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KEY WORDS: AHA Scientific Statements antiplatelet therapy focused update glycoprotein IIb/IIIa inhibitors myocardial infarction non ST elevation percutaneous coronary intervention thienopyridines P2Y12 receptor inhibitor unstable angina Appendix 1. Author Relationships With Industry and Other Entities (Relevant) 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) Committee Member Employment Consultant Speaker s Bureau Ownership/ Partnership/ Principal Personal Research Institutional, Organizational, or Other Financial Benefit Expert Witness Voting Recusals by Section* Hani Jneid, Chair Baylor College of Medicine The Michael E. DeBakey VA Medical Center Assistant Professor of Medicine None None None None None None None Jeffrey L. Anderson, Vice Chair Intermountain Medical Center Associate Chief of Cardiology AstraZeneca None None None None None 3.2.1 R. Scott Wright, Vice Chair Mayo Clinic Professor of Medicine and Consultant in Cardiology Hoffman LaRoche None None None None None None Cynthia D. Adams Community Health Network/The Indiana Heart Hospital Supervisor None None None None None None None Charles R. Bridges University of Pennsylvania Medical Center Chief, Cardiothoracic Surgery, Pennsylvania Hospital; Associate Professor of Surgery AstraZeneca Bayer Pharmaceuticals None None None None 3.2.1 Donald E. Casey, Jr Atlantic Health Vice President of Quality and Chief Medical Officer None None None None None None None Steven M. Ettinger Pennsylvania State University Penn State Heart and Vascular Institute None None None None None None None Francis M. Fesmire Director, Heart-Stroke Center, Assistant Professor None None None None None None None Theodore G. Ganiats University of California San Diego Professor and Interim Chair None None None None None None None A. Michael Lincoff Cleveland Clinic Foundation Cleveland Clinic Lerner College of Medicine Professor of Medicine AstraZeneca Merck None None AstraZeneca Bristol-Myers Squibb Eli Lilly Novartis Pfizer Roche Schering Plough Takeda None None 3.2.1 Eric D. Peterson Duke Clinical Research Institute Duke University Medical Center Professor of Medicine, Director, Cardiovascular Outcomes None None None Eli Lilly Johnson & Johnson None None 3.2.1 George J. Philippides Boston University School of Medicine Associate Professor of Medicine; Associate Chair for Clinical Affairs and Chief Quality Officer, Cardiovascular Section None None None None None None None Pierre Theroux Montreal Heart Institute Professor of Medicine, University of Montreal AstraZeneca Bristol-Myers Squibb Eli Lilly Sanofi Aventis AstraZeneca Boehringer Ingelheim Bristol-Myers Squibb Sanofi Aventis None None Merck None 3.2.1 Nanette K. Wenger Emory University School of Medicine Professor of Medicine (Cardiology) Abbott AstraZeneca Gilead Sciences (formerly CV Therapeutics) Merck Pfizer None None Abbott Eli Lilly Gilead Sciences (formerly CV Therapeutics) Merck Pfizer None None 3.2.1 (Continued) Jneid et al 2012 UA/NSTEMI Focused Update 901 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* James Patrick Zidar Rex Heart and Vascular Specialists Clinical Professor of Medicine, University of North Carolina None None None None None None None This table represents the relationships of committee members with industry and other entities that were determined to be relevant to this document. These relationships were reviewed and updated in conjunction with all meetings and/or conference calls of the writing 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 $10 000 of the fair market value of the business entity; or if funds received by the person from the business entity exceed 5% of the person s gross income for the previous year. 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 ACCF/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.


According to the ACCF/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. Appendix 2.


Section numbers pertain to those in the full-text guideline. Significant relationship. Appendix 2. Reviewer Relationships With Industry and Other Entities (Relevant) 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) Peer Reviewer Representation Employment Consultant Speaker s Bureau Ownership/ Partnership/ Principal Personal Research Institutional, Organizational, or Other Financial Benefit Expert Witness John E. Brush Official Reviewer ACCF Board of Trustees Cardiology Consultants Healthcare Incentives Improvement Institute Board Member* United Healthcare Scientific Advisory Board None None None None None David P. Faxon Official Reviewer AHA Brigham and Women s Hospital Professor of Medicine Boston Scientific Sanofi-aventis None RIVA Medical None Circulation: Cardiovascular Interventions Editor None Robert A. Harrington Official Reviewer AHA Duke Clinical Research Institute Professor of Medicine; Duke University Medical Center Director Bristol-Myers Squibb Genentech* Gilead Sciences Merck Mitsubishi-Tanabe Momenta Pharmaceutical Pfizer* Regado Sanofi-aventis WebMD None None AstraZeneca Bristol-Myers Squibb GlaxoSmithKline Merck Portola Sanofi-aventis The Medicines Company None None Judith S. Hochman Official Reviewer ACCF/AHA Task Force on Practice Guidelines New York University School of Medicine Harold Snyder Family Professor of Cardiology; NYU-HHC Clinical and Translational Science Institute Co-Director; Leon Charney Division of Cardiology Clinical Chief; Cardiovascular Clinical Research Center Director Bristol-Myers Squibb Eli Lilly GlaxoSmithKline Sanofi-aventis None None Bayer Healthcare AG DSMB Johnson & Johnson DSMB Merck, TIMI 50 DSMB Schering-Plough, None None Rodney H. Zimmermann Official Reviewer ACCF Board of Governors Regina General Hospital Director of the Cardiac Catheterization Laboratory AstraZeneca Boehringer Ingelheim Hoffmann-La Roche AstraZeneca Boehringer Ingelheim Merck-Frost None Eli Lilly Schering-Plough None None Joseph C. Cleveland Organizational Reviewer STS University of Colorado Anschutz Medical Center Associate Professor of Surgery; Surgical Director, Cardiac Transplantation and MCS Baxter Biosurgery Sorin None None HeartWare Corporation Thoratec Corporation None None Joseph A. DeGregorio Organizational Reviewer SCAI Englewood Hospital Chief, Invasive Cardiology None None None None None None Deborah B. Diercks Organizational Reviewer ACEP UC Davis Medical Center None None None Beckman Coulter* AHRQ, QUADRICS Trial DSMB* Emergencies in Medicine* Society of Academic Emergency Medicine* Society of Chest Pain Centers and Providers* None Benjamin Hatten Organizational Reviewer ACEP Denver Health Medical Center None None None None None None Loren F. Hiratzka Organizational Reviewer STS Cardiac, Vascular and Thoracic Surgeons Medical Director, Cardiac Surgery None None None None None None Nancy M. Albert Content Reviewer ACCF/AHA Task Force on Practice Guidelines Cleveland Clinic, Kaufman Center for Heart Failure, Nursing Research, Innovation and CNS Senior Director Merck* None None None None None (Continued) Jneid et al 2012 UA/NSTEMI Focused Update 903 Appendix 2.


Continued Peer Reviewer Representation Employment Consultant Speaker s Bureau Ownership/ Partnership/ Principal Personal Research Institutional, Organizational, or Other Financial Benefit Expert Witness Ezra Amsterdam Content Reviewer UC Davis Medical Center, Division of Cardiology None None None None None None Elliott M. Antman Content Reviewer Harvard Medical School Associate Dean for Clinical/Translational Research None None None AstraZeneca Bayer Healthcare Biosite Bristol-Myers Squibb CV Therapeutics Daiichi Sankyo Eli Lilly GlaxoSmithKline Integrated Therapeutics Merck Novartis Nuvelo Ortho-Clinical Diagnostics Pharmaceutical Research Institute Pfizer Roche Diagnostics Sanofi-aventis Sanofi-Synthelabo Recherche Schering-Plough Research Institute None None James C. Blankenship Content Reviewer Geisinger Medical Center Staff Physician; Director, Cardiac Cath Lab None None None Abiomed* AstraZeneca* Boston Scientific* Novartis* Schering-Plough* The Medicines Company* Volcano Corp* None None James A. Burke Content Reviewer ACCF Interventional Scientific Council Lehigh Valley Heart Specialists None None None None None None William A. Chavey Content Reviewer University of Michigan Department of Family Medicine Clinical Assistant Professor None None None None None None John M. Field Content Reviewer Pennsylvania State University, College of Medicine Professor of Medicine and Surgery None None None None None None Christopher B. Granger Content Reviewer Duke Clinical Research Institute Associate Professor of Medicine; Cardiac Care Unit Director AstraZeneca Boehringer Ingelheim Bristol-Myers Squibb GlaxoSmithKline Hoffmann-La Roche Novartis Otsuka Pharmaceuticals Pfizer Sanofi-aventis The Medicines Company None None Astellas AstraZeneca Boehringer Ingelheim Bristol-Myers Squibb GlaxoSmithKline Merck Sanofi-aventis The Medicines Company None None Mary Hand Content Reviewer Agency for Healthcare Research and Quality Health Science Administrator None None None None None None Allan S. Jaffe Content Reviewer Mayo Clinic Cardiovascular Division Professor of Medicine Alere Critical Diagnostics Radiometer None None None None None Sanjay Kaul Content Reviewer Cedars-Sinai Medical Center Director, Cardiology Fellowship Training Program Hoffmann-La Roche None None Hoffmann-La Roche None None (Continued) Appendix 2.


Continued Peer Reviewer Representation Employment Consultant Speaker s Bureau Ownership/ Partnership/ Principal Personal Research Institutional, Organizational, or Other Financial Benefit Expert Witness Lloyd W. Klein Content Reviewer ACCF Interventional Scientific Council Professor of Medicine Rush University Medical Center None None None None None None Harlan M. Krumholz Content Reviewer Yale University School of Medicine Harold H. Hines, Jr, Professor of Medicine and Epidemiology and Public Health United Healthcare (Scientific Advisory Board) None None None None None Frederick G. Kushner Content Reviewer ACCF/AHA Task Force on Practice Guidelines Tulane University Medical Center Clinical Professor; Heart Clinic of Louisiana Medical Director None None None None None None Shamir R. Mehta Content Reviewer Hamilton Health Sciences, General Division HGH McMaster Clinic Director, Coronary Care Unit Astellas AstraZeneca Bristol-Myers Squibb Eli Lilly Sanofi-aventis None None Bristol-Myers Squibb Sanofi-aventis None None Douglass A. Morrison Content Reviewer Yakima Heart Center Professor of Medicine, Radiology; Cardiac Cath Lab Director None None None None None None L. Kristin Newby Content Reviewer Duke University Medical Center Associate Professor of Clinical Medicine AstraZeneca Daiichi Sankyo GlaxoSmithKline Johnson & Johnson Novartis None None Amylin Bristol-Myers Squibb Eli Lilly GlaxoSmithKline Regado Merck None None E. Magnus Ohman Content Reviewer ACCF/AHA Task Force on Practice Guidelines Duke University Medical Center, Department of Medicine, Division of Cardiovascular Medicine Professor of Medicine; Subspecialty Signature Care Director Program for Advanced Coronary Disease Director AstraZeneca Bristol-Myers Squibb Boehringer Ingelheim Gilead Sciences LipoScience Merck Pozen Hoffmann-La Roche Sanofi-aventis The Medicines Company WebMD Boehringer Ingelheim Gilead Sciences None Daiichi Sankyo Eli Lilly None None William A. Tansey III Content Reviewer Summit Medical Group None None None None None None 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 $10 000 of the fair market value of the business entity; or if funds received by the person from the business entity exceed 5% of the person s gross income for the previous year. A relationship is considered to be modest if it is less than significant under the preceding definition. Relationships that exist with no financial benefit are also included for the purpose of transparency. Relationships in this table are modest unless otherwise noted. Names are listed in alphabetical order within each category of review. According to the ACCF/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. *No financial benefit. Significant relationship. ACCF indicates American College of Cardiology Foundation; ACEP, American College of Emergency Physicians; AHA, American Heart Association; AHRQ, Agency for Healthcare Quality and Research; DSMB, data safety monitoring board; SCAI, Society for Cardiovascular Interventions and Angiography; STS, Society of Thoracic Surgeons; and TIMI, Thrombolysis In Myocardial Infarction. Jneid et al 2012 UA/NSTEMI Focused Update 905 Appendix 3.


Jneid et al 2012 UA/NSTEMI Focused Update 905 Appendix 3. Dosing Table for Antiplatelet and Anticoagulant Therapy Discussed in This Focused Update to Support PCI in UA/NSTEMI Drug* During PCI Comments All Patients to Receive ASA Patient Received Initial Medical Treatment (With a P2Y12 Receptor Inhibitor) Patient Did Not Receive Initial Medical Treatment (With a P2Y12 Receptor Inhibitor) Glycoprotein IIb/IIIa Receptor Antagonists Abciximab Of uncertain benefit LD of 0.25 mg/kg IV bolus MD of 0.125 mcg/kg per min (maximum 10 mcg/min) (Class I, LOE: A) Continue for up to 12 h at the discretion of the physician. Eptifibatide Of uncertain benefit LD of 180 mcg/kg IV bolus followed 10 min later by second IV bolus of 180 mcg/kg MD of 2.0 mcg/kg per min, started after first bolus; reduce infusion by 50% in patients with estimated creatinine clearance 50 mL/min (Class I, LOE: A) Double bolus is recommended to support PCI in STEMI as the recommended adult dosage of eptifibatide in patients with normal renal function. Infusion should be continued for 12 to 18 h at the discretion of the physician. Tirofiban Of uncertain benefit LD of 25 mcg/kg IV bolus MD of IV infusion of 0.15 mcg/kg per min; reduce rate of infusion by 50% in patients with estimated creatinine clearance 30 mL/min (Class I, LOE: B) Increased dosing over previous recommendation. Continue for up to 18 h at the discretion of the physician.


Continue for up to 18 h at the discretion of the physician. A lower-dose regimen for tirofiban is FDA approved and has been shown to be effective when used to treat UA/NSTEMI patients who are started on medical therapy and when there is a substantial delay to angiography/ PCI (eg, 48 h): LD of 50 mcg/mL administered at an initial rate of 0.4 mcg/kg per min for 30 min MD of a continuous infusion of 0.1 mcg/kg per min. Continue the infusion through angiography and for 12 to 24 h after angioplasty or atherectomy. P2Y12 Receptor Inhibitors Clopidogrel If 600 mg given orally, then no additional treatment A second LD of 300 mg may be given orally to supplement a prior LD of 300 mg (Class I, LOE: C) LD of 300 600 mg orally (Class I, LOE: A) MD of 75 mg orally per d (Class I, LOE: A) MD of 150 mg orally per d for initial 6 d may be considered (Class IIb, LOE: B) Optimum LD requires clinical consideration. Dose for patients 75 y of age has not been established. There is a recommended duration of therapy for all post-PCI patients receiving a BMS or DES. Caution should be exercised for use with a PPI. Period of withdrawal before surgery should be at least 5 d. (For full explanations, see footnote.) Prasugrel No data are available to guide decision making LD of 60 mg orally (Class I, LOE: B) MD of 10 mg orally per d (Class I, LOE: B) There are no data for treatment with prasugrel before PCI. MD of 5 mg orally per d in special circumstances. Special dosing for patients 60 kg or 75 y of age. There is a recommended duration of therapy for all post-PCI patients receiving a DES.


There is a recommended duration of therapy for all post-PCI patients receiving a DES. Contraindicated for use in patients with prior history of TIA or stroke. Period of withdrawal before surgery should be at least 7 d. (For full explanations, see footnote.) Ticagrelor Patients who are already receiving clopidogrel should receive a loading dose of ticagrelor LD of 180 mg orally (Class I, LOE: B) MD of 90 mg orally twice daily (Class I, LOE: B) The recommended maintenance dose of ASA to be used with ticagrelor is 81 mg daily. Ticagrelor s benefits were observed irrespective of prior therapy with clopidogrel (47% of patients in PLATO received clopidogrel at the time of randomization). Period of withdrawal before surgery should be at least 5 d. Issues of patient compliance may be especially important with twice-daily dosing regimen. Ticagrelor increases the risk of fatal ICH compared with clopidogrel and should be avoided in those with a prior history of ICH. 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. (Continued) Appendix 3. Continued Drug* During PCI Comments All Patients to Receive ASA Patient Received Initial Medical Treatment (With a P2Y12 Receptor Inhibitor) Patient Did Not Receive Initial Medical Treatment (With a P2Y12 Receptor Inhibitor) Parenteral Anticoagulants Bivalirudin For patients who have received UFH, wait 30 min, then give 0.75 mg/kg bolus, then 1.75 mg/kg per h infusion (Class I, LOE: B) 0.75 mg/kg bolus, 1.75 mg/kg per h infusion Bivalirudin may be used to support PCI and UA/NSTEMI with or without previously administered UFH with the addition of 600 mg of clopidogrel. In UA/NSTEMI patients undergoing PCI who are at high risk of bleeding, bivalirudin anticoagulation is reasonable.


In UA/NSTEMI patients undergoing PCI who are at high risk of bleeding, bivalirudin anticoagulation is reasonable. UFH IV GP IIb/IIIa planned: target ACT 200 250 s IV GP IIb/IIIa planned: 50 70 units/kg bolus to achieve an ACT of 200 250 s No IV GP IIb/IIIa planned: target ACT 250 300 s for HemoTec, 300 350 s for Hemochron (Class I, LOE: B) No IV GP IIb/IIIa planned: 70 100 units/kg bolus to achieve target ACT of 250 300 s for HemoTec, 300 350 s for Hemochron (Class I, LOE: B) *This list is in alphabetical order and is not meant to indicate a particular therapy preference. This drug table does not make recommendations for combinations of listed drugs. It is only meant to indicate an approved or recommended dosage if a drug is chosen for a given situation. The optimum LD of clopidogrel has not been established. Randomized trials establishing its efficacy and providing data on bleeding risks used an LD of 300 mg orally followed by a daily oral dose of 75 mg. Higher oral LDs such as 600 mg or more than 900 mg of clopidogrel more rapidly inhibit platelet aggregation and achieve a higher absolute level of inhibition of platelet aggregation, but the additive clinical efficacy and safety of higher oral LD have not been rigorously established. For post-PCI patients receiving a DES, a daily MD should be given for at least 12 mo unless the risk of bleeding outweighs the anticipated net benefit afforded by a P2Y12 receptor inhibitor. For post-PCI patients receiving a BMS, an MD should be given for up to 12 mo (unless the risk of bleeding outweighs the anticipated net benefit afforded by a P2Y12 receptor inhibitor; then it should be given for a minimum of 2 wk).


For post-PCI patients receiving a BMS, an MD should be given for up to 12 mo (unless the risk of bleeding outweighs the anticipated net benefit afforded by a P2Y12 receptor inhibitor; then it should be given for a minimum of 2 wk). The necessity for giving an LD of clopidogrel before PCI is driven by the pharmacokinetics of clopidogrel, for which a period of several hours is required to achieve desired levels of platelet inhibition. Patients who have a reduced-function CYP2C19 allele have significantly lower levels of the active metabolite of clopidogrel, diminished platelet inhibition, and a higher rate of MACE, including stent thrombosis. In UA/NSTEMI patients taking clopidogrel for whom CABG is planned and can be delayed, it is reasonable to discontinue the clopidogrel to allow for dissipation of the antiplatelet effect unless the urgency for revascularization and/or the net benefit of clopidogrel outweigh the potential risks of excess bleeding. The period of withdrawal should be at least 5 d in patients receiving clopidogrel. Patients weighing 60 kg have an increased exposure to the active metabolite of prasugrel and an increased risk of bleeding on a 10-mg once-daily MD. Consider lowering the MD to 5 mg in patients who weigh 60 kg. The effectiveness and safety of the 5-mg dose have not been studied prospectively. For post-PCI patients receiving DES, a daily MD should be given for at least 12 mo unless the risk of bleeding outweighs the anticipated net benefit afforded by a P2Y12 receptor inhibitor. Do not use prasugrel in patients with active pathological bleeding or a history of TIA or stroke.


Do not use prasugrel in patients with active pathological bleeding or a history of TIA or stroke. In patients age 75 y, prasugrel is generally not recommended because of the increased risk of fatal and intracranial bleeding and uncertain benefit, except in high-risk situations (patients with diabetes or a history of prior myocardial infarction), for which its effect appears to be greater and its use may be considered. Do not start prasugrel in patients likely to undergo urgent CABG. When possible, discontinue prasugrel at least 7 d before any surgery. Additional risk factors for bleeding include body weight 60 kg, propensity to bleed, and concomitant use of medications that increase the risk of bleeding (eg, warfarin, heparin, fibrinolytic therapy, or long-term use of nonsteroidal anti-inflammatory drugs). ACT indicates activated clotting time; ASA, aspirin; BMS, bare-metal stent; CABG, coronary artery bypass graft; DES, drug-eluting stent; GP, glycoprotein; FDA, Food and Drug Administration; ICH, intracranial hemorrhage; IV, intravenous; LD, loading dose; LOE, level of evidence; MACE, major adverse cardiac events; MD, maintenance dose; PCI, percutaneous coronary intervention; PLATO, PLATelet inhibition and patient Outcomes trial; PPI, proton pump inhibitor; STEMI, ST-elevation myocardial infarction; TIA, transient ischemic attack; UA/NSTEMI, unstable angina/non ST-elevation myocardial infarction; and UFH, unfractionated heparin. Modified from Wright et al.6 Jneid et al 2012 UA/NSTEMI Focused Update 907 Appendix 4. Comparisons Among Orally Effective P2Y12 Inhibitors Clopidogrel Prasugrel Ticagrelor Pharmacology Prodrug requires conversion to active metabolite that irreversibly blocks P2Y12 receptor Prodrug requires conversion to active metabolite that irreversibly blocks P2Y12 receptor.


Comparisons Among Orally Effective P2Y12 Inhibitors Clopidogrel Prasugrel Ticagrelor Pharmacology Prodrug requires conversion to active metabolite that irreversibly blocks P2Y12 receptor Prodrug requires conversion to active metabolite that irreversibly blocks P2Y12 receptor. Conversion to active metabolite occurs more rapidly and to a greater degree than with clopidogrel Parent compound is active and no biotransformation is required for reversible inhibition of P2Y12 receptor Effect on platelet aggregation There is a delay of several hours before maximal antiplatelet effect is seen Onset of antiplatelet effect is faster and extent of inhibition of aggregation is greater than with clopidogrel (a significant antiplatelet effect was observed within 30 min of loading) Onset of antiplatelet effect is faster and extent of inhibition of aggregation is greater than with clopidogrel (a significant antiplatelet effect was observed within 30 min of loading) Management strategy Conservative Invasive Conservative Invasive Conservative Invasive Loading dose 300 mg 600 mg Generally not recommended for precatheterization use in UA/NSTEMI 60 mg at time of PCI 180 mg 180 mg Timing Initiate on presentation Initiate as soon as possible before or at the time of PCI Initiate as soon as coronary anatomy is known and decision is made to proceed with PCI Initiate on presentation Initiate as soon as possible before or at the time of PCI Maintenance dose 75 mg Optimal approach to dosing in individual patients based on genotype and individual antiplatelet effects not rigorously established Optimal individual dose not rigorously established (see comment to left). (150 mg for first 6 d is an alternative) Consider reduction to 5 mg in patients weighing 60 kg. The efficacy (or benefit) of prasugrel in those age 75 y is uncertain. Contraindicated in patients with a history of stroke or TIA.


Contraindicated in patients with a history of stroke or TIA. 90 mg twice daily (The recommended maintenance dose of ASA to be used with ticagrelor is 81 mg daily) 90 mg twice daily (The recommended maintenance dose of ASA to be used with ticagrelor is 81 mg daily) Duration Ideally up to 12 mo At least 12 mo for patients receiving DES Up to 12 mo for patients receiving BMS At least 12 mo for patients receiving DES Up to 12 mo for patients receiving BMS Ideally up to 12 mo At least 12 mo for patients receiving DES Up to 12 mo for patients receiving BMS Additional considerations Variability of response Greater than with prasugrel or ticagrelor. Factors impacting on response in some patients may include genetic predisposition to convert parent compound to active metabolite and drug interactions (eg, PPIs) Less than with clopidogrel. Impact of genotype and concomitant medications appears less than with clopidogrel. Less compared with clopidogrel. Impact of genotype and concomitant medications appears less than with clopidogrel. Platelet function testing Clinical utility not rigorously established. May be useful in selected patients with ischemic/thrombotic events while compliant with a clopidogrel regimen Clinical utility not rigorously established but less likely to be necessary given lesser degree of variation in response Clinical utility not rigorously established but less likely to be necessary given lesser degree of variation in response Genotyping Identifies patients with a diminished (CYP2C19 *2, *3 alleles) or enhanced (CYP2C17 allele) to form active metabolite. Role of genotyping in clinical management not rigorously established.


May be useful in selected patients with ischemic/thrombotic events while compliant with a clopidogrel regimen Clinical utility not rigorously established but less likely to be necessary given lesser degree of variation in response Clinical utility not rigorously established but less likely to be necessary given lesser degree of variation in response Genotyping Identifies patients with a diminished (CYP2C19 *2, *3 alleles) or enhanced (CYP2C17 allele) to form active metabolite. Role of genotyping in clinical management not rigorously established. Clinical utility not rigorously established but less likely to be necessary given lesser degree of variation in response Clinical utility not rigorously established but less likely to be necessary given lesser degree of variation in response Risk of bleeding Standard dosing with clopidogrel is associated with less bleeding than with prasugrel and ticagrelor. Higher doses of clopidogrel are associated with greater risk of bleeding than standard dose clopidogrel. Risk of spontaneous, instrumented, and fatal bleeds higher with prasugrel compared with standard dose clopidogrel Risk of non-CABG bleeds higher with ticagrelor compared with standard dose clopidogrel Transition to surgery Wait 5 d after last dose Wait 7 d after last dose Wait 5 d after last dose ASA indicates aspirin; BMS, bare-metal stent; DES, drug-eluting stent; CABG, coronary artery bypass graft; PCI, percutaneous coronary intervention; PPI, proton pump inhibitor; TIA, transient ischemic attack; and UA/NSTEMI, unstable angina/non ST-elevation myocardial infarction. Appendix 5. Flowchart for Class I and Class IIa Recommendations for Initial Management of UA/NSTEMI *A loading dose followed by a daily maintenance dose of either clopidogrel (LOE: B), prasugrel (in PCI-treated patients), or ticagrelor (LOE: C) should be administered to UA/NSTEMI patients who are unable to take ASA because of hypersensitivity or major GI intolerance.


Flowchart for Class I and Class IIa Recommendations for Initial Management of UA/NSTEMI *A loading dose followed by a daily maintenance dose of either clopidogrel (LOE: B), prasugrel (in PCI-treated patients), or ticagrelor (LOE: C) should be administered to UA/NSTEMI patients who are unable to take ASA because of hypersensitivity or major GI intolerance. If fondaparinux is used during PCI (Class I, LOE: B), it must be coadministered with another anticoagulant with Factor IIa activity (ie, UFH). Timing of invasive strategy generally is assumed to be 4 to 48 h. If immediate angiography is selected, see STEMI guidelines. Precatheterization triple antiplatelet therapy (ASA, clopidogrel or ticagrelor, GP inhibitors) is a Class IIb, LOE: B recommendation for selected high-risk patients. Also, note that there are no data for therapy with 2 concurrent P2Y12 receptor inhibitors, and this is not recommended in the case of aspirin allergy. ASA indicates aspirin; CABG, coronary artery bypass graft; D/C, discontinue; GI, gastrointestinal; GP, glycoprotein; IV, intravenous; LOE, level of evidence; PCI, percutaneous coronary intervention; STEMI, ST-elevation myocardial infarction; UA/NSTEMI, unstable angina/non ST-elevation myocardial infarction; and UFH, unfractionated heparin. Modified from Wright et al.6 Jneid et al 2012 UA/NSTEMI Focused Update 909 Appendix 6.


Modified from Wright et al.6 Jneid et al 2012 UA/NSTEMI Focused Update 909 Appendix 6. Selection of Initial Treatment Strategy: Invasive Versus Conservative Strategy Generally Preferred Strategy Patient Characteristics Invasive Recurrent angina or ischemia at rest or with low-level activities despite intensive medical therapy Elevated cardiac biomarkers (TnT or TnI) New or presumably new ST-segment depression Signs or symptoms of HF or new or worsening mitral regurgitation High-risk findings from noninvasive testing Hemodynamic instability Sustained ventricular tachycardia PCI within 6 mo Prior CABG High-risk score (eg, TIMI, GRACE) Mild to moderate renal dysfunction Diabetes mellitus Reduced LV function (LVEF 40%) Conservative Low-risk score (eg, TIMI, GRACE) Patient or physician preference in the absence of high-risk features CABG indicates coronary artery bypass graft; GRACE, Global Registry of Acute Coronary Events; HF, heart failure; LV, left ventricular; LVEF, left ventricular ejection fraction; PCI, percutaneous coronary intervention; TIMI, Thrombolysis In Myocardial Infarction; TnI, troponin I; and TnT, troponin T. Reprinted from Anderson et al.4


Purpose The aim of this guideline is to present current and comprehensive recommendations for the diagnosis and treatment of spontaneous intracerebral hemorrhage. Methods A formal literature search of PubMed was performed through the end of August 2013. The writing committee met by teleconference to discuss narrative text and recommendations. Recommendations follow the American Heart Association/American Stroke Association methods of classifying the level of certainty of the treatment effect and the class of evidence. Prerelease review of the draft guideline was performed by 6 expert peer reviewers and by the members of the Stroke Council Scientific Oversight Committee and Stroke Council Leadership Committee. Results Evidence-based guidelines are presented for the care of patients with acute intracerebral hemorrhage. Topics focused on diagnosis, management of coagulopathy and blood pressure, prevention and control of secondary brain injury and intracranial pressure, the role of surgery, outcome prediction, rehabilitation, secondary prevention, and future considerations. Results of new phase 3 trials were incorporated. Conclusions Intracerebral hemorrhage remains a serious condition for which early aggressive care is warranted. These guidelines provide a framework for goal-directed treatment of the patient with intracerebral hemorrhage. Key Words: AHA Scientific Statements blood pressure coagulopathy diagnosis intracerebral hemorrhage intraventricular hemorrhage surgery treatment Guidelines for the Management of Spontaneous Intracerebral Hemorrhage A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association The American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists.


Key Words: AHA Scientific Statements blood pressure coagulopathy diagnosis intracerebral hemorrhage intraventricular hemorrhage surgery treatment Guidelines for the Management of Spontaneous Intracerebral Hemorrhage A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association The American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Endorsed by the American Association of Neurological Surgeons, the Congress of Neurological Surgeons, and the Neurocritical Care Society J. Claude Hemphill III, MD, MAS, FAHA, Chair; Steven M. Greenberg, MD, PhD, Vice-Chair; Craig S. Anderson, MD, PhD; Kyra Becker, MD, FAHA; Bernard R. Bendok, MD, MS, FAHA; Mary Cushman, MD, MSc, FAHA; Gordon L. Fung, MD, MPH, PhD, FAHA; Joshua N. Goldstein, MD, PhD, FAHA; R. Loch Macdonald, MD, PhD, FRCS; Pamela H. Mitchell, RN, PhD, FAHA; Phillip A. Scott, MD, FAHA; Magdy H. Selim, MD, PhD; Daniel Woo, MD, MS; on behalf of the American Heart Association Stroke Council, Council on Cardiovascular and Stroke Nursing, and Council on Clinical Cardiology TheAmerican HeartAssociation makes every effort to avoid any actual or potential 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 writing panel. Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest. This guideline was approved by the American Heart Association Science Advisory and Coordinating Committee on January 28, 2015, and the American Heart Association Executive Committee on February 16, 2015. 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.


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. The American Heart Association requests that this document be cited as follows: Hemphill JC 3rd, Greenberg SM, Anderson CS, Becker K, Bendok BR, Cushman M, Fung GL, Goldstein JN, Macdonald RL, Mitchell PH, Scott PA, Selim MH, Woo D; on behalf of the American Heart Association Stroke Council, Council on Cardiovascular and Stroke Nursing, and Council on Clinical Cardiology. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2015;46:2032 2060. 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. 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. 2015 American Heart Association, Inc. Stroke is available at http://stroke.ahajournals.org DOI: 10.1161/STR.0000000000000069 AHA/ASA Guideline Hemphill et al Management of Spontaneous ICH 2033 Spontaneous, nontraumatic intracerebral hemorrhage (ICH) remains a significant cause of morbidity and mor- tality throughout the world. Although ICH has traditionally lagged behind ischemic stroke and aneurysmal subarach- noid hemorrhage in terms of evidence from clinical trials to guide management, the past decade has seen a dramatic increase in studies of ICH intervention.


Although ICH has traditionally lagged behind ischemic stroke and aneurysmal subarach- noid hemorrhage in terms of evidence from clinical trials to guide management, the past decade has seen a dramatic increase in studies of ICH intervention. Population-based studies show that most patients present with small ICHs that are readily survivable with good medical care.1 This suggests that excellent medical care likely has a potent, direct impact on ICH morbidity and mortality. This guide- line serves several purposes. One is to provide an update to the last American Heart Association/American Stroke Association ICH guideline, published in 2010, incorpo- rating the results of new studies published in the interim.2 Another equally important purpose is to remind clinicians of the importance of their care in determining ICH outcome and to provide an evidence-based framework for that care. To make this review brief and readily useful to practic- ing clinicians, background details of ICH epidemiology are limited, with references provided for readers seeking more Ongoing studies are not discussed substantively because the focus of this guideline is on currently available therapies; however, the increase in clinical studies related to ICH is encouraging, and those interested may go to http:// www.strokecenter.org/trials/ for more information. Also, this 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.


*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. guideline is generally concerned with adults, with issues of hemorrhagic stroke in children and neonates covered in a separate American Heart Association scientific statement on Management of Stroke in Infants and Children. 5 This document serves to update the last ICH guidelines published in 2010,2 and the reader is referred to these guide- lines for additional relevant references not contained here. The development of this update was purposely delayed for 1 year from the intended 3-year review cycle so that results of 2 pivotal phase 3 ICH clinical trials could be incorporated. Differences from recommendations in the 2010 guideline are specified in the current work. The writing group met by phone to determine subcategories to evaluate. These included 15 sections that cov- ered the following: emergency diagnosis and assessment of ICH and its causes; hemostasis and coagulopathy; blood pres- sure (BP) management; inpatient management, including gen- eral monitoring and nursing care, glucose/temperature/seizure management, and other medical complications; procedures, including management of intracranial pressure (ICP), intra- ventricular hemorrhage, and the role of surgical clot removal; outcome prediction; prevention of recurrent ICH; rehabilita- tion; and future considerations. Each subcategory was led by a primary author, with 1 or 2 additional authors making contri- butions. Full PubMed searches were conducted of all English language articles regarding relevant human disease treatment from 2009 through August 2013.


Full PubMed searches were conducted of all English language articles regarding relevant human disease treatment from 2009 through August 2013. Drafts of summaries and rec- ommendations were circulated to the entire writing group for feedback. Several conference calls were held to discuss indi- vidual sections, focusing on controversial issues. Sections were revised and merged by the Chair. The resulting draft was sent to the entire writing group for comment. Comments were incorpo- rated by the Chair andVice-Chair, and the entire committee was asked to approve the final draft. Changes to the document were made by the Chair and Vice-Chair in response to peer review, and the document was again sent to the entire writing group for suggested changes and approval. Recommendations follow the American Heart Association/American Stroke Association's methods of classifying the level of certainty of the treatment effect and the class of evidence (Tables 1 and 2). All Class I recommendations are listed in Table 3. Emergency Diagnosis and Assessment ICH is a medical emergency. Rapid diagnosis and attentive management of patients with ICH is crucial, because early deterioration is common in the first few hours after ICH onset. More than 20% of patients will experience a decrease in the Glasgow Coma Scale (GCS) of 2 or more points between the prehospital emergency medical services (EMS) assessment and the initial evaluation in the emergency department (ED).6 Furthermore, another 15% to 23% of patients demonstrate continued deterioration within the first hours after hospital The risk for early neurological deterioration and the high rate of poor long-term outcomes underscore the need for aggressive early management.


More than 20% of patients will experience a decrease in the Glasgow Coma Scale (GCS) of 2 or more points between the prehospital emergency medical services (EMS) assessment and the initial evaluation in the emergency department (ED).6 Furthermore, another 15% to 23% of patients demonstrate continued deterioration within the first hours after hospital The risk for early neurological deterioration and the high rate of poor long-term outcomes underscore the need for aggressive early management. Prehospital Management Prehospital management for ICH is similar to that for ischemic stroke, as detailed in the recent American Heart Association Guidelines for the Early Management of Patients With Acute The primary objective is to provide airway management if needed, provide cardiovascular support, and transport the patient to the closest facility prepared to care for patients with acute stroke.10 Secondary priorities for EMS pro- viders include obtaining a focused history regarding the tim- ing of symptom onset (or the time the patient was last normal); information about medical history, medication, and drug use; and contact information for family. EMS providers should provide advance notice to the ED of the impending arrival of a potential stroke patient so that critical pathways can be initiated and consulting services alerted. Advance notice by EMS has been demonstrated to significantly shorten time to computed tomography (CT) scanning in the ED.11 Two studies have shown that prehospital CT scanning with an appropri- ately equipped ambulance is feasible and may allow for tri- age to an appropriate hospital and initiation of ICH-specific ED Management Every ED should be prepared to treat patients with ICH or have a plan for rapid transfer to a tertiary care center. The crucial resources necessary to manage patients with ICH include neurology, neuroradiology, neurosurgery, and critical Table 2.