016)  QoL: No significant difference between CPAP and control groups 56 © 2017 American College of Cardiology Foundation.001) groups.001)  6MWT: Significant increase in 6MWT between CPAP vs.. and the Heart Failure Society of America.54)  Mean nocturnal SaO2 optimal medical  Optimal medical therapy for 1+  6MWT therapy on mon 2 endpoints:  QoL combined rates  LVEF <40%  Hospitalizations: No significant  Neurohormones – of death & ht tx.2017 Heart Failure Focused Update Data Supplement     LVEF significantly increased over time in CPAP-suppressed group (p<0. control groups (p=0. Inc.006) and vs. CPAP- unsuppressed (p=0. control groups (p=0.001)  Mean Nocturnal SaO2  Significant increase between CPAP vs. Idiopathic DCM CPAP n=130 CPAP and control groups hypopnea episodes receiving  Stable condition (p=0. control groups (p=0. .001)  LVEF significantly increased in CPAP-suppressed vs.02) stopped early for low Size: 258  Frequency of apnea and  UA enrollment  Cardiac surgery within prior 3 hypopnea episodes mon. OSA  Significant reduction between CPAP vs.

CPAP n=97  AHI (central and obstructive)  Arousals from sleep (102) whether  NYHA II -IV  Mean and lowest SaO2  Sleep structure (time in 19189783 attenuation of HF due to ischemic.  Central OSA  Absence. the American Heart Association. stabilized on Control n=108 Significant Results total sleep time.001).04) but the data Study type:  Pregnancy improvement was significantly  Did not classify arousals as RCT  MI better in the CPAP vs. in last 3 mo. Comparator: bed.001) improves sleep hypopneas  Mean and lowest SaO2 improved Limitations: structure. periodic arousals from  CSA defined as an AHI ≥15. LVEF when awake saturation (%) 57 © 2017 American College of Cardiology Foundation.2017 Heart Failure Focused Update Data Supplement     Neurohormones: Norepinephrine  Significant reduction in CPAP vs. respiratory related.001) and  2 analysis of CANPAP Exclusion criteria: control (p<0. control groups (p=0. w/ and vs. Comparator:  LVESD hypopnea awake and  LVEF <45% by radionuclide Control n=12  Heart rate  Total daytime BP in angiography  Daytime BP  Obstructive pts with HF and  NYHA class II–IV. 2009 To determine  Age 18 . sleep period time. of HF Significant Results  Desaturation index (# hr of exacerbations while receiving sleep) Study type: optimal pharmacologic therapy at 1 endpoint:  Lowest oxyhemoglobin RCT highest tolerated doses. and the Heart Failure Society of America. 2003 Aim: Inclusion criteria: Intervention: 1 endpoint: 2 endpoint: (103) To determine the  HF due to ischemic or CPAP n=12  LVEF when awake  BMI 12660387 effect of CPAP nonischemic dilated CM for >6  LVEDD  Episodes of apnea and on LVEF when mo.009)  Atrial NP: No significant difference between CPAP and control groups Ruttanaumpawan et Aim: Inclusion criteria: Intervention: 1 endpoint: 2 endpoints: al. . percentage in frequency of angiography decreased significantly over BL each sleep stage. and did Size: not examine their timing..  Cardiac surgery within 3 mo of 205 2 endpoints: enrollment  OSA  No significant improvement in arousals from sleep or sleep structure within or between groups (p=0. in both the CPAP (p<0.99) Kaneko et al. the being respiratory or non-  UA control group (p<0. efficiency. sleep in pts w/ HF optimal medical therapy ≥1 mo In the CPAP group.14–0.79 y of age. sleep onset reduces the  LVEF <40% by radionuclide  Central and obstructive AHI latency. Inc. the control group leg movement index) sleep or >50% central apneas & (p<0. CSA by CPAP or idiopathic DCM. hypertensive.

 MI: LVESD Limitations:  Cardiac surgery within 3 mo of  Significant reduction in CPAP  No placebo enrollment (p=0. . and the Heart Failure Society of America.007) but not control group and difference between groups was significant (p=0.009) but not control group  Small sample size and difference between groups was significant (p=0.. the American Heart Association.02) Daytime BP  Significant decrease in systolic BP in CPAP (p=0.02)  Pts unblinded to group Heart Rate  Significant decrease in CPAP (p=0. group or between groups  Arousals/hr of sleep  UA.001) but not control group and difference between groups 58 © 2017 American College of Cardiology Foundation.008)  No significant difference in diastolic BP for either group or between groups 2 endpoint: BMI  No significant difference for either group or between groups Episodes of apnea and hypopnea Total  Significant reduction in CPAP (p<0.001) but not control group  Stage I and II sleep (% of which >50% were obstructive and difference between groups total sleep time) was significant (p=0.009)  Stage III and IV sleep (% of Exclusion criteria: total sleep time)  1 valvular heart disease. LVEDD  REM sleep (% of total sleep  Presence of implanted cardiac  No significant difference for either time) pacemaker.02) but not control group and difference between groups was significant (p=0.2017 Heart Failure Focused Update Data Supplement     OSA defined as ≥20 episodes of  Significant increase in CPAP  Total sleep time Size: 24 apnea and hypopnea /h of sleep of (p<0. Inc.

2017 Heart Failure Focused Update Data Supplement    was significant (p=0.01) Total sleep time  No significant difference for CPAP group or between groups Stage I and II sleep (% of total sleep time)  No significant difference for CPAP group or between groups Stage III and IV sleep sleep (% of total sleep time)  No significant difference for CPAP group or between groups REM sleep (% of total sleep time) 59 © 2017 American College of Cardiology Foundation.001)  Central  No significant difference for CPAP group or between groups Desaturation index (# hr of sleep)  Significant reduction in CPAP (p<0. Inc.001) but not control group and difference between groups was significant (p<0. and the Heart Failure Society of America. .002) Obstructive  Significant reduction in CPAP (p<0..001) but not control group and difference between groups was significant (p=0. the American Heart Association.004) but not control group and difference between groups was significant (p=0.008) Lowest oxyhemoglobin saturation (%)  Significant increase in CPAP (p=0.

003) but not control group and difference between groups was significant (p=0. BP may have effected end  UA. 2004 Aim: Inclusion criteria: Intervention: 1 endpoint: 2 endpoint: (104) To assess long. control between groups in peak Vo2 Study type: apnea and hypopnea /h of sleep of group (p=0.  HF due to ischemic or CPAP X 3 mo  LVEF  Peak Vo2 14597482 term effect of nonischemic dilated CM for >6 n=19  Overnight urinary norepinephrine  NYHA class OSA treatment mo.001) and vs. group (p<0.036) interventions initiated that pacemaker. BP.  Minimum SpO2 saturation sympathetic  Absence.03) Mansfield et al. and the Heart Failure Society of America.  Significant improvement in CPAP  Significant difference  OSA defined as ≥20 episodes of group (p<0. in last 3 mo.04) and mean BP at BL RCT which >50% were obstructive Overnight urinary norepinephrine  Dropout rate = 27% excretion  Higher than expected death Size: Exclusion criteria:  Significant reduction in CPAP rate 44  1 valvular heart disease. of HF Significant Results activity.. control  Higher than expected rate of  Presence of implanted cardiac group (p=0.01) 60 © 2017 American College of Cardiology Foundation. Inc.02) o Social (p=0.  NYHA class II–IV.05) and vs.03) o Mental health (p=0.  No significant difference in CPAP points  MI: group or between groups  Small sample size with only  Cardiac surgery within 3 mo of QoL 3 females enrollment  Significant improvements in most domains within CPAP group SF-36  Significant improvements between groups in 4/8 domains o Physical (p=0.2017 Heart Failure Focused Update Data Supplement     No significant difference for CPAP group or between groups Arousals/h of sleep  Significant reduction in CPAP (p=0. excretion  Epworth sleepiness scale with nocturnal  LVEF <45% by radionuclide Comparator:  BP  BMI CPAP on systolic angiography Control n=21  QoL  AHI events per h heart function.03) o Vitality (p=0. and exacerbations while receiving 1 endpoint: Limitations: QoL in pts with optimal pharmacologic therapy at LVEF  No placebo HF highest tolerated doses. . the American Heart Association.

and the Heart Failure Society of America.     61 © 2017 American College of Cardiology Foundation. control group (p=0. control group (p<0.001) Date: Study selected by the chairs in December 2015 and some trials added by the writing committee. control group (p=0.01) o Emotional well-being (p=0.01) BMI No significant difference CPAP group or between groups AHI events per h  Significant reduction in CPAP group (p<0..2017 Heart Failure Focused Update Data Supplement    Chronic HF questionnaire  Significant improvements between groups in 3/4 domains o Fatigue (p=0.001) Minimum SpO2 saturation  Significant improvement in CPAP group (p<0.02) o Disease mastery (p=0. Inc. the American Heart Association. .001) and vs.02) 2 endpoint: Peak Vo2  No significant difference in CPAP group or between groups NYHA class No significant difference CPAP group or between groups Epworth sleepiness scale  Significant reduction in CPAP vs.001) and vs.

77. digitalis lV.002)..0 Mortality by specific enalapril for ~3 y pts with chronic HF class lV). mean dose rest/NYHA class import aortic/MV mo mortality: 26% in enalapril group and 44% in placebo 2883575 class lV HF 80mg).001) except ACEI (ie. SOLVD+ pts with CI. 95% CI: 11% . Unstable angina. mortality considerably class IV HF treated CONSENSUS time from end of higher among pts not receiving with enalapril or -a RCT. ACE Inhibitors (Section 7.004). Cr>2. right HF b/c 80. Mortality Change in NYHA-FC. MI Incidence of MI. After study to death. SOLVD 1991 Study the effect of RCT Diuretics + Digoxin 2569.126 CAD 73% Severe APE.70% 3. Cr >300 mmol/L 10 y FU of Report on the 10-y open. 127. Severe. and the Heart Failure Society of America. 58 253 randomized Mortality 10 y 5 pts. AF: 8-12% 62 © 2017 American College of Cardiology Foundation. Averaged over the trial randomized in completion of from randomization (double-blind plus open-label 10099910 CONSENSUS.008). y (p=0. Year Therapy (Years) Pretrial standard N (Total) Ischemic/ Inclusion Criteria Exclusion Criteria Primary Secondary Endpoint 1st Year Mortality treatment NonIschemic Endpoint n (Experimental) n (Control) CONSENSUS To Evaluate influence RCT Diuretics 253. Mild Age >80 y. 15. (95% enalapril on mortality heart disease to severe Unstable angina. HR: surgery. planned cardiac nitrates 46%) BP: 120/75.0036) 2057034 and hospitalization in 72% (11% class l/<2% w/in past mo. 52% placebo group and 0. (1st a to death.2. p=0. both SOLVD+/SOLVD. 5-26%. stenosis. .51 y N/A Crude mortality at end of 6 mo of enalapril on (spironolactone HF/symptoms at hemodynamically LV size. extension) risk reduction was 30% (106) study to show questionnaire) Survivors (135) of (p=0. All pts were offered 315. BP: and morbidity from and 350 125/77. NYHA lV label enalapril therapy).46%. Inc. hospitalizations. mg/dL causes.45 y Treating 1000 Reduced mortality by 16%. size >600 mL. open-label pts included in were long-term survivors 1999 follow up of the pts up study (via enalapril therapy analysis of time (p=0. CONSENSUS survival at the 10-y label follow. 1284 Ischemic LVEF <35%. would save ~50 (107) and EF <35% Combined mortality premature deaths LVEF 25%. HR: 80. Mortality Hospitalizations.2) Study Name. double-blind period open ACEI therapy placebo. all in the enalapril group. Cr level 36% enalapril group (6 (primary endpoint). the American Heart Association. Pts in NYHA of pts in analysis of the period. prognostic on the the double-blind improvement by an survival status period included in At end of double-blind study ACEI. completion all pts were offered open. 2017 Heart Failure Focused Update Data Supplement    2013 HF Guideline Data Supplement 18. enalpril group and 44% in group—40% reduction (p =0. Aim of Study Study Type Background Study Size Etiology Patient Population Endpoints Mortality Trial Duration Absolute Benefit P Values & 95% CI: Author. 26% in 1987 prognosis of NYHA 53%. AF 50% of pulm disease.3. 1285. (93%). other Increased heart MI w/in prior 2 mo placebo group) Mortality was reduced by 31% at 1 (105) vasodilators.

enalapril group had died c/w 80. SBP 126 mmHg. despite revascularization hospitalization for any and 10% lower risk of CV mortality 10587334 of ACEI on the risk of dose strategy and treatment with procedure within 2 reason.12 y Reduced mortality: p=0. p=0. CV Death or hospitalization for any hospitalization in dose strategy. ll-lV (mainly class unstable angina ll). Inc. III.95. and severe.5. Intolerant of ACEIs. BP: for HF in pts with EF hospitalization 126/78.021). <35% for HF AF: 4% SOLVD F/U 12-y FU of SOLVD to 12 y f/u of N/A 6784. or hospitalizations. Acute coronary Mortality from Combined risk of all.073) than low-dose group. (p=0. with asymptomatic p=0.8–16. (Treatment for HF sustained or hospitalizations. 12788569 with enalapril among SOLVD-] combined trials In the treatment trial. of HF and and hospitalization rate of EF: 28%. 95% on total mortality and for HF ischemic Asymptomatic. CAD 65% LVEF <=30%.0003). whether a NYHA l-lV Combined prevention and subsequent reduction treatment trials: HR for death was in mortality would 0. ACEIs. 9. and 24% fewer doses of ACEIs have mandated. 50.8% of the (109) pts with HF was Asymptomatic to (95% CI: 2. History of CV mortality. As per SOLVD+ Mortality. diuretics for ≥2 mo mo. development of HF.01). hospitalizations.004). 79. NYHA class: lll (few ll and lV) Post-MI ACEI Use 63 © 2017 American College of Cardiology Foundation. and the Heart Failure Society of America. similar benefits. 16% fewer AIM: Investigate if vasodilators Combined risk of fatal hospitalizations for CV reason low doses and high allowed but not and nonfatal MI plus (p=0.05). digitalis.90 for the enalapril group c/w emerge among those placebo group (95% CI: 0.8% sustained. HR: 75.84–0.9% of the 2003 establish if the RCTs SOLVD+ and median survival by enalapril group had died c/w 56. of the placebo group (p=0. 3393 N/A Participation in N/A Mortality N/A N/A N/A Enalapril extended In the prevention trial.5 mg/dL with CV hospitalizations for any reason HF. ischemic event or all causes cause mortality and of all-cause mortality (p=0. Total number of hospitalizations: reduce morbidity and class II). than the in ED or hospital symptomatic All-cause mortality lower risk than low-dose group. Incidence of HF and 3. large doses that have within 6 mo ventricular combined with CV p=0.002. (110) death and 1568 to the high. ATLAS To compare the RCT N/A 3164.30. or IV. high-dose group had 12% chronic HF.. 2111.4% mortality reduction [SOLVD+ and SOLVD. reason.001). been shown to required for pts in tachycardia. LVEF 23%. 2117 History of EF <35%. the American Heart Association. 2017 Heart Failure Focused Update Data Supplement    SOLVD 1992 Study effect of ACEIs RCT No drug treatment 4228. HR 80. (p=0. 3391. CV mortality combined high-dose group 13% fewer mortality in pts with Prior use of SCr >2. Combined rate of hospitalization CI: -8-21% 1463530 mortality from CV heart disease mortality and for HF causes. ventricular dysfunction.4 mo in the of the placebo group (p=0.128) 1999 low and high doses 1596 to the low.002). 5y High-dose group had 8% lower risk efficacy and safety of NYHA class II. NYHA hospitalization for hospitalizations for HF (p=0. the 85% NYHA class I the incidence (108) (67%) + ll. .

22% (95% CI. p<0. AIRE 1993 Investigated the RCT 2006. 1014. evidence of HF at of HF at any time Prespecified secondary outcomes: any time after an since acute MI risk reduction of 19% for the 1st acute MI. outcome. or 25%).001) for the development of transient therapy would reduce Combination of CV severe HF.008). significantly reduced in the 1386652 long-term Digitalis 26%. not have even requiring vasodilator recurrence of MI). Mortality combined captopril group (228 deaths. Also. Failure to undergo Mortality from Mortality from CV 3. considered to be all causes significantly lower for pts on 8104270 ACEI ramipril. 3-32%. the RR: 19% of acute MI who had the use of an ACEIs surviving pts. 1115. with a Use of an ACEI Mortality from 1. LVEF <40%. death. 5 -35%. 2 endpoints hospitalization. Inc.019). and improve clinical (treatment failure): 1st. RR: 27%. p=0. treatment with ACEI and 2nd. progression to severe or resistant HF. MI. nonfatal reinfarction and stroke between the 2 groups. to validated outcome—namely. 95% Cl: 11- (112) had shown clinical Clinical evidence 40%. lessen mortality and p=0. or (111) administration of Nitrates 51% >21 y of age. the American Heart Association. HF necessitating HR 78. EF 31%. 60% dysfunction but did an agent.5 mg/dl severe CHF or the causes. p=0. 64 © 2017 American College of Cardiology Foundation. (development of p=0. on 10 d before mandatory ramipril compared to pts on survival in pts who randomization. 16 d after the MI. and 25% (95% CI. (95% CI. 37% (95% CI. hospitalization to treat CHD.5 y Mortality from all causes was hypothesis that the 36%.. 2017 Heart Failure Focused Update Data Supplement    SAVE. but Relative with a decrease in the 20%) as c/w the placebo group captopril to survivors <80. 100% randomization within all causes causes. 1116 Ischemic Alive 3 d after MI.31%. p=0. Killip class I — baseline LV or the need for such CV morbidity RR:21% (95% CI. 992 Aged ≥18 y. 20-50%. 1992 To test the RCT Beta-blockers 2231. pulmonary mortality.014) for death from CV (60% of the ps did not have overt HF SCr > 2.002. contraindication to EF of at least 9 units in (275 deaths. baseline/the time cardiac performance. placebo.019) for CHF requiring congestion at deterioration in morbidity. of severe HF 5-40%. compare the severe/resistant HF. of their acute MI.3 y Mortality from all causes was effect of therapy with definite acute MI 3.015) for recurrent MI. p=0. . or stroke incidences of (95% CI: 5% . BP development of overt 113/70. 4-37%. and the Heart Failure Society of America.

follow-up. for HF. nonfatal stroke. Death (any cause). trandolapril was associated with a >2X increase in ≥1 mmol/L).8 y Absolute reduction of 7 major events per 100 Alternativ whether ARB Beta-blockers 1015 70% <40%. (114) coronary revascularization. diabetes mellitus. BP. no ACEI (b/c of severe (<4% class death or hospital admission for CHF or pts threated .4 y Absolute reduction of 4. HR 74. 873 Ischemic Consecutive pts Contraindication to Death from Death from a CV The mortality from all 24 lives were saved During the study period.7%). CONSENSUS Cooperative North Scandinavian Enalapril Survival Study. 28%. coronary revascularization. death due to 0.NNT 14 pts to prevent 1 CV e. p=0. admission. pts not taking e 24%. nonfatal stroke. EF 28%. . AF 27% nonfatal stroke. 1013. 1272 63% <40%. New DM 65 © 2017 American College of Cardiology Foundation. heart failure. and the Heart Failure Society of America. atrial fibrillation. EF: 30%. acute pulmonary embolism. admission. Ischemic 62.91. CAD. reduction in risk. 876. APE. EF NYHA class ll-lV. if ARB + ACEI 55%. Trial Author. chronic heart disease. AF. 304 pts in whether pts who LV Calcium antagonist 100% >18 y hospitalized ACEI or a definite any cause cause. HR 81 ACEI indicates angiotensin-converting-enzyme inhibitor. HR: 0. EF NYHA ll-lV.001). Diuretic with MI. or HF In every subgroup.77 (95% CI: 0. et al. CV death. Cr. ARBs (Section 7. the American Heart Association.3.000 pts as did 369 in the placebo group (113) after MI benefit from 66%. BP 125/75. Study Background Duration Year Aim of Study Type Therapy Study Size Etiology Patient Population Severity Endpoints Mortality (Y) Statistical Results N (Total) Pre-trial n standard (Experimental) Ischemic/ treatment. treatment with accompanied by Hyponatremia (<125 necessitating open.2. Death (any cause). 2013 HF Guideline Data Supplement 19. nonfatal (115) outcomes MI. Inc. Symptomatic HF.3) Study Name. progressive HF.3 mg/dL) (fatal or nonfatal). Progression to severe treating 1. chronic HF e 17%. Digoxin electrocardiographi DM. Elevated SCr level Recurrent infarction LV dysfunction (EF (2. HR: 74-75. RR: 0. Acute Infarction Ramipril Efficacy. AF: 25-26% nonfatal stroke. BP: admission for CHF nonfatal MI. CV.4 pts with events per ADDED. 1276. 2017 Heart Failure Focused Update Data Supplement    TRACE 1995 To determine RCT Beta blocker 16%. c changes. CHF death or hospitalization. creatinine. ED. congestive heart failure. CV death. mild to Composite of CV CV death. 2028.67 - long-term oral ACE 53%.0004 et al. HF. (2003) an ACEI Digoxin 45. hospital 3.011 (2003) improve Digoxin 58. 0. hospital 2. cardiac enzymes. causes at 1 y was 24%. coronary artery disease. <35%). AIRE. admission for CHF nonfatal MI. sudden death. inhibition. C/W. 2548.75-0. CV death. CHD.89).85 (95% CI: 0. Composite of CV CV death. RR: 0. blood pressure. could improve (55%). CHF. uncontrolled HF (hospital admission (42. compared with.96). ATLAS. DM. FU. Criteria for need for them. Treatment with mild to severe (<3% death or hospital admission for CHF or 100 pts treated. p=0. 1749. label ACEI). p=0. nonfatal 13678870 (intolerant) 46% MI.67-0. CHF event of CV death or CHF hospitalization.NNT of 23 to prevent 1 first McMurray in pts with spironolacton ACEI. cardiovascular. intolerance) lV).. 13678869 clincal 59% CHF admission. nonfatal MI. New DM CHARM. Assessment of Treatment with Lisinopril and Survival. n (Control) Non-Ischemic Inclusion Criteria Exclusion Criteria Primary Endpoint Secondary Endpoint 1st Y Mortality CHARM Discover RCT Diuretics. CV death. Nitrates MI: chest pain or Severe. nonfatal MI.78 (95% CI. To investigate RCT Beta blocker. 7477219 dysfunction soon 28%. Symptomatic HF. CHF admission. Ischemic 67. Age >18 y class lV). BP 121/76. after 1 mo of the trandolapril group died (34. emergency department. Change in the wall- motion index (EF) NYHA class 1 - 41%. Granger outcome in spironolacton 130/70.3%).

not applicable. p=0. pts. N/A.2% CAP VAL+CAP and CAP: 0. Pfeffer et effect of an d double blockers.96. heart disease.5% VAL 2. Beta Blockers (Section 7. BSA.11). Inc. TIA. (2001) adding ARB Beta blocker At least 2 wk of severe.027) (118) pts with HF. and 450 vs. NNT.9 cm/BSA HEAAL Compared the RCT Diuretic drugs 3846 IHD 64% >18 y.76–0. Change in EF. p=0. ACEI 43% 3803 3 distinct populations: symptomatic hypotension all-cause mortality. 14.7 y Treating pts with 150 mg dose instead of 50 study.89- 14610160 and the multicenter Captopril-: dysfunct (EF <35%).79–0. Evaluate long RCT Diuretics. Prior intolerance or contra. mortality 4885 SBP >100 mmHg.82-0. SCr > 265 mcmol /L.87. CABG. heart failure.032) reduce blind.88. randomized control trial. ASA.5% CI-. Ischemic 57% Age >18 y. median f/u mg dose would result in 1 additional pt w/out Lancet high-dose vs blockers mg (n=1927) <40%. quality of life. p=0. Use of an ARB 918 [24%]. Planned heart admission.3. blood pressure.04. follow-up. the American Heart Association. CV. lV (only Mortality. RCT. all. Diuretics 83% 7601 pts >18 y. number needed to treat. Bilateral renal artery stenosis. Valsartan Heart Failure Trial.3% VAL--CAP p=0.09). Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity. Val-HeFT. ACEI background meds EF 27%.055. with stable CV Systolic arterial blood HR: 71. p=0. who had reduced 0. BP: 124/77. p=0. MI.0001) >40% in the previous 2 wk ACEI indicates angiotensin-converting-enzyme inhibitor. NYHA ll-lll. clinical Intolerance to ACEI. (2003) ARB.1 y VAL and CAP: 1. For the combined endpoint: RR: 0.009 11759645 to standard 35%. 0. Beta blockers (7599 with NYHA class II–IV for at potassium >5. Spironolacton 3796 pts with LVEF <40% Women of childbearing For all the LVEF was around • Fewer CV deaths (691 [18%] vs 769 [20%]. CV death. EF: 33%. MI.. transient ischemic attack. known NYHA ll-lV (70% ll). AF. Background Trial Author. 28% Additional prespecified the primary event at 4 y for every 31 pts 2009. HEAAL study. heart rate. 0. and the Heart Failure Society of America. Composite: 828 (43%) pts in 150 mg 374: losartan on ARBs (38%). 2499 NYHA ll. Critical aortic CV death or 4% in the placebo p=0. and pts with LVEF previous 4 wk. endpoint of Signs and symptoms of HF CI. myocardial infarction.90 95% CU: 0. 5010.87. 2017 Heart Failure Focused Update Data Supplement    VALIANT. Mild to Combined • NYHA class. ARB. SCr.73 (116) combination trial 4909 (<40% on radionuclide HR: 76 of the 2on VAL + CAP: ventriculography). cardiovascular. admission for • Components: 635 pts in 150 mg group vs.91. DM. ll. 95% CI: 0. Year Aim of Study Study Type Therapy Study Size Etiology Patient Population Severity Endpoints Mortality Duration Statistical Results N (Total) n (Experimental) Inclusion Primary Annualized n (Control) Criteria Exclusion Criteria Endpoint Secondary Endpoint Mortality 1st Y Mortality 66 © 2017 American College of Cardiology Foundation. admitted for HF (0. CHD. QoL scores. 95% CI: to a maximum. lV. serum creatinine. ~2% class lV).5 mmol/L NYHA ll-lV outcome of the death rate among in placebo group died (unadjusted HR: 0. effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure. creatinine. Aimed to find RCT. (n=1919).00. covariate aHR: (116) ARB could . AF.87. EF 35%. systolic blood pressure.83–1. diabetes mellitus. NYHA. BP.703 Ischemic 100% Age >18 y. AF 12% morbidity HF EF <40% and LVID >2. encouraged to start pericarditis. p=0. admission for HF death or CV admission. 19922995 outcomes in Investigators myocarditis.   2013 HF Guideline Data Supplement 20.5% CI-. 889 (46%) in 50 mg group died or 1840-48.84-1. atrial fibrillation. coronary angioplasty. New York Heart Association. cause 12. . • Hospital admissions for CHF (757 [20%] vs ACE. and changes in the 665 in 50 mg group died (HR: 0.99. p=0. unstable angina.006) were currently receiving or open-heart surgery in the for CHF.92 y Mortality similar for the 2 treatment groups. BP: 123/72. beta losartan 150 NYHA class II–IV.82–0. 1. CHF. Preserved. HF. FU. 97.0. 0.78– intolerance) or who or mitral stenosis. Cr <2. serum NYHA ll-lV The primary The annual CV 3. coronary artery bypass graft. LVEF intolerance to ARBs. Cr. 95% Cl: 0. EF. 13. active cause admission. LV. stroke. congestive heart failure. 503 pts whenever possible acute MI. treated. CABG. p<0.90-1.77-0.90. morbidity. left ventricular. beta blocker and titrate transplantation w/in 6 mo. LVD.98 (97. covariate aHR: 0.0 (97. Pregnancy or lactation.24).025) cerebrovascular accident. effects of (77%).98 . or TIA within the previous 12 wk. ACEI blind 9 criteria) by HF. BP 123/76. NYHA l-lV. chronic heart disease.2.97. admitted for HF (HR: 0. patients. outcomes included: death. 2511.012. ischemic heart disease. mortality and (117) therapy for 93% including ACEIs. Only 3% class lV overall program: the placebo group 95% Cl: 0.97. MV. CHARM. SBP. UA.98. Death from any 12. ASA Valsartan:490 (MI inclusion Acute MI complicated indication to ACEI/ asymptomatic. LV systolic ARB severe. angiotensin receptor blockers. and or 50 mg daily medical therapy for at pressure <90 mm Hg. al. Digoxin 43% ACEIs (previous contraception.1 y 886 (23%) pts in candesartan and 945 (25%) Overall out whether parallel. low-dose (72%).5 mg/dL Val-HeFT. and VALIANT. hospital admission group of CHARM. 13678868 the use of an randomized 55% data) least 4 wk. Suspected significant renal artery stenosis CHARM. least 2 wk.0.5% al. 95% Cl: 0.99. Compare the Randomize Beta.94. UA pectoris. mortality and e 17% who were not receiving potential not using adequate component trials: 9% and was only unadjusted HR: 0. Cohn et term effects of Digoxin 67%. HF. severity of heart disease 0. mitral valve. HR. aspirin. Death or Composite endpoint of 4. double. IHD. Active admission. CV p=0. QoL.4) Study Name. left ventricular dilatation. Valsartan in Acute Myocardial Infarction. Significant stenotic valvular death or all-cause group vs. 1. body surface area. ejection fraction.

hospitalization--CV reason.0014 (121) allowed 17. PTCA/CABG w/in 4 mo combination with 0.0001 and committee in decreasing all.53- (120) EF and symptoms placebo <450m).75 y Absolute risk reduction Flather et al. LVEF <25%. Mean All-cause N/A 11.4 mo Treating 1000 pt for 1 . Contra-indication or BP: 130/78.7 cm.90. antagonist in hospitalization Contraindication to beta EF 36% (1/3 with EF hospital hospital admissions 21 mo to avoid one (122) 29%) with CHF w/in a blockers. LVEF at 3 and 12 mo mortality of 17% in (123) with advanced HF were MI. 1067. Ischemic NYHA ll-lV. 1327. Diuretics + 2647.2% Treatm't group 1 y can prevent 1 Group. Mild to severe. resting SBP <100mmHg. 95% CI: w/in the past 6 Significant renal CV hospital admissions 0. and the Heart Failure Society of America. intensive care. . Documented NYHA class lll or Uncontrolled HTN. 95% Chronic HF nonselective beta. Mean mortality 7. the American Heart Association. 4d revascularization/MI/CVA/ Pt global assessment sign VT or VF w/in 2 mo.74-0. p=0. would the results of UA HF rate in the placebo Survival Trial reduce the rate of the DIG trial.00009 of HF controlled heart rate >68 Planned transplant or ICD.8% Treatm't group 0. 0. 2017 Heart Failure Focused Update Data Supplement    CIBIS ll CIBIS Investigate the RCT.0% in pts with placebo group y led to savings of 70 (2002) beneficial in severe (or ARB). 1354. 1156. 1320 Ischemic lV MI/UA w/in previous 3 mo. Mean Combined endpoints (1999) chronic HF placebo l6%] AV-block >1st degree w/o LVEDD: 6.66 (95% CI: ll investigators efficacy of bisoprolol multicenter ACEI. current use of beta HR: 78. Mean BP: 130/80. vasodilators w/in 4. 10376614 pts with decreased randiomised NOT allowed] 40 if 6-min walk blocker. Moderate to severe. p<0. EF 20%. 411 Bucindolol in Pt bucindolol [91% ACE. MI/UA w/in 28 d. Cr >2.10.81). Packer et al. Carvadiolo is blind or IV) + ACEI 1133 67% class lV. Use of beta blocker MERIT-HF. Cardiac revascularization 117/71. inotropes or d. group (33%) died.99.039 mo dysfunction CV mortality CVA w/in 3 mo. p=0.78-1. Mean All CV deaths members cause mortality in randiomised allowed--14.4% in premature deaths 12390947 HF [Amiodarone No positive or IV. Mean mortality or CV mortality or all-cause need to be treated for 15642700 y regardless of EF. [24. Assess effects of RCT Diuretics + 2128. SBP hospital <100mmHg COPERNICUS Investigate whether RCT--double Diuretics (PO 2289. Heart rate <68. Inc. LVEF <35% Candidates for heart EF 23%. mortality hospitalization-any reason. unadjusted p=0. Mean Combined risk of death or recent or recurrent 11. for >18 y transplantation HR 82. The Beta. AF 16-17% mortality in 0. Diuretics + 3991.8 mg/dL SENIORS. Prior h/o Age >70 New HF therapy w/in 6 wk Mild to severe Composite of All-cause mortality N/A N/A 1. adrenergic blocker Before the procedure within the AF 12% reason with NYHA class IV. and any change in placebo group c/w 67 © 2017 American College of Cardiology Foundation.81). SBP Composite of death or heart group was 28% Investigators death from any 12 digoxin <80mmHg transplantation Overall: annual 11386264 cause among pt therapies Decompensated HF.13) Evaluation of vasodilator. mortality admissions 8. double-blind [amiodarone 50% EF: <35% PTCA/CABG w/in Mean HR: 80. Ischemic NYHA class III or Reversible cause of HF NYHA lll or lV (92% Death from any Death from CV causes For pt in NYHA N/A ~2 y 449 pt in placebo Beta-Blocker determine whether tolerated) 1354 59% IV HF present class lll) cause (death due to pump failure or functional class III. Mean EF All-cause death. Blocker and mild publication of previous 60 d Hospitalization because of the annual mortality adjusted p=0. an ischemic event or sudden the annual mortality in the bucindolol group with Advanced hydrochloride.2% Placebo group N/A 1.66 (95% CI: 0. renal failure. For pt CI. Use of positive inotropes Mean HR: 83. all-cause trial (Europe bpm Heart block >1st degree admission to + USA) w/o PPM. Reversible obstruct lung disease. EF: 28%. Mean BP: 123/76.2%. AF: Permanent treatment 10023943 controlled PPM. admission All cause hospital event year or EF <35% beta blockers admissions RR: 0. Ischemic Euvolumic NYHA Pt requiring hospitalized Severe All-cause Combined risk of death or 19. 20% withdrawal (119) trial (Europe) Heart rate < 60bpm.3 y HR: 0.5% in 10. QoL. Heart rate <50 bpm. (1999) lowered mortality in double-blind [Amiodarone LVEF <40% (36. 18-80 y old previous 6 mo. at least 1 mo.54-0. current use of >35%). cardiac Carvedilol group p=0.. 28%. the beta blocker ACEI 1061 CAD in 69% CHF with 1 of the or change in drug therapy Mean BP: 139/81. BP death) rate was 16% in the (30%. Investigate whether RCT-. SBP < 85 mmHg. All-cause All-cause hospital 13. 1991. Composite of CV mortality or CV hospital admissions NYHA class assessment. Combined risk of death or decompensations] 18%] vasodilators w/in Coronary hospitalization--HF reason.7% placebo 18. HR: 0. 24 pts would (2005) Nebivolol in pts >70 (+aldosterone following: w/in 2 wk Mean HR: 79. Hospitalization for any placebo group.86. 6 MWT A Trial of the Designed to RCT ACEIs (if 2708. all-cause Composite of all-cause 4. a 7% ARB].0% Placebo group N/A 1y Treatment of 27 pt for MERIT study Metoprolol CR/XL multicenter ACEI 2001 65% 40-80 y old.02.

Diuretics 1010 CAD 62% >65 y. relative risk. (absolute difference - was the objective of (PROBE) clinically relevant Supine SBP <100 mm Hg hospitalization CV death 1.93.22±0. randomized control trial. AF. 95% CI: -7.2%) with a 16143696 establish the randomized. 3029. NYHA Treatment with an ACEI. 0. on mortality and groups.6 to the CIBIS III trial-. c/w. COPERNICUS. United States of America. CVA. class II or III. PPM. intent to treat. RR.74- (124) pts with HF cause mortality. 178 2005 not currently exist to prospective. echo within the 3 before randomization Heart rate 79. percutaneous transluminal coronary angioplasty. Cr. permanent pacemaker. VF. mild to The primary Combined endpoint at the N/A N/A Mean of In the ITT sample. 84%.019) bisoprolol or treatment enalapril for 6 mo. VT. MWT. RCT. 0. Inc. and 186 (36. endpoint. adjustment within AV block>1° without a noninferiority for hospitalization of 7 d) functioning pacemaker bisoprolol-first versus initial monotherapy Obstructive lung disease enalapril-1st treatment. ACEI indicates angiotensin-converting-enzyme inhibitor. This evaluation HF (without pacemaker or all-cause phase. CABG.94. congestive heart failure. 95% CI 0. Digoxin Bisoprolol 505. New York Heart Association. atrial fibrillation. unstable angina. ICD. To compare the RCT Diuretics.4%. COMET. CIBIS II. patients. Carvedilol Or Metoprolol European Trial. event of components of the primary (maximum bisoprolol-1st group.8%) in the therapy (ACEI vs. and the Heart Failure Society of America. USA. N/A NYHA class ll-lV N/A Mild to severe All-cause N/A N/A N/A 4. BP.it trial. EF. HR: 0. at study end and at of 2. h/o. Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure. 2017 Heart Failure Focused Update Data Supplement    and to assess its required. controlled release/extended release.77–1. Cardiac Insufficiency Bisoprolol Study II. DIG. with either contraindicating bisoprolol p=0. ventricular fibrillation.0017) or all-cause admission (CIBIS) III. HF. ITT.10 y). or a beta blocker moderate CHF endpoint was end of the monotherapy 1. without. MERIT-HF.6%. endpoint Clinically stable without a functioning cause mortality the end of the monotherapy enalapril-1st group beta blocker). Pts. carvedilol prospective randomized cumulative survival. quality of life. COMET. CR/XL. 95% compared the effect 2 parallel diuretic SCr≥220 mmol/L CI: 0.. subgroups defined use became by ethnic discretionary background and [DIG 94%]. cardiovascular. Sufficient data do Multicenter. ARB. NYHA ll or lll. hazard ratio. UA. heart failure. and an ARB. blood pressure.16. ejection fraction. 68 © 2017 American College of Cardiology Foundation. p=0.8 y All-cause mortality Poole-Wilson effects of carvedilol ACEIs 1511 carvedilol. coronary artery bypass graft. ventricular tachycardia. (2003) and metoprolol on 1518 metoprolol Previous CV Composite 40% metoprolol (HR: 12853193 clinical outcome in tartrate admission endpoint of all. phase and the individual y primary endpoint in the (125) optimum order of open-label. creatinine. AV. HR. systolic blood pressure. and w/o. cerebrovascular accident. myocardial infarction. 32% Enalapril 505 LVEF <35% (By for >7 d during the 3 mo LVEF 29%. but the need for concomitant 15% in the bucindolol effect in various thereafter its therapy group. followed by their combination for 6 to 24 mo. NYHA. Digitalis Investigation Group.24 with fluid retention or at rest CV hospitalization 4.83. PTCA. EF <35% mortality 34% carvedilol and et al. SCr. SBP. minute walk test. initiating chronic HF blinded mo) Heart rate at rest <60 bpm SBP 134 combined all. atrioventricular. implantable cardioverter defibrillator. demographic criteria — specifically women and members of minority groups. compared with. serum creatinine. ICD. time-to-the-first.42 pt (35. . CHF. MI. QoL. history of. the American Heart Association. CV. angiotensin receptor blocker.

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