No date restrictions (conducted 7/11/2018) Similar articles searches were also conducted where potentially highly relevant papers were found NONE SPECIFIED, BUT DUE TO AUTOMATIC TERM MAPPING IN PUBMED, SOME MeSH TERMS MAY HAVE BEEN EMPLOYED Social determinants of health Equity Social status Social deprivation Neighborhood Neighborhood conditions Uninsured Housing Immigration Adverse childhood events Social gradient Educational status Inequalities Sexuality Atherosclerosis cardiovascular Team Based Care Search limited to English, 1/1/2010-10/14/2018 (though earlier articles may have been identified through related articles search) Related articles searches were also conducted where potentially highly relevant papers were found NONE SPECIFIED, BUT DUE TO AUTOMATIC TERM MAPPING IN PUBMED, SOME MeSH TERMS MAY HAVE BEEN EMPLOYED team Team care Collaborative care Multidisciplinary team based team approach prevention Primary prevention Cardiovascular disease, Cholesterol Aspirin Smoking Obesity Heart disease Appendix 1. Continued Medical Subject Headings (MeSH) Terms Key Words (Continued) (Continued) Atherosclerosis stroke Shared Decision Making Search limited to English, 1/1/2010-10/24/2018 (though earlier articles may have been identified through related articles search) Related articles searches were also conducted where potentially highly relevant papers were found NONE SPECIFIED, BUT DUE TO AUTOMATIC TERM MAPPING IN PUBMED, SOME MeSH TERMS MAY HAVE BEEN AUTOMATICALLY EMPLOYED Shared decision making Prevention Cardiovascular Atherosclerosis Stroke Heart Hypertension Lipids Cholesterol diabetes Exercise & Physical Activity Search limits: Not ACP Journal Club OR Summaries for patients OR Editorial OR case-report OR letter OR letter OR abstract OR newspaper article OR comment OR baseline characteristics OR study design OR methodology Terms to identify clinical trials/SRs/Mas: Filters: Meta-Analysis, Systematic Reviews, Clinical Trial, Controlled Clinical Trial, Randomized Controlled Trial, From 2011/01/01 to 2018/05/25, Humans, English, Adult: 19+ years Terms to identify observational studies: 2011/01/01 to 2018/12/31, Humans, English, Epidemiologic Studies, Case- Control Studies, Cohort Studies, Cross-Sectional Studies, epidemiolog* AND stud*, case control, cohort stud*, cross sectional, cohort analys*, follow up stud*, longitudinal, retrospective, prospective, observational AND stud* Filters: Adult: 19+ years Waist Circumference Search limited to adult populations, 01/01/2010-10/3/18, English language Acute Coronary Syndrome Acute coronary syndromes Angina Unstable Unstable angina?


Continued Medical Subject Headings (MeSH) Terms Key Words (Continued) (Continued) Atherosclerosis stroke Shared Decision Making Search limited to English, 1/1/2010-10/24/2018 (though earlier articles may have been identified through related articles search) Related articles searches were also conducted where potentially highly relevant papers were found NONE SPECIFIED, BUT DUE TO AUTOMATIC TERM MAPPING IN PUBMED, SOME MeSH TERMS MAY HAVE BEEN AUTOMATICALLY EMPLOYED Shared decision making Prevention Cardiovascular Atherosclerosis Stroke Heart Hypertension Lipids Cholesterol diabetes Exercise & Physical Activity Search limits: Not ACP Journal Club OR Summaries for patients OR Editorial OR case-report OR letter OR letter OR abstract OR newspaper article OR comment OR baseline characteristics OR study design OR methodology Terms to identify clinical trials/SRs/Mas: Filters: Meta-Analysis, Systematic Reviews, Clinical Trial, Controlled Clinical Trial, Randomized Controlled Trial, From 2011/01/01 to 2018/05/25, Humans, English, Adult: 19+ years Terms to identify observational studies: 2011/01/01 to 2018/12/31, Humans, English, Epidemiologic Studies, Case- Control Studies, Cohort Studies, Cross-Sectional Studies, epidemiolog* AND stud*, case control, cohort stud*, cross sectional, cohort analys*, follow up stud*, longitudinal, retrospective, prospective, observational AND stud* Filters: Adult: 19+ years Waist Circumference Search limited to adult populations, 01/01/2010-10/3/18, English language Acute Coronary Syndrome Acute coronary syndromes Angina Unstable Unstable angina?, Angina Unstable Myocardial infarction Myocardial infarctions Shock cardiogenic shock cardiogenic Myocardial Stunning myocardial stunning No Reflow Phenomenon Heart Arrest St elevation myocardial infarction STEMI Non-st elevated myocardial infarction NSTEMI death/sudden cardiac Stroke Brain Infarction Brain Stem Infarctions Lateral Meduallary Syndrome Appendix 1. Continued Medical Subject Headings (MeSH) Terms Key Words CLINICAL STATEMENTS AND GUIDELINES Cerebral Infarction Myocardial ischemia Dementia Multi infarct infarction anterior cerebral artery infarction middle cerebral artery infarction posterior cerebral artery Myocardial revascularization Coronary artery bypass Internal mammary coronary artery anastomosis Angioplasty angioplasty transluminal percutaneous coronary Heart failure Hospitalization Hospitalization? OR rehospitalization?


Continued Medical Subject Headings (MeSH) Terms Key Words CLINICAL STATEMENTS AND GUIDELINES Cerebral Infarction Myocardial ischemia Dementia Multi infarct infarction anterior cerebral artery infarction middle cerebral artery infarction posterior cerebral artery Myocardial revascularization Coronary artery bypass Internal mammary coronary artery anastomosis Angioplasty angioplasty transluminal percutaneous coronary Heart failure Hospitalization Hospitalization? OR rehospitalization? atherectomy coronary Coronary stent CABG bypass grafts Carotid pathology physiopathology Non-coronary revascularization procedure Carotid revascularization? Lower extremity revascularization? Percutaneous transluminal angioplast? Stent placement? Abdominal aortic aneurysm repair? AAA repair? complications Event? OR outcome? OR episode? Risk score Coronary risk modification Cardiovascular diseases Cardiovascular OR CVD Cardiovascular disease Coronary disease coronary Coronary artery disease Myocardial infarction Heart failure CHF OR CHD Cerebrovascular disorders dyspnea paroxysmal edema cardiac Physical fitness Motor activity Exercise tolerance Metabolic equivalent Metabolic equivalent (Continued) (Continued) Exercise test Graded exercise test OR gxt Life style or lifestyle Exercise Training Walking Maximal met Mets Physical activity Maximal metabolic? Acute Coronary Syndrome Acute coronary syndromes Angina Unstable Unstable angina?, Angina Unstable Myocardial infarction Myocardial infarctions Shock cardiogenic shock cardiogenic Myocardial Stunning myocardial stunning No Reflow Phenomenon Heart Arrest St elevation myocardial infarction STEMI Non-st elevated myocardial infarction NSTEMI death/sudden cardiac Stroke Brain Infarction Brain Stem Infarctions Lateral Meduallary Syndrome Cerebral Infarction Myocardial ischemia Dementia Multi infarct infarction anterior cerebral artery infarction middle cerebral artery infarction posterior cerebral artery Myocardial revascularization Coronary artery bypass Internal mammary coronary artery anastomosis Angioplasty angioplasty transluminal percutaneous coronary Heart failure Hospitalization Hospitalization? OR rehospitalization? atherectomy coronary Coronary stent CABG bypass grafts Carotid pathology Appendix 1. Continued Medical Subject Headings (MeSH) Terms Key Words Appendix 1. Continued Medical Subject Headings (MeSH) Terms Key Words CLINICAL STATEMENTS AND GUIDELINES physiopathology Non-coronary revascularization procedure Carotid revascularization? Lower extremity revascularization? Percutaneous transluminal angioplast? Stent placement? Abdominal aortic aneurysm repair? AAA repair? complications Event? OR outcome?


Abdominal aortic aneurysm repair? AAA repair? complications Event? OR outcome? OR episode? Risk score Coronary risk modification Cardiovascular diseases Cardiovascular OR CVD Cardiovascular disease Coronary disease coronary Coronary artery disease Myocardial infarction Heart failure CHF OR CHD Cerebrovascular disorders dyspnea paroxysmal edema cardiac Because of automatic term mapping in PubMed, some MeSH terms may have been used even when not explicitly specified. Appendix 1. Continued Medical Subject Headings (MeSH) Terms Key Words CLINICAL STATEMENTS AND GUIDELINES (Continued) Appendix 2.


Continued Medical Subject Headings (MeSH) Terms Key Words CLINICAL STATEMENTS AND GUIDELINES (Continued) Appendix 2. Author Relationships With Industry and Other Entities (Relevant) 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease Committee Member Employment Consultant Speakers Bureau Ownership/ Partnership/ Principal Personal Research Institutional, Organizational, or Other Financial Benefit Expert Witness Donna K. Arnett, Co-Chair University of Kentucky College of Public Health Dean and Professor of Epidemiology None None None None None None Roger S. Blumenthal, Co-Chair Johns Hopkins University Professor of Medicine and Director, Ciccarone Center for the Prevention of Heart Disease None None None None None None Michelle A. Albert UCSF School of Medicine Professor of Medicine and Director, UCSF NURTURE Center None None None None None None Andrew B. Buroker Faegre Baker Daniels LLP, Partner None None None None None None Zachary D. Goldberger University of Wisconsin School of Medicine and Public Health Associate Professor of Medicine, Division of Cardiology None None None None None None Ellen J. Hahn University of Kentucky College of Nursing Professor & Director, BREATHE, Deputy Director, UK-CARES & Leader, and Community Engagement Core; Marcia A. Dake Professor of Nursing None None None None None None Cheryl Dennison Himmelfarb Johns Hopkins School of Nursing Professor; Associate Dean Research, Office for Science and Innovation; and Deputy Director, Johns Hopkins Institute for Clinical and Translational Research None None None None None None Amit Khera UT Southwestern School of Medicine Professor of Internal Medicine and Director, Preventive Cardiology Program None None None None None None Donald Lloyd-Jones Northwestern University Eileen M. Foell Professor; Senior Associate Dean for Clinical and Translational Research; Chair, Department of Preventive Medicine; and Director, Clinical and Translational Sciences Institute None None None None None None J. William McEvoy National University of Ireland, Galway Campus Professor of Preventive Cardiology; National Institute for Preventive Cardiology, Galway Medical and Research Director; and University Hospital Galway, Ireland Consultant Cardiologist.


Author Relationships With Industry and Other Entities (Relevant) 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease Committee Member Employment Consultant Speakers Bureau Ownership/ Partnership/ Principal Personal Research Institutional, Organizational, or Other Financial Benefit Expert Witness Donna K. Arnett, Co-Chair University of Kentucky College of Public Health Dean and Professor of Epidemiology None None None None None None Roger S. Blumenthal, Co-Chair Johns Hopkins University Professor of Medicine and Director, Ciccarone Center for the Prevention of Heart Disease None None None None None None Michelle A. Albert UCSF School of Medicine Professor of Medicine and Director, UCSF NURTURE Center None None None None None None Andrew B. Buroker Faegre Baker Daniels LLP, Partner None None None None None None Zachary D. Goldberger University of Wisconsin School of Medicine and Public Health Associate Professor of Medicine, Division of Cardiology None None None None None None Ellen J. Hahn University of Kentucky College of Nursing Professor & Director, BREATHE, Deputy Director, UK-CARES & Leader, and Community Engagement Core; Marcia A. Dake Professor of Nursing None None None None None None Cheryl Dennison Himmelfarb Johns Hopkins School of Nursing Professor; Associate Dean Research, Office for Science and Innovation; and Deputy Director, Johns Hopkins Institute for Clinical and Translational Research None None None None None None Amit Khera UT Southwestern School of Medicine Professor of Internal Medicine and Director, Preventive Cardiology Program None None None None None None Donald Lloyd-Jones Northwestern University Eileen M. Foell Professor; Senior Associate Dean for Clinical and Translational Research; Chair, Department of Preventive Medicine; and Director, Clinical and Translational Sciences Institute None None None None None None J. William McEvoy National University of Ireland, Galway Campus Professor of Preventive Cardiology; National Institute for Preventive Cardiology, Galway Medical and Research Director; and University Hospital Galway, Ireland Consultant Cardiologist. None None None None None None Erin D. Michos Johns Hopkins School of Medicine Associate Professor of Medicine and Associate Director of Preventive Cardiology, Ciccarone Center for the Prevention of Heart Disease; Johns Hopkins Bloomberg School of Public Health Associate Professor of Epidemiology None None None None None None Michael D. Miedema Minneapolis Heart Institute Research Cardiologist None None None None None None Daniel Mu oz Vanderbilt University Medical Center Assistant Professor of Medicine, Division of Cardiology, Medical Director for Quality, Vanderbilt Heart & Vascular Institute, and Associate Medical Director, Cardiovascular ICU None None None None None None Sidney C. Smith Jr University of North Carolina, Chapel Hill Professor of Medicine, Division of Cardiology None None None None None None Salim S. Virani Baylor College of Medicine Professor, Section of Cardiovascular Research and Director for Research, Cardiology Fellowship Training Program; Michael E. DeBakey VA Medical Center Staff Cardiologist and Investigator, Health Policy, Quality & Informatics Program, Center for Innovations in Quality, Effectiveness and Safety None None None None None None Kim A. Williams Sr Rush Medical College James B. Herrick Professor and Chief, Division of Cardiology, Department of Internal Medicine None None None None None None CLINICAL STATEMENTS AND GUIDELINES Appendix 3.


None None None None None None Erin D. Michos Johns Hopkins School of Medicine Associate Professor of Medicine and Associate Director of Preventive Cardiology, Ciccarone Center for the Prevention of Heart Disease; Johns Hopkins Bloomberg School of Public Health Associate Professor of Epidemiology None None None None None None Michael D. Miedema Minneapolis Heart Institute Research Cardiologist None None None None None None Daniel Mu oz Vanderbilt University Medical Center Assistant Professor of Medicine, Division of Cardiology, Medical Director for Quality, Vanderbilt Heart & Vascular Institute, and Associate Medical Director, Cardiovascular ICU None None None None None None Sidney C. Smith Jr University of North Carolina, Chapel Hill Professor of Medicine, Division of Cardiology None None None None None None Salim S. Virani Baylor College of Medicine Professor, Section of Cardiovascular Research and Director for Research, Cardiology Fellowship Training Program; Michael E. DeBakey VA Medical Center Staff Cardiologist and Investigator, Health Policy, Quality & Informatics Program, Center for Innovations in Quality, Effectiveness and Safety None None None None None None Kim A. Williams Sr Rush Medical College James B. Herrick Professor and Chief, Division of Cardiology, Department of Internal Medicine None None None None None None CLINICAL STATEMENTS AND GUIDELINES Appendix 3. Reviewer Relationships With Industry and Other Entities (Comprehensive) 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease Reviewer Representation Employment Consultant Speakers Bureau Ownership/ Partnership/ Principal Personal Research Institutional, Organizational, or Other Financial Benefit Expert Witness Salary Amy Peterson Official Reviewer AHA Hospital Affiliations: American Family Children s Hospital; UnityPoint Health Meriter; UW School of Medicine and Public Health Department of Pediatrics None None None None None None None Kim K. Birtcher Official Reviewer ACC/AHA Task Force on Clinical Practice Guidelines Lead Reviewer University of Houston, College of Pharmacy, Clinical Professor Jones & Bartlett Learning None None None Accreditation Council for Clinical Lipidology (Other category) None None Sanjay Gandhi Official Reviewer ACC Metro Health Medical Center Cleveland, Associate Professor, Case Western Reserve University School of Medicine None None None Cleveland Heart Lab Juventas Athersys (Data Safety Monitoring Board) Tendyne (Other category) None None Andrea Price Official Reviewer ACC Science and Quality Committee Quality Databases at Indiana University Health, Director None None None None ACC* None None Jennifer E. Sanner Beauchamp Content Reviewer AHA University of Texas Health Science Center, Cizik School of Nursing, Associate Professor None None None None None None None Glenn N. Levine Content Reviewer ACC/AHA Task Force on Clinical Practice Guidelines Professor of Medicine at Baylor College of Medicine in Houston, Texas None None None None None Out of hospital cardiopulmonary (Defendant)* Out of hospital (Defendant)* None (Continued) Joseph Yeboah Wake Forest Baptist Health Associate Professor, Internal Medicine, Cardiovascular None None None None None None Boback Ziaeian University of California at Los Angeles/US Department of Veterans Affairs Greater Los Angeles Healthcare System, David Geffen School of Medicine Assistant Professor, Division of Cardiology None None None None None None This table represents the relationships of committee members with industry and other entities that were determined to be relevant to this document.


These relationships were reviewed and updated in conjunction with all meetings and/or conference calls of the writing committee during the document development process. The table does not necessarily reflect relationships with industry at the time of publication. A person is deemed to have a significant interest in a business if the interest represents ownership of 5% of the voting stock or share of the business entity, or ownership of $5000 of the fair market value of the business entity; or if funds received by the person from the business entity exceed 5% of the person s gross income for the previous year. Relationships that exist with no financial benefit are also included for the purpose of transparency. Relationships in this table are modest unless otherwise noted. According to the ACC/AHA, a person has a relevant relationship IF: a) the relationship or interest relates to the same or similar subject matter, intellectual property or asset, topic, or issue addressed in the document; or b) the company/entity (with whom the relationship exists) makes a drug, drug class, or device addressed in the document or makes a competing drug or device addressed in the document; or c) the person or a member of the person s household, has a reasonable potential for financial, professional or other personal gain or loss as a result of the issues/content addressed in the document. ACC indicates American College of Cardiology; AHA, American Heart Association; ICU, Intensive Care Unit; LLP, Limited Liability Partnership; UCSF, University of California, San Francisco; UT, University of Texas; and VA, Veterans Affairs. Appendix 2.


ACC indicates American College of Cardiology; AHA, American Heart Association; ICU, Intensive Care Unit; LLP, Limited Liability Partnership; UCSF, University of California, San Francisco; UT, University of Texas; and VA, Veterans Affairs. Appendix 2. Continued Committee Member Employment Consultant Speakers Bureau Ownership/ Partnership/ Principal Personal Research Institutional, Organizational, or Other Financial Benefit Expert Witness CLINICAL STATEMENTS AND GUIDELINES Patrick T. O Gara Content Reviewer ACC/AHA Task Force on Clinical Practice Guidelines Director of Strategic Planning for the Cardiovascular Division at Brigham and Women s Hospital, the Watkins Family Distinguished Chair in Cardiology and Professor of Medicine at Harvard Medical School None None None None Edwards Scientific (Other) Medtronic (Other) NIH (Other)* None None Joshua A. Beckman Content Reviewer ACC/AHA Task Force on Clinical Practice Guidelines Director, Vascular Medicine; Professor of Medicine at Vanderbilt University Aralez Pharmaceuticals* AstraZeneca Pharmaceuticals* Janssen Scientific Affairs* ER Squibb & Sons Boehringer Ingelheim Pharmaceuticals* Merck Sanofi AstraZeneca Pharmaceuticals None Bristol-Myers Squibb* Bayer (Data Safety Monitoring Board)* Novartis Corporation (Data Safety Monitoring Board) Vascular Interventional Advances (Officer, Director, Trustee, or other Fiduciary Role)* EMX JanaCare None None Anita Deswal Content Reviewer ACC/AHA Task Force on Clinical Practice Guidelines Chief, Cardiology, Michael E. DeBakey VA Medical Center & Baylor College of Medicine, Professor, Baylor College of Medicine None None None NIH* ACC/AHA (Other) Novartis Corporation (Other) AHA Get With The Guidelines Steering Committee (Other) Heart Failure Society of America (Other) Immediate Past Chair and Member, AHA Committee on Heart Failure and Transplantation (Other) NIH (Other) None None Federico Gentile Content Reviewer ACC/AHA Task Force on Clinical Practice Guidelines Centro Medico Diagnostico Director, Cardiovascular Disease None None None None None None None Jos A. Joglar Content Reviewer ACC/AHA Task Force on Clinical Practice Guidelines Program Director, Clinical Cardiac Electrophysiology Fellowship Program; Professor, UT Southwestern Medical Center None None None None None None None Duminda N. Wijeysundera Content Reviewer ACC/AHA Task Force on Clinical Practice Guidelines Associate Professor Anesthesia, University of Toronto None None None Canadian Institutes of Health Research* Ministry of Health and Longterm Care of Ontario (Canada)* NIH* PCORI (Data Safety Monitoring Board) None Canadian Institutes of Health Research (Ottawa, Ontario, Canada)* Appendix 3.


Continued Reviewer Representation Employment Consultant Speakers Bureau Ownership/ Partnership/ Principal Personal Research Institutional, Organizational, or Other Financial Benefit Expert Witness Salary (Continued) CLINICAL STATEMENTS AND GUIDELINES Eileen M. Handberg Content Reviewer ACC Research Professor of Medicine; Director, Clinical Trials Program; Program Director, Florida CARES, UF Health Bristol-Myers Squibb Company None None Aastrom Biosciences* Amorcyte, Inc* Biocardia, Inc* Brigham and Women s Hospital* Capricor* Cytori Therapeutics, Inc.* Department of Defense* Direct Flow Medical* Duke Clinical Research Institute* East Carolina University* Everyfit Inc* MEDTRONIC* Merck & Co., Inc.* Mesoblast Inc* NIH* PCORI* Sanofi Aventis* Amgen (Other) AstraZeneca (Other) Boehringer Ingelheim (Other) Daiichi Sankyo (Other) Gilead Sciences, Inc. (Other) Ionis (Other) Relypsa (Other) None None Prem Soman Content Reviewer ACC Associate Professor of Medicine (Cardiology), Director, Nuclear Cardiology, UPMC Alnylam Pharma None American Society of Nuclear Cardiology* Astellas Pharma US* None None None Eric Stecker Content Reviewer ACC Associate Professor of Medicine, Division of Cardiovascular Medicine School of Medicine, OHSU None None Hygeia / Desi MD* American Heart Association* Medical Research Foundation of Oregon* None None None Pamela Morris Content Reviewer ACC Professor, Medical University of South Carolina Amgen Inc. Sanofi Regeneron None None None None None None Andrew Freeman Content Reviewer ACC Director, Clinical Cardiology and Operations; Co- Director, Nuclear Cardiology, National Jewish Health None Boehringer Ingelheim* None None None None None Carl J. Lavie Content Reviewer ACC Medical Director, Cardiac Rehabilitation and Prevention, Ochsner Clinic Foundation None Amgen* ER Squibb & Sons Pfizer* Aralez Pharmaceuticals Amarin Pharma Sanofi Aventis* None None None None None James Stein Content Reviewer ACC Director, UW Health Preventive Cardiology Program, Robert Turell Professor in Cardiovascular Research, UW School of Medicine and Public Health Eli Lilly and Company (DSMB) None None None Up To Date (Other) Wisconsin Alumni Research Foundation (Other) None None Heather Johnson Content Reviewer ACC Associate Professor in the Division of Cardiovascular Medicine at the University of Wisconsin School of Medicine and Public Health None None None None Pfizer None None Nanette Wenger Content Reviewer ACC Professor of Medicine, Division of Cardiology, Emory University School of Medicine Janssen Pharmaceuticals, Inc* Amgen AstraZeneca Gilead Sciences Merck None None Gilead Sciences* NHLBI* Pfizer* Society for Women s Health Research* None None None Appendix 3.


Continued Reviewer Representation Employment Consultant Speakers Bureau Ownership/ Partnership/ Principal Personal Research Institutional, Organizational, or Other Financial Benefit Expert Witness Salary (Continued) CLINICAL STATEMENTS AND GUIDELINES Michael Blaha Content Reviewer AHA Director of Clinical Research, Ciccarone Center for the Prevention of Heart Disease Associate Professor of Medicine, Johns Hopkins Medicine Ferring Pharmaceuticals Regeneron Pharmaceuticals Sanofi-Aventis* Amgen Akcea MedImmune Novartis Novo Nordisk Siemens* ACC None None Aetna Amgen AHA FDA NIH None None None Laurence Sperling Content Reviewer ACC/ AHA Founder and Director of Preventive Cardiology at the Emory Clinic, Co- Director of the Cardiovascular Disease Fellowship Program at Emory, Professor of Medicine (Cardiology) at the Emory University School of Medicine None None None None None None None Seth Martin Content Reviewer ACC/ AHA Director, Advanced Lipid Disorders Program of the Ciccarone Center; Associate Professor of Medicine at Johns Hopkins Medicine Amgen Akcea Therapeutics Quest Diagnostics Sanofi- Regeneron Esperion Novo Nordisk None None Aetna Foundation* Apple* Google* iHealth* Maryland Innovation Initiative* AHA* Corrie Health (Officer, Director, Trustee, or other Fiduciary Role) Co-inventor on pending patent filed by Johns Hopkins University for method of LDL-C estimation (Other) None None Samia Mora Content Reviewer ACC/ AHA Associate Professor of Medicine, Harvard Medicine School Director, Center for Lipid Metabolomics, Brigham and Women s Hospital Pri-Med* Pfizer Quest Diagnostics None None None C3 Conference (Other) European Atherosclerosis Society (Other) FEBS Congress (Other) Oregon Health & Science University (Other) Vascular Biology Working Group Meeting (Other) Atherotech Diagnostics* Pfizer* Quest Diagnostics* NHLBI* NIDDK* None None Clyde Yancy Content Reviewer ACC/ AHA Chief of Cardiology in the Department of Medicine, Northwestern Medicine None None None None JAMA Cardiology (Other)* None None Quinn Pack AACVPR Assistant Professor of Medicine at University of Massachusetts Medical School None None None None None None None Frank Sacks ASN Professor of Cardiovascular Disease Prevention, Harvard School of Public Health Amgen Pfizer* AstraZeneca* None None None None None None Salvatore Lacagnina ACPM System Medical Director of Wellness & Employee Health, Lee Health None None None None None None None Appendix 3.


Continued Reviewer Representation Employment Consultant Speakers Bureau Ownership/ Partnership/ Principal Personal Research Institutional, Organizational, or Other Financial Benefit Expert Witness Salary (Continued) CLINICAL STATEMENTS AND GUIDELINES Ron Blankstein ASPC Co-Director, Cardiovascular Imaging Training Program, Associate Physician, Preventive Cardiology, Director, Cardiac Computed Tomography, Brigham Health, Associate Professor in Medicine and Radiology, Harvard Medical School Ekos Corporation Amgen None None Amgen Astellas Sanofi-Aventis American Society of Nuclear Cardiology (Officer, Director, Trustee, or other Fiduciary Role) Intersocietal Accreditation Commission for Computed Tomography (Officer, Director, Trustee, or other Fiduciary Role) Society of Cardiovascular Computed Tomography (Officer, Director, Trustee, or other Fiduciary Role) None None Jo-Ann Eastwood PCNA Associate Professor, UCLA School of Nursing None None None None None None None Stuart Haines Content Reviewer ACC/ AHA Professor of Pharmacy Practice, University of Mississippi None None Rx Instructional Systems* None American Association of Colleges of Pharmacy (Officer, Director, Trustee, or other Fiduciary Role) None None Michael Rich AGS Professor of Medicine, Washington University School of Medicine in St. Louis None None None None None None None This table represents all relationships of reviewers with industry and other entities that were reported at the time of peer review, including those not deemed to be relevant to this document, at the time this document was under review. The table does not necessarily reflect relationships with industry at the time of publication. A person is deemed to have a significant interest in a business if the interest represents ownership of 5% of the voting stock or share of the business entity, or ownership of $5000 of the fair market value of the business entity; or if funds received by the person from the business entity exceed 5% of the person s gross income for the previous year.


A person is deemed to have a significant interest in a business if the interest represents ownership of 5% of the voting stock or share of the business entity, or ownership of $5000 of the fair market value of the business entity; or if funds received by the person from the business entity exceed 5% of the person s gross income for the previous year. Relationships that exist with no financial benefit are also included for the purpose of transparency. Relationships in this table are modest unless otherwise noted. Names are listed in alphabetical order within each category of review. Please refer to http://www.acc.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. *Significant relationship. No financial benefit. AACVPR indicates American Association of Cardiovascular and Pulmonary Rehabilitation; ACC, American College of Cardiology; ACPM, American College of Preventive Medicine; AGS, American Geriatrics Society; AHA, American Heart Association; ASN, American Society for Nutrition; American Society of Preventive Cardiology; DSMB, Data and Safety Monitoring Board; FDA, US Food and Drug Administration; FEBS, Federation of European Biochemical Societies; JAMA, Journal of the American Medical Association; LDL-C, low-density lipoprotein cholesterol; NHLBI, National Heart, Lung, and Blood Institute; NIDDK, National Institute of Diabetes and Digestive and Kidney Diseases; NIH, National Institutes of Health; OHSU, Oregon Health & Science University; PCNA, Preventive Cardiovascular Nurses Association; PCORI, Patient-Centered Outcomes Research Institute; UCLA, University of California, Los Angeles; UF, University of Florida; UPMC, University of Pittsburgh Medical Center; UT, University of Texas; UW, University of Wisconsin; and VA, Veterans Affairs. Appendix 3. Continued Reviewer Representation Employment Consultant Speakers Bureau Ownership/ Partnership/ Principal Personal Research Institutional, Organizational, or Other Financial Benefit Expert Witness Salary


volume 3 | issue 3 | november 2013 http://www.kidney-international.org Official Journal of the International Society of Nephrology KDIGO Clinical Practice Guideline for Lipid Management in Chronic Kidney Disease KDIGO Clinical Practice Guideline for Lipid Management in Chronic Kidney Disease KDIGO gratefully acknowledges the founding sponsor, National Kidney Foundation, and the following consortium of sponsors that make our initiatives possible: 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, National Kidney Foundation (NKF)-Board of Directors, Novartis, Pharmacosmos, PUMC Pharmaceutical, Robert and Jane Cizik Foundation, Shire, Takeda Pharmaceutical, Transwestern Commercial Services, Vifor Pharma, and Wyeth. Sponsorship Statement: KDIGO is supported by a consortium of sponsors and no funding is accepted for the development of specific guidelines. KDIGO Clinical Practice Guideline for Lipid Management in Chronic Kidney Disease Tables and Figures v KDIGO Board Members vi Reference Keys vii CKD Nomenclature viiii Conversion Factors ix Abbreviations and Acronyms x Notice Foreword Work Group Membership Abstract Summary of Recommendation Statements Introduction: The case for updating and context Chapter 1: Assessment of lipid status in adults with CKD Chapter 2: Pharmacological cholesterol-lowering treatment in adults Chapter 3: Assessment of lipid status in children with CKD Chapter 4: Pharmacological cholesterol-lowering treatment in children Chapter 5: Triglyceride-lowering treatment in adults Chapter 6: Triglyceride-lowering treatment in children Methods for Guideline Development Biographic and Disclosure Information Acknowledgments References http://www.kidney-international.org contents & 2013 KDIGO VOL 3 | ISSUE 3 | NOVEMBER 2013 This journal is a member of, and subscribes to the principles of, the Committee on Publication Ethics (COPE) www.publicationethics.org TABLES Table 1. Secondary causes of dyslipidemias Table 2.


KDIGO Clinical Practice Guideline for Lipid Management in Chronic Kidney Disease Tables and Figures v KDIGO Board Members vi Reference Keys vii CKD Nomenclature viiii Conversion Factors ix Abbreviations and Acronyms x Notice Foreword Work Group Membership Abstract Summary of Recommendation Statements Introduction: The case for updating and context Chapter 1: Assessment of lipid status in adults with CKD Chapter 2: Pharmacological cholesterol-lowering treatment in adults Chapter 3: Assessment of lipid status in children with CKD Chapter 4: Pharmacological cholesterol-lowering treatment in children Chapter 5: Triglyceride-lowering treatment in adults Chapter 6: Triglyceride-lowering treatment in children Methods for Guideline Development Biographic and Disclosure Information Acknowledgments References http://www.kidney-international.org contents & 2013 KDIGO VOL 3 | ISSUE 3 | NOVEMBER 2013 This journal is a member of, and subscribes to the principles of, the Committee on Publication Ethics (COPE) www.publicationethics.org TABLES Table 1. Secondary causes of dyslipidemias Table 2. Examples of situations in which measuring cholesterol level might or might not change the management implied by Recommendation 1.2 Table 3. Rate of coronary death or non-fatal MI (by age and eGFR) Table 4. Recommended doses of statins in adults with CKD Table 5. Plasma lipid concentrations for children and adolescents Table 6. Systematic review topics and screening criteria Table 7. Hierarchy of outcomes Table 8. Literature yield for RCTs Table 9. Work products for the guideline Table 10. Classification of study quality Table 11. GRADE system for grading quality of evidence Table 12. Final grade for overall quality of evidence Table 13. Balance of benefits and harms Table 14. KDIGO nomenclature and description for grading recommendations Table 15. Determinants of strength of recommendation Table 16. The Conference on Guideline Standardization (COGS) checklist for reporting clinical practice guidelines FIGURES Figure 1.


The Conference on Guideline Standardization (COGS) checklist for reporting clinical practice guidelines FIGURES Figure 1. Adjusted relation between LDL-C and HR of myocardial infarction by eGFR as a continuous variable Figure 2. Future 10-year coronary risk based on various patient characteristics Figure 3.


Future 10-year coronary risk based on various patient characteristics Figure 3. Grading the quality of CKD subgroups of non-CKD trials Additional information in the form of supplementary materials can be found online at http://www.kdigo.org/home/guidelines/lipids http://www.kidney-international.org contents & 2013 KDIGO Kidney International Supplements (2013) 3, v v KDIGO Board Members Garabed Eknoyan, MD Norbert Lameire, MD, PhD Founding KDIGO Co-Chairs Kai-Uwe Eckardt, MD Immediate Past Co-Chair Bertram L Kasiske, MD KDIGO Co-Chair David C Wheeler, MD, FRCP KDIGO Co-Chair Omar I Abboud, MD, FRCP Sharon Adler, MD, FASN Rajiv Agarwal, MD Sharon P Andreoli, MD Gavin J Becker, MD, FRACP Fred Brown, MBA, FACHE Daniel C Cattran, MD, FRCPC Allan J Collins, MD, FACP Rosanna Coppo, MD Josef Coresh, MD, PhD Ricardo Correa-Rotter, MD Adrian Covic, MD, PhD Jonathan C Craig, MBChB, MM (Clin Epi), DCH, FRACP, PhD Angel LM de Francisco, MD Paul E de Jong, MD, PhD Ana Figueiredo, RN, MSc, PhD Mohammed Benghanem Gharbi, MD Gordon Guyatt, MD, MSc, BSc, FRCPC David Harris, MD Lai Seong Hooi, MD Enyu Imai, MD, PhD Lesley A Inker, MD, MS, FRCP Michel Jadoul, MD Simon Jenkins, MBE, FRCGP Suhnggwon Kim, MD, PhD Martin K Kuhlmann, MD Nathan W Levin, MD, FACP Philip K-T Li, MD, FRCP, FACP Zhi-Hong Liu, MD Pablo Massari, MD Peter A McCullough, MD, MPH, FACC, FACP Rafique Moosa, MD Miguel C Riella, MD Adibul Hasan Rizvi, MBBS, FRCP Bernardo Rodriquez-Iturbe, MD Robert Schrier, MD Justin Silver, MD, PhD Marcello Tonelli, MD, SM, FRCPC Yusuke Tsukamoto, MD Theodor Vogels, MSW Angela Yee-Moon Wang, MD, PhD, FRCP Christoph Wanner, MD Elena Zakharova, MD, PhD NKF-KDIGO GUIDELINE DEVELOPMENT STAFF Kerry Willis, PhD, Senior Vice-President for Scientific Activities Michael Cheung, MA, Guideline Development Director Sean Slifer, BA, Guideline Development Manager vi Kidney International Supplements (2013) 3, vi http://www.kidney-international.org & 2013 KDIGO Grade Quality of evidence Meaning A High We are confident that the true effect lies close to that of the estimate of the effect.


B Moderate The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. C Low The true effect may be substantially different from the estimate of the effect. D Very low The estimate of effect is very uncertain, and often will be far from the truth. 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 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.


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. NOMENCLATURE AND DESCRIPTION FOR RATING GUIDELINE RECOMMENDATIONS Within each recommendation, the strength of recommendation is indicated as Level 1, Level 2, or Not Graded, and the quality of the supporting evidence is shown as A, B, C, or D. Reference Keys Kidney International Supplements (2013) 3, vii vii http://www.kidney-international.org & 2013 KDIGO CURRENT CHRONIC KIDNEY DISEASE (CKD) NOMENCLATURE USED BY KDIGO CKD is defined as abnormalities of kidney structure or function, present for 43 months, with implications for health. CKD is classified based on Cause, GFR category (G1-G5), and Albuminuria category (A1-A3), abbreviated as CGA. Persistent albuminuria categories Description and range Normal to mildly increased Moderately increased Severely increased GFR categories (ml/min/ m ) Description and range G1 Normal or high 90 Mildly to moderately decreased Moderately to severely decreased Prognosis of CKD by GFR and Albuminuria Categories: Prognosis of CKD by GFR and albuminuria category Green: low risk (if no other markers of kidney disease, no CKD); Yellow: moderately increased risk; Orange: high risk; Red, very high risk. http://www.kidney-international.org & 2013 KDIGO viii Kidney International Supplements (2013) 3, viii CONVERSION FACTORS OF CONVENTIONAL UNITS TO SI UNITS Parameter Conventional unit Conversion factor SI units Cholesterol (total, HDL-C, LDL-C) mg/dl 0.0259 mmol/l Creatinine (serum, plasma) mg/dl 88.4 mmol/l Triglycerides (serum) mg/dl 0.0113 mmol/l Abbreviations: HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol. Note: Conventional unit  conversion factor SI unit.


http://www.kidney-international.org & 2013 KDIGO viii Kidney International Supplements (2013) 3, viii CONVERSION FACTORS OF CONVENTIONAL UNITS TO SI UNITS Parameter Conventional unit Conversion factor SI units Cholesterol (total, HDL-C, LDL-C) mg/dl 0.0259 mmol/l Creatinine (serum, plasma) mg/dl 88.4 mmol/l Triglycerides (serum) mg/dl 0.0113 mmol/l Abbreviations: HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol. Note: Conventional unit  conversion factor SI unit. Kidney International Supplements (2013) 3, ix ix http://www.kidney-international.org & 2013 KDIGO x Kidney International Supplements (2013) 3, x Abbreviations and Acronyms 4D Die Deutsche Diabetes Dialyse Studie ACCORD Action to Control Cardiovascular Risk in Diabetes trial AGREE Appraisal of Guidelines for Research and Evaluation ALERT Assessment of Lescol in Renal Transplantation trial ALLHAT Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial ALLIANCE Aggressive Lipid Lowering Initiation Abates New Cardiac Events trial ApoB Apolipoprotein B ASPEN Atorvastatin as Prevention of Coronary Heart Disease Endpoints in Patients with Non-Insulin- Dependent Diabetes Mellitus trial ASSIGN ASSessing cardiovascular risk using SIGN guidelines ATP Adult Treatment Panel AURORA A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events CARDS Collaborative Atorvastatin Diabetes Study CARE Cholesterol and Recurrent Events trial CHD Coronary heart disease CI Confidence interval CK Creatine kinase CKD Chronic kidney disease CKiD Chronic Kidney Disease in Children study COGS Conference on Guideline Standardization CPG Clinical practice guideline CVD Cardiovascular disease DAIS Diabetes Atherosclerosis Intervention Study eGFR Estimated glomerular filtration rate ERT Evidence review team ESRD End-stage renal disease FIELD Fenofibrate Intervention and Event Lowering in Diabetes trial GFR Glomerular filtration rate GRADE Grading of Recommendations Assessment, Develop- ment, and Evaluation HD Hemodialysis HDL-C High-density lipoprotein cholesterol HR Hazard ratio IDEAL Incremental Decrease in Endpoints Through Aggressive Lipid Lowering trial KDIGO Kidney Disease: Improving Global Outcomes KDOQI Kidney Disease Outcomes Quality Initiative LDL-C Low-density lipoprotein cholesterol Lp(a) Lipoprotein(a) MI Myocardial infarction NKF National Kidney Foundation PDAY Pathobiological Determinants of Atherosclerosis in Youth study PICODD Population, Intervention, Comparator, Outcome, study Design and Duration of follow-up PREVEND IT Prevention of REnal and Vascular ENdstage Disease Intervention Trial PROCAM Prospective Cardiovascular Mu nster PROSPER Prospective Study of Pravastatin in the Elderly at Risk trial PROVE IT Pravastatin or Atorvastatin in Evaluation and Infec- tion Therapy trial QRISK2 QRISK cardiovascular disease risk algorithm RCT Randomized controlled trial RR Relative risk SCORE Systematic Coronary Risk Evaluation Project SCr Serum creatinine SEARCH Study Evaluating Additional Reductions in Choles- terol and Homocysteine SHARP Study of Heart and Renal Protection trial SPARCL Stroke Prevention by Aggressive Reduction in Choles- terol Levels trial TC Total cholesterol TG Triglyceride TLC Therapeutic lifestyle changes TNT Treating to New Targets trial VA-HIT Veterans Affairs high-density lipoprotein interven- tion trial http://www.kidney-international.org & 2013 KDIGO Notice SECTION I: USE OF THE CLINICAL PRACTICE GUIDELINE This Clinical Practice Guideline document is based upon systematic literature searches last conducted in August 2011, supplemented with additional evidence through June 2013.


It is designed to provide information and assist decision making. It is not intended to define a standard of care, and should not be construed as one, nor should it be interpreted as prescribing an exclusive course of management. Variations in practice will inevitably and appropriately occur when clinicians take into account the needs of individual patients, available resources, and limitations unique to an institution or type of practice. Every health-care professional making use of these recommendations is responsible for evaluating the appropriateness of applying them in any particular clinical situation. The recommendations for research contained within this document are general and do not imply a specific protocol. SECTION II: DISCLOSURE Kidney Disease: Improving Global Outcomes (KDIGO) makes every effort to avoid any actual or reasonably perceived conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the Work Group. All members of the Work Group are required to complete, sign, and submit a disclosure and attestation form showing all such relationships that might be perceived as or are actual conflicts of interest. This document is updated annually and information is adjusted accordingly. All reported information is published in its entirely at the end of this document in the Work Group members Biographic and Disclosure Section, and is kept on file at KDIGO. http://www.kidney-international.org & 2013 KDIGO Copyright & 2013 by KDIGO. All rights reserved. Single photocopies may be made for personal use as allowed by national copyright laws. Special rates are available for educational institutions that wish to make photocopies for non-profit educational use.


Special rates are available for educational institutions that wish to make photocopies for non-profit educational use. No part of this publication may be reproduced, amended, or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without explicit permission in writing from KDIGO. Details on how to seek permission for reproduction or translation, and further information about KDIGO s permissions policies can be obtained by contacting Danielle Green, Managing Director, at: danielle.green@kdigo.org To the fullest extent of the law, neither KDIGO, Kidney International Supplements, National Kidney Foundation (KDIGO s former Managing Agent) nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Foreword It is our hope that this document will serve several useful purposes. Our primary goal is to improve patient care. We hope to accomplish this, in the short term, by helping clinicians know and better understand the evidence (or lack of evidence) that determines current practice. By providing comprehensive evidence-based recommendations, this guide- line will also help define areas where evidence is lacking and research is needed. Helping to define a research agenda is an often neglected, but very important, function of clinical practice guideline development. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to rate the quality of evidence and the strength of recommenda- tions.


We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to rate the quality of evidence and the strength of recommenda- tions. In all, there were 3 (27.3%) recommendations in this guideline for which the overall quality of evidence was graded A, whereas 2 (18.2%) were graded B, 4 (36.4%) were graded C, and 2 (18.2%) were graded D. Although there are reasons other than quality of evidence to make a grade 1 or 2 recommendation, in general, there is a correlation between the quality of overall evidence and the strength of the recommendation. Thus, there were 4 recommendations. There were 2 (18.2%) recommendations were not graded. Some argue that recommendations should not be made when evidence is weak. However, clinicians still need to make decisions in their daily practice, and they often ask, What do the experts do in this setting? We opted to give guidance, rather than remain silent. These recommendations are often rated with a low strength of recommendation and a low quality of evidence, or were not graded. It is important for the users of this guideline to be cognizant of this (see Notice). In every case these recommendations are meant to be a place for clinicians to start, not stop, their inquiries into specific management questions pertinent to the patients they see in daily practice. We wish to thank the Work Group Co-Chairs, Drs. Marcello Tonelli and Christoph Wanner, along with all of the Work Group members who volunteered countless hours of their time developing this guideline. We also thank the Evidence Review Team members and staff of the National Kidney Foundation who made this project possible.


We also thank the Evidence Review Team members and staff of the National Kidney Foundation who made this project possible. Finally, we owe a special debt of gratitude to the many KDIGO Board members and individuals who volunteered time reviewing the guideline, and making very helpful suggestions. Bertram L Kasiske, MD David C Wheeler, MD, FRCP KDIGO Co-Chair KDIGO Co-Chair http://www.kidney-international.org & 2013 KDIGO Work Group Membership http://www.kidney-international.org & 2013 KDIGO WORK GROUP CO-CHAIRS Marcello A Tonelli, MD, SM, FRCPC University of Alberta Edmonton, Canada Christoph Wanner, MD University of Wu rzburg Wu rzburg, Germany WORK GROUP EVIDENCE REVIEW TEAM Tufts Center for Kidney Disease Guideline Development and Implementation, Tufts Medical Center, Boston, MA, USA: Ashish Upadhyay, MD, Project Director Ethan M Balk, MD, MPH, Program Director, Evidence Based Medicine Amy Earley, BS, Project Coordinator Shana Haynes, MS, DHSc, Research Assistant Jenny Lamont, MS, Project Manager Alan Cass, MBBS, FRACP, PhD Menzies School of Health Research Darwin, Australia Florian Kronenberg, MD Innsbruck Medical University Innsbruck, Austria Amit X Garg, MD, FRCPC, FACP, PhD London Health Sciences Centre London, Canada Rulan S Parekh, MD, MS, FRCPC, FASN Hospital for Sick Children Toronto, Canada Hallvard Holdaas, MD, PhD Hospital Rikshospitalet Oslo, Norway Tetsuo Shoji, MD, PhD Osaka City University Osaka, Japan Alan G Jardine, MBChB, MD, FRCP BHF Cardiovascular Research Centre Glasgow, United Kingdom Robert J Walker, MBChB, MD (Otago), FRACP, FASN, FAHA University of Otago Dunedin, New Zealand Lixin Jiang, MD, PhD Chinese Academy of Medical Sciences and Peking Union Medical College Beijing, China Abstract The 2013 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for Lipid Management in Chronic Kidney Disease (CKD) provides guidance on lipid management and treatment for all patients with CKD (non-dialysis-dependent, dialysis-dependent, kidney transplant recipients and children).


Bertram L Kasiske, MD David C Wheeler, MD, FRCP KDIGO Co-Chair KDIGO Co-Chair http://www.kidney-international.org & 2013 KDIGO Work Group Membership http://www.kidney-international.org & 2013 KDIGO WORK GROUP CO-CHAIRS Marcello A Tonelli, MD, SM, FRCPC University of Alberta Edmonton, Canada Christoph Wanner, MD University of Wu rzburg Wu rzburg, Germany WORK GROUP EVIDENCE REVIEW TEAM Tufts Center for Kidney Disease Guideline Development and Implementation, Tufts Medical Center, Boston, MA, USA: Ashish Upadhyay, MD, Project Director Ethan M Balk, MD, MPH, Program Director, Evidence Based Medicine Amy Earley, BS, Project Coordinator Shana Haynes, MS, DHSc, Research Assistant Jenny Lamont, MS, Project Manager Alan Cass, MBBS, FRACP, PhD Menzies School of Health Research Darwin, Australia Florian Kronenberg, MD Innsbruck Medical University Innsbruck, Austria Amit X Garg, MD, FRCPC, FACP, PhD London Health Sciences Centre London, Canada Rulan S Parekh, MD, MS, FRCPC, FASN Hospital for Sick Children Toronto, Canada Hallvard Holdaas, MD, PhD Hospital Rikshospitalet Oslo, Norway Tetsuo Shoji, MD, PhD Osaka City University Osaka, Japan Alan G Jardine, MBChB, MD, FRCP BHF Cardiovascular Research Centre Glasgow, United Kingdom Robert J Walker, MBChB, MD (Otago), FRACP, FASN, FAHA University of Otago Dunedin, New Zealand Lixin Jiang, MD, PhD Chinese Academy of Medical Sciences and Peking Union Medical College Beijing, China Abstract The 2013 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for Lipid Management in Chronic Kidney Disease (CKD) provides guidance on lipid management and treatment for all patients with CKD (non-dialysis-dependent, dialysis-dependent, kidney transplant recipients and children). This guideline contains chapters on the assessment of lipid status and treatment for dyslipidemia in adults and children. Development of the guideline followed an explicit process of evidence review and appraisal. Treatment approaches are addressed in each chapter and guideline recommendations are based on systematic reviews of relevant trials.


Treatment approaches are addressed in each chapter and guideline recommendations are based on systematic reviews of relevant trials. Appraisal of the quality of the evidence and the strength of recommendations followed the GRADE approach. Ongoing areas of controversies and limitations of the evidence are discussed and additional suggestions are also provided for future research. Keywords: cholesterol; chronic kidney disease; clinical practice guideline; dyslipidemia; evidence-based recommendation; KDIGO; systematic review; triglycerides CITATION In citing this document, the following format should be used: Kidney Disease: Improving Global Outcomes (KDIGO) Lipid Work Group. KDIGO Clinical Practice Guideline for Lipid Management in Chronic Kidney Disease. Kidney inter., Suppl. 2013; 3: 259 305. http://www.kidney-international.org & 2013 KDIGO Summary of Recommendation Statements http://www.kidney-international.org & 2013 KDIGO Chapter 1: Assessment of lipid status in adults with CKD 1.1: In adults with newly identified CKD (including those treated with chronic dialysis or kidney transplantation), we recommend evaluation with a lipid profile (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides). (1C) 1.2: In adults with CKD (including those treated with chronic dialysis or kidney transplantation), follow-up measurement of lipid levels is not required for the majority of patients. (Not Graded) Chapter 2: Pharmacological cholesterol-lowering treatment in adults but not treated with chronic dialysis or kidney transplantation (GFR categories G3a-G5), we recommend treatment with a statin or statin/ezetimibe (GFR categories G1-G2) we recommend treatment with a statin.


(Not Graded) Chapter 2: Pharmacological cholesterol-lowering treatment in adults but not treated with chronic dialysis or kidney transplantation (GFR categories G3a-G5), we recommend treatment with a statin or statin/ezetimibe (GFR categories G1-G2) we recommend treatment with a statin. (1B) 2.2: In adults aged 18 49 years with CKD but not treated with chronic dialysis or kidney transplantation, we suggest statin treatment in people with one or more of the following (2A): K known coronary disease (myocardial infarction or coronary revascularization) K diabetes mellitus K prior ischemic stroke K estimated 10-year incidence of coronary death or non-fatal myocardial infarction 410% 2.3.1: In adults with dialysis-dependent CKD, we suggest that statins or statin/ezetimibe combination not be 2.3.2: In patients already receiving statins or statin/ezetimibe combination at the time of dialysis initiation, we suggest that these agents be continued. (2C) 2.4: In adult kidney transplant recipients, we suggest treatment with a statin. (2B) Chapter 3: Assessment of lipid status in children with CKD 3.1: In children with newly identified CKD (including those treated with chronic dialysis or kidney transplan- tation), we recommend evaluation with a lipid profile (total cholesterol, LDL cholesterol, HDL cholesterol, 3.2: In children with CKD (including those treated with chronic dialysis or kidney transplantation), we suggest annual follow-up measurement of fasting lipid levels. (Not Graded) Chapter 4: Pharmacological cholesterol-lowering treatment in children 4.1: In children less than 18 years of age with CKD (including those treated with chronic dialysis or kidney transplantation), we suggest that statins or statin/ezetimibe combination not be initiated. (2C) Chapter 5: Triglyceride-lowering treatment in adults 5.1: In adults with CKD (including those treated with chronic dialysis or kidney transplantation) and hypertriglyceridemia, we suggest that therapeutic lifestyle changes be advised.


(2C) Chapter 5: Triglyceride-lowering treatment in adults 5.1: In adults with CKD (including those treated with chronic dialysis or kidney transplantation) and hypertriglyceridemia, we suggest that therapeutic lifestyle changes be advised. (2D) Chapter 6: Triglyceride-lowering treatment in children 6.1: In children with CKD (including those treated with chronic dialysis or kidney transplantation) and hypertriglyceridemia, we suggest that therapeutic lifestyle changes be advised. (2D) summary of recommendation statements Quick summary of the KDIGO recommendations for lipid-lowering treatment in adults with CKD (a) Rule out remediable causes of secondary dyslipidemia. (b) Establish the indication of treatment (YES or NO) and select agent and dose. (c) Treat according to a fire-and-forget strategy: do not measure LDL-C unless the results would alter management. Upon first presentation to establish the diagnosis of CKD, the nephrologist will obtain a full lipid profile as part of routine care. In case of referral and to confirm the CKD diagnosis, a full lipid profile may already be available. Results of the lipid profile should be used together with other clinical data to rule out remediable causes of secondary dyslipidemia. If excluded, the nephrologist will establish whether statin treatment is indicated (YES or NO) based on underlying cardiovascular risk. If the level of risk suggests that statin treatment is indicated, she/he will select a dose of a statin (Table 4) that is available in her/his country and has been tested for safety in people with CKD. Contemporary practice and other clinical practice guidelines emphasize the use of targets for LDL-C (e.g., 1.8 or 2.6 mmol/l [70 or 100 mg/dl]), which require repeated measurements of LDL-C and treatment escalation with higher doses of statin or initiation of combination lipid-lowering therapy ( treat-to-target strategy) when the LDL-C target is not met.


, 1.8 or 2.6 mmol/l [70 or 100 mg/dl]), which require repeated measurements of LDL-C and treatment escalation with higher doses of statin or initiation of combination lipid-lowering therapy ( treat-to-target strategy) when the LDL-C target is not met. The KDIGO Work Group does not recommend the treat-to- target strategy because it has never been proven beneficial in any clinical trial. In addition, higher doses of statins have not been proven to be safe in the setting of CKD. Therefore, the Work Group recommends a fire-and-forget strategy for patients with CKD (see Rationale for Recommendation 1.2). Physicians may choose to perform follow-up measurement of lipid levels in patients for whom these measurements are judged to favorably influence adherence to treatment or other processes of care. summary of recommendation statements Introduction: The case for updating and context In 2003, the US-based KDOQI (Kidney Disease Outcomes Quality Initiative) group published Clinical Practice Guide- lines for Managing Dyslipidemias in Chronic Kidney Disease (CKD). In the absence of randomized controlled trials (RCTs), ATP III Guidelines (Adult Treatment Panel III) were considered to be generally applicable to patients with estimated glomerular filtration rate (eGFR) Z15 ml/min/ (GFR categories G1-G4, formerly CKD stages 1 4) with the exception that: (1) CKD was classified as a coronary heart disease (CHD) risk equivalent, (2) complications of lipid-lowering therapies may result from reduced kidney function, (3) indications for the treatment of dyslipidemias other than preventing acute cardiovascular disease (CVD) may be applicable, and (4) treatment of proteinuria might also be an effective treatment for dyslipidemias.1 At that time the Work Group included children and adolescents with CKD (defined by the onset of puberty) in these guidelines, and recommended that they be managed in the same way as adults.


In the absence of randomized controlled trials (RCTs), ATP III Guidelines (Adult Treatment Panel III) were considered to be generally applicable to patients with estimated glomerular filtration rate (eGFR) Z15 ml/min/ (GFR categories G1-G4, formerly CKD stages 1 4) with the exception that: (1) CKD was classified as a coronary heart disease (CHD) risk equivalent, (2) complications of lipid-lowering therapies may result from reduced kidney function, (3) indications for the treatment of dyslipidemias other than preventing acute cardiovascular disease (CVD) may be applicable, and (4) treatment of proteinuria might also be an effective treatment for dyslipidemias.1 At that time the Work Group included children and adolescents with CKD (defined by the onset of puberty) in these guidelines, and recommended that they be managed in the same way as adults. The 2003 publication anticipated that an update should be performed in about 3 years from the time of publication of major important trials in the general population and in patients with CKD, and recommended to review ALLHAT (Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial), SEARCH (Study Evaluating Additional Reductions in Cholesterol and Homocysteine), TNT (Treat- ing to New Targets), IDEAL (Incremental Decrease in Endpoints Through Aggressive Lipid Lowering), ALLIANCE (Aggressive Lipid Lowering Initiation Abates New Cardiac Events), PROVE IT (Pravastatin or Atorvastatin in Evalua- tion and Infection Therapy), PROSPER (Prospective Study of Pravastatin in the Elderly at Risk), FIELD (Fenofibrate Intervention and Event Lowering in Diabetes), CARDS (Collaborative Atorvastatin Diabetes Study), ASPEN (Atorvastatin as Prevention of Coronary Heart Disease Endpoints in Patients with Non-Insulin-Dependent Diabetes Mellitus), SPARCL (Stroke Prevention by Aggressive Reduc- tion in Cholesterol Levels), and ACCORD (Action to Control Cardiovascular Risk in Diabetes).


The 2003 publication anticipated that an update should be performed in about 3 years from the time of publication of major important trials in the general population and in patients with CKD, and recommended to review ALLHAT (Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial), SEARCH (Study Evaluating Additional Reductions in Cholesterol and Homocysteine), TNT (Treat- ing to New Targets), IDEAL (Incremental Decrease in Endpoints Through Aggressive Lipid Lowering), ALLIANCE (Aggressive Lipid Lowering Initiation Abates New Cardiac Events), PROVE IT (Pravastatin or Atorvastatin in Evalua- tion and Infection Therapy), PROSPER (Prospective Study of Pravastatin in the Elderly at Risk), FIELD (Fenofibrate Intervention and Event Lowering in Diabetes), CARDS (Collaborative Atorvastatin Diabetes Study), ASPEN (Atorvastatin as Prevention of Coronary Heart Disease Endpoints in Patients with Non-Insulin-Dependent Diabetes Mellitus), SPARCL (Stroke Prevention by Aggressive Reduc- tion in Cholesterol Levels), and ACCORD (Action to Control Cardiovascular Risk in Diabetes). Several trials in patients with CKD that were ongoing included ALERT (Assessment of Lescol in Renal Transplantation), 4D (Die Deutsche Diabetes Dialyse Studie), PREVEND IT (Prevention of REnal and Vascular ENdstage Disease Intervention Trial), AURORA (A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events), and SHARP (Study of Heart and Renal Protection). Since that time, all these studies have been published and most have been synthesized in two recent meta-analyses in order to bring all information into context.


Since that time, all these studies have been published and most have been synthesized in two recent meta-analyses in order to bring all information into context. In 2007 KDOQI issued Clinical Practice Guidelines and Clinical Practice Recommendations for Diabetes and Chronic Kidney Disease and included a set of guidelines on Manage- ment of Dyslipidemia in Diabetes and Chronic Kidney The guidelines adopted trends in treating people with very high risk and recommended treatment to target low-density lipoprotein cholesterol (LDL-C) of o2.6 mmol/l (o100 mg/dl) for people with diabetes and eGFR cate- gories G1-G4. The target of o1.8 mmol/l (o70 mg/dl) was considered a therapeutic option. The guidelines included the results of the 4D study, which to the surprise of many, demonstrated that lowering LDL-C with atorvastatin in hemodialysis (HD) patients with type 2 diabetes did not produce statistically significant reductions in the primary outcome measure. The study had strong impact on a recommendation for HD patients which stated that treat- ment with a statin should not be initiated in patients with type 2 diabetes on maintenance HD therapy who do not have a specific cardiovascular indication for treatment. Four years later, AURORA was hoped to provide clarification of whether LDL-C lowering with rosuvastatin would offer any benefit to HD patients. Like 4D, the main results of AURORA were negative. Since then, multiple hypotheses have been raised to explain these unexpected findings. A different cardiovascular pathology with vascular stiffness, calcification, structural heart disease, and sympathetic overactivity contributing to an increasing risk for cardiac arrhythmia and heart failure was deemed responsible. The results of SHARP, a very large inter- national RCT, is highly relevant to this discussion. SHARP showed a significant decrease in major atherosclerotic events with simvastatin and ezetimibe compared with placebo in dialysis-dependent and non-dialysis-dependent patients.


SHARP showed a significant decrease in major atherosclerotic events with simvastatin and ezetimibe compared with placebo in dialysis-dependent and non-dialysis-dependent patients. The overall objective for the guideline is to advise about the management of dyslipidemia and use of cholesterol- lowering medications in adults and children with known CKD. Questions addressed by the guideline include how and when to assess lipid status, and how and when to prescribe lipid-lowering treatment in the target population. The target audience of the guideline includes nephrologists, primary care physicians, non-nephrology specialists (e.g., cardiologists, diabetologists, etc), clinical chemists and other practitioners caring for adults and children with CKD worldwide. The guideline is also expected to be suitable for use in public policy and other healthcare arenas. As a global guideline it is sensitive to issues related to ethnicity and geographical considerations and is written for use in different health care settings. The Work Group included an international group of kidney specialists, diabetologists, cardiologists, epidemiolo- gists, lipidologists and a professional evidence review team introduction http://www.kidney-international.org & 2013 KDIGO (ERT) who provided support. Details of the methods used by the ERT are described in Methods for Guideline Development section, along with the systematic searches for areas identified by Work Group members and performed by the ERT. Research recommendations are described to inform ongoing research agendas in the international community. The recommendations and statements created herein will serve to direct both care and research in the next decade. Several statements in this guideline have obtained a high grade according to the international system, Grading of Recommendations Assessment, Development and Evaluation (GRADE). This document is not intended to serve as a textbook of medicine or nephrology.


This document is not intended to serve as a textbook of medicine or nephrology. Unless otherwise stated, several aspects including drug dosing and interaction, especially in transplanted patients, are still valid with respect to the KDOQI 2003 guidelines. The current guideline synthesized all of the available evidence but is largely driven by a few large RCTs and post hoc analyses of patients with CKD from statin trials of the general population. This guideline proposes a new concept in the management of dyslipidemia in CKD in the hopes of stimulating discussion, generating substantial research, and influencing public policy and laboratory practice. 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. introduction Chapter 1: Assessment of lipid status in adults with CKD 1.1: In adults with newly identified CKD (including those treated with chronic dialysis or kidney transplanta- tion), we recommend evaluation with a lipid profile (total cholesterol, LDL cholesterol, HDL cholesterol, RATIONALE Dyslipidemia is common but not universal in people with CKD. The major determinants of dyslipidemia in CKD patients are glomerular filtration rate (GFR), the presence of diabetes mellitus, severity of proteinuria, use of immuno- suppressive agents, modality of renal replacement therapy [RRT] (treatment by HD, peritoneal dialysis, or transplanta- tion), comorbidity and nutritional status.3 Initial evaluation of the lipid profile mainly serves to establish the diagnosis of severe hypercholesterolemia and/or hypertriglyceridemia and potentially rule out a remediable (secondary) cause if present. Major causes of secondary dyslipidemia should be considered (Table 1).


Major causes of secondary dyslipidemia should be considered (Table 1). The precise levels of serum or plasma lipids that should trigger specialist referral are not supported by evidence, but in the opinion of the Work Group, fasting triglyceride (TG) levels above 11.3 mmol/l (1000 mg/dl) or LDL-C levels above 4.9 mmol/l (190 mg/dl) should prompt consideration of (or specialist referral for) further evaluation. Previous guidelines have emphasized the potential value of LDL-C as an indication for pharmacological treatment with the KDIGO Work Group no longer recommends this approach (see Chapter 2.1). Isolated low high-density lipoprotein cholesterol (HDL-C) does not imply specific therapy in people with CKD; the Work Group suggests that HDL-C be measured as part of the initial lipid panel because it may help to assess overall cardiovascular risk. Measurement of lipoprotein(a) [Lp(a)] and other markers of dyslipidemia require further research before it can be routinely recommended in CKD patients. The lipid profile should ideally be measured in the fasting state; if not feasible, nonfasting values provide useful information as well.4 Fasting will mainly affect TG values and to a lesser extent LDL-C values as estimated from the Friedewald formula. Fasting status does not affect HDL-C.4 6 There is no direct evidence indicating that measurement of lipid status will improve clinical outcomes. However, such measurement is minimally invasive, relatively inexpensive, and has potential to improve the health of people with secondary dyslipidemia. In the judgment of the Work Group, patients with CKD place a high value on this potential benefit and are less concerned about the possibility of adverse events or inconvenience associated with baseline measurement of lipid levels. In the judgment of the Work Group, these considerations justify a strong recommendation despite the low quality of the available evidence.


In the judgment of the Work Group, these considerations justify a strong recommendation despite the low quality of the available evidence. 1.2: In adults with CKD (including those treated with chronic dialysis or kidney transplantation), follow-up measurement of lipid levels is not required for the majority of patients. (Not Graded) RATIONALE Prior guidelines have emphasized treatment escalation to achieve specific LDL-C targets by increasing the dose of statin and/or combination therapy.1,7 Given the lack of data to support this approach in populations with and without the substantial within-person variability in LDL-C and the potential for medication-related toxicity, this approach is no longer recommended for CKD populations (see guideline 2). Since higher cardio- vascular risk and not elevated LDL-C is now the primary indication to initiate or adjust lipid-lowering treatment in CKD patients, follow-up monitoring of LDL-C (after an initial measurement) may not be required for many patients especially given normal variability in LDL-C over time, which reduces the clinical utility of follow- In the judgment of the Work Group, follow-up measure- ment of lipid levels should be reserved for instances where the results would alter management. Potential reasons to measure LDL-C (or the lipid profile) in people with CKD after their initial presentation might include: assessment of adherence to statin treatment; change in RRT modality or concern about the presence of new secondary causes of dyslipidemia (Table 1); or to assess 10-year cardio- vascular risk in patients aged o50 years and not currently receiving a statin (because knowledge of LDL-C in this case might suggest that a statin was required see Recommenda- tion 2.2). In the judgment of the Work Group, it is unnecessary to measure LDL-C in situations where the results would not (or likely would not) change management.


In the judgment of the Work Group, it is unnecessary to measure LDL-C in situations where the results would not (or likely would not) change management. For example, patients already receiving a statin (or in whom statin treatment is clearly indicated/not indicated based on changes in their cardiovascular risk profile or clinical status) would not require follow-up LDL-C measurements because the results would not alter treatment. Similarly, since the association chapter 1 http://www.kidney-international.org & 2013 KDIGO between LDL-C and adverse clinical outcomes is weaker in people with CKD than in the general population, the value of measuring LDL-C to assess prognosis is uncertain. Since low HDL-C and elevated apolipoprotein B (apoB) or non-HDL-C associated with excess risk of future clinicians might choose to measure these parameters in patients not receiving a statin but in whom estimated cardiovascular risk is close to the threshold for initiating statin treatment. Put differently, clinicians could choose to measure HDL-C, apoB and/or non HDL-C if the finding of these tests would influence their decision to prescribe statin treatment. Few data document how frequently CKD patients develop severely elevated fasting TGs 411.3 mmol/l (41000 mg/dl). Since clinical experience suggests that this event is rare, routine measurement of fasting TG levels is not recom- mended. However, clinicians may consider following serum TG levels in patients with known severe hypertriglyceridemia. The ideal frequency of follow-up of LDL-C, HDL-C and serum TGs is unknown. Since any benefits of lipid-lowering treatment are likely to accrue over years rather than months or weeks, the Work Group suggests that cardiovascular risk be assessed annually in most patients with CKD. However, more frequent (or less frequent) follow-up measure- ments may be appropriate based on the clinical status of the patient.


However, more frequent (or less frequent) follow-up measure- ments may be appropriate based on the clinical status of the patient. There is no direct evidence that routine follow-up of lipid levels improves clinical outcomes or adherence to lipid- lowering therapy. In fact, evidence indicates that random within-patient variation in serum cholesterol levels is substantial ( 0.8 mmol/l [31 mg/dl] for total cholesterol [TC]) and therefore that such follow-up measurements may not reliably indicate good or poor compliance.10 However, some patients may prefer to know their lipid levels during follow-up, or may respond favorably to such knowledge (for example, with better adherence to recommended statin use). In the judgment of the Work Group, these considerations favor an ungraded statement. Physicians may choose to perform follow-up measurement of lipid levels in patients for whom these measurements are judged to favorably influence processes of care. Considerations for International Settings If resources are limited, priority should be given to prescribing statins to patients at risk based on clinical criteria, rather than to measuring lipid profiles at baseline or in follow-up. In the opinion of the Work Group, the frequency of pancreatitis due to severe hypertriglyceridemia among CKD patients is sufficiently low that measuring fasting TG levels can be omitted in low-resource settings. Conversely, in settings where documentation of hypercholesterolemia is required to justify prescription of statins (e.g., Japan), more liberal or more frequent measurement of serum lipids may be necessary. Suggested Audit Criteria K Proportion of adults who had a lipid profile measured within 1 month of referral. K Frequency of specialist referral for further evaluation of abnormal lipid abnormalities (e.g., fasting TG levels above 11.3 mmol/l (1000 mg/dl) or LDL-C levels above 4.9 mmol/l (190 mg/dl)).


, fasting TG levels above 11.3 mmol/l (1000 mg/dl) or LDL-C levels above 4.9 mmol/l (190 mg/dl)). KEY POINTS K Dyslipidemia is common in people with CKD but LDL-C does not reliably discriminate between those at low or high risk of cardiovascular events. K Clinicians should measure the lipid profile at initial presentation with CKD. Follow-up of the lipid profile or LDL-C is not required unless the results would change management. Examples of patients in whom knowledge of LDL-C might change management are given in Table 2. RESEARCH RECOMMENDATIONS Future studies should: K Assess the clinical effectiveness and economic merits of interventions to improve adherence to these recommenda- tions, particularly those which are level 1. This includes better understanding of physician and patient barriers to guideline adoption and the contribution of polypharmacy. K Examine secular trends in adherence to recommenda- tions in this clinical practice guideline (CPG) and any secular changes in patient outcomes. K Confirm real practice safety of statin use (outside of restrictive eligibility criteria used in RCTs). Specifically the frequency and severity of clinically relevant statin- drug interactions should be studied in this population to improve the safety of statin prescribing. K Assess the cost implications of less frequent or avoidance of cholesterol measurements, and confirm that less frequent measurements do not adversely affect the clinical benefits of treatment (compared to more frequent measurements). Table 1 | Secondary causes of dyslipidemias Medical Conditions Nephrotic syndrome Excessive alcohol consumption Hypothyroidism Liver disease Diabetes Medications 13-cis-retinoic acid Androgens Anticonvulsants Oral contraceptives Highly active anti-retroviral therapy Corticosteroids Diuretics Cyclosporine Beta-blockers Sirolimus Reproduced from National Kidney Foundation. K/DOQI Clinical Practice Guidelines for Managing Dyslipidemias in Chronic Kidney Disease.


K/DOQI Clinical Practice Guidelines for Managing Dyslipidemias in Chronic Kidney Disease. Am J Kidney Dis 41(Suppl 3): S38, 2003 with permission from the National Kidney Foundation;1 accessed http:// www.kidney.org/professionals/kdoqi/guidelines_dyslipidemia/pdf/ajkd_dyslipidemia_ gls.pdf K Perform time-dependent analysis of lipid values for risk prediction. Since lipid levels show considerable changes during the various stages of CKD, it might be interesting to see whether a data analysis considering all measured values during the entire observation period is more predictive than the classical analysis with one measure- ment at baseline of a certain CKD stage. K Investigate whether the association between serum TGs and risk varies meaningfully as a function of fasting status. K Investigate the independent association between Lp(a), apoB and cardiovascular outcomes in large prospec- tive studies of people with CKD. It should further be investigated whether knowledge of high Lp(a), non-HDL- C, and/or apoB values has any influence on the manage- ment of other risk factors and whether this has an influence on outcomes. DISCLAIMER While every effort is made by the publishers, editorial board, and ISN to see that no inaccurate or misleading data, opinion or statement appears in this Journal, they wish to make it clear that the data and opinions appearing in the articles and advertisements herein are the responsibility of the contributor, copyright holder, or advertiser concerned. Accordingly, the publishers and the ISN, the editorial board and their respective employers, office and agents accept no liability whatsoever for the consequences of any such inaccurate or misleading data, opinion or statement. While every effort is made to ensure that drug doses and other quantities are presented accurately, readers are advised that new methods and techniques involving drug usage, and described within this Journal, should only be followed in conjunction with the drug manufacturer s own published literature.


While every effort is made to ensure that drug doses and other quantities are presented accurately, readers are advised that new methods and techniques involving drug usage, and described within this Journal, should only be followed in conjunction with the drug manufacturer s own published literature. Table 2 | Examples of situations in which measuring cholesterol level might or might not change the management implied by Already receiving statin? Would measuring cholesterol level change management? Y No; patient is already receiving statin N No; statin is already indicated based on Recommendation 2.1.1 and ACR of 110 mg/mmol (1100 mg/g) N No; statin is already indicated based on Recommendation 2.1.2 , who is a smoker and has diabetes and hypertension N No; statin is already indicated based on Recommendation 2.1.3 because predicted 10-year risk of coronary death or MI 410% regardless of cholesterol level , who is a non-smoker without diabetes or hypertension Y No; patient is already receiving statin , who is a non-smoker without diabetes or hypertension N Yes; patient s predicted 10-year risk of coronary death or MI could vary from 5 to 20% based on cholesterol level. This would change the decision to prescribe a statin based on Recommendation 2.1.3 , who is a non-smoker without diabetes or hypertension N No; patient s predicted 10-year risk of coronary death or MI is o10% regardless of cholesterol level Abbreviations: ACR, albumin-to-creatinine ratio; eGFR, estimated glomerular filtration rate; MI, myocardial infarction. Chapter 2: Pharmacological cholesterol-lowering treatment in adults INTRODUCTION Therapeutic lifestyle measures to reduce serum cholesterol levels have been broadly recommended by prior guide- Although clinically appealing, such measures typically reduce serum cholesterol to only a small extent, and have not been shown to improve clinical outcomes (Supplemental Tables 1 5 online).


Chapter 2: Pharmacological cholesterol-lowering treatment in adults INTRODUCTION Therapeutic lifestyle measures to reduce serum cholesterol levels have been broadly recommended by prior guide- Although clinically appealing, such measures typically reduce serum cholesterol to only a small extent, and have not been shown to improve clinical outcomes (Supplemental Tables 1 5 online). The Work Group therefore chose to focus the recommendations for treatment on pharmacological interventions. However, it is important to note that many of these measures may improve general health (independent of any effect on lipid levels). The primary rationale for pharmacological cholesterol- lowering treatment is to reduce morbidity and mortality from atherosclerosis. Although limited clinical data support a link between treatment of dyslipidemia and better renal more recent trials have not confirmed this Although several different medications lower LDL-C, only regimens including a statin (including statin/ezetimibe) have been convincingly shown to reduce the risk of adverse cardiovascular events in CKD populations. Therefore, the recommended approach for pharmacological cholesterol- lowering treatment in CKD focuses on the use of statins (with or without ezetimibe) in people at risk of future cardiovascular events. BACKGROUND LDL-C is not suitable for identifying CKD patients who should receive pharmacological cholesterol-lowering treatment LDL-C is strongly and independently associated with risk of atherosclerotic events in the general population;15 knowledge of this association facilitated the discovery that statins reduce coronary risk. Initially, statin use was limited to those with substantially elevated LDL-C (44.5 mmol/l [4174 mg/dl]), but subsequent work indicated that the relative risk (RR) reduction associated with statin use is relatively constant across a broad range of baseline LDL-C levels, suggesting that absolute benefit from statin treatment is proportional to baseline coronary risk rather than baseline LDL-C. Associations between LDL-C and coronary artery disease in dialysis patients.


Associations between LDL-C and coronary artery disease in dialysis patients. Observational data indicate that dialysis patients with the highest and lowest levels of LDL-C and TC are at the highest risk of adverse outcomes such as all-cause and cardiovascular mortality.16 19 This paradoxical associa- tion between cholesterol and outcomes appears to be due to effect modification by protein energy wasting, inflammation which are all common in kidney failure and are themselves associated with a high risk of adverse outcomes. Put differently, patients with one of more of these three conditions are more likely to also have low cholesterol, which confounds the apparent association between cholesterol and the risk of cardiovascular death. Although cardiovascular risk is increased in dialysis patients with higher LDL-C and TC, elevated cholesterol seems unsuitable as the criterion for statin prescription in patients with kidney failure because it will fail to identify those with low cholesterol who are also at high risk. Associations between LDL-C and coronary artery disease in CKD patients with eGFR Z15 ml/min/1.73 m2 . As eGFR declines, the magnitude of the excess risk associated with increased LDL-C decreases. For instance, the hazard ratio [HR] (95% confidence interval [CI]) of incident myo- cardial infarction (MI) associated with LDL-C 44.9 mmol/l [4190 mg/dl] (as compared to 2.6 3.39 mmol/l [100 (1.59 2.67) for people with eGFR of Z90, 60 89.9 and , respectively. Figure 1 shows the relation between LDL-C and the risk of hospitalization for MI for selected values of baseline eGFR. The figure shows that the relation between LDL-C and the risk of MI appears linear at LDL-C above 2.6 mmol/l (100 mg/dl). The HR (95% CI) of MI associated with each 1 mmol/l (39 mg/dl) increase in LDL-C above 2.6 mmol/l , respectively.


The HR (95% CI) of MI associated with each 1 mmol/l (39 mg/dl) increase in LDL-C above 2.6 mmol/l , respectively. The weaker and potentially misleading associa- tion between LDL-C and coronary risk among those with lower levels of kidney function (a group who is at the highest absolute risk) argue against its use for identifying CKD patients who should receive pharmacological cholesterol- lowering treatment. Which CKD patients should receive pharmacological cholesterol-lowering treatment? To maximize the ratio of benefits to harms and costs, contemporary clinical practice emphasizes three potential determinants of the decision to prescribe lipid-lowering treatment in people with normal kidney function: baseline coronary risk; case-fatality rate following MI; and evidence that lipid-lowering treatment is beneficial.23 Baseline coronary risk. The 10-year incidence risk of coronary death or non-fatal MI (numerically equivalent to the rate of such events per 1000 patient-years) is often used as http://www.kidney-international.org chapter 2 & 2013 KDIGO Hazard ratio LDL-C, mmol/l Hazard ratio LDL-C, mmol/l Hazard ratio LDL-C, mmol/l Hazard ratio LDL-C, mmol/l Hazard ratio LDL-C, mmol/l Figure 1 | Adjusted relation between LDL-C and HR of myocardial infarction by eGFR as a continuous variable. Data are adjusted hazard ratios for MI during a median follow-up period of 48 months. Data are from 836,060 participants in the Alberta Kidney Disease cohort and have been adjusted for age, sex, diabetes, hypertension, Aboriginal status, socioeconomic status, proteinuria categories, statin use, and the Charlson comorbidities (cancer, cerebrovascular disease, congestive heart failure, chronic pulmonary disease, dementia, metastatic solid tumor, MI, liver disease, hemiplegia/paraplegia, peptic ulcer disease, peripheral vascular disease, and rheumatic disease). eGFR, estimated glomerular filtration rate; HR, hazard ratio; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction. Reproduced from Tonelli M, Muntner P, Lloyd A, et al. Association between LDL-C and Risk of Myocardial Infarction in CKD.


Association between LDL-C and Risk of Myocardial Infarction in CKD. J Am Soc Nephrol 2013; 24: 979 986 with permission from American Society of Nephrology22 conveyed through Copyright Clearance Center, Inc; accessed http://jasn.asnjournals.org/ Rates per person years No CKD No CKD No DM No DM No DM Prior MI Prior MI No CKD No DM No DM Prior MI No prior MI No prior MI No prior MI DM No CKD No prior MI No prior MI DM DM CKD CKD CKD CKD CKD+1 or more of DM, MI, PTCA/CABG, CVA/TIA Age 50 Age > 50 MI CHD death or MI Figure 2 | Future 10-year coronary risk based on various patient characteristics. Data are unadjusted rates from 1,268,029 participants in the Alberta Kidney Disease cohort. CKD refers to eGFR 15-59.9 ml/min/1.73 m2 or with proteinuria. CABG, coronary artery bypass grafting; CHD, coronary heart disease; CKD, chronic kidney disease; CVA, cerebrovascular accident; DM, diabetes mellitus; MI, myocardial infarction; PTCA, percutaneous transluminal coronary angioplasty; TIA, transient ischemic attack. the benchmark for assessing future coronary risk; the risk in patients with prior MI (in whom the rate of new MI is 20 per 1000 patient-years) is generally considered as sufficiently high to clearly warrant ongoing statin treatment.12 Most national guidelines for the general population also recommend universal or very liberal use of statin treatment among those with coronary risk that is lower than those with prior MI (but still substantially higher than average), such as those with diabetes or prior stroke.12,24 26 There is no consensus on the level of future coronary risk that is sufficient to justify statin treatment, but in the judgment of the Work Group rates of coronary death or non-fatal MI o10 per 1000 patient-years are unlikely to be broadly accepted as an indication for treatment.


the benchmark for assessing future coronary risk; the risk in patients with prior MI (in whom the rate of new MI is 20 per 1000 patient-years) is generally considered as sufficiently high to clearly warrant ongoing statin treatment.12 Most national guidelines for the general population also recommend universal or very liberal use of statin treatment among those with coronary risk that is lower than those with prior MI (but still substantially higher than average), such as those with diabetes or prior stroke.12,24 26 There is no consensus on the level of future coronary risk that is sufficient to justify statin treatment, but in the judgment of the Work Group rates of coronary death or non-fatal MI o10 per 1000 patient-years are unlikely to be broadly accepted as an indication for treatment. The rate of coronary death or incident MI among patients with CKD (defined by eGFR 15 59.9 ml/min/1.73 m2 or with heavy proteinuria) is similar to or higher than those with diabetes (with or without CKD).27 However, the risk associated with CKD is age-dependent. For example, the rate of coronary death or incident MI among CKD patients aged 450 years (both men and women) is consistently greater than 10 per 1000 patient-years, even in those without diabetes or prior MI) (Figure 2; Table 3). In contrast, the rate of coronary death or incident MI among CKD patients aged r50 years is low in those without diabetes or prior MI (Figure 2) although it is higher than in otherwise comparable people without CKD. Further inspection of the absolute risks indicate that participants aged 40 50 years have average rates of CHD death or incident MI that are consistently less than 10 per 1000 patient-years. Case-fatality rate following myocardial infarction.


Further inspection of the absolute risks indicate that participants aged 40 50 years have average rates of CHD death or incident MI that are consistently less than 10 per 1000 patient-years. Case-fatality rate following myocardial infarction. Multiple studies demonstrate that the risk of death following MI is increased among people with CKD, as compared to otherwise comparable people with normal kidney function.27 The absolute risk of death is especially high in patients treated with chronic dialysis.28 Evidence that pharmacological cholesterol-lowering treatment is beneficial. The evidence supporting the clinical benefits of statin treatment in adults (alone or in combination with ezetimibe) differs substantially by severity of CKD. This evidence is presented in Supplemental Tables 6 18 online and summarized below. Collectively, available evidence argues against the use of LDL-C to identify CKD patients who should receive cholesterol-lowering treatment and suggests focusing instead on two factors: the absolute risk of coronary events, and the evidence that such treatment is beneficial. This is the approach taken in the recommendations that follow. Prior studies convincingly demonstrate that treatments to prevent cardiovascular events are systematically underused in CKD populations despite their high baseline risk.29 31 This suggests that a concerted attempt will be required to identify and treat CKD patients that are likely to benefit from lipid-lowering therapy. How should the dose of pharmacological cholesterol- lowering treatment be determined in CKD patients? Guidelines for the general population recommend that (among patients receiving statin treatment), the dose of statin is titrated to achieve the target level of LDL-C, which in turn is determined by each patient s presumed coronary This approach is widely accepted, although it has never been shown to lead to clinical benefit in a RCT.


Guidelines for the general population recommend that (among patients receiving statin treatment), the dose of statin is titrated to achieve the target level of LDL-C, which in turn is determined by each patient s presumed coronary This approach is widely accepted, although it has never been shown to lead to clinical benefit in a RCT. Instead, existing randomized trials have compared statin and placebo, or compared higher and lower doses of statin (regardless of achieved LDL-C). Taken together, these trials suggest that higher statin doses produce greater clinical benefits, but at the expense of an increased risk of adverse events. CKD patients are at high risk of medication-related adverse events, perhaps because of the reduced renal excretion, frequent polypharmacy and high prevalence of comorbidity in this population. Therefore, reduced doses of statins are generally recommended for patients with advanced CKD. The SHARP trial addressed this issue by using lower dose simvastatin (20 mg/day) and adding ezetimibe (10 mg/day) to achieve an average LDL-C reduc- tion of about 0.83 mmol/l (32 mg/dl), during a 4.9-year period of treatment.14 Subgroup analysis of the TNT trial reported that atorvastatin 80 mg/day reduced major cardiovascular events Table 3 | Rate of coronary death or non-fatal MI (by age and eGFR) Rate (95% CI) of coronary death or non-fatal MI (per 1000 patient-years) Overall Male Female Abbreviations: CI, confidence interval; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; MI, myocardial infarction. Data are unadjusted rates from 1,268,029 participants in the Alberta Kidney Disease cohort. People with diabetes, MI, and other cardiovascular disease were included. Data do not apply to people with kidney transplants.