CABG appears to be associated with lower risk of mortality than is PCI in most patients with diabetes mellitus and complex Fihn et al 2014 Stable Ischemic Heart Disease Focused Update 1759 multivessel disease, although the Heart Team may identify exceptions. To address the important issue of deciding between PCI and CABG in patients with diabetes mellitus and complex multivessel CAD, a Heart Team approach would be beneficial. This was an integral component of the FREEDOM, SYNTAX, and BARI trials59,68,69 and is therefore emphasized in this set- ting. The Heart Team is a multidisciplinary team composed of an interventional cardiologist and a cardiac surgeon who jointly 1) review the patient s medical condition and coronary anatomy, 2) determine that PCI and/or CABG are technically feasible and reasonable, and, 3) discusses revascularization options with the patient before a treatment strategy is selected. Future research may be facilitated by including a field in the National Cardiovascular Data PCI Registry and the STS database to identify cases turned down for the alternative revascularization strategy. Presidents and Staff American College of Cardiology Patrick T. O Gara, MD, MACC, President Shalom Jacobovitz, Chief Executive Officer William J. Oetgen, MD, MBA, FACC, Executive Vice President, Science, Education, and Quality Amelia Scholtz, PhD, Publications Manager, Clinical Policy and Pathways American College of Cardiology/American Heart Association Lisa Bradfield, CAE, Director, Clinical Policy and Guidelines Ezaldeen Ramadhan III, Project Management Team Leader, Science and Clinical Policy American Heart Association Elliott Antman, MD, FACC, FAHA, President Nancy Brown, Chief Executive Officer Rose Marie Robertson, MD, FAHA, Chief Science Officer Gayle R. Whitman, PhD, RN, FAHA, FAAN, Senior Vice President, Office of Science Operations Marco Di Buono, PhD, Vice President, Science, Research, and Professional Education, Office of Science Operations Jody Hundley, Production Manager, Scientific Publications, Office of Science Operations References 1.


Presidents and Staff American College of Cardiology Patrick T. O Gara, MD, MACC, President Shalom Jacobovitz, Chief Executive Officer William J. Oetgen, MD, MBA, FACC, Executive Vice President, Science, Education, and Quality Amelia Scholtz, PhD, Publications Manager, Clinical Policy and Pathways American College of Cardiology/American Heart Association Lisa Bradfield, CAE, Director, Clinical Policy and Guidelines Ezaldeen Ramadhan III, Project Management Team Leader, Science and Clinical Policy American Heart Association Elliott Antman, MD, FACC, FAHA, President Nancy Brown, Chief Executive Officer Rose Marie Robertson, MD, FAHA, Chief Science Officer Gayle R. Whitman, PhD, RN, FAHA, FAAN, Senior Vice President, Office of Science Operations Marco Di Buono, PhD, Vice President, Science, Research, and Professional Education, Office of Science Operations Jody Hundley, Production Manager, Scientific Publications, Office of Science Operations References 1. American College of Cardiology/American Heart Association: Methodology Manual and Policies From the ACCF/AHA Task Force on Practice Guidelines. Available at: http://assets.cardiosource.com/ Methodology_Manual_for_ACC_AHA_Writing_Committees.pdf. J Am Coll Cardiol. Accessed April 29, 2014. 2. Institute of Medicine (U.S.). Finding What Works in Health Care: Standards for Systematic Reviews. Washington, D.C.: NationalAcademies Press, 2011. 3. Institute of Medicine (U.S.). Committee on Standards for Developing Trustworthy Clinical Practice Guidelines: Clinical Practice Guidelines We Can Trust. Washington, D.C.: National Academies Press, 2011. 4. Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/AHA/ACP/AATS/ PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation. 2012;126:e354 471. 5. de Bruyne B, Pijls NHJ, Kalesan B, et al. Fractional flow reserve guided PCI versus medical therapy in stable coronary disease.


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Comparison of coronary artery bypass surgery and percutaneous coronary intervention in patients with diabetes: a meta-analysis of randomised controlled trials. The Lancet Diabetes & Endocrinology. 2013;1:317 28. Key Words: AHA Scientific Statements cardiac catheterization cardiovascular chelation therapy coronary angiography coronary artery bypass counterpulsation diagnostic techniques focused update myocardial ischemia percutaneous coronary intervention. Appendix 1.


Key Words: AHA Scientific Statements cardiac catheterization cardiovascular chelation therapy coronary angiography coronary artery bypass counterpulsation diagnostic techniques focused update myocardial ischemia percutaneous coronary intervention. Appendix 1. Author Relationships With Industry and Other Entities (Relevant) 2014 Acc/Aha/Aats/Pcna/Scai/Sts Focused Update of the Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease Committee Member Employment Consultant Speaker s Bureau Ownership/ Partnership/ Principal Personal Research Institutional, Organizational, or Other Financial Benefit Expert Witness Voting Recusals by Section* Stephan D. Fihn (Chair) Department of Veterans Affairs Director, Office of Analytics and Business Intelligence None None None None None None None James C. Blankenship (Vice Chair) Geisinger Medical Center Staff Physician; Director, Cardiac Catheterization Laboratory None None None AstraZeneca None None 2.2.5 Boston Scientific 4.4.2 Kai Pharmaceutical 4.4.4 The Medicines Company Schering-Plough Volcano Karen P. Alexander Duke University Medical Center Associate Professor of Medicine/ Cardiology None None None Gilead Sanofi-aventis None 2.2.5 John A. Bittl Munroe Regional Medical Center Invasive Cardiologist None None None None None None None John G. Byrne Brigham and Women s Hospital Chief, Division of Cardiac Surgery None None None None None None None Barbara J. Fletcher University of North Florida Clinical Associate Professor, School of Nursing None None None None None None None Gregg C. Fonarow UCLA Cardiomyopathy Center Professor of Medicine Boston Scientific None None None None None 2.2.5 Johnson & Johnson The Medicines Company Medtronic Richard A. Lange University of Texas Health Science Center, San Antonio Professor of Medicine None None None None None None None Glenn N. Levine Baylor College of Medicine Professor of Medicine; Director, Cardiac Care Unit None None None None None None None Thomas M. Maddox VA Eastern Colorado Health Care System Cardiologist None None None None None None None Srihari S. Naidu Winthrop University Hospital Director, Cardiac Catheterization Laboratory None None None None None None None (Continued) Fihn et al 2014 Stable Ischemic Heart Disease Focused Update 1763 Appendix 1.


Author Relationships With Industry and Other Entities (Relevant) 2014 Acc/Aha/Aats/Pcna/Scai/Sts Focused Update of the Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease Committee Member Employment Consultant Speaker s Bureau Ownership/ Partnership/ Principal Personal Research Institutional, Organizational, or Other Financial Benefit Expert Witness Voting Recusals by Section* Stephan D. Fihn (Chair) Department of Veterans Affairs Director, Office of Analytics and Business Intelligence None None None None None None None James C. Blankenship (Vice Chair) Geisinger Medical Center Staff Physician; Director, Cardiac Catheterization Laboratory None None None AstraZeneca None None 2.2.5 Boston Scientific 4.4.2 Kai Pharmaceutical 4.4.4 The Medicines Company Schering-Plough Volcano Karen P. Alexander Duke University Medical Center Associate Professor of Medicine/ Cardiology None None None Gilead Sanofi-aventis None 2.2.5 John A. Bittl Munroe Regional Medical Center Invasive Cardiologist None None None None None None None John G. Byrne Brigham and Women s Hospital Chief, Division of Cardiac Surgery None None None None None None None Barbara J. Fletcher University of North Florida Clinical Associate Professor, School of Nursing None None None None None None None Gregg C. Fonarow UCLA Cardiomyopathy Center Professor of Medicine Boston Scientific None None None None None 2.2.5 Johnson & Johnson The Medicines Company Medtronic Richard A. Lange University of Texas Health Science Center, San Antonio Professor of Medicine None None None None None None None Glenn N. Levine Baylor College of Medicine Professor of Medicine; Director, Cardiac Care Unit None None None None None None None Thomas M. Maddox VA Eastern Colorado Health Care System Cardiologist None None None None None None None Srihari S. Naidu Winthrop University Hospital Director, Cardiac Catheterization Laboratory None None None None None None None (Continued) Fihn et al 2014 Stable Ischemic Heart Disease Focused Update 1763 Appendix 1. Continued Committee Member Employment Consultant Speaker s Bureau Ownership/ Partnership/ Principal Personal Research Institutional, Organizational, or Other Financial Benefit Expert Witness Voting Recusals by Section* E. Magnus Ohman Duke Medicine Professor of Medicine AstraZeneca Gilead Sciences None Daiichi-Sankyo None None 2.2.5 Bristol-Myers Squibb Gilead Sciences Gilead Sciences The Medicines Company Merck Sanofi-aventis Peter K. Smith Duke University Medical Center Professor of Surgery; Chief, Thoracic Surgery None None None None None None None This table represents the relationships of writing group members with industry and other entities that were determined to be relevant to this document.


Continued Committee Member Employment Consultant Speaker s Bureau Ownership/ Partnership/ Principal Personal Research Institutional, Organizational, or Other Financial Benefit Expert Witness Voting Recusals by Section* E. Magnus Ohman Duke Medicine Professor of Medicine AstraZeneca Gilead Sciences None Daiichi-Sankyo None None 2.2.5 Bristol-Myers Squibb Gilead Sciences Gilead Sciences The Medicines Company Merck Sanofi-aventis Peter K. Smith Duke University Medical Center Professor of Surgery; Chief, Thoracic Surgery None None None None None None None This table represents the relationships of writing group 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 group 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 $10000 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.


Relationships that exist with no financial benefit are also included for the purpose of transparency. Relationships in this table are modest unless otherwise noted. According to the ACC/AHA, a person has a relevant relationship IF: a) the relationship or interest relates to the same or similar subject matter, intellectual property or asset, topic, or issue addressed in the document; or b) the company/entity (with whom the relationship exists) makes a drug, drug class, or device addressed in the document, or makes a competing drug or device addressed in the document; or c) the person or a member of the person s household has a reasonable potential for financial, professional, or other personal gain or loss as a result of the issues/content addressed in the document. *Writing group members are required to recuse themselves from voting on sections to which their specific relationships with industry and other entities may apply. Section numbers pertain to those in the full-text guideline. Significant relationship. No financial benefit. AATS indicates American Association for Thoracic Surgery; ACC, American College of Cardiology; AHA, American Heart Association; PCNA, Preventive Cardiovascular Nurses Association; SCAI, Society for Cardiovascular Angiography and Interventions; STS, Society of Thoracic Surgeons; and VA, Veterans Affairs. Appendix 2.


AATS indicates American Association for Thoracic Surgery; ACC, American College of Cardiology; AHA, American Heart Association; PCNA, Preventive Cardiovascular Nurses Association; SCAI, Society for Cardiovascular Angiography and Interventions; STS, Society of Thoracic Surgeons; and VA, Veterans Affairs. Appendix 2. Reviewer Relationships With Industry and Other Entities (Relevant) 2014 Acc/Aha/Aats/Pcna/Scai/Sts Focused Update of the Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease Peer Reviewer Representation Employment Consultant Speaker s Bureau Personal Research Institutional, Organizational, or Other Financial Benefit Judith S. Hochman Official Reviewer ACC/AHA Task Force on Practice Guidelines New York University School of Medicine Clinical Chief of Cardiology None None NIH (PI ISCHEMIA trial)* None Bruce W. Lytle Official Reviewer AHA Cleveland Clinic Foundation Chairman, Thoracic and Cardiovascular Surgery None None None None Margo B. Minissian Official Reviewer ACC Board of Governors Cedar-Sinai s Heart Institute Cardiology Nurse Practitioner; University of California Los Angeles Assistant Clinical Professor None None None Gilead Sciences* C. Michael Valentine Official Reviewer ACC Board of Trustees Centra Lynchburg General Hospital Director, Cardiac Progressive Care Unit; Centra Stroobants Heart Center Director of Clinical Quality None None None None Lani M. Zimmerman Official Reviewer AHA University of Nebraska Medical Center Professor, College of Nursing None None None None Robert S.D.


Reviewer Relationships With Industry and Other Entities (Relevant) 2014 Acc/Aha/Aats/Pcna/Scai/Sts Focused Update of the Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease Peer Reviewer Representation Employment Consultant Speaker s Bureau Personal Research Institutional, Organizational, or Other Financial Benefit Judith S. Hochman Official Reviewer ACC/AHA Task Force on Practice Guidelines New York University School of Medicine Clinical Chief of Cardiology None None NIH (PI ISCHEMIA trial)* None Bruce W. Lytle Official Reviewer AHA Cleveland Clinic Foundation Chairman, Thoracic and Cardiovascular Surgery None None None None Margo B. Minissian Official Reviewer ACC Board of Governors Cedar-Sinai s Heart Institute Cardiology Nurse Practitioner; University of California Los Angeles Assistant Clinical Professor None None None Gilead Sciences* C. Michael Valentine Official Reviewer ACC Board of Trustees Centra Lynchburg General Hospital Director, Cardiac Progressive Care Unit; Centra Stroobants Heart Center Director of Clinical Quality None None None None Lani M. Zimmerman Official Reviewer AHA University of Nebraska Medical Center Professor, College of Nursing None None None None Robert S.D. Higgins Organizational Reviewer STS Ohio State University Director, Division of Cardiac Surgery None None None None Ajay J. Kirtane Organizational Reviewer SCAI Columbia University Medical Center Chief Academic Officer; Director, Interventional Cardiology Fellowship Program; and Assistant Professor of Clinical Medicine None Boston Scientific* Medtronic* None Joseph D. Schmoker Organizational Reviewer AATS University of Vermont Associate Professor of Surgery and Medicine; Fletcher Allen Health Care Director of the Center for Thoracic Aortic Disease None None None None Joanna D. Sikkema Organizational Reviewer PCNA University of Miami Adult Nurse Practitioner, School of Nursing and Health Studies None None None None Nancy M. Albert Content Reviewer ACC/AHA Task Force on Practice Guidelines Cleveland Clinic Foundation Senior Director of Nursing and Research None None None None Mohamed A. Sobhy Aly Content Reviewer AIG Alexandria University Professor of Cardiology, Head of Cardiology Department None None None None Jeffrey L. Anderson Content Reviewer ACC/AHA Task Force on Practice Guidelines Intermountain Medical Center Associate Chief of Cardiology Sanofi-aventis None None None (Continued) Fihn et al 2014 Stable Ischemic Heart Disease Focused Update 1765 Appendix 2.


Higgins Organizational Reviewer STS Ohio State University Director, Division of Cardiac Surgery None None None None Ajay J. Kirtane Organizational Reviewer SCAI Columbia University Medical Center Chief Academic Officer; Director, Interventional Cardiology Fellowship Program; and Assistant Professor of Clinical Medicine None Boston Scientific* Medtronic* None Joseph D. Schmoker Organizational Reviewer AATS University of Vermont Associate Professor of Surgery and Medicine; Fletcher Allen Health Care Director of the Center for Thoracic Aortic Disease None None None None Joanna D. Sikkema Organizational Reviewer PCNA University of Miami Adult Nurse Practitioner, School of Nursing and Health Studies None None None None Nancy M. Albert Content Reviewer ACC/AHA Task Force on Practice Guidelines Cleveland Clinic Foundation Senior Director of Nursing and Research None None None None Mohamed A. Sobhy Aly Content Reviewer AIG Alexandria University Professor of Cardiology, Head of Cardiology Department None None None None Jeffrey L. Anderson Content Reviewer ACC/AHA Task Force on Practice Guidelines Intermountain Medical Center Associate Chief of Cardiology Sanofi-aventis None None None (Continued) Fihn et al 2014 Stable Ischemic Heart Disease Focused Update 1765 Appendix 2. Continued Peer Reviewer Representation Employment Consultant Speaker s Bureau Personal Research Institutional, Organizational, or Other Financial Benefit Eric R. Bates Content Reviewer University of Michigan Health System Professor, Department of Internal Medicine AstraZeneca None None None Bristol-Myers Squibb Daiichi-Sankyo Merck Sanofi-aventis Ralph G. Brindis Content Reviewer ACC/AHA Task Force on Practice Guidelines University of California San Francisco Clinical Professor of Medicine, Department of Medicine and Philip R. Lee Institute for Health Policy Studies None None None None Biykem Bozkurt Content Reviewer ACC/AHA Task Force on Practice Guidelines Michael E. DeBakey VA Medical Center Chief, Cardiology Section; The Mary and Gordon Cain Chair and Professor of Medicine; Director, Winters Center for Heart Failure Research None None None None Steven M. Bradley Content Reviewer VA Eastern Colorado Health Care System Physician None None None None James A. Burke Content Reviewer ACC Interventional Scientific Council Lehigh Valley Heart Specialists Cardiovascular Disease Doctor None None None None John H. Calhoon Content Reviewer University of Texas Health Science Center Professor; Chair, CT Surgery Department None None None None Lesley Curtis Content Reviewer ACC/AHA Task Force on Practice Guidelines Duke University School of Medicine Associate Professor of Medicine None None GE Healthcare* Johnson & Johnson* None Prakash C. Deedwania Content Reviewer University of California San Francisco Chief of Cardiology Gilead Sciences None None None Gregory J. Dehmer Content Reviewer Scott & White Healthcare Director, Division of Cardiology; Texas A&M Health Science Center College of Medicine Professor of Medicine None None None None Linda D. Gillam Content Reviewer ACC Imaging Council Morristown Medical Center Professor of Cardiology; Vice Chair, Cardiovascular Medicine None None Edwards Lifesciences Edwards Lifesciences Christopher B. Granger Content Reviewer AHA Duke Clinical Research Institute Associate Professor of Medicine; Director, Cardiac Care Unit AstraZeneca Bristol-Myers Squibb Daiichi-Sankyo Eli Lilly The Medicines Company None Bristol-Myers Squibb* Medtronic* Merck* Sanofi- aventis* The Medicines Company* GE Healthcare* Medtronic* Philips Medical* (Continued) Appendix 2.


Continued Peer Reviewer Representation Employment Consultant Speakers Bureau Personal Research Institutional, Organizational, or Other Financial Benefit Robert A. Guyton Content Reviewer ACC/AHA Task Force on Practice Guidelines Emory University School of Medicine Professor of Surgery and Chief, Division of Cardiothoracic Surgery Medtronic None None None Jonathan L. Halperin Content Reviewer ACC/AHA Task Force on Practice Guidelines Mt. Sinai Medical Center Professor of Medicine AstraZeneca None None None Boston Scientific Bristol-Myers Squibb Daiichi-Sankyo Johnson & Johnson Medtronic Sanofi-aventis* Mark A. Hlatky Content Reviewer Stanford University School of Medicine Professor of Health Research and Policy Blue Cross/Blue Shield None None None Gilead Sciences HeartFlow* Lloyd W. Klein Content Reviewer Rush University Medical Center Professor, Internal Medicine None None None None Richard J. Kovacs Content Reviewer ACC/AHA Task Force on Practice Guidelines Krannert Institute of Cardiology Professor of Clinical Medicine None None None Cook Medical* Eli Lilly Stephen J. Lahey Content Reviewer University of Connecticut Health Center Professor; Chief of Cardiothoracic Surgery None None None None Michael J. Mack Content Reviewer Baylor Health Care System Director None None Edwards Lifesciences None Daniel B.


Sinai Medical Center Professor of Medicine AstraZeneca None None None Boston Scientific Bristol-Myers Squibb Daiichi-Sankyo Johnson & Johnson Medtronic Sanofi-aventis* Mark A. Hlatky Content Reviewer Stanford University School of Medicine Professor of Health Research and Policy Blue Cross/Blue Shield None None None Gilead Sciences HeartFlow* Lloyd W. Klein Content Reviewer Rush University Medical Center Professor, Internal Medicine None None None None Richard J. Kovacs Content Reviewer ACC/AHA Task Force on Practice Guidelines Krannert Institute of Cardiology Professor of Clinical Medicine None None None Cook Medical* Eli Lilly Stephen J. Lahey Content Reviewer University of Connecticut Health Center Professor; Chief of Cardiothoracic Surgery None None None None Michael J. Mack Content Reviewer Baylor Health Care System Director None None Edwards Lifesciences None Daniel B. Mark Content Reviewer Duke Clinical Research Institute Professor of Medicine None None AstraZeneca Eli Lilly* Eli Lilly* Medtronic* Gilead Sciences Medtronic* David J. Maron Content Reviewer Vanderbilt University Medical Center Director, Vanderbilt Chest Pain Center None None AstraZeneca* None Gilead Sciences* Merck* Hani K. Najm Content Reviewer ACC Surgeons Scientific Council National Guard Health Affairs President, Saudi Heart Association None None None None L. Kristin Newby Content Reviewer Duke University Medical Center Associate Professor, Clinical Medicine AstraZeneca Daiichi-Sankyo Johnson & Johnson Philips Medical WebMD None Amylin Eli Lilly Bristol-Myers Squibb* Merck* Patrick T. O Gara Content Reviewer Brigham and Women s Hospital Director, Clinical Cardiology; Harvard Medical School Professor of Medicine None None None Lantheus Medical (Continued) Fihn et al 2014 Stable Ischemic Heart Disease Focused Update 1767 Appendix 2.


Mark Content Reviewer Duke Clinical Research Institute Professor of Medicine None None AstraZeneca Eli Lilly* Eli Lilly* Medtronic* Gilead Sciences Medtronic* David J. Maron Content Reviewer Vanderbilt University Medical Center Director, Vanderbilt Chest Pain Center None None AstraZeneca* None Gilead Sciences* Merck* Hani K. Najm Content Reviewer ACC Surgeons Scientific Council National Guard Health Affairs President, Saudi Heart Association None None None None L. Kristin Newby Content Reviewer Duke University Medical Center Associate Professor, Clinical Medicine AstraZeneca Daiichi-Sankyo Johnson & Johnson Philips Medical WebMD None Amylin Eli Lilly Bristol-Myers Squibb* Merck* Patrick T. O Gara Content Reviewer Brigham and Women s Hospital Director, Clinical Cardiology; Harvard Medical School Professor of Medicine None None None Lantheus Medical (Continued) Fihn et al 2014 Stable Ischemic Heart Disease Focused Update 1767 Appendix 2. Continued Peer Reviewer Representation Employment Consultant Speakers Bureau Personal Research Institutional, Organizational, or Other Financial Benefit Joseph F. Sabik Content Reviewer ACC Surgeons Scientific Council Cleveland Clinic Department Chair, Thoracic and Cardiovascular Surgery Edwards Lifesciences None Abbott Laboratories None Medtronic Edwards Lifesciences Vikas Saini Content Reviewer The Lown Institute President None None None None Frank W. Sellke Content Reviewer ACC/AHA Task Force on Practice Guidelines Brown Medical School and Lifespan Chief of Cardiothoracic Surgery None None The Medicines Company None William S. Weintraub Content Reviewer Christiana Care Health System Section Chief, Cardiology Bristol-Myers Squibb None None None Daiichi-Sankyo Eli Lilly Christopher J.


Continued Peer Reviewer Representation Employment Consultant Speakers Bureau Personal Research Institutional, Organizational, or Other Financial Benefit Joseph F. Sabik Content Reviewer ACC Surgeons Scientific Council Cleveland Clinic Department Chair, Thoracic and Cardiovascular Surgery Edwards Lifesciences None Abbott Laboratories None Medtronic Edwards Lifesciences Vikas Saini Content Reviewer The Lown Institute President None None None None Frank W. Sellke Content Reviewer ACC/AHA Task Force on Practice Guidelines Brown Medical School and Lifespan Chief of Cardiothoracic Surgery None None The Medicines Company None William S. Weintraub Content Reviewer Christiana Care Health System Section Chief, Cardiology Bristol-Myers Squibb None None None Daiichi-Sankyo Eli Lilly Christopher J. White Content Reviewer Ochsner Health System Director, John Ochsner Heart and Vascular Institute None None None St. Jude Medical (DSMB) Sankey V. Williams Content Reviewer ACP University of Pennsylvania Health System Professor of General Medicine None None None None Poh Shuan Daniel Yeo Content Reviewer AIG Tan Tock Seng Hospital, Department of Cardiology Cardiologist None None None Boston Scientific Merck Schering-Plough No reviewer had a relevant ownership, partnership, or principal position to report. No reviewer reported acting as an expert witness in a relevant matter. This table represents the relationships of reviewers with industry and other entities that were disclosed at the time of peer review and determined to be relevant to this document. It 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 $10000 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 $10000 of the fair market value of the business entity; or if funds received by the person from the business entity exceed 5% of the person s gross income for the previous year. A relationship is considered to be modest if it is less than significant under the preceding definition. Relationships that exist with no financial benefit are also included for the purpose of transparency. Relationships in this table are modest unless otherwise noted. Names are listed in alphabetical order within each category of review. 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. *Significant relationship. No financial benefit. AATS indicates American Association for Thoracic Surgery; ACC, American College of Cardiology; ACP, American College of Physicians; AHA, American Heart Association; AIG, Association of International Governors; DSMB, Data Safety Monitoring Board; ISCHEMIA trial, International Study of Comparative Health Effectiveness With Medical and Invasive Approaches trial; PCNA, Preventive Cardiovascular Nurses Association; PI, principle investigator; SCAI, Society for Cardiovascular Angiography and Interventions; and STS, Society of Thoracic Surgeons.


ACCF/AHA Focused Update 2012 ACCF/AHA Focused Update of the Guideline for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial Infarction (Updating the 2007 Guideline and Replacing the 2011 Focused Update) A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines Developed in Collaboration With the American College of Emergency Physicians, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons 2012 WRITING GROUP MEMBERS* Hani Jneid, MD, FACC, FAHA, Chair ; Jeffrey L. Anderson, MD, FACC, FAHA, Vice Chair ; R. Scott Wright, MD, FACC, FAHA, Vice Chair ; Cynthia D. Adams, RN, PhD, FAHA ; Charles R. Bridges, MD, ScD, FACC, FAHA ; Donald E. Casey, Jr, MD, MPH, MBA, FACP, FAHA ; Steven M. Ettinger, MD, FACC ; Francis M. Fesmire, MD, FACEP ; Theodore G. Ganiats, MD#; A. Michael Lincoff, MD, FACC ; Eric D. Peterson, MD, MPH, FACC, FAHA**; George J. Philippides, MD, FACC, FAHA ; Pierre Theroux, MD, FACC, FAHA ; Nanette K. Wenger, MD, MACC, FAHA ; James Patrick Zidar, MD, FACC, FSCAI 2007 WRITING COMMITTEE MEMBERS Jeffrey L. Anderson, MD, FACC, FAHA, Chair; Cynthia D. Adams, RN, PhD, FAHA; Elliott M. Antman, MD, FACC, FAHA; Charles R. Bridges, MD, ScD, FACC, FAHA; Robert M. Califf, MD, MACC; Donald E. Casey, Jr, MD, MPH, MBA, FACP; William E. Chavey II, MD, MS; Francis M. Fesmire, MD, FACEP; Judith S. Hochman, MD, FACC, FAHA; Thomas N. Levin, MD, FACC, FSCAI; A. Michael Lincoff, MD, FACC; Eric D. Peterson, MD, MPH, FACC, FAHA; Pierre Theroux, MD, FACC, FAHA; Nanette K. Wenger, MD, MACC, FAHA; R. Scott Wright, MD, FACC, FAHA *Writing committee members are required to recuse themselves from voting on sections to which their specific relationships with industry and other entities may apply; see Appendix 1 for recusal information.


ACCF/AHA Representative. ACCF/AHA Task Force on Practice Guidelines Liaison. Society of Thoracic Surgeons Representative. American College of Physicians Representative. American College of Emergency Physicians Representative. #American Academy of Family Physicians Representative. **ACCF/AHA Task Force on Performance Measures Liaison. Society for Cardiovascular Angiography and Interventions Representative. The online-only Data Supplement is available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIR.0b013e318256f1e0/-/DC1. The online-only Comprehensive Relationships Table is available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/ CIR.0b013e318256f1e0/-/DC2. This document was approved by the American College of Cardiology Foundation Board of Trustees and the American Heart Association Science Advisory and Coordinating Committee in March 2012. The American Heart Association requests that this document be cited as follows: Jneid H, Anderson JL, Wright RS, Adams CD, Bridges CR, Casey DE Jr, Ettinger SM, Fesmire FM, Ganiats TG, Lincoff AM, Peterson ED, Philippides GJ, Theroux P, Wenger NK, Zidar JP. 2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/non ST-elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2012;126:875 910. This article is copublished in the Journal of the American College of Cardiology. Copies: This document is available on the World Wide Web sites of the American College of Cardiology (www.cardiosource.org) and the American Heart Association (my.americanheart.org). A copy of the document is available at http://my.americanheart.org/statements by selecting either the By Topic link or the By Publication Date link. To purchase additional reprints, call 843-216-2533 or e-mail kelle.ramsay@wolterskluwer.com. Expert peer review of AHA Scientific Statements is conducted by the AHA Office of Science Operations. For more on AHA statements and guidelines development, visit http://my.americanheart.org/statements and select the Policies and Development link.


For more on AHA statements and guidelines development, visit http://my.americanheart.org/statements and select the Policies and Development link. Permissions: Multiple copies, modification, alteration, enhancement, and/or distribution of this document are not permitted without the express permission of the American Heart Association. Instructions for obtaining permission are located at http://www.heart.org/HEARTORG/General/Copyright- Permission-Guidelines_UCM_300404_Article.jsp. A link to the Copyright Permissions Request Form appears on the right side of the page. 2012 by the American College of Cardiology Foundation and the American Heart Association, Inc. Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIR.0b013e318256f1e0 ACCF/AHA TASK FORCE MEMBERS Alice K. Jacobs, MD, FACC, FAHA, Immediate Past Chair; Jeffrey L. Anderson, MD, FACC, FAHA, Chair; Jonathan L. Halperin, MD, FACC, FAHA, Chair-Elect; Nancy M. Albert, PhD, CCNS, CCRN, FAHA; Mark A. Creager, MD, FACC, FAHA; David DeMets, PhD; Steven M. Ettinger, MD, FACC; Robert A. Guyton, MD, FACC; Judith S. Hochman, MD, FACC, FAHA; Frederick G. Kushner, MD, FACC, FAHA; E. Magnus Ohman, MD, FACC; William G. Stevenson, MD, FACC, FAHA; Clyde W. Yancy, MD, FACC, FAHA Table of Contents Preamble 876 1. Introduction 879 1.1. Methodology and Evidence Review 879 1.2. Organization of the Writing Group 879 1.3. Document Review and Approval 879 3. Early Hospital Care 879 3.2. Antiplatelet/Anticoagulant Therapy in Patients for Whom Diagnosis of UA/NSTEMI Is Likely or Definite: Recommendations 879 3.2.1. Antiplatelet Therapy: Recommendations 879 3.2.3. Additional Management of Antiplatelet and Anticoagulant Therapy: Recommendations 879 Therapy in Patients for Whom Diagnosis of UA/NSTEMI Is Likely or Definite 879 Inhibitors 879 Receptor Inhibitors for PCI in UA/NSTEMI 881 3.2.3.1.2.1. Timing of Discontinuation of P2Y12 Receptor Inhibitor Therapy for Surgical Procedures 882 Variability in Responsiveness to Clopidogrel 882 3.2.3.1.4. Optimal Loading and Maintenance Dosages of Clopidogrel 883 3.2.3.1.5. Proton Pump Inhibitors and Dual Antiplatelet Therapy for ACS 883 3.2.3.1.6. Glycoprotein IIb/IIIa Receptor Antagonists 884 3.3.


Proton Pump Inhibitors and Dual Antiplatelet Therapy for ACS 883 3.2.3.1.6. Glycoprotein IIb/IIIa Receptor Antagonists 884 3.3. Initial Invasive Versus Initial Conservative Strategies: Recommendations 885 3.3.3.1. Timing of Invasive Therapy 885 5. Late Hospital Care, Hospital Discharge, and Posthospital Discharge Care 890 5.2. Long-Term Medical Therapy and Secondary Prevention 890 5.2.1. Convalescent and Long-Term Antiplatelet Therapy: Recommendations 890 5.2.6. Warfarin Therapy: Recommendations 892 6. Special Groups 892 6.2. Diabetes Mellitus: Recommendations 892 6.2.1.1. Intensive Glucose Control 892 6.5. Chronic Kidney Disease: Recommendations 893 6.5.1. Angiography in Patients With CKD 893 7. Conclusions and Future Directions 895 7.1. Quality of Care and Outcomes for UA/NSTEMI: Recommendation 895 7.1.1. Quality Care and Outcomes 895 Appendix 1. Author Relationships With Industry and Other Entities (Relevant) 901 Appendix 2. Reviewer Relationships With Industry and Other Entities (Relevant) 903 Appendix 3. Dosing Table for Antiplatelet and Anticoagulant Therapy Discussed in This Focused Update to Support PCI in UA/NSTEMI 906 Appendix 4. Comparisons Among Orally Effective P2Y12 Inhibitors 908 Appendix 5. Flowchart for Class I and Class IIa Recommendations for Initial Management of UA/NSTEMI 909 Appendix 6. Selection of Initial Treatment Strategy: Invasive Versus Conservative Strategy 910 Preamble Keeping pace with the stream of new data and evolving evidence on which guideline recommendations are based is an ongoing challenge to timely development of clinical practice guidelines. In an effort to respond promptly to new evidence, the American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) Task Force on Practice Guidelines (Task Force) has created a focused update process to revise the existing guideline recommendations that are affected by the evolving data or opinion. New evidence is reviewed in an ongoing fashion to more efficiently respond to important science and treatment trends that could have a major impact on patient outcomes and quality of care.


New evidence is reviewed in an ongoing fashion to more efficiently respond to important science and treatment trends that could have a major impact on patient outcomes and quality of care. Evidence is reviewed at least twice a year, and updates are initiated on an as-needed basis and completed as quickly as possible while maintaining the rigorous methodology that the ACCF and AHA have developed during their partnership of more than 20 years. These focused updates are prompted following a thorough review of late-breaking clinical trials presented at national and international meetings in addition to other new published data deemed to have an impact on patient care (Section 1.1, Methodology and Evidence Review). Through a broad-based vetting process, the studies included are identified as being important to the relevant patient population. The focused update is not intended to be based on a complete literature review from the date of the previous guideline publication but rather to include pivotal new evidence that may affect changes to current recommendations. Specific criteria/consid- erations for inclusion of new data include the following: publication in a peer-reviewed journal; large, randomized, placebo-controlled trial(s); nonrandomized data deemed important on the basis of results affecting current safety and efficacy assumptions, including observational studies and meta-analyses; strength/weakness of research methodology and findings; likelihood of additional studies influencing current findings; impact on current and/or likelihood of need to develop new performance measure(s); request(s) and requirement(s) for review and update from the practice community, key stakeholders, and other sources free of industry relationships or other potential bias; number of previous trials showing consistent results; and need for consistency with a new guideline or guideline updates or revisions.


Specific criteria/consid- erations for inclusion of new data include the following: publication in a peer-reviewed journal; large, randomized, placebo-controlled trial(s); nonrandomized data deemed important on the basis of results affecting current safety and efficacy assumptions, including observational studies and meta-analyses; strength/weakness of research methodology and findings; likelihood of additional studies influencing current findings; impact on current and/or likelihood of need to develop new performance measure(s); request(s) and requirement(s) for review and update from the practice community, key stakeholders, and other sources free of industry relationships or other potential bias; number of previous trials showing consistent results; and need for consistency with a new guideline or guideline updates or revisions. In analyzing the data and developing recommendations and supporting text, the writing group uses evidence-based method- ologies developed by the Task Force.1 The Class of Recommen- dation (COR) is an estimate of the size of the treatment effect considering risks versus benefits in addition to evidence and/or agreement that a given treatment or procedure is or is not useful/effective and in some situations may cause harm. The Level of Evidence (LOE) is an estimate of the certainty or precision of the treatment effect. The writing group reviews and ranks evidence supporting each recommendation with the weight of evidence ranked as LOE A, B, or C using specific definitions that are included in Table 1. Studies are identified as observational, retrospective, prospective, or randomized where appropriate. For certain conditions for which inadequate data are available, recommendations are based on expert consensus and clinical experience and ranked as LOE C. When recommenda- tions at LOE C are supported by historical clinical data, appropriate references (including clinical reviews) are cited if available.


For certain conditions for which inadequate data are available, recommendations are based on expert consensus and clinical experience and ranked as LOE C. When recommenda- tions at LOE C are supported by historical clinical data, appropriate references (including clinical reviews) are cited if available. For issues for which sparse data are available, a survey of current practice among the clinicians on the writing group is the basis for LOE C recommendations, and no references are cited. The schema for COR and LOE is summarized in Table 1, which also provides suggested phrases for writing recommen- dations within each COR. A new addition to this methodology is separation of the Class III recommendations to delineate whether the recommendation is determined to be of no benefit or is associated with harm to the patient. In addition, in view of the increasing number of comparative effectiveness studies, comparator verbs and suggested phrases for writing recommendations for the comparative effectiveness of one treatment/strategy with respect to another for COR I and IIa, LOE A or B only. In view of the advances in medical therapy across the spectrum of cardiovascular diseases, the Task Force has designated the term guideline-directed medical therapy (GDMT) to represent optimal medical therapy as defined by ACCF/AHA guideline (primarily Class I) recommended ther- apies. This new term, GDMT, will be used herein and throughout all future guidelines. Because the ACCF/AHA practice guidelines address pa- tient populations (and healthcare providers) residing in North America, drugs that are not currently available in North America are discussed in the text without a specific COR.


Because the ACCF/AHA practice guidelines address pa- tient populations (and healthcare providers) residing in North America, drugs that are not currently available in North America are discussed in the text without a specific COR. For studies performed in large numbers of subjects outside North America, each writing group reviews the potential impact of different practice patterns and patient populations on the treatment effect and relevance to the ACCF/AHA target population to determine whether the findings should inform a specific recommendation. The ACCF/AHA practice guidelines are intended to assist healthcare providers in clinical decision making by describing a range of generally acceptable approaches to the diagnosis, management, and prevention of specific diseases or conditions. The guidelines attempt to define practices that meet the needs of most patients in most circumstances. The ultimate judgment regarding care of a particular patient must be made by the healthcare provider and patient in light of all the circumstances presented by that patient. As a result, situations may arise in which deviations from these guidelines may be appropriate. Clinical decision making should consider the quality and avail- ability of expertise in the area where care is provided. When these guidelines are used as the basis for regulatory or payer decisions, the goal should be improvement in quality of care. The Task Force recognizes that situations arise for which additional data are needed to inform patient care more effec- tively; these areas will be identified within each respective guideline when appropriate. Prescribed courses of treatment in accordance with these recommendations are effective only if they are followed. Because lack of patient understanding and adherence may adversely affect outcomes, physicians and other healthcare providers should make every effort to engage the patient s active participation in prescribed medical regimens and lifestyles.


Because lack of patient understanding and adherence may adversely affect outcomes, physicians and other healthcare providers should make every effort to engage the patient s active participation in prescribed medical regimens and lifestyles. In addition, patients should be informed of the risks, benefits, and alternatives to a particular treatment and be involved in shared decision making whenever feasible, particularly for COR IIa and IIb, for which the benefit-to-risk ratio may be lower. The Task Force makes every effort to avoid actual, potential, or perceived conflicts of interest that may arise as a result of industry relationships or personal interests among the members of the writing group. All writing group members and peer reviewers of the guideline are required to disclose all current healthcare-related relationships, including those ex- isting 12 months before initiation of the writing effort. In December 2009, the ACCF and AHA implemented a new policy for relationships with industry and other entities (RWI) that requires the writing group chair plus a minimum of 50% of the writing group to have no relevant RWI (Appendix 1 for the ACCF/AHA definition of relevance). These statements are reviewed by the Task Force and all members during each Jneid et al 2012 UA/NSTEMI Focused Update 877 conference call and/or meeting of the writing group and are updated as changes occur. All guideline recommendations require a confidential vote by the writing group and must be approved by a consensus of the voting members. Members are not permitted to draft or vote on any text or recommen- dations pertaining to their RWI. Members who recused them- selves from voting are indicated in the list of writing group members, and specific section recusals are noted in Appendix 1. Authors and peer reviewers RWI pertinent to this guideline are disclosed in Appendixes 1 and 2, respectively.


Authors and peer reviewers RWI pertinent to this guideline are disclosed in Appendixes 1 and 2, respectively. Additionally, to ensure complete transparency, writing group members compre- hensive disclosure information including RWI not pertinent to this document is available as an online supplement. Compre- hensive disclosure information for the Task Force is also available online at http://www.cardiosource.org/ACC/About- ACC/Leadership/Guidelines-and-Documents-Task-Forces.aspx. The work of the writing group is supported exclusively by the ACCF and AHA without commercial support. Writing group members volunteered their time for this activity. In an effort to maintain relevance at the point of care for practicing physicians, the Task Force continues to oversee an ongoing process improvement initiative. As a result, in response to pilot projects, several changes to these guidelines will be apparent, including limited narrative text, a focus on Table 1. Applying Classification of Recommendations and Level of Evidence A recommendation with Level of Evidence B or C does not imply that the recommendation is weak. Many important clinical questions addressed in the guidelines do not lend themselves to clinical trials. Although randomized trials are unavailable, there may be a very clear clinical consensus that a particular test or therapy is useful or effective. *Data available from clinical trials or registries about the usefulness/efficacy in different subpopulations, such as sex, age, history of diabetes, history of prior myocardial infarction, history of heart failure, and prior aspirin use. For comparative effectiveness recommendations (Class I and IIa; Level of Evidence A and B only), studies that support the use of comparator verbs should involve direct comparisons of the treatments or strategies being evaluated. summary and evidence tables (with references linked to abstracts in PubMed), and more liberal use of summary recommendation tables (with references that support LOE) to serve as a quick reference.


summary and evidence tables (with references linked to abstracts in PubMed), and more liberal use of summary recommendation tables (with references that support LOE) to serve as a quick reference. In April 2011, the Institute of Medicine released 2 reports: Clinical Practice Guidelines We Can Trust and Finding What Works in Health Care: Standards for Systematic Reviews.2,3 It is noteworthy that the ACCF/AHA practice guidelines were cited as being compliant with many of the standards that were proposed. A thorough review of these reports and our current methodology is under way, with further enhancements anticipated. The recommendations in this focused update are consid- ered current until they are superseded in another focused update or the full-text guideline is revised. Guidelines are official policy of both the ACCF and AHA. Jeffrey L. Anderson, MD, FACC, FAHA Chair, ACCF/AHA Task Force on Practice Guidelines 1.1. Methodology and Evidence Review The standing guideline writing committee along with the parent Task Force identified trials and other key data through October 2011 that may impact guideline recom- mendations. On the basis of the criteria/considerations noted in the Preamble and the approval of new oral antiplatelets, a focused update was initiated to provide guidance on how to incorporate these agents into daily practice. Now that multiple agents are available, a com- parison of their use in various settings within clinical practice is provided.


Now that multiple agents are available, a com- parison of their use in various settings within clinical practice is provided. This iteration replaces the sections in the 2007 ACC/AHA Guidelines for the Management of Patients With Unstable Angina/Non ST-Elevation Myo- that were updated by the 2011 ACCF/ AHA Focused Update of the Guidelines for the Manage- ment of Patients With Unstable Angina/Non ST-Elevation To provide clinicians with a comprehensive set of data, whenever deemed appropriate or when published, the abso- lute risk difference and number needed to treat or harm are provided in the guideline, along with confidence intervals (CI) and data related to the relative treatment effects such as odds ratio (OR), relative risk (RR), hazard ratio (HR), and incidence rate ratio. Consult the full-text version of the 2007 ACC/AHA Guidelines for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial Infarction4 for policy on clinical areas not covered by the current document. Individual recommendations updated in this focused update will be incorporated into future revisions and/or updates of the full-text guidelines. 1.2. Organization of the Writing Group For this focused update, members of the 2011 Unstable Angina/Non ST-Elevation Myocardial Infarction (UA/ NSTEMI) focused update writing group were invited and all agreed to participate (referred to as the 2012 focused update writing group). Members were required to disclose all RWI relevant to the data under consideration. The writing group included representatives from the ACCF, AHA, American Academy of Family Physicians, American College of Emer- gency Physicians, American College of Physicians, Society for Cardiovascular Angiography and Interventions, and So- ciety of Thoracic Surgeons. 1.3.


The writing group included representatives from the ACCF, AHA, American Academy of Family Physicians, American College of Emer- gency Physicians, American College of Physicians, Society for Cardiovascular Angiography and Interventions, and So- ciety of Thoracic Surgeons. 1.3. Document Review and Approval This document was reviewed by 2 official reviewers each nominated by the ACCF and the AHA, as well as 1 or 2 reviewers each from the American College of Emergency Physicians, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons, and 29 individual content reviewers, including members of the ACCF Interventional Scientific Council. The information on reviewers RWI was distributed to the writing group and is published in this document (Appendix 2). This document was approved for publication by the governing bodies of the ACCF and the AHA and endorsed by the American College of Emergency Physicians, Soci- ety for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. 3. Early Hospital Care 3.2. Antiplatelet/Anticoagulant Therapy in Patients for Whom Diagnosis of UA/NSTEMI Is Likely or Definite: Recommendations 3.2.1. Antiplatelet Therapy: Recommendations Supplement.) 3.2.3. Additional Management of Antiplatelet and Anticoagulant Therapy: Recommendations Supplement.) 3.2.3.1. Antiplatelet/Anticoagulant Therapy in Patients for Whom Diagnosis of UA/NSTEMI Is Likely or Definite tor therapy is an important component of antiplatelet therapy in patients with UA/NSTEMI and has been tested in several large trial populations with UA/NSTEMI. The last version of the guideline recommended the use of clopidogrel in patients with UA/NSTEMI because it was the only US Food and Drug Administration (FDA) approved P2Y12 receptor inhibitor in this patient population at that time.6 Since the publication of the last guideline,6 the FDA has approved 2 additional P2Y12 receptor inhibitors for use in patients with UA/NSTEMI.


The last version of the guideline recommended the use of clopidogrel in patients with UA/NSTEMI because it was the only US Food and Drug Administration (FDA) approved P2Y12 receptor inhibitor in this patient population at that time.6 Since the publication of the last guideline,6 the FDA has approved 2 additional P2Y12 receptor inhibitors for use in patients with UA/NSTEMI. The FDA approved the use of prasugrel and ticagrelor based on data from head-to-head comparison trials with clopidogrel, in which prasugrel and ticagrelor were respectively superior to clopidogrel in reducing clinical events but at the expense of an increased risk of bleeding. The pivotal trial for prasugrel, TRITON TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel Thrombolysis in Myocar- dial Infarction),7 focused on patients with acute coronary syndrome (ACS) who were referred for percutaneous coro- nary intervention (PCI). TRITON TIMI 38 randomly as- Jneid et al 2012 UA/NSTEMI Focused Update 879 signed 13 608 patients with moderate- to high-risk ACS, of whom 10 074 (74%) had UA/NSTEMI, to receive prasugrel (a 60-mg loading dose and a 10-mg daily maintenance dose) or clopidogrel (a 300-mg loading dose and a 75-mg daily maintenance dose) for a median follow-up of 14.5 months. Acetylsalicylic acid (aspirin) was prescribed within 24 hours of PCI. Clinical endpoints were assessed at 30 and 90 days and then at 3-month intervals for 6 to 15 months. Among patients with UA/NSTEMI undergoing PCI, a prasugrel loading dose was administered before, during, or within 1 hour after PCI but only after coronary anatomy had been defined. Patients taking any thienopyridine within 5 days of randomization were excluded.


Patients taking any thienopyridine within 5 days of randomization were excluded. Prasugrel was associated with a significant 2.2% abso- lute reduction and a 19% relative reduction in the primary efficacy endpoint, a composite of the rate of death due to cardiovascular causes (including arrhythmia, congestive heart failure, shock, and sudden or unwitnessed death), nonfatal myocardial infarction (MI), or nonfatal stroke during the follow-up period (see Online Data Supplement). The primary efficacy endpoint occurred in 9.9% of patients receiving prasugrel and 12.1% of patients receiving clopi- dogrel (HR for prasugrel versus clopidogrel: 0.81; 95% CI: lar death, MI, and stroke by 138 events (number needed to treat 46). The difference in the primary endpoint was largely related to the difference in rates of nonfatal MI (7.3% for prasugrel versus 9.5% for clopidogrel; HR: 0.76; death (2.1% versus 2.4%; P 0.31) and nonfatal stroke (1.0% versus 1.0%; P 0.93) were not reduced by prasu- grel relative to clopidogrel. Rates of stent thrombosis were significantly reduced from 2.4% to 1.1% (P 0.001) by prasugrel. Prasugrel was associated with a significant increase in the rate of bleeding, notably TIMI (Thrombolysis In Myocardial Infarction) major hemorrhage, which was ob- served in 2.4% of patients taking prasugrel and in 1.8% of patients taking clopidogrel (HR for prasugrel versus clopi- was associated with a significant increase in fatal bleeding compared with clopidogrel (0.4% versus 0.1%; P 0.002).


Prasugrel was associated with a significant increase in the rate of bleeding, notably TIMI (Thrombolysis In Myocardial Infarction) major hemorrhage, which was ob- served in 2.4% of patients taking prasugrel and in 1.8% of patients taking clopidogrel (HR for prasugrel versus clopi- was associated with a significant increase in fatal bleeding compared with clopidogrel (0.4% versus 0.1%; P 0.002). From the standpoint of safety, prasugrel was associated with an increase of 35 TIMI major and non coronary artery graft bypass (CABG) bleeds (number needed to harm 167).7 Also, greater rates of life-threatening bleed- ing were evident in the prasugrel group than in the clopidogrel group: 1.4% versus 0.9%, respectively (HR for patients who underwent CABG, TIMI major bleeding through 15 months was also greater with prasugrel than with clopidogrel (13.4% versus 3.2%, respectively; HR for net clinical benefit in the TRITON TIMI 38 study dem- onstrated a primary efficacy and safety endpoint rate of 13.9% in the clopidogrel group versus 12.2% in the P 0.004). A post hoc analysis suggested there were 3 subgroups of ACS patients who did not have a favorable net clinical benefit (defined as the rate of death due to any cause, nonfatal MI, nonfatal stroke, or non CABG-related nonfatal TIMI major bleeding) from the use of prasugrel or who had net harm: Patients with a history of stroke or transient ischemic attack before enrollment had net harm from prasugrel (HR: 1.54; no net benefit from prasugrel (HR: 0.99; 95% CI: 0.81 to 1.21; P 0.92); and patients with a body weight of 60 kg had no net benefit from prasugrel (HR: 1.03; 95% CI: 0.69 to 1.53; P 0.89).


A post hoc analysis suggested there were 3 subgroups of ACS patients who did not have a favorable net clinical benefit (defined as the rate of death due to any cause, nonfatal MI, nonfatal stroke, or non CABG-related nonfatal TIMI major bleeding) from the use of prasugrel or who had net harm: Patients with a history of stroke or transient ischemic attack before enrollment had net harm from prasugrel (HR: 1.54; no net benefit from prasugrel (HR: 0.99; 95% CI: 0.81 to 1.21; P 0.92); and patients with a body weight of 60 kg had no net benefit from prasugrel (HR: 1.03; 95% CI: 0.69 to 1.53; P 0.89). In both treatment groups, patients with at least 1 of these risk factors had higher rates of bleeding than those The FDA approved prasugrel on July 10, 2009, and cited a contraindication against its use in patients with a history of transient ischemic attack or stroke or with active pathological bleeding.8 The FDA labeling information includes a general warning against the use of prasugrel in patients age 75 years because of concerns of an increased risk of fatal and intra- cranial bleeding and uncertain benefit except in high-risk situations (patients with diabetes or a history of prior MI), in which case the net benefit appears to be greater and its use may be considered.8 In focusing specifically on pa- tients with UA/NSTEMI, the rate of the primary efficacy endpoint was significantly reduced in favor of prasugrel The pivotal trial for ticagrelor, PLATO (Study of Platelet Inhibition and Patient Outcomes),9 was a multi- center, international, randomized controlled trial compar- ing ticagrelor with clopidogrel (on a background of aspirin therapy) to determine whether ticagrelor is superior to clopidogrel for the prevention of vascular events and death in a broad population of patients with ACS (see Online Data Supplement).


In both treatment groups, patients with at least 1 of these risk factors had higher rates of bleeding than those The FDA approved prasugrel on July 10, 2009, and cited a contraindication against its use in patients with a history of transient ischemic attack or stroke or with active pathological bleeding.8 The FDA labeling information includes a general warning against the use of prasugrel in patients age 75 years because of concerns of an increased risk of fatal and intra- cranial bleeding and uncertain benefit except in high-risk situations (patients with diabetes or a history of prior MI), in which case the net benefit appears to be greater and its use may be considered.8 In focusing specifically on pa- tients with UA/NSTEMI, the rate of the primary efficacy endpoint was significantly reduced in favor of prasugrel The pivotal trial for ticagrelor, PLATO (Study of Platelet Inhibition and Patient Outcomes),9 was a multi- center, international, randomized controlled trial compar- ing ticagrelor with clopidogrel (on a background of aspirin therapy) to determine whether ticagrelor is superior to clopidogrel for the prevention of vascular events and death in a broad population of patients with ACS (see Online Data Supplement). A total of 18 624 patients hospitalized with an ACS were randomized at 862 centers (from 2006 through 2008). Of those, 11 598 patients had UA/NSTEMI (patients with UA and NSTEMI made up 16.7% and 42.7% of the overall population, respectively), whereas 7026 patients had STEMI. The primary efficacy endpoint was the time to first occurrence of the composite of vascular death, MI, or stroke. The primary safety endpoint was the first occur- rence of any major bleeding event.


The primary safety endpoint was the first occur- rence of any major bleeding event. The randomized treat- ment was scheduled to continue for 12 months; however, patients were allowed to leave the trial at 6 to 9 months if the event-driven study achieved its targeted number of primary events. Overall, the median duration of study drug administration was 277 days. Using a double-blind, double-dummy design, ticagrelor (180-mg loading dose followed by 90 mg twice daily) was compared with clopidogrel (300- to 600-mg loading dose followed by 75 mg daily).9 At 24 hours after randomization, 79% of patients treated with clopidogrel received at least 300 mg, and nearly 20% received at least 600 mg. Overall, 64.3% of patients underwent PCI during the index hospitalization and 60.6% had stent implantation. Median times from the start of hospitalization to initiation of study treatment were 4.9 and 5.3 hours for ticagrelor and clopidogrel, respectively. At 12 months, ticagrelor was associated with a 1.9% absolute reduction and 16% relative reduction in the primary composite outcome compared with clopidogrel which was driven by lower rates of MI (5.8% versus 6.9%; benefits of ticagrelor appeared consistent across most subgroups studied, with no significant interaction being observed between the treatment effect and type of ACS. In focusing specifically on patients with UA/NSTEMI, ti- cagrelor was associated with a significant reduction in the primary efficacy endpoint among NSTEMI patients CI: 0.73 to 0.94) but not among UA patients (n 3112 1.22), although caution is urged against overinterpreting subgroup analyses. The benefits of ticagrelor in PLATO appeared within the first 30 days, persisted for up to 360 days, and were evident irrespective of clopidogrel pretreat- ment and whether patients had invasive or medical man- agement planned.


The benefits of ticagrelor in PLATO appeared within the first 30 days, persisted for up to 360 days, and were evident irrespective of clopidogrel pretreat- ment and whether patients had invasive or medical man- agement planned. Notably, ticagrelor was associated with a 1.4% absolute reduction in all-cause mortality (4.5% lower rates of definite stent thrombosis (1.3% versus 1.90%; HR: 0.67; 95% CI: 0.50 to 0.91). There were no significant differences between the ticagre- lor and clopidogrel groups in rates of major bleeding (the primary safety endpoint: composite of major life-threatening and other major bleeding events, PLATO study criteria; CI: 0.48 to 1.59).9 There were also no differences in major bleeding in patients undergoing CABG, in whom clopidogrel and ticagrelor were discontinued before the procedure for 5 days and 24 to 72 hours, respectively, per study protocol. Ticagrelor, however, was associated with a higher rate of non CABG-related major bleeding (4.5% versus 3.8%, P 0.03). In addition, ticagrelor caused a higher incidence of 2.02; although not necessitating drug discontinuation except in a few cases), mild increases in creatinine and uric acid levels, and a higher rate of ventricular pauses 3 seconds in the first week (5.8% versus 3.6%, P 0.01; but without causing differences in syncope or pacemaker implantation). Overall, discontinuation of the study drug due to adverse events occurred more frequently with ticagrelor than with clopidogrel (7.4% versus 6.0%; P 0.001). Patients with a history of bleeding were excluded in PLATO, and 4% of patients had a prior history of nonhemorrhagic stroke.9 The efficacy and safety of ticagrelor in patients with prior tran- sient ischemic attack or stroke were not reported in PLATO,9 and the balance of risks and benefits of ticagrelor in this patient population remains unclear.


Patients with a history of bleeding were excluded in PLATO, and 4% of patients had a prior history of nonhemorrhagic stroke.9 The efficacy and safety of ticagrelor in patients with prior tran- sient ischemic attack or stroke were not reported in PLATO,9 and the balance of risks and benefits of ticagrelor in this patient population remains unclear. A separate analysis was performed for the 5216 patients in PLATO admitted with ACS and prespecified as planned for noninvasive management (constituting 28% of the overall PLATO study population).10 Compared with clopidogrel, ticagrelor was associated with a lower incidence of the 0.73 to 1.00; P 0.04) and overall mortality without increas- ing major bleeding. These results indicate the benefits of intensified P2Y12 inhibition with ticagrelor applied broadly for patients regardless of the intended or actualized manage- The benefits of ticagrelor in PLATO appeared to be attenuated in patients weighing less than the median weight for their sex and those not taking lipid-lowering therapies at randomization.9 There was a significant interaction between treatment and geographic region, with patients enrolled in North America having no statistically significant differences between ticagrelor and clopidogrel with respect to the pri- mary efficacy endpoint.9 Extensive additional analyses were conducted to explore potential explanations for this interac- tion between treatment effect in PLATO and geographic region and whether this could be explained by specific patient characteristics or concomitant therapies.11 Mahaffey and colleagues11 noted that a significantly higher proportion of patients in the United States received a median aspirin dose of 300 mg daily compared with the rest of the world (53.6% versus 1.7%). Indeed, of all 37 baseline and postrandomiza- tion variables explored, only aspirin maintenance dose ap- peared to explain a substantial fraction of the regional interaction.


Indeed, of all 37 baseline and postrandomiza- tion variables explored, only aspirin maintenance dose ap- peared to explain a substantial fraction of the regional interaction. Of note, subgroup analysis consistently showed the same aspirin-dose effect outside the United States. With- out being able to fully rule out the play of chance or other factors related to clinical care in North America as explana- tions for the regional interaction, PLATO concluded that a low aspirin maintenance dose ( 100 mg daily) is likely to be associated with the most favorable outcomes when using the potent P2Y12 inhibitor ticagrelor in patients with ACS.11 Because of its reversible inhibition of the P2Y12 receptor, ticagrelor is associated with more rapid functional recovery of circulating platelets and, consequently, a faster offset of effect than clopidogrel. Although this may represent a poten- tial advantage for patients with ACS undergoing early CABG, it may theoretically pose a problem for noncompliant patients (especially given its twice-daily dosing regimen). The FDA approved ticagrelor on July 20, 2011.12 The FDA also issued a Boxed Warning indicating that aspirin daily maintenance doses of 100 mg decrease the effec- tiveness of ticagrelor, cautioned against its use in patients with active bleeding or a history of intracranial hemor- rhage, and advocated a Risk Evaluation and Mitigation Strategy, a plan to help ensure that the benefits of ticagrelor outweigh its risks. As part of that plan, the manufacturer is mandated to conduct educational outreach programs to alert physicians about the risk of using higher doses of aspirin.


As part of that plan, the manufacturer is mandated to conduct educational outreach programs to alert physicians about the risk of using higher doses of aspirin. Dual antiplatelet therapy with aspirin and either clopi- dogrel or prasugrel has increased the risk of intracranial hemorrhage in several clinical trials and patient populations (especially in those with prior stroke).7,13a,13b,13c In PLATO, the number of patients with prior stroke was small, limiting the power to detect treatment differences in intracranial bleeding in this subgroup.13d Patients with prior stroke or TIA have been excluded from PEGASUS (Prevention of Cardio- vascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of an ongoing trial of ticagrelor versus placebo in addition to aspirin in patients with stable coronary artery disease. Until further data become available, it seems prudent to weigh the possible increased risk of intracranial bleeding when considering the addition of ticagrelor to aspirin in patients with prior stroke or TIA.13f 3.2.3.1.2. Choice of P2Y12 Receptor Inhibitors for PCI in UA/NSTEMI. The writing group cautions that data on the use of prasugrel and ticagrelor come solely from the TRITON TIMI 38 and PLATO trials, respectively, and their use in clinical practice should carefully follow how they were tested in these studies.7,9 Prasugrel was administered only after a decision to proceed to PCI was made, whereas ticagrelor was studied in all-comer patients with UA/NSTEMI, including invasively and medically managed patients. The writing group does not recommend that prasugrel be administered routinely to patients with UA/NSTEMI before angiography, Jneid et al 2012 UA/NSTEMI Focused Update 881 such as in an emergency department, or used in patients with UA/NSTEMI who have not undergone PCI.


The writing group does not recommend that prasugrel be administered routinely to patients with UA/NSTEMI before angiography, Jneid et al 2012 UA/NSTEMI Focused Update 881 such as in an emergency department, or used in patients with UA/NSTEMI who have not undergone PCI. The FDA pack- age label suggests that it is reasonable to consider selective use of prasugrel before catheterization in subgroups of patients for whom a decision to proceed to angiography and PCI has already been established for any reason.8 The writing group acknowledges this flexibility, but it is not its intention to make more specific recommendations about which sub- groups of patients might benefit from prasugrel or ticagrelor instead of clopidogrel. The writing group does wish to caution clinicians about the potential increased bleeding risks associated with prasugrel and ticagrelor compared with clopi- dogrel in specific settings and especially among the sub- groups identified in the package insert and clinical trials.7 9,12 This guideline explicitly does not endorse one of the P2Y12 receptor inhibitors over the other. There were several reasons for this decision. Although the composite efficacy endpoint in TRITON TIMI 38 favored prasugrel, driven predominantly by a difference in nonfatal MIs (mostly asymptomatic), with deaths and nonfatal strokes being similar, bleeding was increased in the prasugrel group.7 On the other hand, the composite efficacy endpoint in PLATO favoring ticagrelor over clopidogrel was driven by differences in both vascular death and nonfatal MIs, with stroke rates being similar. Ticagre- lor was also associated with a notable reduction in all-cause mortality in PLATO.


Ticagre- lor was also associated with a notable reduction in all-cause mortality in PLATO. Compared with clopidogrel, ticagrelor was associated with a higher rate of non CABG-related major bleeding and slightly more frequent discontinuation of the study drug due to adverse events.9 On the other hand, prasugrel was associated with a significant increase in the rate of TIMI major hemorrhage, TIMI major and non-CABG bleeding, as well as higher fatal and life-threatening bleeding. There was a signifi- cant interaction between the treatment effect in PLATO and the geographic region, with lack of benefit in the United States for ticagrelor versus clopidogrel (with the explanation depending on a post hoc analysis of aspirin maintenance dose, as noted in the preceding text)11 (see Online Data Supplement). It must be recognized, however, that the 2 newer P2Y12 receptor inhibitors were studied in different patient popula- tions and that there is no head-to-head comparative trial of these agents. Also, the loading dose of clopidogrel in TRITON TIMI 38 was lower than is currently recommended in this guideline.7 Furthermore, some emerging studies sug- gest there may be some patients who are resistant to clopi- dogrel, but there is little information about the use of strategies to select patients who might do better with newer P2Y12 receptor inhibitors. Considerations of efficacy in the prevention of thrombosis and risk of an adverse effect related to bleeding and experience with a given medication may best guide decisions about the choice of P2Y12 receptor inhibitor for individual patients14 (Appendix 4). 3.2.3.1.2.1. Timing of Discontinuation of P2Y12 Receptor Inhibitor Therapy for Surgical Procedures.


Timing of Discontinuation of P2Y12 Receptor Inhibitor Therapy for Surgical Procedures. The writing group weighed the current data on the use of P2Y12 receptor inhibitor therapy in patients who remain hospitalized after UA/NSTEMI and are candidates for CABG and retained the 2007 recommendation4 of empirical discontinuation of clopi- dogrel therapy for at least 5 days13 and advocated a period of at least 7 days in patients receiving prasugrel and a period of at least 5 days in patients receiving ticagrelor for their respective discontinuation before planned CABG.8,12 Ulti- mately, the patient s clinical status will determine the risk- to-benefit ratio of CABG compared with awaiting restoration of platelet function. It is the opinion of the writing group that physicians and patients should be cautioned against early discontinuation of P2Y12 receptor inhibitors for elective noncardiac procedures. Given the increased hazard of recurrent cardiovascular events from premature discontinuation of P2Y12 inhibitors and the increased bleeding risk in patients undergoing procedures on therapy (eg, colonoscopy with biopsy, dental procedures), it is advisable to consult a cardiologist and preferably defer elective noncardiac procedures until the patient finishes the appropriate course of P2Y12 receptor inhibition therapy, especially in UA/NSTEMI patients who received 12 months of treatment with dual antiplatelet therapy after deployment of a drug-eluting stent (DES).15 3.2.3.1.3. Interindividual Variability in Responsiveness to Clopidogrel.