D Very low The estimate of effect is very uncertain, and often will be far from the truth. Table 13 | Balance of benefits and harms When there was evidence to determine the balance of medical benefits and harms of an intervention to a patient, conclusions were categorized as follows: K For statistically significant benefit or harm, report as benefit [or harm] of drug X. K For non statistically significant benefit or harm, report as possible benefit [or harm] of drug X. K In instances where studies are inconsistent, report as possible benefit [or harm] of drug X. K No difference can only be reported if a study is not imprecise. K Insufficient evidence is reported if imprecision is a factor. Table 14 | KDIGO nomenclature and description for grading recommendations Implications Grade* Patients Clinicians Policy-makers We recommend Most people in your situation would want the recommended course of action and only a small proportion would not. Most patients should receive the recommended course of action. The recommendation can be evaluated as a candidate for developing a policy or a performance measure. We suggest The majority of people in your situation would want the recommended course of action, but many would not. Different choices will be appropriate for different patients. Each patient needs help to arrive at a management decision consistent with her or his values and preferences. The recommendation is likely to require substantial debate and involvement of stakeholders before policy can be determined. *The additional category Not Graded was used, typically, to provide guidance based on common sense or where the topic does not allow adequate application of evidence. The most common examples include recommendations regarding monitoring intervals, counseling, and referral to other clinical specialists.


The most common examples include recommendations regarding monitoring intervals, counseling, and referral to other clinical specialists. The ungraded recommendations are generally written as simple declarative statements, but are not meant to be interpreted as being stronger recommendations than Level 1 or 2 recommendations. Table 15 | Determinants of strength of recommendation Factor Comment Balance between desirable and undesirable effects The larger the difference between the desirable and undesirable effects, the more likely a strong recommendation is warranted. The narrower the gradient, the more likely a weak recommendation is warranted. Quality of the evidence The higher the quality of evidence, the more likely a strong recommendation is warranted. Values and preferences The more variability in values and preferences, or the more uncertainty in values and preferences, the more likely a weak recommendation is warranted. Values and preferences were obtained from the literature where possible or were assessed in the judgment of the Work Group where robust evidence was not identified. Costs (resource allocation) The higher the costs of an intervention that is, the more resources consumed the less likely a strong recommendation is warranted. methods for guideline development Table 16 | The Conference on Guideline Standardization (COGS)112 checklist for reporting clinical practice guidelines Topic Description Discussed in KDIGO Clinical Practice Guideline for Lipid Management in Chronic Kidney Disease 1. Overview material Provide a structured abstract that includes the guideline s release date, status (original, revised, updated), and print and electronic sources. Abstract and Methods for Guideline Development. 2. Focus Describe the primary disease/condition and intervention/ service/technology that the guideline addresses. Indicate any alternative preventative, diagnostic or therapeutic interventions that were considered during development. Management of elevated levels of TC, LDL-C, or HDL-C or TGs and lipid-lowering agents in adults and children with CKD (non-dialysis-dependent or dialysis) or a kidney transplant. 3.


Management of elevated levels of TC, LDL-C, or HDL-C or TGs and lipid-lowering agents in adults and children with CKD (non-dialysis-dependent or dialysis) or a kidney transplant. 3. Goal Describe the goal that following the guideline is expected to achieve, including the rationale for development of a guideline on this topic. This CPG is intended to assist the practitioner caring for patients with CKD and dyslipidemia and to prevent deaths, CVD events, and progression to kidney failure while optimizing patients quality of life. 4. User/setting Describe the intended users of the guideline (e.g., provider types, patients) and the settings in which the guideline is intended to be used. Target audience is practicing nephrologists and other healthcare providers for adults and children with CKD and dyslipidemia. 5. Target population Describe the patient population eligible for guideline recommendations and list any exclusion criteria. Adults and children with CKD and dyslipidemia. 6. Developer Identify the organization(s) responsible for guideline development and the names/credentials/potential conflicts of interest of individuals involved in the guideline s development. Organization: KDIGO Names/credentials/potential conflicts of interest of individuals involved in the guideline s development are disclosed in the Biographic and Disclosure Information. 7. Funding source/ sponsor Identify the funding source/sponsor and describe its role in developing and/or reporting the guideline. Disclose potential conflict of interest. KDIGO is supported by the following consortium of sponsors: Abbott, Amgen, Bayer Schering Pharma, Belo Foundation, Bristol-Myers Squibb, Chugai Pharmaceutical, Coca-Cola Company, Dole Food Company, Fresenius Medical Care, Genzyme, Hoffmann-LaRoche, International Society of Nephrology, JC Penney, Kyowa Hakko Kirin, NATCO The Organization for Transplant Professionals, NKF-Board of Directors, Novartis, Pharmacosmos, PUMC Pharmaceutical, Robert and Jane Cizik Foundation, Shire, Takeda Pharmaceutical, Transwestern Commercial Services, Vifor Pharma, and Wyeth. No funding is accepted for the development or reporting of specific guidelines.


No funding is accepted for the development or reporting of specific guidelines. All stakeholders could participate in open review. 8. Evidence collection Describe the methods used to search the scientific literature, including the range of dates and databases searched, and criteria applied to filter the retrieved evidence. Topics were triaged either to a) systematic review, b) systematic search followed by narrative summary, or c) narrative summary. For systematic reviews on treatment with different lipid-lowering agents or lifestyle modifications, we searched for RCTs in MEDLINE, Cochrane Central Registry for trials, and Cochrane database of systematic reviews. Screening criteria are outlined in the Methods for Guideline Development chapter. The search was updated through August 2011 and supplemented by articles identified by Work Group members through June 2013. We also searched for pertinent existing guidelines and systematic reviews. grading criteria Describe the criteria used to rate the quality of evidence that supports the recommendations and the system for describing the strength of the recommendations. Recommendation strength communicates the importance of adherence to a recommendation and is based on both the quality of the evidence and the magnitude of anticipated benefits and harms. Quality of individual studies was graded in a three-tiered grading system (see Table 10). Quality of evidence and strength of recommendations were graded following the GRADE approach (Tables 12 and 14). The Work Group could provide general guidance in unngraded statements. 10. Method for synthesizing evidence Describe how evidence was used to create recommendations, e.g., evidence tables, meta-analysis, decision analysis. For systematic review topics, summary tables and evidence profiles were generated. For recommendations on treatment interventions, the steps outlined by GRADE were followed. 11. Prerelease review Describe how the guideline developer reviewed and/or tested the guidelines prior to release.


Prerelease review Describe how the guideline developer reviewed and/or tested the guidelines prior to release. The guideline had undergone internal review by the KDIGO Board in August 2012 and external public review in November 2012. Public review comments were compiled and fed back to the Work Group, which considered comments in its revision of the guideline. 12. Update plan State whether or not there is a plan to update the guideline and, if applicable, an expiration date for this version of the guideline. The requirement for an update will be assessed in five years from the publication date or earlier if important new evidence becomes available in the interim. Such evidence might, for example, lead to changes to the recommendations or may modify information provided on the balance between benefits and harms of a particular therapeutic intervention. methods for guideline development available evidence and the strength of that recommendation. However, Table 15 shows that the strength of a recommenda- tion is determined not only by the quality of the evidence but also by other, often complex judgments regarding the size of the net medical benefit (potential risks versus benefit), values, and preferences, and costs. Formal decision analyses includ- ing cost analysis were not conducted. Ungraded statements. This category was designed to allow the Work Group to issue general advice. Typically an ungraded statement meets the following criteria: it provides guidance based on common sense, it provides reminders of the obvious, and it is not sufficiently specific to allow for application of evidence to the issue and therefore it is not based on systematic evidence review. Common examples include recommendations about frequency of testing, referral to specialists, and routine medical care. We strove to minimize the use of ungraded recommendations.


Common examples include recommendations about frequency of testing, referral to specialists, and routine medical care. We strove to minimize the use of ungraded recommendations. This grading scheme, with two levels for the strength of a recommendation together with four levels of grading the quality of the evidence, as well as the option of an ungraded statement for general guidance, was adopted by the KDIGO Board in December 2008. The Work Group took on the primary role of writing the recommendations and rationale statements and retained final responsibility for the content of the guideline statements and the accompanying narrative. The ERT reviewed draft recommendations and grades for consistency with the conclusions of the evidence review. Format for guideline recommendations. Each chapter contains one or more specific recommendations. Within each recommendation, the strength of recommendation is indicated as level 1 or level 2 and the quality of the supporting evidence is shown as A, B, C, or D. The recommendation statements and grades are followed by the rationale text summarizing the key points of the evidence base and the judgments supporting the recommendation. In relevant sections, considerations of the guideline state- ments in international settings and suggested audit criteria are also provided where applicable. Important key points and research recommendations suggesting future research to resolve current uncertainties are also outlined at the conclu- sion of each chapter. Limitations of Approach Although the literature searches were intended to be comprehensive, they were not exhaustive. MEDLINE was Table 16 | Continued Topic Description Discussed in KDIGO Clinical Practice Guideline for Lipid Management in Chronic Kidney Disease 13. Definitions Define unfamiliar terms and those critical to correct application of the guideline that might be subject to misinterpretation. Abbreviations and Acronyms.


Definitions Define unfamiliar terms and those critical to correct application of the guideline that might be subject to misinterpretation. Abbreviations and Acronyms. tions and rationale State the recommended action precisely and the specific circumstances under which to perform it. Justify each recommendation by describing the linkage between the recommendation and its supporting evidence. Indicate the quality of evidence and the recommendation strength, based on the criteria described in Topic 9. Each guideline chapter contains recommendations for lipid management in CKD patients. Each recommendation builds on a supporting rationale with evidence tables if available. The strength of the recommendation and the quality of evidence are provided in parenthesis within each recommendation. 15. Potential benefits and harms Describe anticipated benefits and potential risks associated with implementation of guideline recommendations. The benefits and harm for each comparison of interventions are provided in summary tables and summarized in evidence profiles. The estimated balance between potential benefits and harm was considered when formulating the recommendations. preferences Describe the role of patient preferences when a recommendation involves a substantial element of personal choice or values. Recommendations that are level 2 or discretionary indicate a greater need to help each patient arrive at a management decision consistent with her or his values and preferences. 17. Algorithm Provide (when appropriate) a graphical description of the stages and decisions in clinical care described by the guideline. No overall algorithm. considerations Describe anticipated barriers to application of the recommendations. Provide reference to any auxiliary documents for providers or patients that are intended to facilitate implementation. Suggest review criteria for measuring changes in care when the guideline is implemented. These recommendations are intended for a global audience. Review criteria were not suggested because implementation with prioritization and development of review criteria have to proceed locally.


Review criteria were not suggested because implementation with prioritization and development of review criteria have to proceed locally. Furthermore, most recommendations are discretionary, requiring substantial discussion among stakeholders before they can be adopted as review criteria. Suggested audit criteria were provided to assess impact of guideline after publication. Research recommendations were also outlined to address current gaps in the evidence base. Abbreviations: CKD, chronic kidney disease; CPG, clinical practice guideline; CVD, cardiovascular disease; GRADE, Grading of Recommendations Assessment, Development and Evaluation; HDL-C, high-density lipoprotein cholesterol; KDIGO, Kidney Disease: Improving Global Outcomes; LDC-C, low-density lipoprotein cholesterol; RCT, randomized controlled trial; TC, total cholesterol; TG, triglyceride. methods for guideline development the only database searched. Hand searches of journals were not performed, and review articles and textbook chapters were not systematically searched. However, any important studies known to domain experts that were missed by the electronic literature searches were added to retrieved articles and reviewed by the Work Group. Review of Guideline Development Process Several tools and checklists have been developed to assess the quality of the methodological process for systematic review and guideline development. These include the Appraisal of Guidelines for Research and Evaluation (AGREE 2) the Conference on Guideline Standardization and the Institute of Medicine s recent Standards for Systematic Reviews113 and Clinical Practice Guidelines We Can Trust.114 Table 16 and Supplemental Appendix 2 online show, respectively, the criteria which correspond to the COGS checklist and the Institute of Medicine standards, and how each one of them is addressed in this guideline. SUPPLEMENTARY MATERIAL Supplemental Appendix 1: Online search strategies. Supplemental Appendix 2: Concurrence with Institute of Medicine standards for systematic reviews and for guidelines.


Supplemental Appendix 2: Concurrence with Institute of Medicine standards for systematic reviews and for guidelines. Supplementary material is linked to the online version of the paper at http://www.kdigo.org/home/guidelines/lipids methods for guideline development Biographic and disclosure information Marcello A Tonelli, MD, SM, FRCPC (Work Group Co-Chair), received an MD from the University of Western Ontario, specialist certification in nephrology (FRCPC) at Dalhousie University, and an SM in epidemio- logy from Harvard University. He is a nephrologist and Associate Professor at the University of Alberta. He serves as Associate Editor of American Journal of Kidney Diseases, the Cochrane Renal Group and the Journal of Nephrology, and is a member of the Editorial Board for Journal of the American Society of Nephrology. Dr. Tonelli is the President of the Canadian Society of Nephrology, a Councillor of the International Society of Nephrology and a past member of the Minister s Expert Committee for Drug Evaluation for the Province of Alberta. In March 2010, Dr. Tonelli was named the chair of the Canadian Task Force for Preventive Health Care, a national panel of experts that will make recommen- dations about preventive health services to Canada s more than 36,000 family physicians. Dr. Tonelli holds a Health Scholar award from the Alberta Heritage Foundation for Medical Research (AHFMR) and a Canada Research Chair in the optimal care of people with CKD. He is a founding member of the Alberta Kidney Disease Network and co-leader of the AHFMR Interdisciplinary Chronic Disease Collaboration (ICDC) research team. Since 2005, Dr. Tonelli has been the co-leader of a joint initiative between the University of Alberta and the Hospital Civil de Guadalajara, aimed at prevention of kidney failure among the poor of Jalisco, Mexico.


Since 2005, Dr. Tonelli has been the co-leader of a joint initiative between the University of Alberta and the Hospital Civil de Guadalajara, aimed at prevention of kidney failure among the poor of Jalisco, Mexico. Consultant: Merck (honorarium donated to charity) Speaker: Merck (honorarium donated to charity) Christoph Wanner, MD (Work Group Co-Chair), is Head of Nephrology, Department of Medicine at University of Wu rzburg, where he also obtained his MD. He then trained in Internal Medi- cine and subsequently Nephrology, in Freiburg, Germany. Dr Wanner has maintained an active research interest in the role of lipids in progression of kidney disease, having participated in two major trials conducted in this area: 4D and SHARP. His research also includes the elucidation of the inflammatory response syndrome in diabetic nephropathy, CKD and ESRD; pathogenesis and treatment for Fabry disease; and identification of risk factors for CKD progression and CVD in large study cohorts. Dr. Wanner has authored over 400 publications, including serving presently as Editor-in-Chief of Journal of Renal Nutrition and editorial board member for Clinical Nephrology, Current Opinion in Nephrology & Hyper- tension, Kidney International, and Nephrology Dialysis Trans- plantation. He is also President of the International Society of Renal Nutrition and Metabolism and Chairman of ERA-EDTA Renal Registry. In recognition of his contributions to nephrology, he was awarded the International Distinguished Medal from the US NKF in 2007 and nominated as honorary member of the Polish Society of Nephrology in 2011. In 2012 he obtained a doctor honoris causa from the Charles University of Prague.


In 2012 he obtained a doctor honoris causa from the Charles University of Prague. Advisory Board: Boehringer Ingelheim; Keryx; Reata Consultant: AMAG; Baxter; Boehringer Ingelheim; Reata Development of Educational Materials: Mitsubishi Grant/Research Support: Genzyme* Speaker: Abbott; Amgen; Astellas; AstraZeneca; Bristol- Myers Squibb; Fresenius Medical Care; Genzyme; Merck Sharp & Dohme; Mitsubishi; Roche *monies paid to institution Alan Cass, MBBS, FRACP, PhD, is Director of the Menzies School of Health Research in Darwin, Australia and previously served as Senior Director, Renal and Metabolic Division, The George Institute for Global Health in Sydney, Australia. Dr Cass completed his nephrology training and PhD studies at the University of Sydney where he investigated the social determinants of ESRD. His current research encompasses the use of rigorous quantitative and qualitative methods to foster the development, implementation and evaluation of strate- gies to address the growing burden of CKD. He also conducts primary care intervention research aiming to reduce barriers to necessary care for Indigenous Australians and enhance access to renal services in remote areas, thereby improving their health outcomes. Dr Cass is President-Elect for the Australian and New Zealand Society of Nephrology (ANZSN), a member of the Executive of the Australasian Kidney Trials Network and International Society of Nephrol- http://www.kidney-international.org biographic and disclosure information & 2013 KDIGO ogy (ISN) CKD Policy Task Force. An author of over 150 publications, he recently received the 2012 NSW Aboriginal Health Award for Closing the Gap through Excellence in Chronic Care, and the 2013 T J Neale Award for Outstanding Contribution to Nephrological Science from ANZSN.


An author of over 150 publications, he recently received the 2012 NSW Aboriginal Health Award for Closing the Gap through Excellence in Chronic Care, and the 2013 T J Neale Award for Outstanding Contribution to Nephrological Science from ANZSN. Advisory Board: Abbott; Merck Consultant: Baxter Expert Testimony: Merck Grant/Research Support: Amgen;* Baxter;* Merck;* Novartis* Speaker: Fresenius Medical Care *monies paid to institution Amit X Garg, MD, FRCPC, FACP, PhD, is a Professor of Medicine, Epidemiology and Biostatistics at the University of Western Ontario. He practices nephro- logy at the London Health Sciences Centre and cares for patients with CKD, acute kidney injury (AKI) and individuals wishing to donate a kidney to a loved one. Dr. Garg conducts clinical and health services research to improve health outcomes for patients with kidney diseases including those receiving dialysis or a kidney transplant. He also aims to improve the efficiency by which renal care is delivered. He currently holds a Clinician Scientist Award from the Canadian Institutes of Health Research. He is the current Director of the London Kidney Clinical Research Unit and Scientific Director of the Institute for Clinical Evaluative Sciences at Western Facility. Dr Garg reported no relevant financial relationships Hallvard Holdaas, MD, PhD, is senior consultant in Nephrology at Department of Transplant Medicine, Oslo University Hospital, Rikshospitalet, Norway, where he also received his training in transplant medicine. His primary research interests are immunosuppression, dyslipidemia, and CVD in renal transplant recipients. He was the PI in the ALERT trial (fluvastatin) and co-PI in the AURORA and SHARP trials. Dr Holdaas is a member of numerous professional organizations including American Society of Nephrology, American Society of Transplantation, European Dialysis and Transplant Associa- tion and European Society for Organ Transplantation.


Dr Holdaas is a member of numerous professional organizations including American Society of Nephrology, American Society of Transplantation, European Dialysis and Transplant Associa- tion and European Society for Organ Transplantation. He has published more than 170 original articles, reviews and book chapters in the fields of nephrology, dialysis and transplantation. Speaker: Abbott; Astellas; AstraZeneca; Novartis Alan G Jardine, MBChB, MD, FRCP, graduated in Physiology (1981) and Medicine (1984) from the University of Glasgow. He undertook postgraduate research training as a Clinical Training Fellow in the MRC Blood Pressure Unit, where he pursued studies on the phy- siology, pharmacology and therapeutic potential of natriuretic peptides. He trained initially in Endocrinology and subsequently Nephrology, in Glasgow and Aberdeen, UK. Since 1994 he has been on the staff of the University of Glasgow, where he has been Professor of Renal Medicine since 2006. He has pursued a variety of research themes that center on accelerated vascular disease and long- term adverse outcomes in patients with renal disease and transplantation, their pathophysiological and genetic deter- minants, and their management. His current research combines laboratory work, clinical research and clinical trials, and he is the leader of the Renal Research Group in the BHF Glasgow Cardiovascular Research Centre. Since 2010 he has been the Head of the Undergraduate Medical School in Glasgow. He is a member of the Council of the European Society for Transplantation.


He is a member of the Council of the European Society for Transplantation. Consultant: Abbott; Novartis; Pfizer;* Opsona* Development of Educational Materials: Pfizer* Expert Testimony: Commission on Human Medicines (UK); European Medicines Agency; US Food and Drug Adminis- tration Speaker: Astellas; Bristol-Myers Squibb; Genzyme (Sanofi); Merck Sharp & Dohme; Pfizer* *monies paid to institution Lixin Jiang, MD, PhD, is the Director for National Cardiovascular Bio-bank Centre, Co-Director for China Oxford Centre for International Health Research, and Deputy Director for Center of Dyslipidemia and Cardiovascular Disease of Fuwai Hospital. She is also Editor-in-Chief for The Lancet Chinese Edition, Editorial Board Member for the journal Circulation: Cardiovascular Quality and Out- comes and a Doctoral mentor at Chinese Academy of Medical Sciences and Peking Union Medical College. Dr. Jiang obtained her medical degree from the Chinese Academy of Medical Sciences and Peking Union Medical College. Her main research interests involve large RCTs, epidemiological studies, pharmacogenomics studies and outcomes research. She serves as the Executive Member in the Young and Middle-Aged Scholar Committee of Stroke Screening and Prevention, National Health and Family Planning Commission of China, and the Advisory Expert on the Panel on Cardiovascular Disease, Committee of Experts on Rational Drug Use, National Health and Family Planning Commission of China. biographic and disclosure information As the Steering Committee member and site PI in China, Dr. Jiang has successfully run several international large- scale clinical trials including: ISCHEMIA, HPS3/TIMI55: TRACER, and INTER-HEART. Moreover, she is the PI of four national key research projects funded by Chinese government, including China Patient-centered Evaluative Assessment of Cardiac Events (China PEACE) (2012 2014), The Study on Hereditary Susceptibility to Statin-related Myopathy (2011 2015), Establishment of the Bio-bank of Chinese Cardiovascular & Cerebro- vascular Disease (2011 2015), and China PEACE-stent (2013 2014).


Moreover, she is the PI of four national key research projects funded by Chinese government, including China Patient-centered Evaluative Assessment of Cardiac Events (China PEACE) (2012 2014), The Study on Hereditary Susceptibility to Statin-related Myopathy (2011 2015), Establishment of the Bio-bank of Chinese Cardiovascular & Cerebro- vascular Disease (2011 2015), and China PEACE-stent (2013 2014). Dr. Jiang started her international collaboration with the Oxford University in the 1980 s and since then she has been cooperating with different top research institu- tions worldwide. Presently, her collaborative partners include Oxford University, Yale University, NHLBI, NIH, University of Edinburgh, Duke University, Merck Research Laboratories, etc. Through years of research operation, Dr. Jiang has set up a reliable and stable national coopera- tion network of over 200 hospitals within 31 provinces in China. Her achievements in the field of evidence-based medicine have attracted international recognition and acclaim. Sir Richard Peto, Co-Director of Clinical Trials Service Unit and Epidemiological Studies Unit at Oxford University, once said that she has been a whirlwind force for evidence and The Lancet commented that she is at the heart of China s evidence base. Dr Jiang reported no relevant financial relationships Florian Kronenberg, MD, received his MD from the University of Innsbruck, Austria. After specializing in Medical Genetics he worked two years each at the University of Utah, Salt Lake City, USA and the Institute of Epidemiology at the Helmholtz Center, Munich, Germany. In 2004, he became Full Professor for Genetic Epidemiology at the Innsbruck Medical University where he presently heads the Department of Medical Genetics, Molecular and Clinical Pharmacology. Dr. Kronenberg served as PI in several studies on genetic risk factors for atherosclerosis and biomarkers for the progression of CKD including the Mild to Moderate Kidney Disease Study00 (MMKD).


Dr. Kronenberg served as PI in several studies on genetic risk factors for atherosclerosis and biomarkers for the progression of CKD including the Mild to Moderate Kidney Disease Study00 (MMKD). He served as a workgroup member of the NKF K/DOQI Guidelines on Cardiovascular Disease in Dialysis Patients and is Associate Editor of Atherosclerosis and Academic Editor of PLoS One. Advisory Board: Genzyme, Keryx Speaker: Amgen; Genzyme Rulan S Parekh, MD, MS, FRCP(C), FASN, is a Clinician Scientist and Associate Professor of Medicine and Paediatrics at the University of Toronto, The Hospital for Sick Children and University Health Net- work. The focus of Dr. Parekh s research is to study risk factors both clinically and genetically leading to progression of CKD and CVD. She has published over 80 peer reviewed manuscripts and book chapters, and has mentored over 25 postdoctoral fellows and students. She leads the NIH-NIDDK sponsored Predictors in Arrhythmic and Cardiovascular Disease in End Stage Renal Disease (PACE) , a new cohort study in dialysis patients to identify risk factors for sudden cardiac death. She is currently the chair of the American Kidney Fund Clinical Scientist Committee and on the Board of Trustees of the American Kidney Fund. She has recently been inducted into the American Society of Clinical Investigation and Society for Pediatric Research and has received awards for Advising, Teaching and Mentoring Award from the Johns Hopkins Bloomberg School of Public Health. She is presently an Associate Editor for BMC Nephrology and on the editorial board of the Clinical Journal of the American Society of Nephrology. Trustee: American Kidney Fund (no compensation) Grant/Research Support: Physician Services Inc* *monies paid to institution Tetsuo Shoji, MD, PhD, is affiliated with the Department of Geriatrics and Vascular Medicine, Osaka City Univer- sity Graduate School of Medicine, Osaka, Japan.


Trustee: American Kidney Fund (no compensation) Grant/Research Support: Physician Services Inc* *monies paid to institution Tetsuo Shoji, MD, PhD, is affiliated with the Department of Geriatrics and Vascular Medicine, Osaka City Univer- sity Graduate School of Medicine, Osaka, Japan. He studied medicine in the medical school of Osaka City University and then worked at the Second Department of Internal Medicine, Osaka City University Hospital. He is interested in dyslipidemia, and other metabolic and endocrine alterations as factors affecting CVD in patients with CKD. He is a member of the Japanese Society for Dialysis Therapy (JSDT), the Japanese Society of Nephrology (JSN), the Japan Atherosclerosis Society (JAS), the Japan Diabetes Society (JDS) and others. He was the recipient of the Society Award from JSDT and a Work Group Member for the following guideline groups: 2011 JSDT Guidelines for the Evaluation and Treatment of Cardiovascular Complications in HD Patients; 2012 JSDT Guideline for CKD-Mineral Bone Disorder; 2012 JAS Guidelines for Prevention of Atherosclerotic CVD; and 2013 JSN Guideline for the Treatment of CKD. Grant/Research Support: Astellas;* Daiichi Sankyo;* Dainippon Sumitomo;* Mochida;* Shionogi* Speaker: Astellas; Daiichi Sankyo; Kowa; Kyowa Hakko Kirin; Merck Sharp & Dohme; Mochida; Pfizer; Shionogi *monies paid to institution biographic and disclosure information Robert J Walker, MBChB, MD (Otago), FRACP, FASN, FAHA, is Professor of Medicine and Head of the Department of Medicine at Dunedin School of Medicine, University of Otago, New Zealand. He is also a Consultant Nephrologist and Head of Nephrology at Healthcare Otago. Dr Walker has a broad base of translational renal research with interests in renal pharmacology, renal pathophysiology and drug nephrotoxicity, linked to the ongoing clinical research interests in the regulation of renal and cardiovascular hemodynamics and AKI.


Dr Walker has a broad base of translational renal research with interests in renal pharmacology, renal pathophysiology and drug nephrotoxicity, linked to the ongoing clinical research interests in the regulation of renal and cardiovascular hemodynamics and AKI. His clinical research program addresses a long- standing interest in renal hemodynamics, drug-induced alterations in renal function and nephrotoxicity, the role of renovascular hormones in the control of hypertension and renal disease, and cardiovascular risk factors in kidney disease. Dr Walker has also participated in a number of pivotal trials including IDEAL, SHARP, ASFAST, and PERFECT, and authored over 180 publications. Until 2011, he was actively involved in the Scientific Programme and Education Commit- tee for the ANZSN, responsible for the scientific program of its annual scientific meeting as well as overseeing the society s education program. Professor Walker is a member of the ISN Nexus and Forefronts Committees, as well as serving on the Caring for Australasians with Renal Impairment guideline committees for cardiovascular risk factors in renal disease and dialysis adequacy. He is also an Executive Council member of Asian Pacific Society of Nephrology and has a strong interest in developing links between Australia & New Zealand with South East Asia and the Pacific to further advance the scientific knowledge and research in all aspects of nephrology. Advisory Board: Fresenius SE Asia (no compensation) KDIGO CHAIRS Bertram L Kasiske, MD, is Professor of Medicine at the University of Minnesota, USA. He received his medical degree from the University of Iowa and completed his Internal Medicine residency and fellowship training in Nephrology at Hennepin County Medical Center where he is currently Director of Nephrology. Dr Kasiske is former Deputy Director of the United States Renal Data System and former Editor-in-Chief of American Journal of Kidney Diseases.


Dr Kasiske is former Deputy Director of the United States Renal Data System and former Editor-in-Chief of American Journal of Kidney Diseases. He has served as Secretary/Treasurer and on the Board of Directors of the American Society of Transplantation, and on the Organ Procurement and Transplantation Network/United Network of Organ Sharing Board of Directors, and the Scientific Advisory Board of the US NKF. He is currently serving on the Board of Councilors of the ISN and he is the PI for a National Institutes of Health- sponsored, multicenter study of long-term outcomes after kidney donation. Dr Kasiske is the Director of the Scientific Registry of Transplant Recipients and has over 160 scientific publications in major peer-reviewed journals, and 230 review articles, editorials and textbook chapters. Dr Kasiske is also a recipient of the US NKF s Garabed Eknoyan Award in 2003. Advisory Board: Litholink/Labcorp Speaker: Merck Japan David C Wheeler, MD, FRCP, holds an academic position in Nephrology (Reader) at University College London, UK and is an Honorary Consultant Nephrologist at the Royal Free Hospital. His research is focused on the cardiovascular complications of CKD and the role of vascular risk factors in progression of kidney damage. Dr Wheeler is a member of the International Steering Committee of SHARP and was UK National Coordinator for the trial. He is involved in several other randomized trials and observational studies involving patients with CKD. Dr Wheeler is Co-Chair of KDIGO, having served previously on its Executive Committee and Board. He received an International Distinguished Medal from the US NKF in recognition of his contribution to guideline development. In the UK, he has been elected President of the Renal Association for the term 2012-2014.


In the UK, he has been elected President of the Renal Association for the term 2012-2014. Dr Wheeler has served on the editorial boards of American Journal of Kidney Diseases and Journal of the American Society of Nephrology and is presently Co-Editor for Nephrology Dialysis Transplantation. Consultant: Amgen; Astellas; Baxter; Merck Sharp & Dohme; Otsuka; Vifor Grant/Research Support: Abbott;* AstraZeneca;* Genzyme* Speaker: Abbott; Amgen; Astellas; Fresenius Medical Care; Genzyme; Otsuka; Shire *monies paid to institution EVIDENCE REVIEW TEAM Ashish Upadhyay, MD, is Assistant Professor, Renal Section and Associate Director, Internal Medicine Residency Program at Boston University School of Medicine, Boston, MA, USA. Dr Upadhyay was previously Assistant Professor at Tufts University School of Medicine and staff physician in the William B Schwartz, MD, Division of Nephrology at Tufts Medical Center. He joined the ERT in July 2009 and served as the Assistant Project Director for the KDIGO Management of Blood Pressure in CKD and Anemia in CKD Guidelines. In the role as lead project director for this guideline, Dr Upadhyay coordinated and assisted in the collection, evaluation, grading, and synthesis of evidence, and played a critical role in the revisions of the final evidence report. He also provided methodological guidance and training of Work Group members on topic refinement, key question formula- tion, data extraction, study assessment, evidence grading, and recommendation formulation. Dr Upadhyay s past research involved studying kidney disease epidemiology in the Framingham Heart Study. He has published in areas ranging from arterial stiffness in CKD and inflammation in kidney biographic and disclosure information disease to dialysis complications and epidemiology of hyponatremia.


He has published in areas ranging from arterial stiffness in CKD and inflammation in kidney biographic and disclosure information disease to dialysis complications and epidemiology of hyponatremia. Dr Upadhyay reported no relevant financial relationships Ethan M Balk, MD, MPH, is Director, Evidence-based Medicine at the Tufts Center for Kidney Disease Guideline Development and Implementation, in Boston, MA, USA, Associate Director of the Tufts Evidence-based Practice Center, and Associate Professor of Medicine at Tufts University School of Medicine. Dr Balk graduated from Tufts University School of Medicine and completed a fellowship in Clinical Care Research. As Program Director for this guideline, he played a role in providing methodological expertise in the guideline development process and assisted in the collection, evaluation, grading, and synthesis of evidence and the revisions of the final evidence report. Dr Balk also provided methodological guidance and training of Work Group members regarding topic refinement, key question formulation, data extraction, study assessment, evidence grading, and recommendation formulation. His primary research interests are evidence-based medicine, systematic review, clinical practice guideline deve- lopment, and critical literature appraisal. Dr Balk reported no relevant financial relationships Amy Earley, BS, is a project coordinator at the Tufts Center for Kidney Disease Guideline Development and Implementation in Boston, MA, USA. She is key in coordinating the guideline development activities within the ERT, especially in the development of the evidence reports for all guidelines. Ms Earley also heads the actual evidence review, which includes running searches, screening, data extraction, drafting of tables and methods sections, proofing of guideline drafts, and critical literature appraisals. She participates in the conduct of research projects at the Center and actively collaborates with other members of the Center on independent research topics and manuscript submissions.


She participates in the conduct of research projects at the Center and actively collaborates with other members of the Center on independent research topics and manuscript submissions. Ms Earley reported no relevant financial relationships Shana Haynes, MS, DHSc, is a research assistant at the Tufts Center for Kidney Disease Guideline Development and Implementation in Boston, MA, USA. She participates in all aspects of evidence review and guideline development. She screens abstracts and articles, extracts data, and assists in the drafting and editing of evidence tables. Dr Haynes also assists in the development of clinical practice guidelines and conducts systematic reviews and critical literature appraisals. Dr Haynes reported no relevant financial relationships Jenny Lamont, MS, is a project manager and medical writer at the Tufts Center for Kidney Disease Guideline Development and Implementation in Boston, MA, USA. She participates in all aspects of evidence review and guideline development, assists in the preparation of talks and manuscripts, and edits KDIGO draft guidelines currently in progress. Ms Lamont reported no relevant financial relationships. biographic and disclosure information Acknowledgments A special debt of gratitude is owed to the KDIGO Co-Chairs, Bertram Kasiske and David Wheeler, and the KDIGO Board for their invaluable guidance throughout the development of this guideline. In particular, we thank the ERT members: Ashish Upadhyay, Ethan Balk, Amy Earley, Shana Haynes, and Jenny Lamont for their substantial contribution to the rigorous assessment of the available evidence. We are also especially grateful to the Work Group members for their expertise throughout the entire process of literature review, data extraction, meeting participation, the critical writing and editing of the statements and rationale, which made the publication of this guideline possible. The generous gift of their time and dedication is greatly appreciated.


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CLINICAL STATEMENTS AND GUIDELINES WRITING GROUP MEMBERS* Clyde W. Yancy, MD, MSc, MACC, FAHA, FHFSA, Chair Mariell Jessup, MD, FACC, FAHA, Vice Chair Biykem Bozkurt, MD, PhD, FACC, FAHA* Javed Butler, MD, MBA, MPH, FACC, FAHA* Donald E. Casey Jr, MD, MPH, MBA, FACC Monica M. Colvin, MD, FAHA Mark H. Drazner, MD, MSc, FACC, FAHA, FHFSA Gerasimos S. Filippatos, MD* Gregg C. Fonarow, MD, FACC, FAHA, FHFSA* Michael M. Givertz, MD, FACC, FHFSA* Steven M. Hollenberg, MD, FACC# JoAnn Lindenfeld, MD, FACC, FAHA, FHFSA* Frederick A. Masoudi, MD, MSPH, FACC** Patrick E. McBride, MD, MPH, FACC Pamela N. Peterson, MD, FACC, FAHA Lynne Warner Stevenson, MD, FACC* Cheryl Westlake, PhD, RN, ACNS-BC, FAHA, FHFSA Developed in Collaboration with the American Academy of Family Physicians, American College of Chest Physicians, and International Society for Heart and Lung Trans- plantation ACC/AHA Task Force Members, see page e150 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America 2017 by the American College of Cardiology Foundation, the American Heart Association, Inc., and the Heart Failure Society of America ACC/AHA/HFSA FOCUSED UPDATE Key Words: AHA Scientific Statements angioedema angiotensin-converting enzyme inhibitors angiotensin receptor blockers angiotensin receptor- neprilysin inhibitor beta blockers ferric carboxymaltose focused update heart failure hypertension iron deficiency ivabradine natriuretic peptides natriuretic peptide biomarker sleep apnea *Writing group members are required to recuse themselves from voting on sections to which their specific relationships with industry may apply; see Appendix 1 for detailed information. ACC/AHA Task Force on Clinical Practice Guidelines Liaison. ACC/AHA Representative. ACP Representative. ISHLT Representative. HFSA Representative. #CHEST Representative. **ACC/AHA Task Force on Performance Measures Representative. AAFP Representative.


#CHEST Representative. **ACC/AHA Task Force on Performance Measures Representative. AAFP Representative. The American Heart Association requests that this document be cited as follows: Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Colvin MM, Drazner MH, Filippatos GS, Fonarow GC, Givertz MM, Hollenberg SM, Lindenfeld J, Masoudi FA, McBride PE, Peterson PN, Stevenson LW, Westlake C. 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation. 2017;136:e137 e161. DOI: 10.1161/CIR.0000000000000509. Yancy et al TABLE OF CONTENTS Preamble e138 Methodology and Evidence Review e140 Organization of the Writing Group e141 Document Review and Approval e141 Initial and Serial Evaluation of the HF Patient e141 Biomarkers for Prevention: Recommendation e142 Biomarkers for Diagnosis: Recommendation e142 Biomarkers for Prognosis or Added Risk Stratification: Recommendations e142 Treatment of Stages A to D e144 Pharmacological Treatment for Stage C HF With Reduced Ejection Fraction: 7.3.2.10. Renin-Angiotensin System Inhibition With Angiotensin- Converting Enzyme Inhibitor or Angiotensin Receptor Blocker or ARNI: Recommendations e144 Pharmacological Treatment for Stage C HFpEF: Recommendations e146 Important Comorbidities in HF e147 Hypertension (New Section) e149 Treating Hypertension to Reduce the Incidence of HF: Recommendation e149 Treating Hypertension in Stage C HFrEF: Recommendation e149 Treating Hypertension in Stage C HFpEF: Recommendation e149 9.6. Sleep-Disordered Breathing: Appendix 1. Author Relationships With Industry and Other Entities (Relevant) e156 Appendix 2. Reviewer Relationships With Industry and Other Entities (Comprehensive) e158 PREAMBLE Since 1980, the American College of Cardiology (ACC) and American Heart Association (AHA) have translat- ed scientific evidence into clinical practice guidelines (guidelines) with recommendations to improve cardio- vascular health.


Reviewer Relationships With Industry and Other Entities (Comprehensive) e158 PREAMBLE Since 1980, the American College of Cardiology (ACC) and American Heart Association (AHA) have translat- ed scientific evidence into clinical practice guidelines (guidelines) with recommendations to improve cardio- vascular health. These guidelines, which are based on systematic methods to evaluate and classify evidence, provide a cornerstone for quality cardiovascular care. The ACC and AHA sponsor the development and pub- lication of guidelines without commercial support, and members of each organization volunteer their time to the writing and review efforts. Guidelines are official policy of the ACC and AHA. Intended Use Practice guidelines provide recommendations applica- ble to patients with or at risk of developing cardiovas- cular disease. The focus is on medical practice in the United States, but guidelines developed in collabora- tion with other organizations may have a global impact. Although guidelines may be used to inform regulatory or payer decisions, their intent is to improve patients quality of care and align with patients interests. Guide- lines are intended to define practices meeting the needs of patients in most, but not all, circumstances and should not replace clinical judgment. Clinical Implementation Guideline recommended management is effective only when followed by healthcare providers and patients. Adherence to recommendations can be enhanced by shared decision making between healthcare providers and patients, with patient engagement in selecting interventions based on individual values, preferences, and associated conditions and comorbidities. Methodology and Modernization The ACC/AHA Task Force on Clinical Practice Guidelines (Task Force) continuously reviews, updates, and modi- fies guideline methodology on the basis of published standards from organizations including the Institute of and on the basis of internal reevaluation.


Methodology and Modernization The ACC/AHA Task Force on Clinical Practice Guidelines (Task Force) continuously reviews, updates, and modi- fies guideline methodology on the basis of published standards from organizations including the Institute of and on the basis of internal reevaluation. Similarly, the presentation and delivery of guidelines are reevaluated and modified on the basis of evolving tech- nologies and other factors to facilitate optimal dissemi- nation of information at the point of care to healthcare professionals. Given time constraints of busy healthcare providers and the need to limit text, the current guideline format delineates that each recommendation be support- ed by limited text (ideally, <250 words) and hyperlinks to supportive evidence summary tables. Ongoing efforts to further limit text are underway. Recognizing the impor- tance of cost-value considerations in certain guidelines, when appropriate and feasible, an analysis of the value of a drug, device, or intervention may be performed in accordance with the ACC/AHA methodology.3 To ensure that guideline recommendations remain current, new data are reviewed on an ongoing basis, with full guideline revisions commissioned in approxi- mately 6-year cycles. Publication of new, potentially practice-changing study results that are relevant to an existing or new drug, device, or management strategy will prompt evaluation by the Task Force, in consultation with the relevant guideline writing committee, to de- termine whether a focused update should be commis- sioned. For additional information and policies regard- ing guideline development, we encourage readers to 2017 ACC/AHA/HFSA Heart Failure Focused Update CLINICAL STATEMENTS AND GUIDELINES consult the ACC/AHA guideline methodology manual4 and other methodology articles.5 8 Selection of Writing Committee Members The Task Force strives to avoid bias by selecting experts from a broad array of backgrounds. Writing commit- tee members represent different geographic regions, sexes, ethnicities, races, intellectual perspectives/biases, and scopes of clinical practice.


Writing commit- tee members represent different geographic regions, sexes, ethnicities, races, intellectual perspectives/biases, and scopes of clinical practice. The Task Force may also invite organizations and professional societies with re- lated interests and expertise to participate as partners, collaborators, or endorsers. Relationships With Industry and Other Entities The ACC and AHA have rigorous policies and meth- ods to ensure that guidelines are developed without bias or improper influence. The complete relationships with industry and other entities (RWI) policy can be found online. Appendix 1 of the current document lists writing committee members relevant RWI. For the purposes of full transparency, writing committee mem- bers comprehensive disclosure information is available online. Comprehensive disclosure information for the Task Force is also available online. Evidence Review and Evidence Review Committees When developing recommendations, the writing com- mittee uses evidence-based methodologies that are based on all available data.4 7 Literature searches focus on randomized controlled trials (RCTs) but also include registries, nonrandomized comparative and descriptive studies, case series, cohort studies, systematic reviews, and expert opinion. Only key references are cited. An independent evidence review committee (ERC) is commissioned when there are 1 or more questions deemed of utmost clinical importance that merit formal systematic review. This systematic review will strive to de- termine which patients are most likely to benefit from a drug, device, or treatment strategy and to what degree. Criteria for commissioning an ERC and formal systematic review include: a) the absence of a current authoritative systematic review, b) the feasibility of defining the ben- efit and risk in a time frame consistent with the writing of a guideline, c) the relevance to a substantial number of patients, and d) the likelihood that the findings can be translated into actionable recommendations. ERC members may include methodologists, epidemiologists, healthcare providers, and biostatisticians.


ERC members may include methodologists, epidemiologists, healthcare providers, and biostatisticians. When a formal systematic review has been commissioned, the recom- mendations developed by the writing committee on the basis of the systematic review are marked with SR . Guideline-Directed Management and Therapy The term guideline-directed management and therapy (GDMT) encompasses clinical evaluation, diagnostic testing, and pharmacological and procedural treat- ments. For these and all recommended drug treat- ment regimens, the reader should confirm the dosage by reviewing product insert material and evaluate the treatment regimen for contraindications and interac- tions. The recommendations are limited to drugs, de- vices, and treatments approved for clinical use in the United States. Class of Recommendation and Level of Evidence The Class of Recommendation (COR) indicates the strength of the recommendation, encompassing the estimated magnitude and certainty of benefit in pro- portion to risk. The Level of Evidence (LOE) rates the quality of scientific evidence that supports the inter- vention on the basis of the type, quantity, and con- sistency of data from clinical trials and other sources Glenn N. Levine, MD, FACC, FAHA Chair, ACC/AHA Task Force on Clinical Practice Guidelines The purpose of this focused update is to update the 2013 ACCF/AHA Guideline for the Management of (2013 HF guideline) in areas in which new evidence has emerged since its publication. For this update and future heart failure (HF) guidelines, the Heart Failure Society of America (HFSA) has partnered with the ACC and AHA to provide coordinated guid- ance on the management of HF.


For this update and future heart failure (HF) guidelines, the Heart Failure Society of America (HFSA) has partnered with the ACC and AHA to provide coordinated guid- ance on the management of HF. The scope of the focused update includes revision to the sections on biomarkers; new therapies indicated for stage C HF with reduced ejection fraction (HFrEF); updates on HF with preserved ejection fraction (HFpEF); new data on important comorbidities, including sleep apnea, anemia, and hypertension; and new insights into the prevention of HF. This focused update represents the second part of a 2-stage publication; with the first part having been pub- lished as the 2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure, 10 which introduced guidance on new therapies, specifi- cally for the use of an angiotensin receptor neprilysin inhibitor (ARNI) (valsartan/sacubitril) and a sinoatrial node modulator (ivabradine). That focused update was published concurrently with the European Society of Cardiology s complete guideline, 2016 ESC Guidelines Yancy et al for the Diagnosis and Treatment of Acute and Chronic 1.1. Methodology and Evidence Review To identify key data that influence guideline recommen- dations, the Task Force and members of the 2013 HF guideline writing committee reviewed clinical trials that were presented at the annual scientific meetings of the ACC, AHA, and European Society of Cardiology and other scientific meetings and that were published in peer-reviewed format from April 2013 through Novem- ber 2016. The evidence is summarized in tables in the Online Data Supplement. All recommendations (new, modified, and unchanged) for each clinical section are included to provide a comprehensive assessment. The text explains new and modified recommendations, whereas recommendations from the previous guideline Table 1.


The text explains new and modified recommendations, whereas recommendations from the previous guideline Table 1. Applying Class of Recommendation and Level of Evidence to Clinical Strategies, Interventions, Treatments, or Diagnostic Testing in Patient Care* (Updated August 2015) 2017 ACC/AHA/HFSA Heart Failure Focused Update CLINICAL STATEMENTS AND GUIDELINES that have been deleted or superseded no longer ap- pear. Please consult the full-text version of the 2013 for text and evidence tables supporting the unchanged recommendations and for clinical areas not addressed in this focused update. Individual recom- mendations in this focused update will be incorporated into the full-text guideline in the future. Recommenda- tions from the prior guideline that remain current have been included for completeness, but the LOE reflects the COR/LOE system used when the recommendations were initially developed. New and modified recommen- dations in this focused update reflect the latest COR/ LOE system, in which LOE B and C are subcategorized for greater specificity.4 6 The section numbers corre- spond to the full-text guideline sections. 1.2. Organization of the Writing Group For this focused update, representative members of the 2013 HF guideline writing committee were invit- ed to participate. They were joined by additional in- vited members to form a new writing group, which is referred to as the 2017 HF focused update writing group. Members were required to disclose all RWI rel- evant to the data under consideration. The group was composed of experts representing general cardiolo- gists, HF and transplantation specialists, electrophysi- ologists, pharmacists, and general internists. The 2017 HF focused update writing group included representa- tives from the ACC, AHA, and HFSA, as well as the American Academy of Family Physicians, American College of Chest Physicians, American College of Phy- sicians, and International Society for Heart and Lung Transplantation. 1.3.


The 2017 HF focused update writing group included representa- tives from the ACC, AHA, and HFSA, as well as the American Academy of Family Physicians, American College of Chest Physicians, American College of Phy- sicians, and International Society for Heart and Lung Transplantation. 1.3. Document Review and Approval The focused update was reviewed by 2 official reviewers each nominated by the ACC, AHA, and HFSA; 1 reviewer each from the American Academy of Family Physicians, American College of Chest Physicians, and International Society for Heart and Lung Transplantation; and 19 in- dividual content reviewers. Reviewers RWI information is published in this document (Appendix 2). This document was approved for publication by the governing bodies of the ACC, AHA, and HFSA. 6. INITIAL AND SERIAL EVALUATION OF THE HF PATIENT Assays for BNP (B-type natriuretic peptide) and NT- proBNP (N-terminal pro-B-type natriuretic peptide), which are both natriuretic peptide biomarkers, have been used increasingly to establish the presence and severity of HF. In general, both natriuretic peptide bio- marker values track similarly, and either can be used in patient care settings as long as their respective ab- solute values and cutpoints are not used interchange- ably. Notably, BNP, but not NT-proBNP, is a substrate for neprilysin. Therefore, ARNI increases BNP levels12 but not NT-proBNP levels.13 Note that the type of natri- uretic peptide assay that has been performed must be considered during interpretation of natriuretic peptide biomarker levels in patients on ARNI.


Therefore, ARNI increases BNP levels12 but not NT-proBNP levels.13 Note that the type of natri- uretic peptide assay that has been performed must be considered during interpretation of natriuretic peptide biomarker levels in patients on ARNI. In 2 studies with ARNI, NT-proBNP levels were reduced,12,14 with the reduction in 1 study being associated with improved A substantial evidence base exists that supports the use of natriuretic peptide biomarkers to assist in the di- agnosis or exclusion of HF as a cause of symptoms (eg, dyspnea, weight gain) in the setting of chronic ambula- or in the setting of acute care with decom- especially when the cause of dyspnea is unclear. The role of natriuretic peptide biomarkers in population screening to detect incident HF is emerg- Elevated plasma levels of natriuretic peptide biomarkers are associated with a wide variety of cardiac and noncardiac causes (Table 2).38 42 Obesity may be as- sociated with lower natriuretic peptide concentrations, and this may modestly reduce diagnostic sensitivity in morbidly obese patients.42 Table 2. Selected Potential Causes of Elevated Natriuretic Peptide Levels38 41 Cardiac HF, including RV syndromes Acute coronary syndromes Heart muscle disease, including LVH Valvular heart disease Pericardial disease Atrial fibrillation Myocarditis Cardiac surgery Cardioversion Toxic-metabolic myocardial insults, including cancer chemotherapy Noncardiac Advancing age Anemia Renal failure Pulmonary: obstructive sleep apnea, severe pneumonia Pulmonary hypertension Critical illness Bacterial sepsis Severe burns Modified from Table 8 of the 2013 HF guideline.9 HF, indicates heart failure; LVH, left ventricular hypertrophy; and RV, right ventricular.


Selected Potential Causes of Elevated Natriuretic Peptide Levels38 41 Cardiac HF, including RV syndromes Acute coronary syndromes Heart muscle disease, including LVH Valvular heart disease Pericardial disease Atrial fibrillation Myocarditis Cardiac surgery Cardioversion Toxic-metabolic myocardial insults, including cancer chemotherapy Noncardiac Advancing age Anemia Renal failure Pulmonary: obstructive sleep apnea, severe pneumonia Pulmonary hypertension Critical illness Bacterial sepsis Severe burns Modified from Table 8 of the 2013 HF guideline.9 HF, indicates heart failure; LVH, left ventricular hypertrophy; and RV, right ventricular. Yancy et al Because of the absence of clear and consistent evi- dence for improvement in mortality and cardiovascular there are insufficient data to inform spe- cific guideline recommendations related to natriuretic peptide guided therapy or serial measurements of BNP or NT-proBNP levels for the purpose of reducing hospi- talization or deaths in the present document. Like natriuretic peptides, cardiac troponin levels may be elevated in the setting of chronic or acute decom- pensated HF, suggesting myocyte injury or necrosis.63 Troponins I and T respond similarly for acute coronary syndromes and acute decompensated HF.


Like natriuretic peptides, cardiac troponin levels may be elevated in the setting of chronic or acute decom- pensated HF, suggesting myocyte injury or necrosis.63 Troponins I and T respond similarly for acute coronary syndromes and acute decompensated HF. Elevations in either troponin I or T levels in the setting of acute HF are of prognostic significance and must be interpreted in the clinical context.64 In addition to natriuretic peptides and troponins,65 67 multiple other biomarkers, including those of inflam- mation, oxidative stress, vascular dysfunction, and myo- cardial and matrix remodeling, have been implicated in Biomarkers of myocardial fibrosis, soluble ST2 receptor, and galectin-3 are predictive of hospitaliza- tion and death and may provide incremental prognos- tic value over natriuretic peptide levels in patients with Strategies that combine multiple biomarkers may ultimately prove beneficial in guiding HF therapy in the future, but multicenter studies with larger deri- vation and validation cohorts are needed.75,76 Several emerging biomarkers await validation with well-defined outcome measures and prognostic accuracy before they can reach the clinical arena.77 84 This section categorizes the role of biomarkers into prevention, diagnosis, prognosis, and added risk strati- fication to clarify evidence-based objectives of their use in clinical practice. 6.3.1 Biomarkers for Prevention: Recommendation Biomarkers: Recommendation for Prevention of HF COR LOE Recommendation Comment/Rationale IIa B-R For patients at risk of developing HF, natriuretic peptide biomarker based screening followed by team-based care, including a cardiovascular specialist optimizing GDMT, can be useful to prevent the development of left ventricular dysfunction (systolic or diastolic) or NEW: New data suggest that natriuretic peptide biomarker screening and early intervention may prevent HF. See Online Data Supplements A and B.


6.3.1 Biomarkers for Prevention: Recommendation Biomarkers: Recommendation for Prevention of HF COR LOE Recommendation Comment/Rationale IIa B-R For patients at risk of developing HF, natriuretic peptide biomarker based screening followed by team-based care, including a cardiovascular specialist optimizing GDMT, can be useful to prevent the development of left ventricular dysfunction (systolic or diastolic) or NEW: New data suggest that natriuretic peptide biomarker screening and early intervention may prevent HF. See Online Data Supplements A and B. In a large-scale unblinded single-center study (STOP-HF [The St Vincent s Screening to Prevent Heart Failure]),85 patients at risk of HF (identified by the presence of hypertension, diabetes mellitus, or known vascular disease [eg, stage A HF]), but without established left ventricular systolic dysfunction or symptomatic HF at baseline, were randomly assigned to receive screening with BNP testing or usual primary care. Intervention-group participants with BNP levels of 50 pg/mL underwent echocardiography and were referred to a cardiovascular specialist who decided on further investigation and management. All patients received further coaching by a specialist nurse who emphasized individual risk and the importance of adherence to medication and healthy lifestyle behaviors. BNP-based screening reduced the composite endpoint of asymptomatic left ventricular dysfunction (systolic or diastolic) with or without newly diagnosed HF.85 Similarly, in another small, single-center RCT, accelerated up-titration of renin-angiotensin-aldosterone system antagonists and beta blockers reduced cardiac events in patients with diabetes mellitus and elevated NT-proBNP levels but without cardiac disease at Developing a standardized strategy to screen and intervene in patients at risk of HF can be difficult because of different definitions of HF risk, heterogeneity of prevalence in different populations, variable duration until clinical HF or left ventricular dysfunction develops, and variable interventions for risk factor modification or treatment.


BNP-based screening reduced the composite endpoint of asymptomatic left ventricular dysfunction (systolic or diastolic) with or without newly diagnosed HF.85 Similarly, in another small, single-center RCT, accelerated up-titration of renin-angiotensin-aldosterone system antagonists and beta blockers reduced cardiac events in patients with diabetes mellitus and elevated NT-proBNP levels but without cardiac disease at Developing a standardized strategy to screen and intervene in patients at risk of HF can be difficult because of different definitions of HF risk, heterogeneity of prevalence in different populations, variable duration until clinical HF or left ventricular dysfunction develops, and variable interventions for risk factor modification or treatment. Further studies are needed to determine cost-effectiveness and risk of such screening, as well as its impact on quality of life (QoL) and mortality rate. 6.3.2 Biomarkers for Diagnosis: Recommendation Biomarkers: Recommendation for Diagnosis COR LOE Recommendation Comment/Rationale I A In patients presenting with dyspnea, measurement of natriuretic peptide biomarkers is useful to support a diagnosis or exclusion MODIFIED: 2013 acute and chronic recommendations have been combined into a diagnosis section.


6.3.2 Biomarkers for Diagnosis: Recommendation Biomarkers: Recommendation for Diagnosis COR LOE Recommendation Comment/Rationale I A In patients presenting with dyspnea, measurement of natriuretic peptide biomarkers is useful to support a diagnosis or exclusion MODIFIED: 2013 acute and chronic recommendations have been combined into a diagnosis section. See Online Data Supplements A and B. Natriuretic peptide biomarker testing in the setting of chronic ambulatory HF provides incremental diagnostic value to clinical judgment, especially when the etiology of dyspnea is unclear.15 21 In emergency settings, natriuretic peptide biomarker levels usually have higher sensitivity than specificity and may be more useful for ruling out than ruling in HF.20 Although lower values of natriuretic peptide biomarkers exclude the presence of HF, and higher values have reasonably high positive predictive value to diagnose HF, clinicians should be aware that elevated plasma levels for both natriuretic peptides have been associated with a wide variety of cardiac and noncardiac causes (Table 2).38 41 6.3.3 Biomarkers for Prognosis or Added Risk Stratification: Recommendations Biomarkers: Recommendations for Prognosis COR LOE Recommendations Comment/Rationale I A Measurement of BNP or NT-proBNP is useful for establishing prognosis or disease severity in chronic HF.16,87 92 2013 recommendation remains current. 2017 ACC/AHA/HFSA Heart Failure Focused Update CLINICAL STATEMENTS AND GUIDELINES Figure 1. Biomarkers Indications for Use. Colors correspond to COR in Table 1. *Other biomarkers of injury or fibrosis include soluble ST2 receptor, galectin-3, and high- sensitivity troponin. ACC indicates American College of Cardiology; AHA, American Heart Association; ADHF, acute decom- pensated heart failure; BNP, B-type natriuretic peptide; COR, Class of Recommendation; ED, emergency department; HF, heart failure; NT-proBNP, N-terminal pro-B-type natriuretic peptide; NYHA, New York Heart Association; and pts, patients.


ACC indicates American College of Cardiology; AHA, American Heart Association; ADHF, acute decom- pensated heart failure; BNP, B-type natriuretic peptide; COR, Class of Recommendation; ED, emergency department; HF, heart failure; NT-proBNP, N-terminal pro-B-type natriuretic peptide; NYHA, New York Heart Association; and pts, patients. I A Measurement of baseline levels of natriuretic peptide biomarkers and/ or cardiac troponin on admission to the hospital is useful to establish a prognosis in acutely decompensated HF.27,93 100 MODIFIED: Current recommendation emphasizes that it is admission levels of natriuretic peptide biomarkers that are useful. See Online Data Supplements A and B. Higher levels of natriuretic peptide biomarkers on admission are usually associated with greater risk for clinical outcomes, including all-cause and cardiovascular mortality, morbidity, and composite outcomes, across different time intervals in patients with decompensated HF.20,27,29,93 101 Similarly, abnormal levels of circulating cardiac troponin are commonly found in patients with acute decompensated HF, often without obvious myocardial ischemia or underlying coronary artery disease (CAD), and this is associated with worse clinical outcomes and higher risk of death.95,99,102,103 Studies have demonstrated incremental prognostic value of these biomarkers to standard approaches of cardiovascular disease risk assessment.29,95 However, there were differences in the risk prediction models, assay cutpoints, and lengths of follow-up.29 Furthermore, not all patients may need biomarker measurement for prognostication, especially if they already have advanced HF with established poor prognosis or persistently elevated levels of biomarkers in former settings. Therefore, assays of natriuretic peptide biomarkers for incremental prognostication should not preclude good clinical judgment; an individualized approach to each patient is paramount. IIa B-NR During a HF hospitalization, a predischarge natriuretic peptide level can be useful to establish a postdischarge prognosis.93,96,104 113 NEW: Current recommendation reflects new observational studies.


IIa B-NR During a HF hospitalization, a predischarge natriuretic peptide level can be useful to establish a postdischarge prognosis.93,96,104 113 NEW: Current recommendation reflects new observational studies. See Online Data Supplements A and B. Predischarge natriuretic peptide biomarker levels and the relative change in levels during hospital treatment are strong predictors of the risk of death or hospital readmission for HF.93,96,104 113 Several studies have suggested that predischarge natriuretic peptide biomarker levels had higher reclassification and discrimination value than clinical variables in predicting outcomes.96,106,108 111 Patients with higher predischarge levels and patients who do not have a decrease in natriuretic peptide biomarker levels during hospitalization have worse outcomes.96,106,108 111 Although observational or retrospective studies have suggested that patients with natriuretic peptide biomarker reduction had better outcomes than those without any changes or with a biomarker rise,93,107,112,113 targeting a certain threshold, value, or relative change in these biomarker levels during hospitalization may not be practical or safe for every patient and has not been tested in a prospective large-scale trial. Clinical assessment and adherence to GDMT should be the emphasis, and the prognostic value of a predischarge value or relative changes does not imply the necessity for serial and repeated biomarker measurements during hospitalization. IIb B-NR In patients with chronic HF, measurement of other clinically available tests, such as biomarkers of myocardial injury or fibrosis, may be considered for additive risk stratification.27,95,98,99,103,114 119 MODIFIED: 2013 recommendations have been combined into prognosis section, resulting in LOE change from A to B-NR.