real-world practice files/syllabus... · michael bloch, md is a member of speakers bureaus for...

Making the Case for ACS:

Applying New Data and Guidelines to Real-World Practice

8:00 AM–3:30 PMSaturday, November 15, 2008

New York, NY

Pri-Med Clinical Focus for Cardiologists

New York, NY

November 15, 2008 8:00AM –3:30 PM

Education Sponsor Education Partner Commercial Supporters

This program is supported by educational grants from Daiichi Sankyo Inc. and Eli Lilly and Company, GlaxoSmithKline, and sanofi-aventis U.S.

Pri-Med is an M|C Communications, LLC program 101 Huntington Avenue, Boston, MA 02199 | 877.477.4633 | www.pri-med.com

Dear Clinician: Welcome to Pri-Med Clinical Focus for Cardiologists, continuing education for healthcare providers that’s focused on clinically relevant, practice and patient-care oriented issues from nationally recognized experts. What began as one live program in Boston in 1995 has developed into over 135 meetings around the country that present the latest evidence-based research and guidelines and real-life case studies, delivered by a faculty of expert speakers in an interactive learning environment. This year’s curriculum for the Pri-Med Clinical Focus for Cardiologists is comprised of practice-based topics derived from a comprehensive needs assessment and feedback from you and your colleagues—timely sessions designed to support your patient diagnoses, treatment, and management. We welcome your questions and encourage you to participate in the audience response portion of this activity. After the sessions, be sure to take advantage of our other multi-channel offerings, all of which are designed to complement the learning you’ll take away from this Pri-Med Clinical Focus for Cardiologists. For example, you can go online to Pri-Med.com and interact with thought leaders through our online CME Expert Perspectives. Whether you are a first-time attendee to one of our programs or a seasoned Pri-Med veteran, our goal remains the same: to give you a complete and targeted educational experience, one that lets you make informed decisions with greater confidence and deliver the highest levels of quality care. Thank you for joining us at Pri-Med Clinical Focus for Cardiologists. We look forward to meeting you and hearing your input throughout the program. If you have any questions about Pri-Med, please visit us on the web at www.pri-med.com. You may also contact us and share your feedback via email at [email protected]. Sincerely,

John M. Connolly Chief Executive Officer Pri-Med

Marissa Seligman, PharmD Chief Clinical & Regulatory Affairs Officer & Senior Vice President Pri-Med Institute

http://www.pri-med.com/

mailto:[email protected]

Pri-Med programs are owned and operated by M|C Communications, LLC located in Boston, MA. The clinical education division of M|C Communications, LLC is Pri-Med Institute, which was established in 2001 and is structured to provide accredited continuing education programs.

Pri-Med Institute Identifying the needs of health care professionals and ensuring these needs are met with world-class educational programs is the goal of Pri-Med Institute. Accredited by the ACCME and ACPE and approved as a provider of contact hours by the AANP and ANCC, Pri-Med Institute (PMI) is an integral part of Pri-Med educational programs. From needs assessment to accreditation to partnering with content collaborators, Pri-Med Institute ensures that Pri-Med continuing education programs are high-quality credited learning experiences for participants, faculty speakers, and supporters alike. Pri-Med Institute sponsors conferences as well as other innovative forms of distance education in order to contribute to the continuing professional development of health care providers. The offerings are intended to enhance physicians’ and other health care professionals’ ongoing professional development and influence their clinical practice behaviors for the purpose of improving health outcomes. Pri-Med Institute Disclosure Information Medical Advisory Board Financial Disclosure George Mejicano, MD has nothing to disclose. Victor Diaz, MD has nothing to disclose. Stephen Goldfinger, MD has nothing to disclose. Michael Bloch, MD is a member of speakers bureaus for AstraZeneca Pharmaceuticals LP, Novartis Pharmaceuticals Corporation, Pfizer Inc., and sanofi-aventis US; and receives research support from AstraZeneca Pharmaceuticals LP and Novartis Pharmaceuticals Corporation. He also receives honorarium from Pfizer Inc. and sanofi-aventis U.S.

PMI Clinical Staff, University of Wisconsin School of Medicine and Public Health Expert and Tufts Health Care Institute Peer Reviewer Financial Disclosure As a continuing medical education provider accredited by the ACCME, it is the policy of Pri-Med Institute to require any individual in a position to influence educational content to disclose the existence of any financial interest or other personal relationship with the manufacturer(s) of any commercial product(s). Pri-Med clinical staff and University of Wisconsin School of Medicine and Public Health and Tufts Health Care Institute expert content reviewers have provided financial disclosure. Carolyn Skowronski, PMI Clinical Editor, has disclosed that she owns stock in Merck. All others have no financial disclosure or conflicts of interest to resolve for each of the sessions related to this activity. Conflict of Interest Resolution Statement When individuals in a position to control content have reported financial relationships with one or more commercial interests, as listed above, Pri-Med Institute works with them to resolve such conflicts to ensure that the content presented is free of commercial bias. The content of this presentation was vetted by the following mechanisms and modified as required to meet this standard:

• Content peer review by external topic expert • Content validation by external topic expert and internal Pri-Med Institute clinical editorial staff

© 2008 M/C Communications, LLC. All rights reserved. Pri-Med is a registered trademark and KNOWLEDGE THAT TOUCHES PATIENTS is a trademark of M/C Communications, LLC. All other trademarks are the property of their respective owners.

Zorba Paster, MD is a member of speakers bureaus for Ortho-McNeil, Pfizer Inc., and T Pharmaceuticaleceives research support from Pfizer Inc., T Pharmaceutical Inc., Aventis, and

akeda s Northakeda s North America America Inc., and r

Endo Pharmaceuticals.

L E A R N E R B I L L O F R I G H T S

ri-MmeIns

ed Institute recognizes that you are a life-long learner who has chosen to engage in continuing dical education to identify or fill a gap in knowledge, skill, or performance. As part of Pri-Med titute’s duty to you as a learner, you have the right to expect that your continuing medical education

experience will include: Content that:

Is driven and based on independent survey and analysis of learner needs

Promotes improvements or quality in health care

Is current, valid, reliable, accurate, and evidence-based

Offers balanced presentations that are free of commercial bias for, or against, a product/service

Is vetted through a process that resolves any conflicts of interests of planners and faculty

Is driven and based on learning needs, not commercial interests

Addresses the stated objectives or purpose

Is evaluated for its effectiveness in meeting the identified educational need

A learning environment that:

Is based on adult learning principles that support the use of various modalities

Supports learners’ ability to meet their individual needs

Respects and attends to any special needs of the learners

Respects the diversity of groups of learners

Is free of promotional, commercial, and/or sales activities

Disclosure of:

Relevant financial relationships planners, teachers, and authors have with commercial interests related to the content of the activity

Commercial support (funding or in-kind resources) of the activity

P

Making the Case for ACS: Applying New Data and Guidelines to Real World Practice

To access the full set of presented slides, please visit www.pri-med.com/57MAN08A/syllabus and click on the “Print Syllabus” link. Upon completion of the educational activities, learners should be able to: • Outline evidence-based treatment of ACS as recommended by recently updated ACC/AHA

guidelines. • Apply strategies for improving ACS care in their own clinical practices and system(s) of care. • Discuss emerging science relative to the management of acute ACS.

8:00 – 8:05 Welcome and Introduction (E. Magnus Ohman, MD)

Session 1 8:05 – 8:50 STEMI Patient Case Simulation (Charles Pollack, MD) STEMI patient case will be introduced and, through advanced case simulation, the participants will walk through the optimal triage, diagnosis, and treatment of the patient from symptom onset to post-discharge, incorporating new evidence, guidelines, and registry data into the discussion, with regard to:

Reducing time to reperfusion Reperfusion method selection Adjunctive pharmacotherapy Discharge therapy

• Examine updated ACC/AHA STEMI guidelines. • Apply evidence-based STEMI guidelines to ACS patient scenarios. • Implement changes in your practice based on review and application of the updated STEMI

guidelines. 8:50 – 9:20 STEMI Guideline Update (E. Magnus Ohman, MD) • Examine updated ACC/AHA STEMI guidelines. • Apply evidence-based STEMI guidelines to ACS patient scenarios. • Implement changes in your practice based on review and application of the updated STEMI

guidelines. Session 2 9:20 – 9:35 Case Discussion and Q&A (Faculty and Attendees) Key learning points will be reviewed in a Q&A session with attendees. • Examine updated ACC/AHA STEMI guidelines. • Apply evidence-based STEMI guidelines to ACS patient scenario. • Implement changes in your practice based on review and application of the updated STEMI

guidelines.

Session 3 9:35 – 10:20 NSTEMI Patient Case Simulation (Attendees) NSTEMI patient case will be introduced and, through advanced case simulation, the participants will walk through the optimal triage, diagnosis, and treatment of the patient from symptom onset to post-discharge, incorporating new evidence, guidelines, and registry data into the discussion, with regard to:

Optimal diagnosis Invasive versus conservative strategy Adjunctive pharmacotherapy Discharge therapy

• Examine updated ACC/AHA UA/NSTEMI guidelines. • Apply evidence-based UA/NSTEMI guidelines to ACS patient scenarios. • Implement changes in your practice based on review and application of the updated UA/NSTEMI

guidelines. 10:20 – 10:35 Break Session 4 10:35 – 11:05 NSTEMI Guideline Update (James de Lemos, MD) • Examine updated ACC/AHA UA/NSTEMI guidelines. • Apply evidence-based UA/NSTEMI guidelines to ACS patient scenarios. • Implement changes in your practice based on review and application of the updated UA/NSTEMI

guidelines. Session 5 11:05 – 11:20 Case Discussion and Q&A (Faculty and Attendees) Key learning points will be reviewed in a Q&A session with attendees • Examine updated ACC/AHA UA/NSTEMI guidelines. • Apply evidence-based UA/NSTEMI guidelines to ACS patient scenario. • Implement changes in your practice based on review and application of the updated UA/NSTEMI

guidelines. Session 6 11:20 – 12:35 Bridging the Gap Between Emergency Medicine and Cardiology (Charles Pollack, MD) A 45-minute presentation concerning the barriers and gaps to translating new guidelines and evidence into ACS practice and ensuring continuity of care. Optimal critical care treatment for the ACS patient, as well as barriers to such treatment, will be identified utilizing interactive ARS technology to foster attendee participation and discussion of experiences in their own practice areas. 30-minute faculty-led discussion of effective practices to enhance communication and cooperation between emergency and cardiology departments, based on barriers to improved processes identified during the preceding presentation, with the overall goal of improving patient outcomes in ACS emergent medical care. • Analyze the implications of updated ACC/AHA ACS guidelines for emergency medical care.

• Enhance cooperation between the emergency department (ED) and the emergency transport team, hospital administration, catheterization laboratory, and cardiac care unit (CCU) so as to improve ACS patient care.

• Adapt quality improvement strategies and evidence-based algorithms to align STEMI and UA/NSTEMI ED practice with current scientific data.

12:35 – 1:20 Lunch Session 7 1:20 – 2:05 Bleeding and Transfusion: Recognizing the Impact on Vascular Outcomes (James de Lemos, MD) Antithrombotic/antiplatelets (existing and emerging); the link between bleeding and worse outcomes; and implications for targeting therapies to specific patients. • Delineate the implications of major bleeding in the ACS patient. • Analyze the bleeding risks posed by various therapeutic interventions in ACS. • Enumerate strategies for reducing bleeding risk in diverse ACS patients.

Session 8 2:05 – 2:35 The Future of ACS Treatment: New Therapies in Development (E. Magnus Ohman, MD) Exploration of new science related to anticoagulants and stents in development with a focus on potential effects of treatment: bioavailability, variability, predictability of response, and safety—especially within certain populations. • Identify emerging pharmacotherapies for the ACS patient. • Compare and contrast the roles of existing and evolving therapies in different ACS patient

populations.

Session 9 2:35 – 3:20 Solutions for Toughest Cases (Attendees and Faculty) Participants will be able to submit their tough cases and questions for discussion. They will be able to either submit a word file, 1-2 PowerPoint slides, or an audio or video question. Several cases will be selected for presentation and discussion. • Apply evidence-based ACS care to complex patient cases. • Probe difficult ACS issues in light of research evidence and common medical practice.

3:20 – 3:35 Final Q&A (Attendees and Faculty)

Sessions with this symbol have related Online activities. See full list following agenda or visit www.pri-med.com to reinforce your learning and earn additional CME credits.

Reinforce your learning and earn additional credits by completing these related Online CME activities

Improving MI Outcomes From Symptoms to Discharge and Beyond Complications due to cardiovascular disease are the chief cause of morbidity and mortality in the US, but recently updated treatment guidelines may improve that profile. Three patients are currently in our virtual waiting room; log on and see if you agree with the choices their clinicians make at each treatment juncture.

www.pri-med.com/activity/122948

For more Online CME from Pri-Med visit www.pri-med.com

®

TM

Making the Case for ACS: Applying New Data and Guidelines to Real-World Practice Learning Objectives

• Outline evidence-based treatment of acute coronary syndrome (ACS) as recommended by recently updated American College of Cardiology (ACC)/American Heart Association (AHA) guidelines.

• Apply strategies for improving ACS care in your own clinical practices and system(s) of care. • Discuss emerging science relative to the management of acute ACS.

Faculty

E. Magnus Ohman, MD, Chair Professor of Medicine Director, Program for Advanced Coronary Disease Duke University Medical Center Durham, North Carolina

E. Magnus Ohman, MD, received his medical degree from the Royal College of Surgeons in Dublin, Ireland, in 1981, followed by residencies in general internal medicine at St. Laurence’s Hospital and St. Vincent’s Hospital in Ireland and fellowships in cardiology at St. Laurence’s Hospital and at Duke University Medical Center. He is a Fellow of the Royal College of Physicians of Ireland, the European Society of Cardiology, and the American College of Cardiology. Dr Ohman’s clinical interests focus on interventional cardiology, the treatment of advanced/complex coronary disease, and secondary prevention. The main focus of his research is on the management of acute myocardial infarction, including the use of interventional procedures such as balloon angioplasty, intra-aortic balloon pumping, and other support devices. Through participating in and designing a number of randomized trials, he has helped crystallize the management to sustain patency of the infarct-related coronary artery in acute myocardial infarction. Furthermore, he has conducted several large multicenter clinical trials on the use of intra-aortic counterpulsation and angioplasty to better understand the pathophysiology of interventional procedures. Another major focus has been in the area of risk stratification in acute myocardial infarction. Early observations done abroad have led him to use new cardiac markers to identify high- and low-risk patients. Further research in this area will integrate early and rapid triage along with monitoring of the effect of thrombolysis after reperfusion in patients. A patent in the latter category has already been issued. His continued focus in the performance of multi-center international clinical trials has allowed him to explore different treatment strategies for the management of acute myocardial infarction from an international perspective. He has also collected angioplasty data on nearly 6000 patients from around North America to further explore international differences in the management of patients using percutaneous interventions.

James A. de Lemos, MD Director, Coronary Care Unit Parkland Memorial Hospital Director, Cardiology Fellowship Associate Professor of Medicine University of Texas Southwestern Medical School Dallas, Texas

James A. de Lemos, MD, is director of the Coronary Care Unit at Parkland Memorial Hospital and an associate professor of medicine at the University of Texas Southwestern Medical School in Dallas, where he holds the J. Fred Schoelkopf Endowed Chair in Cardiology Research. He is closely affiliated with the Thrombolysis in Myocardial Ischemia/Infarction (TIMI) research group and is an active investigator with the Donald W. Reynolds Clinical Research Center. A graduate of Harvard Medical School, Dr de Lemos completed an internal medicine residency at the University of Texas Southwestern Medical Center, where he also served as chief medical resident. He completed a fellowship in cardiovascular medicine at the Brigham and Women’s Hospital in Boston, and served on the faculty of the Brigham and Women’s Hospital and Harvard Medical School before moving to the University of Texas Southwestern Medical School. Dr de Lemos’ primary research interests include risk assessment and the management of acute and chronic coronary artery disease. Other research interests include electrocardiography as a means of assessing coronary microcirculation after thrombolysis or percutaneous coronary intervention, and the use of novel biomarkers for prognostic assessment among patients with coronary artery disease. He has worked extensively with biomarkers such as BNP, monocyte chemoattractant protein-1, and soluble CD40 ligand. Dr de Lemos was the lead author of the Z phase of the A to Z trial, investigating different cholesterol-lowering strategies in patients with ACS. Dr de Lemos is the author of more than 120 manuscripts or book chapters, and he has won several teaching awards.

Charles V. Pollack, Jr, MA, MD Professor and Chairman Department of Emergency Medicine Pennsylvania Hospital University of Pennsylvania Philadelphia, Pennsylvania

Charles Pollack, MD, is professor of emergency medicine at the University of Pennsylvania School of Medicine and is chair of emergency medicine at Pennsylvania Hospital in Philadelphia. From 1992-2001, Dr Pollack served in various positions in the Department of Emergency Medicine at Maricopa Medical Center in Phoenix, an urban, tertiary care teaching hospital affiliated with the Medical College of the University of Arizona and the Mayo Graduate School of Medicine. He was research director from 1994 to 2000, and he chaired the department from 1997 to 2001. From 2000 through mid-2001, Dr Pollack was also director of emergency medicine at Arizona Heart Hospital. He graduated summa cum laude from Emory University with bachelor’s degrees in history and chemistry and with a master’s degree in the history of science and medicine. He was also elected to Phi Beta Kappa. Dr Pollack earned his medical degree from Tulane University School of Medicine and is a member of Alpha Omega Alpha. Dr Pollack has long been active in teaching and clinical research and is an international leader in emergency medicine. He is the only physician to have received the American College of Emergency Physicians’ highest national awards in both teaching and research; he also received the national teaching award from the Council of

Emergency Medicine Residency Directors. His primary research interests are in the management of cardiopulmonary emergencies, especially acute thrombosis and acutely decompensated heart failure. He has published more than 300 original articles, reviews, editorials, book chapters, and electronic publications, and serves on the editorial boards of several journals and on the steering committees of multiple cardiology trials. Dr Pollack also lectures widely on many varied topics in emergency medicine. Dr Pollack is the PI of the new VELOCITY and EMPEROR studies, and he serves on the Executive Committee for the ongoing CHAMPION trials. Faculty Financial Disclosure Statement As a continuing medical education provider accredited by the ACCME, it is the policy of Pri-Med Institute to require any individual in a position to influence educational content to disclose the existence of any financial interest or other personal relationship with the manufacturer(s) of any commercial product(s). The presenting faculty reported the following: Dr de Lemos receives honoraria from Bristol-Myers Squibb/sanofi-aventis U.S. Dr Ohman receives grant support from Bristol-Myers Squibb; sanofi-aventis U.S.; Schering-Plough Pharmaceuticals; Millennium Pharmaceuticals; Eli Lilly and Company; Daiichi Sankyo, Inc.; and The Medicines Company; he serves as a consultant to Inovise, Liposcience, Response Biomedical, The Medicines Company, Datascope, and Abiomed; he serves on a speakers bureau for CV Therapeutics, Schering-Plough Pharmaceuticals, and The Medicines Company; and owns stock in Inovise and Medtronic. Dr Pollack receives direct research support from GlaxoSmithKline; serves on speakers bureaus for Schering-Plough Pharmaceuticals and sanofi-aventis U.S.; and serves as a consultant for sanofi-aventis U.S., Schering-Plough Pharmaceuticals, and The Medicines Company. Education Partner Financial Disclosure Statement The content collaborators at INNOVIA Education Institute have nothing to disclose. Conflict of Interest Resolution Statement When individuals in a position to control content have reported financial relationships with one or more commercial interests, as listed above, Pri-Med Institute works with them to resolve such conflicts to ensure that the content presented is free of commercial bias. The content of this presentation was vetted by the following mechanisms and modified as required to meet this standard:

• Content peer review by external topic expert • Content validation by external topic expert and internal Pri-Med Institute clinical editorial staff

Off-label/Investigational Disclosure In accordance with Pri-Med Institute policy, the audience is advised that Drs Ohman and Pollack indicated they may discuss unlabeled or unapproved use of drugs or devices. Drug List Generic Trade abciximab ReoPro acetaminophen various alteplase Activase APC (drotrecogin alfa) Xigris aspirin various atorvastatin Lipitor bivalirudin Angiomax, Cangrelor clopidogrel Plavix enoxaparin Lovenox eptifibatide Integrilin fondaparinux Arixtra hydrochlorothiazide various lisinopril Prinivil, Zestril

Generic Trade metoprolol Lopressor, Toprol-XL paclitaxel Taxol reteplase Retavase simvastatin Zocor streptokinase Streptase tenecteplase TNKase ticlopidine Ticlid tirofiban Aggrastat unfractionated heparin Tramadol Ultram

Investigational apixaban AZD6140 BX667 dabigatran (Pradaxa) DU-176b DX-9065a E5555 idraparinux INS50589 NCX-4016

otamixaban prasugrel (Effient) PRT-054021 PRT128 reviparin ridogrel S18886 SCH530348 STM (ART-123) YM150

Suggested Reading List Alexander KP, Chen AY, Roe MT, et al. Excess dosing of antiplatelet and antithrombin agents in the treatment of non-ST-segment elevation acute coronary syndromes. JAMA. 2005;294(24):3108-3016. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction) developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons, and endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. J Am Coll Cardiol. 2007;50:e1-e157. Antman EM, Anbe DT, Armstrong PW et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction – executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to revise the 1999 guidelines for the management of patients with acute myocardial infarction). J Am Coll Cardiol. 2004;44(3):671-719. Antman EM, Hand M, Armstrong PW et al. 2007 Focused Update of the ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: developed in collaboration With the Canadian Cardiovascular Society endorsed by the American Academy of Family Physicians: 2007 Writing Group to Review New Evidence and Update the ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction, Writing on Behalf of the 2004 Writing Committee. Circulation. 2008;117(2):296-329. Antman EM, Morrow, DA, McCabe, CH et al., Enoxaparin versus unfractionated heparin with fibrinolysis for ST-elevation myocardial infarction. N Engl J Med. 2006;354(14):1477-1488. Boden WE, Eagle K, and Granger CB. Reperfusion strategies in acute ST-segment elevation myocardial infarction: a comprehensive review of contemporary management options. J Am Coll Cardiol. 2007;50(10):917-929. Cannon CP, Husted S, Harrington RA, et al. Safety, tolerability, and initial efficacy of AZD6140, the first reversible oral adenosine diphosphate receptor antagonist, compared with clopidogrel, in patients with non-ST-segment elevation acute coronary syndrome: primary results of the DISPERSE-2 trial. J Am Coll Cardiol. 2007;50(19):1844-1851. Chen ZM, Jiang LX, Chen YP et al. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet. 2005;366:1607-1621. Ferguson JJ, Califf RM, Antman EM, et al. Enoxaparin vs unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndromes managed with an intended early invasive strategy: primary results of the SYNERGY randomized trial. JAMA. 2004;292(1):45-54. Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators, Yusuf S, Mehta SR, et al. Comparison of fondaparinux and enoxaparin in acute coronary syndromes. J Am Coll Cardiol. 2007;49:734-739.

Grines CL, Bonow RO, Casey DE, Jr., et al. Prevention of premature discontinuation of dual antiplatelet therapy in patients with coronary artery stents: a science advisory from the American Heart Association, American College of Cardiology, Society for Cardiovascular Angiography and Interventions, American College of Surgeons, and American Dental Association, with representation from the American College of Physicians. J Am Coll Cardiol. 2007;50(10):917-929. Jacobs AK, Antman EM, Ellrodt G, et al. Recommendation to develop strategies to increase the number of ST-segment-elevation myocardial infarction patients with timely access to primary percutaneous coronary intervention. Circulation. 2006;113(17):2152-2163. King SB III, Smith SC Jr, Hirshfeld JW Jr, et al. 2007 Focused Update of the ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: 2007 Writing Group to Review New Evidence and Update the ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention, Writing on Behalf of the 2005 Writing Committee. Circulation. 2008;117:261-295. Moscucci M, Fox KA, Cannon CP et al. Predictors of major bleeding in acute coronary syndromes: the Global Registry of Acute Coronary Events (GRACE). Eur Heart J. 2003;(20):1815-1823. Peterson ED, Roe MT, Mulgund J, et al. Association between hospital process performance and outcomes among patients with acute coronary syndromes. JAMA. 2006;295:1912-1920. Pollack CV Jr. and Braunwald E. 2007 update to the ACC/AHA guidelines for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction: implications for emergency department practice. Ann Emerg Med. 2008;51(5):591-606. Pollack CV Jr., Antman EM, and Hollander JE. 2007 focused update to the ACC/AHA guidelines for the management of patients with ST-segment elevation myocardial infarction: implications for emergency department practice. Ann Emerg Med. May 31, 2008 [Epub ahead of print]. Rao SV, O’Grady K, Pieper KS, et al. Impact of bleeding severity on clinical outcomes among patients with acute coronary syndromes. Am J Cardiol. 2005;96(9):1200-1206. Sabatine MS, Morrow DA, Montalescot G, et al. Angiographic and clinical outcomes in patients receiving low-molecular-weight heparin versus unfractionated heparin in ST-elevation myocardial infarction treated with fibrinolytics in the CLARITY-TIMI 28 Trial. Circulation. 2005;112:3846-3854. Spencer FA, Moscucci M, Granger CG et al. Does comorbidity account for the excess mortality in patients with major bleeding in acute myocardial infarction? Circulation. 2007;116(24):2793-2801. Steinhubl SR, Kastrati A, and Berger PB. Variation in the definitions of bleeding in clinical trials of patients with acute coronary syndromes and undergoing percutaneous coronary interventions and its impact on the apparent safety of antithrombotic drugs. Am Heart J. 2007;154(1):3-11. Steinhubl SR, Schneider DJ, Berger PB, et al. Determining the efficacy of antiplatelet therapies for the individual: lessons from clinical trials. J Thromb Thrombolysis. 2008;26(1):8-13. Stone GW, Ware JH, Bertrand ME, et al. Antithrombotic strategies in patients with acute coronary syndromes undergoing early invasive management: one-year results from the ACUITY trial. JAMA. 2007;298(21):2497-2506. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357:2001-2015. Yusuf S, Mehta SR, Chrolavicius S, et al. Effects of fondaparinux on mortality and reinfarction in patients with acute ST-segment elevation myocardial infarction: the OASIS-6 randomized trial. JAMA. 2006;295(13):1519-1530.

Disclosure Policy

It is the policy of the Pri-Med Institute and M|C Communications, LLC, to ensure balance, independence, objectivity and scientific rigor in all its sponsored educational programs. All faculty participating in the sponsored programs are expected to disclose to the program audiences any real or apparent conflict(s) of interest related to the content of their presentation(s).

During the course of their presentations, the faculty may mention uses of products that have not been approved in the United States for the indication being discussed. Faculty have been instructed to notify participants when they are discussing unapproved uses or investigational agents. Views presented during this program related to unapproved uses of products are solely those of the presenter and are not endorsed by Pri-Med Institute or M|C Communications, LLC.

Copyright notice: No part of the Pri-Med Clinical Focus for Cardiologists syllabus may be reproduced or otherwise incorporated into any information retrieval system, without the written permission of Pri-Med Institute, a division of M|C Communications, LLC.

The opinions, ideas, recommendations, and perspectives expressed in the syllabus and accompanying presentations for Pri-Med Clinical Focus for Cardiologists are those of the faculty only and do not necessarily reflect the opinions, ideas, recommendations or perspectives of their affiliated institutions, Pri-Med Institute, Pri-Med Institute Advisory Boards and Consultants, M|C Communications, LLC, or commercial supporters. Clinical judgment must guide each clinician in weighing the benefit of any diagnostic intervention or treatment approach or intervention against the risk of the intervention or treatment. Dosage, indications and methods of use for products referred to in this activity are not necessarily the same as indicated in the package insert for the product and may reflect the clinical experience or expertise of the individual faculty speaker. Any diagnostic procedures or treatments should not be utilized by clinicians or other healthcare professionals without evaluation of their patients’ conditions, and of possible contraindications or risks and without a review of any applicable manufacturer's product information and comparison with the recommendations of other authorities. Copyright notice: No part of the Pri-Med Clinical Focus for Cardiologists syllabus may be reproduced, distributed or otherwise incorporated into any information retrieval system, without the written permission of Pri-Med Institute, a division of M|C Communications, LLC.

Check out your CME Tracker at Pri-Med.com today: www.Pri-Med.com

Getting your CME certifi cate from any Pri-Med live program

is easier than ever. By visiting Pri-Med.com, you can quickly

see what credits you’ve earned, and then print or save your

certifi cates.

How does it work? We simply send you an email when

your certifi cate is online and ready to print. See other side

for easy instructions on how to print your certifi cate(s)

on Pri-Med.com

www.Pri-Med.com

Our CME tracker lets you:

• Store an electronic library

of your CME certifi cates

• Print and download

your certifi cate as soon

as it’s ready

• Print a summary of

credits earned to submit

to licensing board

• Enter non-Pri-Med CME

activities for a complete

summary of all of your

credits earned through

the year

Get your CME certifi cates faster with Pri-Med’s online CME Tracker.

®

TM

Visit www.Pri-Med.com today

HOW TO PRINT YOUR CERTIFICATE IN THREE EASY STEPS:

1

2

Visit www.Pri-Med.com. Log in using your

username and password** Our improved “Forgot My Password”

management can help you retrieve a forgotten username or password.

Scroll down to “Credit Summary” at the bottom of the page and click “View All.”

Once logged in, you’ll see your “Summary of Credits Earned.” Click on “Print Certifi cate.” After opening your certifi cate, you can print it and/or save it to your computer.

3

NatioNal Schedule FoR PRiMaRY caRe®

TM

dates subject to change. 6/08

Pri-Med Conference & ExhibitionFor over 14 years, Pri-Med conference & exhibition has provided continuing medical education on the best available patient care practices as well as insights into the latest advances in research, treatment protocols, and technology that physicians will need to deliver cutting-edge medical care. over the course of Pre-conference Symposia day* and 3 core Program days, Pri-Med conference & exhibition provides a diverse spectrum of learning opportunities from national experts in 1 place, offering up to 30 AMA PRA Category 1 Credit(s)™.

CITY DATES Pri-Med New York New York, NY october 2-5, 2008 Pri-Med east Boston, Ma November 6-9, 2008 Pri-Med Mid-atlantic Baltimore, Md december 3-6, 2008 Pri-Med South Fort lauderdale, Fl February 12-15, 2009 Pri-Med Midwest Rosemont, il March 4-7, 2009 Pri-Med Southwest houston, tX March 18-21, 2009 Pri-Med West anaheim, ca May 6-9, 2009

Pri-Med Updates – The Next GenerationPri-Med updates features the latest practice-based education. Now, experience an enhanced cMe environment while also benefiting from opportunities to engage in interactive non-cMe activities. in addition to a prominent keynote speaker, you’ll experience 2 track-based, information-filled days of therapeutically aligned cMe content and informative discussions around the most advanced clinical updates and treatment options.

Plus, for the first time, we’re providing an innovative networking area where you can meet with industry representatives. With individual interactions and group presentations, you’ll get the latest, most up-to-date perspectives on practice and patient care management in multiple clinical areas. earn up to 13.5 complimentary AMA PRA Category 1 Credit(s)™.

FALL 2008 cincinnati, oh october 29-30 houston, tX September 19-20 long Beach, ca october 10-11

Pri-Med Updates and Conference & Exhibition Locations

Pri-Med UpdatesPri-Med updates is designed to reflect the practitioner’s patient appointment schedule. the curriculum is composed of different sessions, each focused on a specific clinical condition and each presented by nationally recognized speakers. Sessions include didactic presentations as well as interactive, case-based learning opportunities. earn complimentary AMA PRA Category 1 Credit(s)™ or aaNP contact hours.

FALL 2008 atlanta, Ga december 2-3 charlotte, Nc September 3-4 chicago, il december 2-3 dallas, tX September 23-24 dearborn, Mi october 28-29 los angeles, ca November 13-14 Melville, NY November 19-20 Minneapolis, MN September 19 New orleans, la October 23-24 oakbrook, il october 30-31 orlando, Fl November 6-7 Philadelphia, Pa November 4-5 Phoenix, aZ october 2 Pittsburgh, Pa december 11-12 Portland, oR october 22 Princeton, NJ September 4-5 San Jose, ca November 19 Seattle, Wa September 26 St louis, Mo November 13-14 tampa, Fl december 4 Washington, dc october 16-17

For a complete list of Pri-Med events or to register, visit www.pri-med.com or call 877-477-4633.

Welcome to Pri-Med®, the industry leader in continuing Medical education. our mission is to help you access the best medical education available and we want to make it easy for you to do so. through our partnerships with leading academic institutions and teaching centers—including the faculty and thought leaders on the front lines of discovery and patient care—we bring you comprehensive continuing medical education curriculums delivered through live meetings, print publications on a monthly and quarterly basis, and online platforms with new content added daily. We have created this national schedule to highlight the cMe opportunities available to you throughout the year.

* This activity is sponsored by Pri-Med Institute.

NatioNal Schedule FoR PRiMaRY caRe®

TM

Diabetes In Depth diabetes in depth is a cMe program designed to meet the education and practice needs of clinicians who regularly diagnose and manage patients with diabetes. at every session, leading experts will provide world-class information on the comorbidities and risk factors associated with diabetes. earn up to 8.5 complimentary AMA PRA Category 1 Credit(s)™ or aaNP contact hours.

Presented in collaboration with the American Diabetes Association

FALL 2008cleveland, oh december 11houston, tX November 8Kansas city, Mo october 25Melville, NY december 10Nashville, tN November 22Phoenix, aZ November 6 Pittsburgh, Pa September 25 Rosemont, il September 4San diego, ca october 24tampa, Fl october 18

Clinical Focus in Cardiovascular Risk

Join faculty from the american college of cardiology Foundation (accF) in this 31/2-hour session focused on cardiovascular risk stratification and evidence-based primary prevention approaches and strategies. the accF, the leading cardiovascular educator, recognizes the pivotal role that primary care physicians play in managing the burden of cardiovascular disease and developed this interactive, case-based program to help improve patient outcomes. earn up to 3.5 complimentary AMA PRA Category 1 Credit(s)™ or aaNP contact hours.

Co-sponsored by Pri-Med Institute and the American College of Cardiology Foundation

FALL 2008dallas, tX September 25Melville, NY November 21 orlando, Fl November 8Phoenix, aZ october 3Seattle, Wa September 27Washington, dc october 18

Pri-Med Clinical Focus in ADHD

Pri-Med clinical Focus in adhd is a 3-hour, in-depth session dedicated to innovations in attention-deficit/hyperactivity disorder management. the curriculum will feature case-based patient simulation provided by a faculty composed of primary care physicians, psychiatrists, and pediatricians. earn up to 3 complimentary AMA PRA Category 1 Credit(s)™ or aaNP contact hours.

FALL 2008dallas, tX September 25Melville, NY November 21Washington, dc october 18

Online CME

over 300 no-cost online cMe activities covering key therapeutic topics in primary care help extend the learning of topics presented at live programs. thoroughly examine any topic through 4 learning formats: patient case studies, clinical reviews, expert perspectives, and slide lecture series.

certified for category 1 credit toward the aMa Physician’s Recognition award. Select activities are certified for aaNP contact hours, which includes hours of pharmacology.

Print CME

Primary care–focused cMe publications available online:

Pri-Med in Practice, a 12- to 16-page newsletter covering key topics in primary care.

Pri-Med Pocket Guides, a series of 32- to 48-page single-topic reference guides.

Pri-Med Hospital CME, poster-sized cMe designed to promote improvements in hospital care.

For a complete list of Pri-Med events or to register, visit www.pri-med.com or call 877-477-4633.

STATE OF THE UNION: NEW YORK HEALTH FACTS

Totals for the Top Five Causes of Death** for

New York, 2005

Rank Cause of Death Totals

- All Causes 150,987 1 Diseases of the Heart 52,002 2 Malignant Neoplasms (Cancer) 35,303 3 Chronic Lower Respiratory Diseases 6,805 4 Cerebrovascular Disease 6,566 5 Influenza and Pneumonia 5,549

** Data based on continuous file of records received from the States and does not include contributory diagnoses

Sources: Vital Statistics of New York State-2005 Tables. New York Department of Public

Health; 2008.

Comparison of Health Statistics: New York vs. US Cigarette Smoking Rate by Gender, 2007

NY% vs. US% Male 21 21 Female 16 17 Number of Deaths: Rate per 100,000 Population by Race/Ethnicity, 2004

NY% vs. US White 732 786 Black 810 1027 Other 376 478

Number of Diabetes Deaths: Rate per 100,000 Population by Race/Ethnicity, 2005

NY% vs. US White 17 23 Black 38 47 Other 12 21 Number of Heart Disease Deaths: Rate per 100,000 Population by Race/Ethnicity, 2004

NY vs. US White 246 213 Black 276 281 Other 134 123

Pri-Med Institute Health Facts November 2008

Number of Stroke and other Cerebrovascular Disease Deaths: Rate per 100,000 Population by Race/Ethnicity, 2004


Overweight and Obesity Rate by Race/Ethnicity, 2007

*Not Sufficient Data

NY% vs. US% White 58 59 Black 64 69 Hispanic 62 62 Asian/ Pacific Islander NSD* 38 American Indian/ Alaska Native NSD* 63 Other 60 60

Number of Cancer Deaths: Rate per 100,000 Population by Race/Ethnicity, 2004


Percent of Mothers Beginning Prenatal Care in the First Trimester by Race/Ethnicity, 2004

NY% vs. US% White 82 89 Black 61 77 Hispanic 61 78 Total 77 84

Statistical Sources for facts and figures: 1) New York State Department of Health. http://www.health.state.ny.us/. Accessed 6/20/08. 2) Centers for Disease Control and Prevention, Behavioral Risk Factor Surveillance System Survey Data (BRFSS),

2007, unpublished data. Information about the BRFSS is available at http://www.cdc.gov/brfss/index.htm. 3) United States Department of Health and Human Services (US DHHS), Centers for Disease Control and

Prevention (CDC), National Center for Health Statistics (NCHS), Compressed Mortality File (CMF) compiled from 1999-2004, Series 20, No. 2J 2007 on CDC WONDER On-line Database, queried November 2007.

4) United States Department of Health and Human Services (US DHHS), Centers for Disease Control and Prevention (CDC), National Center for Health Statistics (NCHS), Compressed Mortality File (CMF) compiled from 2005, Series 20, No. 2K 2008 on CDC WONDER On-line Database.

5) United States Department of Health and Human Services (US DHHS), Centers for Disease Control and Prevention (CDC), National Center for Health Statistics (NCHS), Compressed Mortality File (CMF) compiled from 1999-2004, CDC WONDER On-line Database.

6) Centers for Disease Control and Prevention, Behavioral Risk Factor Surveillance System Survey Data, 2007, unpublished data. Information about the BRFSS is available at http://www.cdc.gov/brfss/index.htm.

7) United States Department of Health and Human Services (US DHHS), Centers for Disease Control and Prevention (CDC), National Center for Health Statistics (NCHS), Compressed Mortality File (CMF) compiled from 1999-2004,CDC WONDER On-line Database.

8) Martin JA, et. al., Births: Final Data for 2004, Table 26(a) and Table 26(b), National Vital Statistics Report, Vol. 55, No. 1, September 29, 2006, Division of Vital Statistics, National Center for Health Statistics. Available at http://www.cdc.gov/nchs/data/nvsr/nvsr55/nvsr55_01.pdf.

Pri-Med Institute Health Facts November 2008

Acute Coronary Syndrome

• Coronary heart disease (CHD) caused 1 in 5 US deaths in 2004. o Single largest killer of American men and women o 50% of men and 64% of women who die suddenly of CHD had no previous symptoms

• While in-hospital acute myocardial infarction (MI) mortality declined by more than 15% in the last decade, it remains approximately 10%.

• Mortality increases for every 30 minutes that elapse before an ST-segment elevation myocardial infarction patient is treated.

• In the United States, approximately 850,000 drug-eluting stents (DES) are used each year. o Average number of stents per patient: 1.45 o 60% of DES usage is off-label

• The number of discharges with ACS from hospitals in 2004 was 840,000. o Of these, an estimated 476,000 are male and 364,000 were female. o This figure was derived by adding the first-listed inpatient hospital discharges for MI

(732,000) to those for unstable angina (108,000) • When including secondary discharge diagnoses in 2004, the corresponding numbers of inpatient

hospital discharges were: o 1.57 million unique hospitalizations for ACS o 896,000 for MI o 669,000 for unstable angina o 21,000 hospitalizations received both diagnoses

• According to studies, 21% of ACS patients have ST-elevation MI. • Comorbidities are typically more frequent in women; previous coronary disease and typical anginal

pain on admission are more frequent in men. AHA Statistics Committee and Stroke Subcommittee. Heart Disease and Stroke Statistics--2007 Update. Published online Dec 28, 2006. Available at: http://circ.ahajournals.org. Wiviott SD, Morrow DA, Frederick PD, et al. Performance of the thrombolysis in myocardial infarction risk index in the National Registry of Myocardial Infarction-3 and -4: a simple index that predicts mortality in ST-segment elevation myocardial infarction. J Am Coll Cardiol. 2004;44:783-789.

®

TM

Notes ___________________________________________________________________________________________________

___________________________________________________________________________________________________

___________________________________________________________________________________________________

___________________________________________________________________________________________________

___________________________________________________________________________________________________

___________________________________________________________________________________________________

___________________________________________________________________________________________________

___________________________________________________________________________________________________

___________________________________________________________________________________________________

___________________________________________________________________________________________________

___________________________________________________________________________________________________

___________________________________________________________________________________________________

___________________________________________________________________________________________________

___________________________________________________________________________________________________

___________________________________________________________________________________________________

___________________________________________________________________________________________________

___________________________________________________________________________________________________

___________________________________________________________________________________________________

___________________________________________________________________________________________________

___________________________________________________________________________________________________

___________________________________________________________________________________________________

___________________________________________________________________________________________________

___________________________________________________________________________________________________

___________________________________________________________________________________________________

___________________________________________________________________________________________________

___________________________________________________________________________________________________

___________________________________________________________________________________________________

___________________________________________________________________________________________________

___________________________________________________________________________________________________

1

Accredited Provider:

Pri-Med Institute

Session: 8:00 AM – 3:35 PM

Making the Case for ACS:Applying New Data and Guidelines to

Real-World Practice

Speakers:E. Magnus Ohman, MDJames A. de Lemos, MD

Charles V. Pollack, Jr., MD

Accredited Provider:

Pri-Med Institute

Presenter Disclosure InformationThe following relationships exist related to this presentation:

Off Label/Investigational DiscussionIn accordance with Pri-Med Institute policy, faculty have been asked to disclose discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations.

Dr. de Lemos has received honoraria from Bristol-Myers Squibb/sanofi-aventis.

Dr. Ohman has received grant support from Bristol-Myers Squibb, sanofi-aventis U.S., Schering-Plough Pharmaceuticals, Millennium Pharmaceuticals, Eli Lilly and Company, Daiichi Sankyo, Inc., and The Medicines Company; has served as a consultant to Inovise, Liposcience, Response Biomedical, The Medicines Company, Datascope, and Abiomed; has served on a speakers bureau for CV Therapeutics, Schering-Plough Pharmaceuticals, and The Medicines Company; and owns stock in Inovise and Medtronic.

Dr. Pollack has received direct research support from GlaxoSmithKline; has served on speakers’ bureaus for Schering-Plough and sanofi-aventis; and has served as a consultant for sanofi-aventis, Schering-Plough, and The Medicines Company.

Making the Case for ACS:Applying New Data and Guidelines to

Real‐world Practice

•Outline evidence‐based treatment of ACS as recommended by recently

updated ACC/AHA guidelines

•Apply strategies for improving ACS care in your own clinical

practices and system(s) of care

•Discuss emerging science relative to the management

of acute ACS

Learning Objectives

What degree of improvement is required for the treatment of acute myocardial infarction in the US?

1. A great deal2. A fair amount 3. Somewhat4. Not at all

STEMI Patient Simulation

Charles V. Pollack Jr., MDProfessor and Chairman

Department of Emergency MedicinePennsylvania Hospital

Philadelphia, PA

2

2007 ACC/AHA STEMI Focused Update

E. Magnus Ohman, MDDirector, Program for Advanced Coronary Disease

Duke University Medical CenterDurham, NC

•Examine updated ACC/AHA STEMI guidelines

•Apply evidence‐based STEMI guidelines to ACS patient

scenarios

•Implement changes in your practice based on review and

application of the updated STEMI guidelines

Learning Objectives

Antman EM, et al. Circulation. 2004;110:588-636.


Class I

Benefit >>> Risk

Procedure/ Treatment SHOULD be performed/ administered

Class IIa

Benefit >> RiskAdditional studies with focused objectives needed

IT IS REASONABLE to perform procedure/administer treatment

Class IIb

Benefit ≥ RiskAdditional studies with broad objectives needed; Additional registry data would be helpful

Procedure/Treatment MAY BE CONSIDERED

Class III

Risk ≥ BenefitNo additional studies needed

Procedure/Treatment should NOT be performed/administeredSINCE IT IS NOT HELPFUL AND MAY BE HARMFUL

Applying Classification of Recommendations and Level of Evidence

Level A: Recommendation based on evidence from multiple randomized trials or meta-analyses Multiple (3-5) population risk strata evaluated; General consistency of direction and magnitude of effect

Level B: Recommendation based on evidence from a single randomized trial or non-randomized studies Limited (2-3) population risk strata evaluated

Level C: Recommendation based on expert opinion, case studies, or standard-of-care Very limited (1-2) population risk strata evaluated

Beta-Blockers

Effects of Metoprolol

Chen ZM, Pan, HC, Chen YP, et al. Lancet. 2005;366:1622-1632.

Death13%

P=0.0006

ReMI22%

P=0.0002

VF15%

P=0.002

Totality of Evidence (N=52,411)COMMIT (N=45,852)

Increased early risk of

shock

Risk factors for cardiogenic shock: heart failure, age > 70, systolic blood pressure < 120, sinus tachycardia > 110 or heart rate < 60, increased time since onset of STEMI symptoms

3

Oral beta-blocker therapy should be initiated in the first 24 hours for patients who do not have any of the following: 1) signs of heart failure, 2) evidence of a low output state, 3) increased risk* for cardiogenic shock, or 4) other relative contraindications to beta blockade (PR interval > 0.24 sec, 2nd- or 3rd-degree heart block, active asthma, or reactive airway disease).

It is reasonable to administer an IV beta blocker at the time of presentation to STEMI patients who are hypertensive and who do not have any of the following: 1) signs of heart failure, 2) evidence of a low output state, 3) increased risk* for cardiogenic shock, or 4) other relative contraindications to beta blockade (PR interval > 0.24 sec, 2nd- or 3rd-degree heart block, active asthma, or reactive airway disease).

Beta-Blockers

III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII



IV beta blockers should not be administered to STEMI patients who have any of the following: 1) signs of heart failure, 2) evidence of a low output state, 3) increased risk* for cardiogenic shock, or 4) other relative contraindications to beta blockade (PR interval > 0.24 sec, 2nd- or 3rd-degree heart block, active asthma, or reactive airway disease).

Beta-Blockers



Primary PCI

Mortality Rates by Age and Reperfusion Strategy: PCAT-2

Alexander KP, et al. Circulation. 2007;115:2570-2589.

0.0

5.0

10.0

15.0

20.0

25.0

30.0

< 65 yrs 65-74 yrs 75-84 yrs > 85 yrs

Dea

th in

Tre

atm

ent A

rms

(%)

Lytics

PCI

Reperfusion Therapy for STEMI by Age, NRMI 2-4

0%

10%

20%

30%

40%

50%

60%

70%

80%

<65 (N=360,101)

65‐74 (N=191,093)

75‐84 (N=160,534)

>85 (N=63,952)

Primary PCI

Lytics


Options for Transport of Patients With STEMI and Initial Reperfusion Treatment

EMS Transport

Onset of symptoms of

STEMI

9-1-1EMS

Dispatch

EMS on-scene• Encourage 12-lead ECGs.• Consider prehospital fibrinolytic if

capable and EMS-to-needle within 30 min.

GOALS

PCIcapable

Not PCIcapable

Hospital fibrinolysis: Door-to-Needle within 30 min.

EMS Triage Plan

Inter-HospitalTransfer

Golden Hour = first 60 min. Total ischemic time: within 120 min.

Patient EMS Prehospital fibrinolysisEMS-to-needlewithin 30 min.

EMS transportEMS-to-balloon within 90 min.

Patient self-transportHospital door-to-balloon

within 90 min.Dispatch

1 min.

5 min.

8 min.

Antman EM, et al. J Am Coll Cardiol. 2008. Published ahead of print on December 10, 2007. Available at http://content.onlinejacc.org/cgi/content/full/j.jacc.2007.10.001.

4

Primary PCI

STEMI patients presenting to a hospital with PCI capability should be treated with primary PCI within 90 min of first medical contact as a systems goal.

STEMI patients presenting to a hospital without PCI capability, and who cannot be transferred to a PCI center and undergo PCI within 90 min of first medical contact, should be treated with fibrinolytic therapy within 30 min of hospital presentation as a systems goal, unless fibrinolytic therapy is contraindicated.




Facilitated PCI

Meta-analysis: Facilitated PCI vsPrimary PCI

1.03(0.15-7.13)

3.07(0.18-52.0)

1.43(1.01-2.02)

1.03(0.49-2.17)

Mortality Reinfarction Major Bleeding

Fac. PCIBetter

PPCIBetter

Fac. PCIBetter

PPCIBetter

Fac. PCIBetter

PPCIBetter

Keeley E, et al. Lancet. 2006;367:579.

0.1 1 10 0.1 1 10 0.1 1 10

1.38 (1.01-1.87)

1.71(1.16 - 2.51)

1.51(1.10 - 2.08 )

Lytic alone N=2953

IIb/IIIa alone N=1148

Lytic +IIb/IIIaN=399

All (N=4500)

1.40 (0.49-3.98)

1.81 (1.19-2.77)

A planned reperfusion strategy using full-dose fibrinolytic therapy followed by immediate PCI is not recommended and may be harmful.

Facilitated PCI using regimens other than full-dose fibrinolytic therapy might be considered as a reperfusion strategy when all of the following are present:a. Patients are at high risk,b. PCI is not immediately available within 90 minutes, andc. Bleeding risk is low (younger age, absence of poorly controlled hypertension, normal body weight).

Facilitated PCI




Rescue PCI

Wijeysundera HC, et al. J Am Coll Cardiol. 2007;49:422-430.

Meta-analysis: Rescue PCI vs Conservative Tx

Outcome Rescue PCI Conservative Treatment

RR (95% CI) P

Mortality, %(n)

7.3(454)

10.4(457)

0.69(0.46–1.05)

.09

HF, % (n)

12.7(424)

17.8(427)

0.73(0.54–1.00)

.05

Reinfarction,% (n)

6.1(346)

10.7(354)

0.58(0.35–0.97)

.04

Stroke, % (n) 3.4(297)

0.7(295)

4.98(1.10–22.48)

.04

Minor bleeding,% (n)

16.6(313)

3.6(307)

4.58(2.46–8.55)

<.001

In 3 trials, enrolling 700 patients that reported the composite end point of all-cause mortality, reinfarction, and HF, rescue PCI was associated with a significant RR reduction of 28% (RR 0.72; 95% CI, 0.59-0.88; P=.001)

5

A strategy of coronary angiography with intent toperform PCI (or emergency CABG) isrecommended in patients who have receivedfibrinolytic therapy and have:

a. Cardiogenic shock in patients < 75 years who are suitable candidates for revascularization

b. Severe congestive heart failure and/or pulmonary edema (Killip class III)

c. Hemodynamically compromising ventricular arrhythmias.




Rescue PCI


Rescue PCI

Reasonable in patients ≥ 75 years who havereceived fibrinolytic therapy, and are incardiogenic shock, provided they are suitablecandidates for revascularization.



III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII Reasonable for patients in whom fibrinolytic therapy has failed and a moderate or large area of myocardium at risk [anterior MI, inferior MI with right ventricular involvement or precordial ST-segment depression].

Rescue PCI

Might be reasonable in the absence of any of the above Class I or IIa indications in moderate- or high-risk patients, but its benefits and risks are not well established. The benefits of rescue PCI are greater the earlier it is initiated after the onset of ischemic discomfort.



Anticoagulants

Unfractionated Heparin

Indirect thrombin inhibitor so does not inhibit clot-bound thrombin Nonspecific binding to:― Serine proteases― Endothelial cells

(can lead to variability in level of anticoagulation)

Reduced effect in ACS― Inhibited by PF-4

Causes platelet aggregation

Nonlinear pharmacokinetics

Risk of HIT

DisadvantagesImmediate anticoagulation

Multiple sites of action in coagulation cascade

Long history of successful clinical use

Readily monitored by aPTTand ACT

Advantages

aPTT=activated partial thromboplastin time; ACT=activated coagulation time; PF-4=platelet factor 4; HIT=heparin-induced thrombocytopenia.

Hirsh J, et al. Circulation. 2001;103:2994-3018.

ExTRACT-TIMI 25: Primary End Point (ITT) Death or Nonfatal MI

0

3

6

9

12

15

0 5 10 15 20 25 30

Prim

ary

End

Poin

t (%

)

Enoxaparin

UFH

Relative Risk0.83 (95% CI, 0.77 to 0.90)

P<.001

Days after Randomization

9.9%

12.0%

Lost to follow-up = 3

17% RRR

Adapted with permission from Antman EM, et al. N Engl J Med. 2006;354:1477-1488.

6

Low-MolecularWeight Heparin

Indirect thrombin inhibitorLess reversibleDifficult to monitor(no aPTT or ACT)Renally clearedLong half-lifeRisk of HIT

DisadvantagesIncreased anti-Xa to anti-IIa activity → inhibits thrombin generation more effectivelyInduces ↑ release of TFPI vs UFH Not neutralized by platelet factor 4Less binding to plasma proteins (eg, acute-phase reactant proteins) → more consistent anticoagulationLower rate of HIT vs UFH Lower fibrinogen levels Easy to administer (SC administration)Long history of clinical studies and experience, FDA-approved indicationsMonitoring typically unnecessary

Advantages

TFPI=tissue factor pathway inhibitor; UFH=unfractionated heparin; SC=subcutaneous; aPTT=activated partial thromboplastin time; ACT=activated coagulation time.

Hirsh J, et al. Circulation. 2001;103:2994-3018.

OASIS-6 Trial: Results

15%

Primary End Point: Death/Reinfarction (%)

P=.008 P=.003 P=.008

Freq

uenc

y

12%

9%

6%

3%

0%

9.7%11.2%

7.4%8.9%

13.4%14.8%

30 days 9 days 3-6 months

Fondaparinux (n=6036) Control (n=6056)

14%

Reduction in Death/MI at 30 days: Stratum 1 (No UFH indicated)

P<.05

Reduction in Death/MI: Stratum 2(UFH Indicated)

P=NS

p=0.97p=0.97

12%

10%

8%

6%

4%

2%

0%

11.2%

14%

Fondaparinux Placebo

14%12%10%8%6%4%2%0%

Fondaparinux UFH

8.3% 8.7%

Yusuf S, et al. JAMA. 2006;295:1519-1530. Adapted with permission from www.clinicaltrialresults.org.

Fondaparinux

• Difficult to monitor (no aPTTor ACT)

• Long half-life• Catheter thrombosis during

PCI

DisadvantagesAdvantages• SC administration

― Potential exists for outpatient management

• Once-daily administration• Predictable anticoagulant

response• Fixed dose• No antigenicity• Potentially no need for

serologic parameters• Does not cross the placenta• HIT antibodies do not cross-

react• Decreased bleeding

complications vs UFH or LMWH

Simoons ML, et al. J Am Coll Cardiol. 2004;43:2183-2190.Yusuf S, et al. N Engl J Med. 2066;354:1464-1476.

12.2

8.45.5

9.3

5.0 5.5

0

5

10

15

20

Net adverse clinicalevents

Major bleeding* MACE**

30 d

ay e

vent

rate

s (%

)Heparin + GP IIb/IIIa inhibitor (N=1802) Bivalirudin monotherapy (N=1800)

HR = 1.00HR = 1.00 [0.75, 1.32]P = 0.98P = 0.98

HORIZONS AMI: Primary Outcome Measures (ITT)

HR = HR = 0.59 [0.45, 0.76]P P dd 0.00010.0001

HR = HR = 0.75 [0.62, 0.92]PP = 0.006= 0.006

*Not related to CABG*Not related to CABG**MACE=All cause death, **MACE=All cause death, reinfarctionreinfarction, ischemic TVR or stroke, ischemic TVR or stroke

Stone GW, et al. N Engl J Med. 2008;358:2218-2230.

HORIZONS AMI: 30 Day Stent ThrombosisHORIZONS AMI: 30 Day Stent ThrombosisUFH + UFH +

GP GP IIb/IIIaIIb/IIIa(N=1802)(N=1802)

BivalirudinBivalirudin(N=1800)(N=1800)

PPValueValue

ARC definite or probable* 1.9%1.9% 2.5%2.5% 0.300.30

- definite 1.4%1.4% 2.2%2.2% 0.090.09

- probable 0.5%0.5% 0.3%0.3% 0.240.24

- acute (≤ 24 hrs) 0.3%0.3% 1.3%1.3% <0.001<0.001

- subacute (> 24 h – 30 d) 1.7%1.7% 1.2%1.2% 0.280.28

*Protocol definition of stent thrombosis, CEC adjudicatedARC= Academic Research Consortium

Stone GW, et al. N Engl J Med. 2008;358:2218-2230.

Anticoagulants

Patients undergoing reperfusion with fibrinolyticsshould receive anticoagulant therapy for a minimum of 48 hours (Level of Evidence: C) and preferably for the duration of the index hospitalization, up to 8 days (regimens other than unfractionated heparin [UFH] are recommended if anticoagulant therapy is given for more than 48 hours because of the risk of heparin-induced thrombocytopenia with prolonged UFH treatment). (Level of Evidence: A)

Anticoagulant regimens with established efficacy include:♥ UFH (LOE: C)♥ Enoxaparin (LOE:A)♥ Fondaparinux (LOE:B)




7

Anticoagulants

For patients undergoing PCI after havingreceived an anticoagulant regimen, the

followingdosing recommendations should be followed:

a. For prior treatment with UFH: administer additional boluses of UFH as needed to support the procedure taking into account whether GP IIb/IIIa receptor antagonists have been administered. (Level of Evidence: C) Bivalirudin may also be used in patients treated previously with UFH. (Level of Evidence: C)


Recommendation continues on the next slide. Antman EM, et al. Circulation. 2008;117:296-329.

Anticoagulants

b. For prior treatment with enoxaparin: if the last SC dose was administered within the prior 8 hours, no additional enoxaparin should be given; if the last SC dose was administered at least 8 to 12 hours earlier, an IV dose of 0.3 mg/kg of enoxaparin should be given.

c. For prior treatment with fondaparinux: administer additional intravenous treatment with an anticoagulant possessing anti-IIa activity taking into account whether GP IIb/IIIa receptor antagonists have been administered.




Anticoagulants

Because of the risk of catheter thrombosis,fondaparinux should not be used as the soleanticoagulant to support PCI. An additionalanticoagulant with anti-IIa activity should beadministered.



It is reasonable for patients with STEMI who do not undergo reperfusion therapy to be treated with anticoagulant therapy (non-UFH regimen) for the duration of the index hospitalization, up to 8 days.

Convenient strategies that can be used include those with LMWH (Level of Evidence: C) or fondaparinux (Level of Evidence: B)using the same dosing regimens as for patients who receive fibrinolytic therapy.

Anticoagulants





Thienopyridines

CLARITY-TIMI 28 Primary Endpoint:Occluded Artery (or D/MI thru Angio/HD)*

PlaceboClopidogrelLD 300 mgMD 75 mg

P=0.00000036P=0.00000036

Odds Ratio 0.64(95% CI 0.53-0.76)

Odds Ratio 0.64(95% CI 0.53-0.76)

Clopidogrelbetter

Placebobetter

n=1752 n=1739

D/MI thru Angio/HD, death or myocardial infarction before angiography or hospital discharge.Sabatine MS. N Eng J Med. 2005;352:1179.

STEMI, Age 18-75

15.0

21.7

0

5

10

15

20

25

Occ

lude

d A

rter

y or

Dea

th/M

I (%

)

1.00.4 0.6 0.8 1.2 1.6

36%Odds Reduction

36%Odds Reduction

8

Dea

d (%

)

Days Since Randomization (up to 28 days)

Placebo + ASA: 1,846 deaths (8.1%)

Clopidogrel + ASA:1,728 deaths (7.5%)

0.6% ARD7% RRR P = 0.03

N = 45,852 No Age limit ; 26% > 70 y

Lytic Rx 50%

No LD given

COMMIT: Effect of CLOPIDOGREL on Death in Hospital

LD=lodading dose.Chen ZM, et al. Lancet. 2005;366:1607.

Clopidogrel 75 mg per day orally should be added to aspirin in patients with STEMI regardless of whether they undergo reperfusion with fibrinolytic therapy or do not receive reperfusion therapy.

Treatment with clopidogrel should continue for at least 14 days.

Thienopyridines




In patients < 75 years who receive fibrinolytictherapy or who do not receive reperfusion therapy, it is reasonable to administer an oral clopidogrel loading dose of 300 mg. (No data are available to guide decision making regarding an oral loading dose in patients ≥75 years of age.)

Long-term maintenance therapy (e.g., 1 year) with clopidogrel (75 mg per day orally) can be useful in STEMI patients regardless of whether they undergo reperfusion with fibrinolytic therapy or do not receive reperfusion therapy.


Thienopyridines



Secondary Prevention and Long-term Management

Secondary Prevention

• Smoking– Ask, advise, assess, and assist patients to stop smoking – I

(B)• BP control

– < 140/90 or < 130/80 mm Hg if diabetes or CKD – I (B)– Treat with beta blockers and or ACE-I as tolerated – I (A)

• Lipid management– LDL-C < 100 mg/dL – I (A)– LDL-C < 70 mg/dL is reasonable – IIa (A)– Reasonable to encourage increased consumption of omega-3

fatty acids for risk reduction – IIb (B)• Physical activity

– 30 min 7 d/wk, minimum 5 d/wk – I (B)• Weight management

– BMI 18.5 to 24.9 kg/m2 – I (B)– Waist circumference: Men < 40 in, women < 35 in – I (B)


Secondary Prevention (cont.)

• Diabetes management– HbA1c < 7% - I (B)

• Aspirin 75 to 162 mg daily– Indefinitely post-PCI – I (B)– Reasonable initially post-PCI if bleeding risk is a concern - IIa

(C)• Clopidogrel 75 mg daily

– PCI – I (B) – no PCI – IIa (C)

• RAAS Blockade– ACE-I or ARB if ACE-I intolerant if LVEF < 40% - I (A)– Reasonable with normal LVEF – IIa (B)– ARB therapy beneficial if ACE-I intolerant and hypertensive – I

(B)• Annual influenza vaccination – I (B)


9

Questions NSTEMI Patient Simulation

Please log in now…Please log in now…

2007 ACC/AHA UA/NSTEMI Updated Guidelines

James A. de Lemos, MDDirector, Coronary Care UnitParkland Memorial Hospital

Dallas, TX

•Examine updated ACC/AHA UA/NSTEMI guidelines

•Apply evidence‐based UA/NSTEMI guidelines to ACS

patient scenarios

•Implement changes in your practice based on review and

application of the updated UA/NSTEMI guidelines

Learning Objectives

UA/NSTEMI Guidelines Slide Set

ACC/AHA 2007 Guidelines for the Management of Patients with Unstable Angina/Non–ST-Elevation Myocardial Infarction

Developed In Collaboration with the American College of Emergency Physicians, the Society for

Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons

Endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the

Society for Academic Emergency Medicine

Special Thanks to

The UA/NSTEMI Guidelines Writing Committee Members

Jeffrey L. Anderson, MD, FACC, FAHA, Chair Francis M. Fesmire, MD, FACEP

Cynthia D. Adams, RN, PhD, FAHA Judith S. Hochman, MD, FACC, FAHA

Elliott M. Antman, MD, FACC, FAHA Thomas N. Levin, MD, FACC, FSCAI

Charles R. Bridges, ScD, MD, FACC, FAHA A. Michael Lincoff, MD, FACC

Robert M. Califf, MD, MACC Eric D. Peterson, MD, MPH, FACC, FAHA

Donald E. Casey, Jr, MD, MPH, MBA, FACP Nanette Kass Wenger, MD, FACC, FAHA

William E. Chavey II, MD, MS R. Scott Wright, MD, FACC, FAHA

Slide Set EditorNanette Kass Wenger, MD, FACC, FAHA

10

Select Management Strategy:

Initial Invasive Versus Initial Conservative Strategy

Major ChangesNew Trial Data

Selection of Initial Treatment Strategy: Initial Invasive vs Conservative Strategy

Invasive Recurrent angina/ischemia at rest with low-level activities despite intensive medical therapyElevated cardiac biomarkers (TnT or TnI)New/presumably new ST-segment depression

Signs/symptoms of heart failure or new/worsening mitral regurgitationHigh-risk findings from noninvasive testingHemodynamic instabilitySustained ventricular tachycardiaPCI within 6 monthsPrior CABGHigh risk score (eg, TIMI, GRACE)Reduced left ventricular function (LVEF < 40%)

Conservative Low risk score (eg, TIMI, GRACE)Patient/physician preference in the absence of high-risk features

Initial Invasive Strategy

Major Changes•New Drugs•Longer Duration of Antiplatelet Rx•Revised Algorithm

Algorithm for Patients with UA/NSTEMI Managed by an Initial Invasive Strategy

Proceed to Diagnostic Angiography

ASA (Class I, LOE: A)Clopidogrel if ASA intolerant (Class I,

LOE: A)

Diagnosis of UA/NSTEMI is Likely or Definite

Invasive StrategyInit ACT (Class I, LOE: A)

Acceptable options: enoxaparin or UFH (Class I, LOE: A) bivalirudin or fondaparinux (Class I, LOE: B)

Select Management StrategyProceed with an

Initial Conservative

Strategy

ACT=anticoagulation therapy; LOE=level of evidence. Anderson JL, et al. J Am Coll Cardiol. 2007;50:e1-e157.

A

B

B1

B2

Prior to AngiographyInit at least one (Class I, LOE: A) or

both (Class IIa, LOE: B) of the following:

ClopidogrelIV GP IIb/IIIa inhibitor

Factors favoring admin of both clopidogrel and GP IIb/IIIa inhibitor include delay to

angiography, high-risk features, and early recurrent ischemic discomfort

Initial Invasive Strategy: Antiplatelet TherapyFor UA/NSTEMI patients in whom an initial invasive strategy is selected, antiplatelet therapy in addition to ASA should be initiated before diagnostic angiography (upstream) with either clopidogrel (loading dose followed by daily maintenance dose)* or an IV GP IIb/IIIa inhibitor.

Abciximab as the choice for upstream GP IIb/IIIatherapy is indicated only if there is no appreciable delay to angiography and PCI is likely to be performed; otherwise, IV eptifibatideor tirofiban is the preferred choice of GP IIb/IIIainhibitor.†


*Some uncertainty exists about optimum dosing of clopidogrel. Randomized trials establishing its efficacy and providing data on bleeding risks used a loading dose of 300 mg orally followed by a daily oral maintenance dose of 75 mg. Higher oral loading doses such as 600 or 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 the safety of higher oral loading doses have not been rigorously established; †Factors favoring administration of both clopidogrel and a GP IIb/IIIainhibitor include: delay to angiography, high-risk features, and early ischemic discomfort.


Clopidogrel in UA/NSTEMI to preventRecurrent ischemic Events (CURE)

•12,562 patients within 24 h UA/NSTEMI•Placebo vs clopidogrel (LD 300 mg → 75 mg qd)•Other meds: ASA•↓ CV death, MI, or stroke, rate of recurrent ischemia & revasc with clopidogrel•↑ Major (non–life-threatening) bleeding with clopidogrel•No routine inv strategy, 23% revasc during initial admission•Although well tolerated, < 10% GP IIb/IIIa + ASA + clopidogrel + heparin use in study patients

Yusuf S, et al. N Engl J Med. 2001;345:494–502.

11

Platelet glycoprotein IIb/IIIa in UA/NSTEMI: Receptor Suppression Using InTegrilin

(PURSUIT)•10,948 patients within 24 h UA/NSTEMI•Low-dose eptifibatide (n=1,487) vs high-dose eptifibatide (n=4,722) vs placebo (n=4,739)•Other meds: ASA, heparin•↓ Death/MI @ 96 hours, 7 d, 30 d with eptifibatide

― 1.5% ARR 4–30 d― ↑ major bleeding― no diff stroke

•↑ Event rate in 11% of patients not treated with concomitant heparin

ARR=absolute risk reduction.The PURSUIT Trial Investigators. N Engl J Med 1998;339:436–43.

Boersma E, et al. Circulation 2000;101:2557–2567.

Platelet Receptor Inhibition in Ischemic Syndrome Management

in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS)

•1,915 patients within 12 h UA/NSTEMI

•Tirofiban alone, UFH alone, or both for 48–108 h.

•Tirofiban-alone arm discontinued d/t ↑ mortality rate.

•↓ Death, MI, or refractory ischemia at 7 d, 30 d & 6 mo by tirofiban + heparin

•High rate of angio could have contributed to important ↓ in event rates

•Recommend: Tirofiban + heparin for medical rx or during PCI

PRISM-PLUS Study Investigators. N Engl J Med 1998;338:1488–1497.

Initial Invasive Strategy:Antiplatelet Therapy

For UA/NSTEMI patients in whom an initial invasive strategy is selected, it is reasonable to initiate antiplatelet therapy with both clopidogrel(loading dose followed by daily maintenance dose)* and an intravenous GP IIb/IIIa inhibitor.

Abciximab as the choice for upstream GP IIb/IIIatherapy is indicated only if there is no appreciable delay to angiography and PCI is likely to be performed; otherwise, IV eptifibatideor tirofiban is the preferred choice of GP IIb/IIIainhibitor.†

*Some uncertainty exists about optimum dosing of clopidogrel. Randomized trials establishing its efficacy and providing data on bleeding risks used a loading dose of 300 mg orally followed by a daily oral maintenance dose of 75 mg. Higher oral loading doses such as 600 or 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 the safety of higher oral loading doses have not been rigorously established; †Factors favoring administration of both clopidogrel and a GP IIb/IIIainhibitor include: delay to angiography, high-risk features, and early ischemic discomfort.



Intracoronary Stenting andAntithrombotic Regimen–Rapid Early Action for

Coronary Treatment (ISAR-REACT)-2

•2,022 patients within 48 h high-risk UA/NSTEMI•ASA + clopidogrel + abciximab vs ASA + clopidogrel•600 mg LD clopidogrel ≥ 2 h before PCI → abciximab or placebo•↓ Death, MI, or urgent TVR by 30 d with abciximab

― ↓ If cTnT +; no diff if cTnT –•No diff major/minor bleeding•Recommend: GP IIb/IIIa + clopidogrel if inv strategy used and high risk (Class IIa, LOE: B)

LD=loading dose; LOE=level of evidence.Kastrati A, et al. JAMA 2006;295:1531–1538.

Initial Invasive Strategy:Antiplatelet TherapyFor UA/NSTEMI patients in whom an initial invasive strategy is selected, it is reasonable to omit upstream administration of an intravenous GP IIb/IIIa antagonist before diagnostic angiography if bivalirudin is selected as the anticoagulant and at least 300 mg of clopidogrel was administered at least 6 h earlier than planned catheterization or PCI.


New Drug

Initial Invasive Strategy:Anticoagulant Therapy

Anticoagulant therapy should be added to antiplatelet therapy in UA/NSTEMI patients as soon as possible after presentation.

•For patients in whom an invasive strategy is selected, regimens with established efficacy at a Level of Evidence: A include enoxaparinand unfractionated heparin (UFH), and those with established efficacy at a Level of Evidence: B include bivalirudin and fondaparinux.



New Drugs

12

Efficacy and Safety ofSubcutaneous Enoxaparin in Non-Q-Wave

Coronary Events (ESSENCE) Trial


•Enoxaparin vs UFH

•Other meds: ASA

•↓ Death, MI or recurrent angina for enox @ 14 d, 30d and 1 y

― minor bleeding ↑

― major bleeding ↔

Cohen M, et al. N Engl J Med. 1997;337:447–452. Cohen M, et al. Am J Cardiol. 1998;82:19L–24L (bleeding).

Goodman SG, et al. J Am Coll Cardiol. 2000;36:6934–6938 (1-y results).

Thrombolysis In Myocardial Ischemia trial, phase 11B (TIMI 11B)



•Other meds: ASA

•↓ Death, MI or urgent revasc for enox @ 48 h, 8 d, 14 d, & 43 d

•↑ major & minor bleeding (inhosp) with enox

Antman EM, et al. Circulation. 1999;100:1593–1601.

Superior Yield of the New strategy ofEnoxaparin, Revascularization and GlYcoprotein

IIb/IIIa Inhibitors (SYNERGY)

Ferguson JJ, et al. JAMA. 2004;292:45–54. Mahaffey KW, et al. Am Heart J. 2005;149:S81–S90 (6 mo & 1-y results).

•9,978 patients within 24 h high-risk UA/NSTEMI

•Enoxaparin vs UFH → early inv strategy

•Other meds: ASA, GP IIb/IIIa @ physician discretion

•Enox noninferior for death/MI @ 30 d, 6 mo 1 y

•↑ Major bleeding with enox

― ? due to crossover to UFH @ time of PCI

SYNERGY Primary Outcomes

14.5 14

0

2

4

6

8

10

12

14

16

Death or MIat 30 d

UFHEnoxaparin

Absolute Risk Reduction 0.5Hazard Ratio 0.9695% CI 0.86–1.06p 0.40

Free

dom

from

Dea

th/M

I

0.8

0.85

0.9

0.95

1.0

0 5 10 15 20 25 30

Days from Randomization

Kaplan Meier Curve

UFH

Enoxaparin

Reprinted with permission from Ferguson JJ, et al. JAMA. 2004;292:45–54.

Antithrombotic CombinationUsing Tirofiban and Enoxaparin (ACUTE II)

•525 patients within 24 h UA/NSTEMI •Enoxaparin vs UFH •Other meds: ASA, tirofiban LD 0.4 mcg/kg over 30 min →0.1 mcg/kg/min

•No ↓ death/MI during first 30 d― Trend to lower event rates with enox

•No ↓ major/minor bleeding

LD=loading dose.Cohen M, et al. Am Heart J 2002;144:470–477.

INTegrilin and Enoxaparin Randomized Assessment of Acute Coronary syndrome

Treatment (INTERACT)•746 patients within 24 h high-risk UA/NSTEMI


•Other meds: ASA, eptifibatide 180 mcg/kg IV bolus → 2.0 mcg/kg/min infusion for 48 hours

•↓ Death/MI for enox @ 30 d

•Minor bleeding - ↑ for enox @ 96 h, no diff by 30 d

•Major bleeding - ↓ for enox @ 96 h (1o safety endpoint)

Goodman SG, et al. Circulation. 2003;107:238–244.

13

Aggrastat to Zocor (A to Z)

•3,987 patients within 24 h UA/NSTEMI on ASA & tirofiban•Enoxaparin vs UFH •Coronary angio in 60% of pts•No ↓ all-cause mortality, MI or refractory ischemia w/in 7 d by enox― Nonsig trend to ↓ ischemic events with enox

•↑ Major bleeding with enox

Blazing MA, et al. JAMA 2004;292:55–64.

Acute Catheterization and Urgent Intervention Triage strategY (ACUITY)

•Within 24 h UA/NSTEMI → heparin (enox/UFH) ± upstream GP IIb/IIIa (n=4603) vs bivalirudin (bival) ± upstream GP IIb/IIIa(n=4604) vs bival alone + provisional GP IIb/IIIa (n=4612)•Compared to heparin + GP IIb/IIa:― Bival + GP IIb/IIIa noninferior for composite ischemia, major

bleeding & net clinical outcomes @ 30 d― Bival alone noninferior for composite ischemia; ↓ major bleeding; ↓ net clinical outcomes @ 30 d

•Caution using bival alone, esp with delay to angio and high-risk features, or if early ischemic discomfort occurs after initial

antithrombotic strategy implemented•Recommend: Concomitant use of GP IIb/IIIa or thienopyridinebefore angio whether bival-based or heparin-based strategy used

Stone GW, et al. N Engl J Med. 2006;355:2203–2216.

7.3

5.7

11.7

7.7

5.3

11.8

0

2

4

6

8

10

12

14

ACUITY Compositeischemia endpoint at 30

days

ACUITY Major bleeding at30 days

ACUITY Net clinicaloutcome at 30 days

UFH or Enoxaparin + GP IIb/IIIa

Bivalirudin + GP IIb/IIIa

ACUITY Clinical Outcomes at 30 d

Absolute Risk Reduction -0.4 0.4 -0.1Hazard Ratio 1.07 0.93 1.0195% CI 0.92–1.23 0.78–1.10 0.90–1.12p 0.007* < 0.001* < 0.001* *p for noninferiority.


Net

clin

ical

out

com

e (%

)

ACUITY Composite Ischemia and Bleeding Outcomes

Absolute Risk Reduction -0.5 0.3 -2.0 2.7Hazard Ratio 1.08 0.97 1.29 0.5395% CI 0.93–1.24 0.80–1.17 1.03–1.63 0.43–0.65p 0.32 0.054 (for interaction) < 0.001


7.3 7.3 7.1

5.7

7.8

7.0

9.1

3.0

0

1

2

3

4

5

6

7

8

9

10

ACUITY Composite ischemiaendpoint at 30 days

Ischemia endpoint bythienopyridine loading before angiography or PCI YES

Ischemia endpoint bythienopyridine loading before

angiography or PCI No

ACUITY Major bleeding at 30days

UFH + GP IIb/IIIa

Bivalirudin alone

Isch

emia

/ble

edin

g ou

tcom

es (%

)

Organization toAssess Strategies for Ischaemic

Syndromes (OASIS-5)•Fondaparinux (fonda) (2.5 mg/day, n=10,057) vs enox (1.0 mg/kg BID, n=10,021) in UA/NSTEMI patients― Enox patients undergoing PCI → UFH if last dose of enox > 6 h

before PCI•Other meds: ASA, clopidogrel, GP IIb/IIIa @ investigator discretion•No ↓ death, MI or refractory ischemia @ 9 d by fonda

― Noninferiority criteria met•↓ Major bleeding with fonda•↓ Death @ 30 d and 180 d and ↓ death, MI and stroke @ 180 d with fonda•↑ Catheter-assoc thrombus with fondaYusuf S, et al. N Engl J Med. 2006;354:1464–1476.

Also see Section 3.2.5.5 in Anderson JL, et al. J Am Coll Cardiol. 2007;50:e1-e157 for detailed discussion of trial results and dosing protocol.

OASIS 5 Cumulative Risk of Death, MI, or Refractory Ischemia

*p for noninferiority; †p for superiority. Yusuf S, et al. N Engl J Med. 2006;354:1464–1476.

5.7

4.1

9.0

5.8

2.2

7.3

0123456789

10

OASIS 5 Death, MI, or refractoryischemia at 9 days

OASIS 5 Major bleeding at 9 days

OASIS 5 Composite primaryoutcome and major bleeding at 9 days

Enoxaparin

Fondaparinux

Absolute Risk Reduction -0.1 1.9 1.7Hazard Ratio 1.01 0.52 0.81Confidence Interval 0.90–1.13 0.44–0.61 0.73–0.89p 0.007* < 0.001† < 0.001†

Mai

n ef

ficac

y an

d sa

fety

out

com

es (%

)

14

Initial Conservative Strategy

Major Changes•New Drugs•Longer Duration of Antiplatelet Rx•Revised Algorithm

Init clopidogrel (Class I, LOE: A) Consider adding IV eptifibatide or tirofiban

(Class IIb, LOE: B)

Conservative StrategyInit ACT (Class I, LOE: A):

Acceptable options: enoxaparin or UFH (Class I, LOE: A) or fondaparinux (Class I, LOE: B), but

enoxaparin or fondaparinux are preferable (Class IIa, LOE: B)

Select Management Strategy

ASA (Class I, LOE: A)Clopidogrel if ASA intolerant (Class I, LOE:

A)

Diagnosis of UA/NSTEMI is Likely or Definite

Algorithm for Patients with UA/NSTEMI Managed by an Initial Conservative Strategy

Proceed with Invasive Strategy

(Continued)ACT=anticoagulation therapy.

LOE=level of evidence.Anderson JL, et al. J Am Coll Cardiol. 2007;50:e1-e157.

C2

C1

A

Any subsequent events necessitating angiography?

EF greater than 40%

Evaluate LVEF

Low Risk

Cont ASA (Class I, LOE A) Cont clopidogrel (Class I, LOE A) and ideally up to 1 yr (Class I, LOE B)

DC IV GP IIb/IIIa if started previously (Class I, LOE A) DC ACT (Class I, LOE A)

(Class I, LOE: B)

Proceed to DxAngiography

Yes

EF 40% or less Stress Test

(Class I, LOE: A)

No

Not Low Risk

(Class IIa, LOE: B)

Algorithm for Patients with UA/NSTEMI Managed by an Initial Conservative Strategy

(Continued)

ACT=anticoagulation therapy; LOE=level of evidence. Anderson JL, et al. J Am Coll Cardiol. 2007;50:e1-e157.

(Class I, LOE: A)

(Class IIa, LOE: B)

O

L

MN

K

E-1 E-2

D

(Class I,

LOE: B)

(Class I, LOE: A)

Initial Conservative Strategy:Antiplatelet TherapyFor UA/NSTEMI patients in whom an initial conservative (ie, noninvasive) strategy is selected, clopidogrel (loading dose followed by daily maintenance dose)* should be added to ASA and anticoagulant therapy as soon as possible after admission and administered for at least 1 month (Level of Evidence: A) and ideally up to 1 year. (Level of Evidence: B)


*Some uncertainty exists about optimum dosing of clopidogrel. Randomized trials establishing its efficacy and providing data on bleeding risks used a loading dose of 300 mg orally followed by a daily oral maintenance dose of 75 mg. Higher oral loading doses such as 600 or 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 the safety of higher oral loading doses have not been rigorously established.


Antiplatelet therapy forReduction of MYocardial Damage during

Angioplasty (ARMYDA-2)•Patients with stable angina or UA/NSTEMI

•Clopidogrel 600 mg LD (n=126) vs clopidogrel 300 mg LD (n=129) 4 to 8 h before PCI

•↓ Death, MI or TVR up to 30 days by 600 mg LD

― Benefit d/t ↓ periprocedural MI

•Small study of relatively low-risk patients, low use of GP IIb/IIIa

LD=loading dose.Patti G, et al. Circulation. 2005;111:2099 –2106.

Initial Conservative Strategy:Antiplatelet Therapy

For UA/NSTEMI patients in whom an initial conservative strategy is selected, if recurrent symptoms/ischemia, HF, or serious arrhythmias subsequently appear, then diagnostic angiography should be performed. (Level of Evidence: A) Either an IV GP IIb/IIIa inhibitor (eptifibatide or tirofiban; Level of Evidence: A) or clopidogrel (loading dose followed by daily maintenance dose; Level of Evidence: A)* should be added to ASA and anticoagulant therapy before diagnostic angiography (upstream). (Level of Evidence: C)


*Some uncertainty exists about optimum dosing of clopidogrel. Randomized trials establishing its efficacy and providing data on bleeding risks used a loading dose of 300 mg orally followed by a daily oral maintenance dose of 75 mg. Higher oral loading doses such as 600 or 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 the safety of higher oral loading doses have not been rigorously established.

See recommendation

for LOE

15

Platelet Receptor Inhibition in Ischemic Syndrome Management

(PRISM)•3,232 patients within 24 h UA/NSTEMI

•Tirofiban vs UFH over 48 h

•Other meds: ASA

•↓ Death, MI, or refractory ischemia at 48 h & 7 d by tirofiban

― ↓ Death/MI @ 30 d

― No ↑ bleeding; thrombocytopenia ↑

PRISM Study Investigators. N Engl J Med. 1998;338:1498–1505.

Initial Conservative Strategy:Antiplatelet TherapyFor UA/NSTEMI patients in whom an initial conservative strategy is selected and who have recurrent ischemic discomfort with clopidogrel, ASA, and anticoagulant therapy, it is reasonable to add a GP IIb/IIIaantagonist before diagnostic angiography.


Initial Conservative Strategy:Antiplatelet TherapyFor UA/NSTEMI patients in whom an initial conservative (ie, noninvasive) strategy is selected, it may be reasonable to add eptifibatide or tirofiban to anticoagulant and oral antiplatelet therapy.

Abciximab should not be administered to patients in whom PCI is not planned.



Initial Conservative Strategy:Anticoagulant Therapy

Anticoagulant therapy should be added to antiplatelet therapy in UA/NSTEMI patients as soon as possible after presentation.

•For patients in whom a conservative strategy is selected, regimens using either enoxaparin* or UFH (Level of Evidence: A) or fondaparinux (Level of Evidence: B) have established efficacy.

•In patients in whom a conservative strategy is selected and who have an increased risk of bleeding, fondaparinux is preferable.



*Limited data are available for the use of other low-molecular-weight heparins (LMWHs), eg, dalteparin.

New Drugs

Initial Conservative Strategy:Anticoagulant Therapy

For UA/NSTEMI patients in whom an initial conservative strategy is selected, enoxaparin* or fondaparinux is preferable to UFH as anticoagulant therapy, unless CABG is planned within 24 h.


*Limited data are available for the use of other low-molecular-weight heparins (LMWHs), eg, dalteparin.

Initial Conservative Strategy:Additional Management Considerations

For UA/NSTEMI patients in whom an initial conservative strategy is selected and no subsequent features appear that would necessitate diagnostic angiography (recurrent symptoms/ischemia, HF, or serious arrhythmias), a stress test should be performed.

a. If, after stress testing, the patient is classified as not at low risk, diagnostic angiography should be performed.


This recommendation continues on the next slide.


16


b. If, after stress testing, the patient is classified as being at low risk, the instructions noted below should be followed in preparation for discharge:

1. Continue ASA indefinitely. (Level of Evidence: A)2. Continue clopidogrel for at least 1 month (Level of Evidence: A) and ideally up to 1 year. (Level of Evidence: B)3. Discontinue IV GP IIb/IIIa inhibitor if started previously. (Level of Evidence: A)4. Continue UFH for 48 h or administer enoxaparin or fondaparinux for the duration of hospitalization, up to 8 d, and then discontinue anticoagulant therapy. (Level of Evidence: A)



For UA/NSTEMI patients in whom a conservative strategy is selected and who do not undergo angiography or stress testing, the instructions noted below should be followed:

a. Continue ASA indefinitely. (Level of Evidence: A)b. Continue clopidogrel for at least 1 month (Level of Evidence: A) and ideally up to 1 year. (Level of Evidence: B)c. Discontinue IV GP IIb/IIIa inhibitor if started previously. (Level of Evidence: A)d. Continue UFH for 48 h or administer enoxaparin or fondaparinux for the duration of hospitalization, up to 8 d, and then discontinue anticoagulant therapy. (Level of Evidence: A)


See a-d for LOE


For UA/NSTEMI patients in whom an initial conservative strategy is selected and in whom no subsequent features appear that would necessitate diagnostic angiography (recurrent symptoms/ischemia, HF, or serious arrhythmias), LVEF should be measured.

If LVEF is ≤ 40%, it is reasonable to perform diagnostic angiography.

If LVEF is > 40%, it is reasonable to perform a stress test.

III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII



Additional Management Considerations for Antiplatelet and Anticoagulant Therapy

Intravenous fibrinolytic therapy is not indicated in patients without acute ST-segment elevation, a true posterior MI, or a presumed new left bundle-branch block.

III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII

Cardiac cath

CAD No

Discharge from protocol

Yes

Left main disease Yes CABG

No

1- or 2-Vessel

Disease

3- or 2-vessel disease with proximal LAD involvement

LV dysfunction or treated diabetes*

No

PCI or CABG

Medial Therapy,

PCI or CABG

Yes CABG

*There is conflicting information about these patients. Most consider CABG to be preferable to PCI.

Anderson JL, et al. J Am Coll Cardiol. 2007;50:e1–e157.

Revascularization Strategy in UA/NSTEMI

Long-term Antithrombotic Therapy at Hospital Discharge after UA/NSTEMI

Medical Therapy

without Stent

Bare Metal Stent Group

Drug Eluting Stent Group

ASA 162 to 325 mg/d for at least 1 month, then 75 to 162

mg/d indefinitely (Class I, LOE: A)

&Clopidogrel 75 mg/d for at least

1 month and up to 1 year (Class I, LOE:B)

Add: Warfarin (INR 2.0 to 2.5) (Class IIb, LOE: B)

Continue with dual antiplatelet therapy as above

Yes

No

Indication for Anticoagulation?

ASA 75 to 162 mg/d indefinitely (Class I, LOE: A)

&

Clopidogrel 75 mg/d at least 1 month (Class I, LOE: A) and up to 1 year (Class I,

LOE: B)

ASA 162 to 325 mg/d for at least 3 to 6 months, then

75 to 162 mg/d indefinitely (Class I, LOE: A)

&

Clopidogrel 75 mg/d for at least 1 year (Class I, LOE:

B)

INR=international normalized ratio; LOE=level of evidence.Anderson JL, et al. J Am Coll Cardiol. 2007;50:e1–e157.

UA/NSTEMI Patient Groups

at Discharge

New

17

Questions Bridging the Gap Between Emergency Medicine and

Cardiology

Charles V. Pollack Jr., MDProfessor and Chairman

Department of Emergency MedicinePennsylvania Hospital

Philadelphia, PA

•Analyze the implications of updated ACC/AHA ACS guidelines for emergency

medical care

•Enhance cooperation between the emergency department (ED) and the emergency transport team, hospital

administration, catheterization laboratory, and CCU

•Adapt quality improvement strategies and evidence‐based algorithms to align STEMI and UA/NSTEMI ED practice with

current scientific data

Learning Objectives What Is the State of Emergency Care?

Y=2.86 (±1.46) + 0.0045X1 + 0.000043X2

P<.001

Trends in ED Visits: US 1995-2005

5,000

4,500

4,000

3,500

3,000

2,500

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005

Num

ber o

f em

erge

ncy

depa

rtm

ents

Visits

Emergency departments

00

90

95

100

105

110

115

120

Num

ber o

f em

erge

ncy

depa

rtm

ent v

isits

in

mill

ions

Trends in numbers of emergency departments and related visits: United States 1995-2005

Nawar EW, et al. Advance Data. 2007;29(386):1.

18

Trends in ED Visits: US 1995-2005

5,000

4,500

4,000

3,500

3,000

2,500

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005

Num

ber o

f em

erge

ncy

depa

rtm

ents

Visits

Emergency departments

00

90

95

100

105

110

115

120

Num

ber o

f em

erge

ncy

depa

rtm

ent v

isits

in

mill

ions

Trends in numbers of emergency departments and related visits: United States 1995-2005

Nawar EW, et al. Advance Data. 2007;29(386):1.

••In the last 10 years ED visits have In the last 10 years ED visits have increased by 20% while the number increased by 20% while the number of of EDsEDs has decreased by 7%has decreased by 7%

••The second most common reason The second most common reason given by patients for coming to the given by patients for coming to the ED is chest pain and related ED is chest pain and related symptomssymptoms

Does Evidence-based ACS Care

Matter?

RCTs Exclude the Elderly: Review of 593 UA/MI Trials

0102030405060708090

100

1966–70 1971–80 1981–90 1991–95 1996–00

Explicit exclusion > 75 No patient > 75 enrolled

Tria

ls n

ot in

clud

ing

elde

rly (%

)

Lee PY, et al. JAMA. 2001;286:708-713.

Comparison of Co-morbid Burden in Trials

Age group (%) Trials

Community1624

211

HTN (%)Trials

Community5975

5773

Diabetes (%)Trials

Community2536

2025

CHF (%)Trials

Community1626

2236

Prior stroke (%)Trials

Community9

178

18

ST depression (%)Trials

Community6142

6440

Age 75–84 Age ≥ 85


CRUSADE Community and VIGOUR Trials

Lower Guideline Adherence = Poorer Outcomes

No. of events (%) by hospital adherence quartile

Population 1 (lowest) 2 3 4 (highest) P Value

Overall (N=64,775)

(n=12,329) (n=15,255) (n=18,364) (n=18,827)

Death 784 (6.36) 772 (5.06) 850 (4.63) 786 (4.17) < .001

Death/MI 1119 (9.08) 1280 (8.39) 1223 (6.66) 1201 (6.38) < .001

Stroke 96 (0.78) 146 (0.96) 171 (0.93) 134 (0.71) .31

CHF 908 (7.36) 1747 (11.45) 1727 (9.40) 1541 (8.19) .24

Peterson ED, et al. JAMA.2006;295:1912-1920.

In-hospital Mortality in Elderly and Very Elderly NSTE-ACS Patients and

Guideline Adherence

Skolnick, AH et al. JACC. 2007;49:1790-1797.

20

25

15

10

5

00-25 26-50 51-75 76-100

Percent Adherence Score

In-H

ospi

tal M

orta

lity

(%)

Age ≥ 90 Age 75-89

P-value for trend <0.001

P-value for age-treatment interaction = NS14.7

18.9

11.08.3

10.2

6.7

11.1

6.2

19

What Is the State of Evidence-based ACS

Care in the ED?

What degree of improvement is required for the treatment of acute myocardial infarction in the US?

1. A great deal2. A fair amount 3. Somewhat4. Not at all

More than Half of Surveyed US Physicians Point to Need for

Improved MI Treatment

Peacock WF, et al. Tex Heart Inst J. 2008;35(2):152-161.

How would you characterize your familiarity with the ACC/AHA STEMI Guidelines?

1. Very familiar2. Familiar3. Somewhat familiar4. Not at all familiar

STEMI Guideline Familiarity Still Lacking


Physician Views of Hospital Conformance with STEMI Guidelines

78% of surveyed physicians indicated their hospital had a written MI treatment protocol, but

23% deemed the protocol ineffective in helping providers determine AMI treatment50% said that the protocol was followed only sometimes or rarely

40% believed time to reperfusion could be significantly improved, but

Most (69%) did not believe primary PCI within 90 minutes was realistic in transfer patients20% viewed performing PCI in less than 90 minutes as unrealistic even in a PCI-capable facility


20

What Is Your Experience?Does your hospital have a written STEMI protocol?

1. Yes2. No3. Unsure

If your hospital has a written STEMI protocol, is it implemented?

1. Yes2. No3. Unsure4. Not applicable

Does the written STEMI protocol at your hospital improve MI care?

1. Yes2. No3. Unsure4. Not applicable

Which of the following best characterizes your hospital (select one)?

1. No catheterization lab2. Interventional catheterization

capability3. Diagnostic catheterization capability4. Interventional catheterization and

CABG capability

What is the estimated mean time to balloon inflation in your hospital for STEMI patients?

1. 60 minutes or less 2. 90 minutes3. 120 minutes4. More than 120 minutes5. Not applicable6. Unsure

Do you think achievement of primary PCI in 90 minutes or less is feasible when a patient must be transferred?

1. Yes2. No3. Unsure

21

Time from Symptom Onset to TreatmentPredicts 1-year Mortality after Primary PCI

The relative risk of 1-year mortality increases by 7.5% for each 30-minute delay

De Luca G, et al. Circulation. 2004;109:1223-1225.

Y=2.86 (±1.46) + 0.0045X1 + 0.000043X2

P<.001

0

2

4

6

8

10

12

14

60 120 180 240 300 360

Ischemic time (minutes)

1-Ye

ar m

orta

lity

(%)

In Other Words…

=

MuscleTime

Rapid Reperfusion in STEMI?

Up to one-third of eligible patients with STEMI receive no reperfusion therapy acutely

National Registry of Myocardial Infarction

Boden WE, et al. JACC. 2007;50:917-929.

Often NotWhy?

Age (75 years or older)Female gender Presentation without chest painHistory of cardiovascular disease Failure to identify high-risk ECG



Missed Opportunities for Reperfusion in STEMI: The Emergency Department Quality

in Myocardial Infarction (EDQMI) Study

Examples of why reperfusion was withheld: Currently asymptomaticProlonged painPain alleviated with other medicationsOld ageWarfarin recently stopped (but INR not elevated)Concern for abdominal aortic aneurysm (but CT negative)

Tricomi AJ, et al. Am H J. 2008;155:471-477.

Missed Opportunities for Reperfusion in STEMI: The Emergency Department Quality

in Myocardial Infarction (EDQMI) Study

Tricomi AJ, et al. Am H J. 2008;155:471-477.

22

Rates of Reperfusion By Patient Subgroup

Nallamothu BK, et al. Am J Med. 2007;120:693-699.

6560

5550

80

75

70

95

90

85

100

Patie

nts

(%)

June 1994 to May 1997



Age ≥ 75

Women

Non-whites

No chest pain

Delayed presentation

Atypical Symptoms in Elderly STEMI Patients in NRMI

Population < 65 yr(%)

65-74 yr(%)

75-84 yr(%)

≥ 85 yr(%)

Killip class II-IV

11.7 23.4 33.3 44.6

LBBB 4.8 14.7 24.0 33.8

Chest pain 89.9 80.1 69.9 56.8


Reperfusion Therapy Based on Age in NRMI


Primary PCI

Lytics

< 65N=360,101

65-74191,093

75-84160,534

> 8563,952

Patient Age

2030405060

8070

100

% o

f Age

Gro

up

Absolute Mortality Advantage of PCI Over Fibrinolysis

1.04.2

5.1

6.9

(501) (452) (69) (78)(958)(894)(1892)(1919)No. of patients

< 65 yrs 65-74 yrs 75-84 yrs ≥ 85 yrs

Adapted from the Primary Coronary Angioplasty Trialist’s (PCAT)-2 Investigators.Boersma E, The Primary Coronary Angioplasty vs Thrombolysis Group. Eur Heart J. 2006;27(7):779-788.

0

5

10

15

20

25

30D

eath

in tr

eatm

ent a

rms

(%)

3.53.5

2.52.5

9.79.7

5.55.5

19.019.0

13.913.9

26.126.1

19.219.2

Primary PCI

Lytics

The Problem with Primary PCI

60% to 70% of STEMI patients present initially to hospitals without ready access to primary PCIData from NRMI-3 and -4 registries show that only 4% of STEMI patients who are transferred for primary PCI achieve door-to-balloon times of 90 min



ACC/AHA 2004 STEMI Guidelines: Recommendations for Reperfusion Therapy

Early presentation ≤ 3 hrs of symptom onset and delay to invasive strategy

Invasive strategy is not an optionCatheterization lab occupied/not availableVascular access difficultiesLack of access to a skilled PCI lab (operator experience > 75 PCI cases/yr; team experience > 36 PCI cases/yr)

Delay to invasive strategyProlonged transport(Door-to-balloon) – (door-to-needle) time is > 1 hrMedical contact-to-balloon time is > 90 min

Primary PCI Preferred

Skilled PCI laboratory available with surgical backup

Medical contact-to-balloon time is < 90 min;(door-to-balloon) – (door-to-needle time) is< 1 hr

High risk from STEMICardiogenic shock Killip class ≥ 3

Contraindications to fibrinolysisIncluding increased risk of bleeding and ICH

Late presentationSymptom onset > 3 hrs ago

Diagnosis of STEMI is in doubt

Fibrinolytic Preferred

ICH=intracranial hemorrhage; PCI=percutaneous coronary intervention.

Antman EM, et al. J Am Coll Cardiol. 2004;44:671-719.

If presentation is < 3 hours and there is no delay to an invasive strategy, there is no preference for either strategy

23

Time to PCI Associated with Equilibration of PCI and Fibrinolysis

Fibr

inol

ysis

Bet

ter

PCI B

ette

r

2.0

1.5

1.25

1.0

0.8

0.560 75 90 105 114 135 150 165 180

Odd

s of

Dea

th w

ith F

ibrin

olys

is

PCI Related Delay (DB-DN) (min)Ant=anterior; NonAnt=non anterior; DB=door-to-balloon time; DN=door-to-needle time.

Based on a multivariate model that included: treatment type, age, gender, race, diabetes mellitus, hypertension, angina, Killip class 2/3, Killip class 4, previous infarction, current smoking, stroke, pulse,

systolic blood pressure, payer, symptom duration, infarct location, and discharge year.Pinto DS, et al. Circulation. 2006;114:2019.

Ant=anterior; NonAnt=non anteriorBased on a multivariate model that included: treatment type, age, gender, race, diabetes mellitus,

hypertension, angina, Killip class 2/3, Killip class 4, previous infarction, current smoking, stroke, pulse, systolic blood pressure, payer, symptom duration, infarct location, and discharge year.

Pinto DS, et al. Circulation. 2006;114:2019.

PCI R

elat

ed D

elay

(DB

-DN

) W

here

PC

I and

Fib

rinol

ytic

Mor

talit

y A

re E

qual

(Min

)

0-120 PrehospitalDelay (min)

121+

N=125,737

179

168148

107 103

58 43

40

Factors Associated with Equilibration of Mortality Benefit with Fibrinolysis

67%

7%

39%

0%

20%

40%

60%

80%

DTB ? 90 min—non-transfer in

DTB ? 90 min—transferin

DTN ? 30 min—all

Impact of Transfer on Door-to-balloon and –needle Time in STEMI Patients

DTB, 1st door to balloon for primary PCI; DTN, door to needle for lytics.NCDR ACTION Registry®–GWTGTM data: January 1, 2007–December 31, 2007 (n=19,523).

http://www.ncdr.com/webncdr/ACTION/Default.aspx

% o

f pat

ient

s

Door-to-balloon Time for Patients Transferred for Primary PCI

(N=4278)

Total door-to-balloon time (hours)

% o

f pat

ient

s

Nallamothu BK, et al. Circulation. 2005;111:761–767.

0.3

15.9

33.2

21.8

13.6

7.8

4.43.0

0

5

10

15

20

25

30

35

<1 1 to <2 2 to <3 3 to <4 4 to <5 5 to <6 6 to <7 >=7

Mortality rate for in-hospital fibrinolysis

00.

020.

040.

060.

080.

100.

120.

14

Mor

talit

y ra

te fo

r pre

-hos

pita

l fib

rinol

ysis

0 0.02 0.04 0.06 0.08 0.10 0.12 0.14

Favors in-hospital fibrinolysis

Favors pre-hospital fibrinolysis

Mortality Benefit with Pre-hospital Fibrinolysis vs In-hospital Fibrinolysis

Morrison LJ, et al. JAMA. 2000;283:2686–2692.

Six (6) studies were included in meta-analysis. Plot shows rate of hospital mortality measured in each study, demonstrating consistent outcome rates favoring pre-hospital fibrinolysis.

ED-Pertinent Changes in STEMI Guideline RecommendationsPrimary PCI vs Fibrinolysis

Primary PCI is recommended within 90 minutes as a systems goal (I-A)Fibrinolysis is recommended within 30 minutes as a system goal if primary PCI cannot be accomplished within 90 minutes (I-B)

Pollack CV, et al. Ann Emerg Med. 2008 [Epub ahead of print].

24

Choice of Fibrinolytic

Streptokinase Alteplase Reteplase TenecteplaseDose 1.5 MU over

30-60 min≤ 100 mg in 90 min (based on

weight)*

10 U x 2 each over 2 min

30-50 mg based on weight‡

Weight-based dosing

No Yes No Yes

Method of administration

Infusion Bolus+infusion Double bolus Bolus

90-min patency rates

50 75 80 75

TIMI grade 3 flow (%)

32 54 60 63

*Bolus 15 mg, infusion 0.75 mg/kg times 30 min (max. 50 mg), then 0.5 mg/kg not to exceed 35 mg over the next 60 min to an overall max. of 100 mg.

‡30 mg for weight < 60 kg; 35 mg for 60-60 kg; 40 mg for 70-79; 45 mg for 80-89 kg; 50 mg for ≥ 90 kg.

Antman EM, et al. J Am Coll Cardiol. 2004;44:671-719.

Simplified Decision Algorithm for Reperfusion

Patient presents to ED with chest pain < 3 hrs after symptom onset

ECG, evaluation, confirmation of STEMI

Hospital has no PCI facility

Transfer?

Will the patient be transferred and be able to undergo PCI in

> 90 min?

NoYes

Pharmacologic reperfusion

Hospital has PCI facility

Is it available/staffed?

Yes No

PCI

When will it be?< 90 min

> 90 min

< 90 min

Peacock WF, et al. Am J Em Med. 2007;25:353-366.

Door to ECG Time and Clinical Outcome in i*trACS

i*trACS=Internet Tracking Registry For Acute Coronary Syndromes

Dierks DB, et al. Am J Emer Med. 2006;24:1-7.

Perc

ent o

f Pat

ient

s

45

40

35

30

25

20

15

10

5

0360

180150

12090

6030

100

Time to ECG (min) i*trACS=Internet Tracking Registry For Acute Coronary Syndromes

Dierks DB, et al. Am J Emer Med. 2006;24:1-7.

OR 95% CI PECG > 10 min 3.95 1.06-

14.720.040

Risk of recurrent MI or death in or out of the hospital

Perc

ent o

f Pat

ient

s45

40

35

30

25

20

15

10

5

0360

180150

12090

6030

100

Time to ECG (min)

Door to ECG Time and Clinical Outcome in i*trACS

NRMI-4: Rates of Pre-hospital ECG Use

P for trend ≤ 0.001

4.5

8.0

Curtis JP, et al. JACC. 2006;47:1544-1552.

Patie

nts

rece

ivin

g pr

e-ho

spita

l EC

G (%

) PCI

Lytics

NRMI-4: Effect of Pre-hospital ECG on Door-to-needle/balloon Times

60.6

22.0

17.430.9

28.3

40.8

36.6

30.3

33.155.2

24.6

20.2

100%

80%

60%

40%

20%

0%Without phECG With phECG

< 3030 to 45

> 45

80%

60%

40%

20%

0%Without phECG With phECG

< 9090 to 120

> 120

phECG=pre-hospital ECG. Curtis JP, et al. JACC. 2006;47:1544-1552.

25

ED Activation of and Immediate Transfer to Cath Lab Saves Time

Cardiol eval

Cath lab activation

Cath lab staff arrival

Cath lab setup

Transfer to cath lab

Door

EKG

ED eval

Cath/PCI

Cardiology Activation/Routine Transfer ED Activation/Immediate Transfer

Cath lab Transfer to Cath lab Cardiolactivation cath lab setup eval

Door

EKG

ED eval

Cath/PCI

5% with door-to-balloon < 60 min

17% with door-to-balloon

< 60 min*

*P<0.0001; proportion of patients treated within < 60 minutes. Khot UN, et al. Circulation. 2007;116:67-76.

RACE Regions and Hospitals According to Reperfusion System

RACE: Reperfusion of Acute Myocardial Infarction in North Caroline Emergency DepartmentsJollis JG, et al. JAMA. 2007;298(20):2371-2380.

RACE: Treatment Times for Patients at PCI Hospitals

Pre-intervention

Post-intervention

P value

All primary PCI patients N=266 N=359Door-to-device, median (min) 106 90 < .001% Patients < 90 min 36.5% 51.3% < .001

Patients presenting directly to PCI hospital

N=164 n=232

Door-to-device median (min) 85 74 < .001% Patients < 90 min 56.7% 72.0% .002

Patients transferred to PCI hospital

N=102 N=127

Door-to-device median (min) 165 128 < .001% Patients < 90 min 3.9 13.4 .01

Jollis JG, et al. JAMA. 2007;298(20):2371-2380.

RACE: Treatment Times for Patients at non-PCI Hospitals

Pre-intervention

Post-intervention

P value

All patients N=515 N=404Door-in to door-out, median (min) 120 71 < .001% Patients < 60 min 15.7% 37.6% < .001% Patients < 30 min 3.1% 10.2% < .001

Patients at fibrinolysis hospitals N=239 N=201Door-in to door-out, median (min) 125 87 < .001% Patients < 60 min 5.4% 18.4% < .001% Patients < 30 min 0.8% 0.5% .67

Fibrinolysis N=233 N=158Door-to-needle, median (min) 35 29 .002% Patients < 30 min 34.8% 51.9% < .001

Jollis JG, et al. JAMA. 2007;298(20):2371-2380.

Identification: Medic paramedics are trained to acquire and read 12-lead electrocardiograms (ECG) on patients suspected of a heart attack. The ECG result is quickly transmitted from the field to an ED physician at CMC.Activation: If the ECG shows specific changes in certain electrical impulses (ST segments) within the heart, the Emergency physician activates “Code STEMI” initiating an immediate response from the Code STEMI Team. Treatment: Patient is received by Code STEMI Team upon arrival to CMC ED with a rapid triage process to confirm STEMI and then immediately transported to the cardiac catheterization lab where the coronary artery is opened

Program objective: develop a coordinated system of care - modeled after Code Trauma - that streamlines the identification, activation, and provision of

treatment for STEMI that surpasses national targets.

New CMC ProcessCode STEMI – Protocol Driven Program

Carolinas Medical Center, 2008.

Critical Success FactorsEMS and ED Physician initiate Code STEMI Single page activates entire team => parallel actions commence

ED and Cath Lab begin preparationsOn-Call Cardiologist and CCU Nurse go to EDRespiratory Care and Laboratory are available in EDJoint assessment occurs in the EDCardiologist and CCU Nurse assist EMS in transporting patient to Cath LabPatient is prepared for PCIBed Management finds accommodations

Trust in revised roles and responsibilitiesCarolinas Medical Center, 2008.

26

Lessons Learned fromCarolinas Medical Center

It takes real commitment from the Multi-disciplinary TeamEMS, ED Physicians, Cardiologists, ED Staff, Cath Lab, CCU, Bed Management, Lab, Radiology, Respiratory Care, House Supervisor

Establish a specific goal to Meet or Exceed ACC Standard Adopt a continuous process improvement philosophy => on-going monitoring and modification of the processIntensive education for EMS on acquiring and interpreting ECGsRecognize that a cultural change is necessaryBe flexible – forward thinking => all play in same sandboxTrust in revised roles and responsibilities

Carolinas Medical Center, 2008.

Two Questions the ED Should Answer for Patients Presenting

with Potential ACS

Pollack CV, Jr. and Braunwald E. Ann Emerg Med. 2008;51:591-606.

What is the likelihood that the presenting symptoms represent acute coronary syndrome as a result of coronary artery disease?What is the likelihood of an adverse cardiovascular outcome?

ACC/AHA 2007 UA/NSTEMI Guidelines: Features that Make ACS Secondary to CAD Highly Likely

Anderson JL, et al. JACC. 2007;50(7):1-157.

Feature Any of the following:History Chest or left arm pain or discomfort as chief symptom

reproducing prior documented anginaKnown history of CAD, including MI

Examination Transient MR, murmur, hypotension, diaphoresis, pulmonary edema, or rales

ECG New, or presumably new, transient ST-segment deviation (1 mm or greater) or T-wave inversion in multiple precordial leads

Cardiac markers

Elevated cardiac Tnl, TnT, or CK-MB

Serum Cardiac Biomarker Concentrations Following AMI

cTn=cardiac troponin.

Wu AHB, et al. Clin Chem. 1999;45:1104-1121.

A. Early release of myoglobin or CKMBB. cTn after AMIC. CKMB after AMID. cTn after UA

D.

C.

B.

A.

5

10

20

50

0

1

2

4 5 6 7 81 2 30

Days After Onset of AMI

Mul

tiple

s of

the

AM

I Cut

off L

imit

AMI decision limitUpper reference limit

Odds of ACS: Concordant and Discordant Biomarkers in NSTEMI

Patients

Storrow AB, et al. Ann Emerg Med. 2006;48:660-665.

Biomarkers Odds Ratio 95% CI (Odds Ratio)

CKMB(+)/CK(-) 5.70 (4.38-7.40)

CKMB(+)/CK(+) 4.36 (3.64-5.23)

CKMB(-)/cTn(+) 4.79 (3.40-6.76)

CKMB(+)/cTn(-) 2.17 (1.72-2.75)

CKMB(+)/cTn(+) 26.58 (18.00-39.30)

ACC/AHA 2007 UA/NSTEMI Guidelines: Short-term High Risk of Death or Nonfatal

MI in UA/NSTEMI Patients

Anderson JL, et al. JACC. 2007;50(7):1-157.

Feature At least one of the following:History Accelerating ischemic symptoms in preceding 48 hrs

Character of pain

Prolonged ongoing (greater than 20 min) rest pain

Clinical findings

- Pulmonary edema, most likely due to ischemia- New or worsening MR murmur- S3 or new/worsening rales- Hypotension, bradycardia, tachycardia- Age > 75 years

ECG - Angina at rest with transient ST-segment changes > .5 mm- BBB, new or presumed new- Sustained ventricular tachycardia

Cardiac markers

Elevated cardiac TnT, TnI, or CK-MB

27

ACC/AHA 2007 UA/NSTEMI Guidelines: Early Risk Stratification for Likely ACS

Patients

*Level of evidenceAnderson JL, et al. JACC. 2007;50(7):1-157.

Class I RecommendationsRapid determination of risk of obstructive CAD (C)*Determine risk of CV events (C)12-lead ECG within 10 min of ED arrival (B)

Serial ECGs for symptomatic patients with nondiagnostic initial ECG (B)Measure cardiac biomarkers (B)- Cardiac-specific troponin is preferred (B)- Remeasure at 8-12 h if initially negative

Consider noncoronary causes for unexplained symptoms (C)

ACC/AHA 2007 UA/NSTEMI Guidelines: Early Risk Stratification for Likely ACS

Patients

*Level of evidenceAnderson JL, et al. JACC. 2007;50(7):1-157.

Class IIa Recommendations

Risk-stratification models (eg, TIMI/GRACE risk score or PURSUIT risk model) can be useful (B)*

Reasonable to remeasure positive biomarkers at 6- to 8-h to assess infarct size/necrosis (B)

Reasonable to obtain supplemental ECG leads V7-V9 in patients with initial nondiagnostic ECG (B)

Continuous 12-lead ECG in appropriate patients (B)

LMWH Dosing Often Incorrect in NSTEMI Patients

LaPointe NM, et al. Am J Med. 2007;167(14):1539-1544.

2000

0

6000

4000

Patie

nts

(num

ber)

Lower-than-recommended

doseExcess

dose

> -100 -100to

< -30

-30to

< -10

-10to10

> 10to30

> 30to

100

> 100

Administered dose-recommended dose (mg/d)

Improper LMWH Dosing Has Negative Consequences

LaPointe NM, et al. Am J Med. 2007;167(14):1539-1544.

10

0

20

15

5Patie

nts

(%)

Lower-than-recommended doseRecommended doseExcess dose

Major bleeding Death(%) (%)

7.9 7.3

14.2

3.3 2.4

5.6

P = .50

P < .001

P = .11

P < .001

In-hospital Impact of GP IIb/IIIaInhibitor Use: CRUSADE Data

* Upstream GP IIb/IIIa inhibitors vs periprocedural GP IIb/IIIa inhibitors; † No GP IIb/IIIa inhibitors versus upstream GP IIb/IIIa inhibitor.

Tricoci P, et al. Am J Cardiol. 2007;99(10):1389-93.

IIb/IIIaOverall

(%)UpstreamIIb/IIIa (%)

Peri-proceduralIIb/IIIa (%)

P value*

No IIb/IIIa (%)

P value†

Death 1.3 1.3 1.4 .352 2.1 < .001

Recurrent MI 3.0 2.8 3.1 .085 3.4 .009

Death or reinfarction 4.1 3.8 4.3 .046 5.0 .001

Cardiogenicshock 2.3 2.1 2.5 .029 2.7 .004

Heart failure 4.7 4.9 4.5 .151 7.0 < .001

Stroke 0.4 0.3 0.4 .285 0.6 .003

Any RBC transfusion 7.1 7.3 7.0 .323 1.06 < .001

ED-pertinent Data on NonheparinAnticoagulation in STEMI Therapy

Anticoagulant Efficacy with Lysis

Safety with Lysis Use in Primary PCI

Use in PCI after Lysis

Enoxaparin Superior to UFH

Increased major bleeding events, but not ICH, compared with UFH

Not adequately studied

Can be used to support PCI without additional anticoagulation

Fondaparinux* Superior to UFH/placebo (relative performance uncertain)

Trend toward fewer major bleeding events compared with UFH/placebo

Increased risk of catheter thrombosis


Bivalirudin* Not adequately studied


Appears to be noninferior to UFH+GPI for efficacy with reduced bleeding

Not specifically studied

*Not approved by FDA for indicationPollack CV, et al. Ann Emerg Med. 2008 [Epub ahead of print].

28

Recommendations for Antithrombotic Therapy in NSTEMI ACS Patients in the

2007 ACC/AHA Guidelines

LOE=Level of evidenceAdapted from Pollack CV, Jr. and Braunwald E. Ann Emerg Med. 2008;51:591-606.

Agent Invasive Strategy (LOE)*

Conservative Strategy (LOE)*

UFH Initiate(I-A) Initiate (I-A)Enoxaparin Initiate (I-A) Initiate (I-A)Fondaparinux Initiate (I-B) Initiate (I-B)Bivalirudin Initiate (I-B) -

Recommendations for Antiplatelet Therapy in NSTEMI ACS in 2007 ACC/AHA Guidelines

Agent Recommendation Level of Evidence

ASA Initiate promptly I-A

Clopidogrel 1. Initiate promptly in ASA-allergy (loading dose)2. EIS: Initiate with loading dose ASAP OR give

small molecule GPI3. Hold if CABG planned within 5-7 days4. SIS: Initiate with loading dose ASAP OR give

small-molecule GPI

1. I-A2. I-A

3. I-B

4. I-A

Small-molecule GPI

1. EIS: Initiate OR give loading dose of clopidogrel2. EIS: Initiate AND give loading dose of clopidogrel3. SIS with later high risk: Initiate upstream4. EIS: May omit upstream GPI if patient receives

bivalirudin and at least 300 mg clopidogrel <6 h before cath and PCI

1. I-A2. IIa-B3. IIa-C4. IIa-B

Large-molecule GPI

1. EIS: initiate2. Not appropriate for medical management when

PCI not planned < 24 h

1. I-A2. III-A

EIS-Early invasive strategy; SIS-Selective invasive strategy; GPI – Iib/IIIa glycoprotein inhibitorAdapted from Pollack CV, Jr. and Braunwald E. Ann Emerg Med. 2008;51:591-606.

Do you think primary PCI is unduly preferred over fibrinolysis? If so, why?

What strategies has your hospital implemented to shorten time to

reperfusion in STEMI?

What are the barriers to system-wide changes to reduce

time to reperfusion in STEMI?

How can EDs improve evidence-based

MI and ACS care for the elderly?

For women?

Questions for Discussion

166

Bleeding and TransfusionRecognizing the Impact on

Vascular Outcomes

James A. de Lemos, MDDirector, Coronary Care UnitParkland Memorial Hospital

Dallas, TX

167

•Delineate the implications of major bleeding in the ACS

patient•Analyze the bleeding risks

posed by various therapeutic interventions in ACS

•Enumerate strategies for reducing bleeding risk in

diverse ACS patients

Learning Objectives In your view, which is more important in acute ACS treatment?

1. Reperfusion success2. Avoiding bleeding3. Both are equally important4. Unsure

29

Which statement most closely reflects your point of view in the context of acute ACS therapy?

1. Major bleeding is the necessary cost of improved reperfusion therapies

2. Little can be done to avoid major bleeding3. Newer anticoagulants can significantly

reduce major bleeding4. Newer anticoagulants make major bleeding

a more likely outcome

Moscucci M, et al. Eur Heart J. 2003;24:1815-1823.

Rates of Major Bleeding in ACS:The GRACE Registry

• Life-threatening with transfusion ≥ 2 units• Life-threatening with decrease in HCT >10%• Resulting in death• Hemorrhagic, subdural hematoma

3.9

2.3

4.7 4.8

0

1

2

3

4

5

6

OverallACS

UnstableAngina

NSTEMI STEMI

Major BleedingMajor Bleeding

Patie

nts

(%)

Patie

nts

(%)

(N=24,045)

171

How Is Bleeding Defined (and Does It Matter)?

Temporal Trends in Major Bleeding: The University of Michigan Experience

Motivala AA, et al. Am J Cardiol. 2007;100:1359-1363.

Which of the following have been included in major bleeding criteria in clinical trials?

1. Intracranial hemorrhage2. Decreased hematocrit3. Need for transfusion4. Pulse above 120 bpm5. 1, 2, and 36. All of the above

Bleeding Classifications

ICH=intracranial hemorrhage; Hb=hemoglobin. TIMI definitions take transfusion into account, so Hb and hematocrit

are adjusted by 1 g/dl or 3%, respectively, for each unit of blood transfused.The GUSTO Investigators. NEJM. 1993;329:673-682.

Chesebro JH, et al. Circulation. 1987;76:142-154.Rao SV, et al. JACC. 2006;47:809-816.

TIMI Bleeding ClassificationMajor ICH or a ≥ 5 g/dl decrease in Hb or a ≥ 15% absolute decrease in hematocrit

Minor Observed blood loss: ≥ 3 g/dl decrease in Hb or ≥ 10% decrease in hematocritNo observed blood loss: ≥ 4 g/dl decrease in Hb or ≥ 12% decrease in hematocrit

Minimal Any clinically overt sign of hemorrhage (including imaging) that is associated with a < 3 g/dl decrease in Hb or < 9%decrease in hematocrit

GUSTO Bleeding ClassificationSevere or life-threatening

Either ICH or bleeding causing hemodynamic compromise and requiring intervention

Moderate Bleeding requiring blood transfusion but not resulting in hemodynamic compromise

Mild Bleeding that doesn’t meet Severe/Moderate criteria

30

Variability in Major Bleeding Criteria in Recent ACS/PCI Trials Evaluating

Antithrombotic Drugs

Analysis included 13 randomized trials with over 178,000 patients comparing antithrombotic agents in STEMI, NSTEMI, and PCI.

Of the 13 trials, 9 used definitions other than TIMI or GUSTO; the 5 exclusively STEMI trials used 5 different definitions; 4 different definitions used in the 5 NSTEMI trials.

Steinhubl SR, et al. Am Heart J. 2007;154:3-11.

Bleeding site Decrease in Hb (g/dL)

Transfusion Hemorrhagic death

Other

Intracranial, retroperitoneal,

intraocular

> 5, ≥ 4, or ≥ 3 Transfusion calculated for

decrease in Hb, or transfusion criterion on its own with ≥ 1, ≥ 2, or ≥ 4 units

of blood

Included, not included, or

reported separately

Cardiac tamponade, hemodynamic compromise,

hematoma ≥ 5 cm in diameter, reoperation, hypotension requiring

inotropic drugs, disabling bleeding

Variation in Bleeding Rates Depending on Definition: STEEPLE Trial

Montalescot G, et al. NEJM. 2006;355:1006-1017.Steinhubl SR, et al. Am Heart J. 2007;154:3-11.

STEEPLE major

TIMI major

GUSTO moderateor severe

Bleeding definition

Patie

nts

with

ble

edin

g ev

ent (

%)

0

0.5

1

1.5

2

2.5

3UFH

Enoxaparin 0.5 mg/kg

Enoxaparin 0.75 mg/kg

P=.007P=.004

P=.69

P=1.00

P=.13

P=.03

Variation in Bleeding Rates in CABG Patients Depending on Definition: CURE Trial

Bleeding definition

CURE major

CURE-life threatening

TIMI major

0

2

4

6

8

10

12PlaceboClopidogrel

OR 1.2795% CI 0.95-1.69

OR 1.2495% CI 0.89-1.73

OR 0.9095% CI 0.52-1.63

OR 1.4095% CI 0.88-2.23

GUSTO severe/life threatening

Patie

nts

with

ble

edin

g ev

ent (

%)

Fox KA, et al. Circulation. 2004;110:1202-1208.Steinhubl SR, et al. Am Heart J. 2007;154:3-11.

Varying Rates of Bleeding Depending on Definition and Severity: PURSUIT and PARAGON B

8.5 8.2

12.7

1.2

11.4

19.2

0

5

10

15

20

25

GUSTOMild

GUSTOMod

GUSTO Sev TIMI Mini TIMI Min TIMI Maj

%

N=15,858

Mini=minimal. Rao SV, et al. J Am Coll Cardiol. 2006;47:809-816.

Clinical Implications of Different Bleeding Classification Schemes

GUSTOMild

GUSTOModerate

GUSTOSevere

TIMIMinimal

TIMIMinor

TIMIMajor

1.00 1.00

1.19 (1.01-1.41)

1.92 (1.58-2.34)

3.48 (2.56-4.73)

1.13 (0.97-1.33)

1.08 (0.85-1.36)

1.19 (1.03-1.38)

1.48 (1.22-1.79)

3.22 (2.43-4.26)

1.02 (0.88-1.18)

1.06 (0.86-1.30)

0.94 (0.81-1.10)

Data from PURSUIT (n=10,798) and PARAGON B (n=5,225) trials (NSTEMI) were pooled for analysis.Adjusted for age, gender, weight, site, diabetes, smoking status,

prior angina, peripheral vascular disease, pre-randomization therapy, MI at enrollment, SBP/DBP at randomization, heart rate at randomization, Killip class, assigned treatment, blood transfusion.

Rao SV, et al. JACC. 2006;47:809-816.

30-day Death/MI 6-month Death/MI

Adjusted Hazard Ratio

180

Questions for DiscussionWhat constitutes the optimal

measure of bleeding in a clinical trial?

What measures of bleeding are important

in practice?

31

181

Does Bleeding Matter? Correlates of Bleeding

in ACS

TRUE or FALSE? Major bleeding in an acute ACS care episode has been linked to increased mortality.

1. True2. False3. Unsure

Relationship Between Major Bleeding and In-hospital Death Rates for ACS

Patients: GRACE Registry

Moscucci M et al. Eur Heart J. 2003;24:1815-1823.

GRACE Registry: Impact of In-hospital Major Bleeding on Patient

Mortality

40,087 patients, 53% STEMI, 47% NSTEMI.Major in-hospital bleeding: life-threatening bleeding requiring a transfusion of ≥ 2 U of packed RBCs,

resulting in a decrease in hematocrit of ≥ 10%, occurring intracerebrally, or resulting in stroke or death.Spencer FA, et al. Circulation. 2007;116:2793-2801.

In-hospital bleeding: 293 deaths among 1140 patients

No bleeding: 3,605 deaths among 38,647 patients

Days since admission

Cum

ulat

ive

deat

h ra

te

0 20 40 60 80 100 120 140 160 1800.000.040.080.120.160.200.240.280.320.36

Impact of Bleeding on Mortality in ACS: Bleeding Severity and Survival

Kaplan Meier Curves for 30-day Death, Stratified by Bleed Severity

Rao SV, et al. Am J Cardiol. 2005;96:1200-1206.

REPLACE-2: Impact of Major Bleeding on 1-year Mortality

Feit F, et al. Am J Cardiol. 2007;100:1364-1369.

0 60 120 180 240 300 3600

2

4

6

8

10

Cum

ulat

ive

mor

talit

y (%

)

Time from randomization (days)

8.7%

1.9%

P<0.0001

Without major hemorrhageWith major hemorrhage

N=6,001

32

Impact of Baseline Hemoglobin Levels on CV Death: STEMI

41,637 patients from 16 TIMI trials, 25,419 STEMI patients,14,503 NSTEMI patients.Sabatine MS, et al. Circulation.2005;111:2042-2049.

Impact of Baseline Hemoglobin Levels on CV Death: NSTEMI

41,637 patients from 16 TIMI trials, 25,419 STEMI patients, 14,503 NSTEMI patients.Sabatine MS, et al. Circulation. 2005;111:2042-2049.

GUSTO-1: In-hospital Predictors of Late Death

Califf RM, et al. Circulation. 2000;101:2231-2238.

Is Bleeding Associated with Higher Mortality? TIMI Major Bleeding


Bleeding definition

Patient population

Early mortality and/or other major CV events (in-hospital or 30-day)

Late mortality (6-month or 1-year)

TIMI major bleeding

STEMI ― ―

NSTEMI Higher adjusted mortality/MI rates

Higher adjusted mortality/MI rates

PCI Independent predictor Higher mortality rates, but not an independent

predictorOverall

ConclusionYes Conflicting

Is Bleeding Associated with Higher Mortality?GUSTO Moderate or Severe Bleeding


Bleeding definition

Patient Population

Early mortality and/or other major CV events (in-hospital or 30-day)

Late mortality (6-month or 1-year)

GUSTO moderate or severe bleeding

STEMI Higher mortality/MI rates

Higher mortality rates, but not an independent

predictor in 30-day survivors

NSTEMI Higher mortality/MI rates; independent

predictor

Higher adjusted mortality/MI hazard

PCI ― ―Overall

conclusionYes Conflicting

Is Bleeding Associated with Higher Mortality?Blood Transfusion and Hemoglobin Levels

Bleeding definition

Patient population Early mortality and/or other major

cardiovascular events (in-hospital or 30-day)

Late mortality (6-month or

1-year)

Blood transfusion STEMI Not a predictor ―

NSTEMI Higher mortality rates ―

Both STEMI and NSTEMI

Mortality association depending on hematocrit

levels and NSTEMI vs. STEMI

―

PCI Independent predictor Independent predictor

Overall conclusion Conflicting Yes

Drop in hemoglobin

Both STEMI and NSTEMI

Independent predictor ―

Overall conclusion Yes ―


33

193

Is It the Bleeding?What factors have been shown to be linked with bleeding in ACS?

1. Female gender2. Excessive anticoagulant dosing3. Renal insufficiency4. Older age5. All of the above6. None of the above

ACUITY: Predictors of Major Bleeding

Age ≥75 yearsFemale gender

DiabetesHypertensionNo prior PCI

Anemia*Renal insufficiency†

Baseline ST-segment deviation ≥1 mmBaseline cardiac biomarker elevation

Heparin‡ plus GPI vs bivalirudin monotherapy

0 1 2 3

1.64 (1.32-2.02) <0.0001

Odds ratio ± 95% CI OR (95% CI) P Value

1.92 (1.61-2.29)

<0.00011.20 (1.00-1.44) 0.0571.92 (1.61-2.29)

0.0401.32 (1.08-1.62) 0.0061.87 (1.54-2.28) <0.00011.53 (1.24-1.90) <0.00011.35 (1.13-1.61) 0.00081.43 (1.19-1.74) 0.00021.95 (1.56-2.44) <0.0001

*Anemia defined as baseline hemoglobin < 13 g/dl in men and < 12 g/dl in women.†Renal insufficiency defined as creatinine clearance < 60 ml/min.

‡Unfractionated heparin or enoxaparin.Manoukian SV, et al. JACC. 2007;49:1362-1368.

REPLACE-2: Baseline and Periprocedural Predictors of Major

Hemorrhage

Feit F, et al. Am J Cardiol. 2007;100:1364-1369.

Factors OR (95% CI) P ValueAge ≥ 75 years 1.48 (1.01-2.18) 0.045Gender (women vs. men) 1.54 (1.12-2.10) 0.007Previous angina pectoris 1.59 (1.08-2.35) 0.02Creatinine clearance 1.01 (1.00-1.01) 0.006No previous PCI 1.59 (1.14-2.23) 0.007Anemia 1.40 (1.02-1.94) 0.040Periprocedural PredictorsTrtmt grp (hep+GPI vs. bivalirudin)

1.97 (1.37-2.84) 0.0003

Provisional GPI received 2.68 (1.59-4.51) 0.0002Procedure duration > 1 hr 2.05 (1.22-3.45) 0.007Time to sheath removal > 6 hr 1.61 (1.06-2.45) 0.024ICU stay 1.25 (1.18-1.32) <0.0001Intra-aortic balloon pump 8.71 (3.43-22.07) <0.0001No previous thienopyridine 1.66 (1.07-2.59) 0.023

REPLACE-2: Predictors of 1-year Mortality

LVEF=Left ventricular ejection fraction.Feit F, et al. Am J Cardiol. 2007;100:1364-1369.

Predictor OR (95% CI) P Value

Age ≥ 75 yrs 2.28 (1.51-3.46) 0.0001

Preprocedural anemia 2.12 (1.43-3.13) 0.0002

BMI 20-25 (vs > 25) kg/m2 1.64 (1.08-2.50) 0.007

Preprocedural LVEF ≤ 50% 2.15 (1.44-3.21) 0.0002

Congestive heart failure 3.58 (2.27-5.65) < 0.0001

Previous angina pectoris 2.16 (1.25-3.75) 0.006

Major hemorrhage 2.66 (1.44-4.92) 0.002

MI (30-d) 2.46 (1.44-4.20) 0.001

Urgent repeat revascularization (30-d)

3.30 (1.36-8.00) 0.008

Predictors of Bleeding in PCI:Bleeding and Anemia

0.0%

1.0%

2.0%

3.0%

4.0%

5.0%

6.0%

Non-Anemic Anemic

Overall REPLACE-2 Major bleeding = 3.2%

Maj

or B

leed

ing

2.8%

4.9%

P=0.0001

Protocol definition: > 3g/dL drop in HgB, intracranial, retroperitoneal, 2U transfusion

Voeltz MD, Patel AD, Feit F, Fazel R, Lincoff AM, Manoukian SV. Am J Cardiol. 2007;99:1513-1981517.

REPLACE-2REPLACEREPLACE--22

34

Predictors of In-hospital Bleeding Within 30 Days: GRACE Registry, Patient Characteristics

Variable Total Cohort,† HR (95% CI)

History of prior bleeding 2.70 (1.84-3.96)

Glomerular filtration rate < 30mL/min‡Early bleeding (0-2d)/Late bleeding (3-30 d) 2.40 (1.76-3.29)/1.83 (1.25-2.68)

Pulmonary artery catheterEarly bleeding (0-1 d)/ Late bleeding (2-30 d)

1.65 (1.18-2.29)/2.04 (1.53-2.72)

Female sexEarly bleeding (0-2 d)/Late bleeding (3-30 d)

1.36 (1.12-1.65)/1.84 (1.44-2.35)

Age per 10-y increaseEarly bleeding (0-2 d)/Late bleeding (3-30 d) 1.35 (1.25-1.47)/1.53 (1.36-1.72)

ST deviation on initial ECG 1.47 (1.21-1.80)

Glomerular filtration rate 30-59 mL/minEarly bleeding (0-2 d)/Late bleeding (3-30 d) 1.44 (1.16-1.79)/1.12 (0.85-1.46)

History of atrial fibrillationEarly bleeding (0-2 d)/Late bleeding (3-30 d) 0.95 (0.69-1.31)/1.41 (1.01-1.96)

†Data for n=28,327 patients with complete covariate information, 766 with major bleeding; ‡Reference category: glomerular filtration rate ≥ 60 mL/min

Spencer FA, et al. Circulation. 2007;116:2793-2801.

Predictors of In-hospital Bleeding Within 30 Days: GRACE Registry,

Patient Characteristics (con’t) Variable Total Cohort,† HR (95% CI)

History of peripheral arterial disease 1.37 (1.11-1.68)

History of smoking 1.23 (1.0-1.44)

Heart rate per 30 bpm increaseEarly bleeding (0-1 d)/Late bleeding (2-30 d) 1.05 (0.92-1.20)/1.16 (1.03-1.30)

History of hypertensionEarly bleeding (0-1 d)/Late bleeding (2-30 d) 0.79 (0.64-0.98)/1.22 (0.98-1.53)

History of atrial fibrillationEarly bleeding (0-2 d)/Late bleeding (3-30 d) 0.95 (0.69-1.31)/1.41 (1.01-1.96)

ST elevation on initial ECGEarly bleeding (0-2 d)/Late bleeding (3-30 d)

0.81 (0.64-1.02)/0.46 (0.35-0.61)

†Data for n=28,327 patients with complete covariate information, 766 with major bleeding Spencer FA, et al. Circulation. 2007;116:2793-2801.

Predictors of In-hospital Bleeding Within 30 Days: GRACE Registry, Treatment

Characteristics Variable Total Cohort,† HR (95% CI)

Pulmonary artery catheterEarly bleeding (0-1 d)/ Late bleeding (2-30 d)

1.65 (1.18-2.29)/2.04 (1.53-2.72)

PCI 1.94 (1.51-2.50)

Treatment with IV vasopressors in first 24 h 1.94 (1.57-2.39)

Fibrinolytic therapy 1.50 (1.16-1.92)

Treatment with GP IIb/IIIa inhibitor in first 24 h 1.48 (1.23-1.77)

Intra-aortic balloon pulsation device 1.46 (1.12-1.91)

Cardiac catheterization 1.42 (1.10-1.83)

Treated with LMWH in first 24 hEarly bleeding (0-1 d)/Late bleeding (2-30 d) 0.43 (0.33-0.55)/0.95 (0.76-1.19)

Treated with UFH in first 24 h 0.74 (0.62-0.89)

Treated with ASA in first 24 h 0.56 (0.47-0.68)

†Data for n=28,327 patients with complete covariate information, 766 with major bleeding Spencer FA, et al. Circulation. 2007;116:2793-2801.

In-hospital Mortality Among Patients Experiencing Major Bleeding Whose Antithrombotic Medication

was Continued vs Discontinued

0

10

20

30

40

50

60

70

Perc

ent

Therapy discontinued after day 1†

Therapy continued after day 1‡

Aspirin* THN* LMWH UFH** GP IIb/IIIan/N †

‡43/8344/353

26/4529/218

17/5714/72

47/17922/140

31/1494/29

506 patients suffered major bleeding on or the day after admission for AMI and had received at least 1 antithrombotic medication.

THN=thienopyridine; LMWH=low molecular weight heparin; UFH=unfractionated heparin.*P<0.001; **P<0.05.


Conclusions from GRACE Investigators

“…bleeding remained associated with in-hospital mortality after controlling for important confounders.”

“…although patients in our study who suffered major bleeding experienced higher postdischarge mortality (7.9% vs 5.2%), bleeding was no longer a predictor of late mortality after controlling for differences in clinical and treatment characteristics.”

“…our data suggest that in the community setting, bleeding, although still associated with worse outcomes, also is a marker for patients with more severe illness or comorbidities.”


ACS Patient Trends: The University of Michigan

Motivala AA, et al. Am J Cardiol. 2007;100:1359-1363.

35

ACS Treatment Trends: The University of Michigan

Motivala AA, et al. Am J Cardiol. 2007;100:1359-1363. Peters RJG, et al. Circulation. 2003;108:1682-1687.

Aspirin Dose Clopidogrel + ASA (%) Placebo + ASA (%)

≤ 100 mg 3.0 1.9

101–199 mg 3.4 2.8

≥ 200 mg 4.9 3.7

Aspirin and Bleeding: CURE Results

COMMIT: Bleeding Endpoints

Chen ZM, et al. Lancet. 2005;366:1607-1621.

Clopidogreln=22,961 (%)

Placebon=22,891 (%) P value

Stroke 216 (0.9) 249 (1.1) NS

Major Bleeding 134 (0.6) 125 (0.5) NS

TRITON-TIMI 38: TIMI Bleeding Endpoints in the Overall Cohort at 15 Months

TIMI=thrombolysis in myocardial infarction.*Most frequent sites of life threatening bleeding: gastrointestinal, intracranial, the puncture site, and retroperitoneal sites.

%Total number of patients were all patients receiving at least one dose of study drugbefore undergoing CABG; ratio is odds ratio.

Prasugrel is not yet approved by the FDA for use.Wiviott SD, et al. N Engl J Med. 2007;357:2001-2015.

End Point Prasugrel(N=6741)

Clopidogrel(N=6716)

PrasugrelHR (95% CI)

P Value

no. of patients (%)

Non-CABG-related TIMI major bleeding

146 (2.4) 111 (1.8) 1.32(1.03-1.68)

.03

Life-threatening* 85 (1.4) 56 (0.9) 1.52(1.08-2.13)

.01

Major or minor TIMI bleeding

303 (5.0) 231 (3.8) 1.31 (1.11-1.56)

.002

Bleeding requiring transfusion

244 (4.0) 182 (3.0) 1.34(1.11-1.63)

< .001

CABG-related TIMI major bleeding%

24 (13.4) 6 (3.2) 4.73(1.90-11.82)

< .001

TRITON-TIMI 38: 50% Reduction in Stent Thrombosis with Prasugrel vs Clopidogrel

UA/NSTEMI

STEMI

0.1 1 2

Pras (%) Clop (%) Reductionin risk (%)

1.6 2.8 42

1.0 2.2 57

Favors prasugrel Favors clopidogrel

Any stent (n=12,844) Prasugrel Clopidogrel HR (95% CI) P Value

Definite ST 0.88% 2.03% 0.42 (0.31-0.59) < .0001

Definite/probable ST 1.13% 2.35% 0.48 (0.36-0.64) < .0001

Definite/probable/possible ST

1.54% 2.75% 0.56 (0.43-0.73) < .0001

ST=stent thrombosis.Prasugrel is not yet approved by the FDA for use.

Wiviott SD, et al. Lancet. 2008;371:1353-1363.

TRITON-TIMI 38: Age Subgroup Analysis for Rate of Primary Efficacy Endpoint at 15 Months


Overall

Baseline characteristics

Age

Hazard Ratio for Prasugrel Efficacy(95% CI)

Total No.of Patients

Pras ClopReduction

in Risk (%)

13,608

(%)

9.9 12.1 19

1,809 17.2 18.3 6

0.5 0.6 0.7 0.8 0.9 1.00 2.00

Prasugrel Better Clopidogrel Better

< 65 yr

65-74 yr

≥ 75 yr

8,322 8.1 10.6 25

3,477 10.7 12.3 14

P values for interaction were not significant

Patient targeting of therapy

36

TRITON-TIMI 38: Efficacy and Safety of Prasugrel vs Clopidogrel in

Patients with Prior Stroke or TIA

N=13,608; 10,704 with UA/NSTEMI; 3,534 with STEMI.Prasugrel is not yet approved by the FDA for use.

Wiviott SD, et al. N Engl J Med. 2007;357:2001-2015.

End Point Prasugrel Clopidogrel Hazard Ratio for Prasugrel

P Value

History of stroke or TIA No. of patients/total no. (%) (95% CI)

Death from cardiovascular causes, nonfatal MI, or nonfatal stroke

47/262 (19.1) 35/256 (14.4) 1.37(0.89-2.13)

0.15


14/257 (5.0) 6/252 (2.9) 2.46(0.94-6.42)

0.06

Death from any cause, nonfatal MI, nonfatal stroke, or non-CABG-related nonfatal TIMI major bleeding

57/262 (23.0) 39/256 (16.0) 1.54(1.02-2.32)

0.04

No. (%) of Patients

HR (95% CI) P value

Placebo or UFH

(n=6056)

Fondaparinux

(n=6036)

All cases 130 (2.1) 107 (1.8) 0.83 (0.64-1.06) 0.14

Stratum 1

(vs placebo)

57 (2.0) 39 (1.4) 0.68 (0.45-1.02) 0.07

Stratum 2

(vs UFH)

73 (2.3) 68 (2.1) 0.93 (0.67-1.30) 0.69

No PCI 42 (3.2) 28 (2.2) 0.66 (0.41-1.07) 0.09

PCI 31 (1.7) 40 (2.2) 1.30 (0.81-2.08) 0.27

The OASIS-6 Trial Group. JAMA. 2006;295:1519-1530.

OASIS-6: Bleeding at 9 DaysMajor Bleeds

OASIS-6 PCI Complications: Primary PCI

No. of EventsControln = 1898

Fondan = 1890 P-value

UFH 1832 245

Vascular site complications 44 32 NS

PCI-related coronary complications 97 124 0.057

Catheter thrombus 0 22 < 0.001

Death/MI at 30 days 93 114 NS

Severe bleeds at 30 days 9 16 NS

Fonda=fondaparinux

The OASIS-6 Trial group. JAMA. 2006;295:1519-1530.

ExTRACT-TIMI 25 Net Clinical Benefit at 30 Days

1 1.250.90.8

Death or nonfatal MI or nonfatal ICH

Death or nonfatal MI or nonfatal major bleed

Death or nonfatal MI ornonfatal disabl. stroke

Enox Better UFH BetterRR

UFH (%) Enox (%) RRR (%)

12.3 10.1 18

12.8 11.0 14

10.1

Prespecified Definitions

P<0.0001

P<0.0001

P<0.000112.2 17

ExTRACT-TIMI 25 Investigators. N Engl J Med. 2006;354(14):1477-1488.

Enox (n=1103) UFH (n=1075) RR (95% CI) P-value

Individual end points

Death 3.8% (42) 4.0% (43) 0.96 (0.63-1.44) 0.817

MI 9.7% (107) 13.3% (143) 0.73 (0.58-0.92) 0.008

Stroke 0.4% (4) 0.8% (9) 0.43 (0.13-1.40) 0.173

TIMI major bleeding 1.8% (20) 2.4% (26) 0.75 (0.42-1.34) 0.328

TIMI minor bleeding 3.7% (41) 3.6% (39) 1.03 (0.67-1.58) 0.909

Composite end points

Death/nonfatal MI 13.0% (143) 16.7% (180) 0.77 (0.63-0.95) 0.013

Death/nonfatal MI/nonfatal major bleeding

14.0% (154) 18.3% (197) 0.76 (0.63-0.92) 0.006

Enox=enoxaparin; UFH=unfractionated heparin; PCI=percutaneous coronary intervention; MI=myocardial infarction.

Gibson CM, et al. JACC. 2007;49;2238-2246.

PCI ExTRACT-TIMI 25: Clinical and Safety Outcomes

ACUITY: First Randomization —Antithrombin Therapy

Medicalmanagement

PCI

CABG

Ischemic composite* Bleeding†

Net clinical

outcome†

7.3 % 5.7 % 11.7 %

7.7 % 5.3 % 11.8 %

7.8 % 3.0 % 10.1 %

Endpoints: Death, MI, and unplanned revascularization for ischemia (30 days and 1 year); major bleeding (30 days); composite of the above (30 days)

*p=0.01; †p<0.001. All P values are for noninferiority.Stone GW, et al. N Engl J Med. 2006;355;2203-2216.

UFH orEnoxaparin+ GP IIb/IIIa

Moderate–high-risk

ACS

ASA in allclopidogrel

dosing and timingper local practice

Bivalirudin+ GP IIb/IIIa

Bivalirudinalone

R

Moderate–high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,800)

37

Age and ACS Outcomes: CRUSADE Registry Data

Alexander KP, et al. JAMA. 2005;294:3108-3116.

Anticoagulant Dosing and Age in ACS: CRUSADE Registry Data

P<.001 for all 3 treatment groups.Alexander KP, et al. JAMA. 2005;294:3108-3116.

0.0

10.0

20.0

30.0

40.0

50.0

60.0

70.0

UFH LMWH GP IIb/IIIa Inhibitors

< 65 65-74 > 75Patient Age, y

n = 4300

n = 2054

n = 2586

n = 4293 n = 2278

n = 3410

n = 5610

n = 2450

n = 2319

Exce

ss D

ose

Am

ong

All

Patie

nts

Rec

eivi

ng T

reat

men

t, %

Patient-level and Practice-level Predictors of Excess Antithrombotic Dosing

Alexander KP, et al. JAMA. 2005;294:3108-3116.

Patient Characteristics

UFH LMWH GP IIb/IIIa Inhibitor

Age, y65-74

> 75

0.93 (0.79-1.11)

0.81 (0.68-0.96)

0.76(0.65-0.89)

0.75 (0.63-0.89)

4.23 (3.67-4.86)

14.39 (12.24-6.90)

Renal insufficiency 1.25 (1.07-1.46) 0.82 (0.67-1.00) 4.2 (2.95-5.75)

Women 0.92 (0.80-1.46) 0.73 (0.63-0.84) 3.74 (3.29-4.25)

Diabetes mellitus 1.04 (0.93-1.16) 1.16 (1.03-1.31) 1.35 (1.20-1.51)

Prior congestive heart failure

0.86 (0.73-1.02) 1.14 (0.97-1.33) 1.49 (1.23-1.81)

Weight, per 5-kg decrease 1.28 (1.22-1.35) 1.26 (1.23-1.29) 1.02 (1.00-1.04)

Academic hospital 1.02 (0.55-1.58) 1.26 (1.03-1.54) 0.93 (0.76-1.15)

Cardiologist 0.90 (0.77-1.06) 1.17 (1.02-1.34) 0.94 (0.82-1.06)

Medication adherence,per 5% decrease

1.12 (0.97-1.30) 1.02 (0.97-1.08) 1.06 (1.01-1.12)

Likelihood of Receiving Excess Dose, Adjusted OR (95% CI)

Antithrombotic Dosing and Major Bleeding: CRUSADE Registry

P<.001 for UFH and GP IIb/IIa; P=.25 for LMWH.Alexander KP, et al. JAMA. 2005;294:3108-3116.

0.0

5.0

10.0

15.0

20.0

25.0

30.0

35.0

UFH LMWH GP IIb/IIIa Inhibitors

Underdosed Recommended Mild ExcessDose Group

Major Excess

Maj

or B

leed

ing,

%

n = 2074 n = 2063n = 2073

n = 714

n = 2327n = 3998

n =922

n = 237

n = 5879

n = 1955

n = 178

UFH Infusion and Bolus Dosing in ACS and Major Bleeding: CRUSADE Registry Data

Melloni C, et al. Am H J. 2008;156:209-215.

Factors Associated with Excessive UFH Dosing: CRUSADE Registry Data

Melloni C, et al. Am H J. 2008;156:209-215.

Variable OR 95% CI Χ 2 P value

Diabetes 0.77 0.73-0.81 03.1 <.0001

Female 1.45 1.33-1.59 69.4 <.0001

Age (per 10-y increase) 1.11 1.08-1.15 40.8 <.0001

Hypertension 0.86 0.81-0.91 31.3 <.0001

Baseline HCT (per 5% decrease) 0.95 0.93-0.97 24.7 <.0001

Prior stroke 1.15 1.07-1.24 14.6 .0001

Prior PAD 1.13 1.04-1.22 8.4 .0038

Prior MI 1.08 1.02-1.13 7.7 .0054

SBP (per 10-mm Hg increase) 0.99 0.98-1.00 6.1 .0138

White (vs. others) 0.93 0.87-0.99 4.9 .0267

Prior CHF 0.92 0.86-0.99 4.8 .0283

GFR (per 10 mL/min decrease) 1.01 1.00-1.02 4.1 .0434

38

Evidence-based Care for the Very Old ACS Patient

Skolnick AH, et al. JACC. 2007;49:1790-1797.

In-hospital Outcomes for the Very Old ACS Patient


Number of Therapies and the Very Old


Excessive Dosing by Gender, Cr, and Patient Age

Parameters are independent & cumulative


0.0

10.0

20.0

30.0

40.0

50.0

60.0

70.0

80.0

90.0

100.0

Overall Men Women >2.0 mg/dL<=2.0 mg/dL< 75 yrs >= 75 yrs

Sex Serum Creatinine Patient Age

Among CrCL < 50 mL/min

% E

xces

s D

ose

26.9%

17.2%

46.4%

62.9%

90.8%

16.0%

64.2%

Major Bleeding by Gender and GP IIb/IIIa Inhibitor Use


0.0

5.0

10.0

15.0

20.0

25.0

Men Women

% M

ajor

Ble

edin

g

P=0.08

P<0.0001P<0.0001

P<0.0001 No GP IIb/IIa

GP IIb/IIIa (Appropriate)

GP IIb/IIIa (Excess)

Transfusion Trends in ACS Patients: CRUSADE Registry Data

Alexander KP, et al. Am H J. 2008;155:1047-1053.

Hospital-level transfusion quartiles (low to high % transfusion)

Quartile 1st 2nd 3rd 4th

Any transfusion (%) 0 7.3 11.4 19.1

Baseline HCT 40.5 (39.4, 42.0) 40.9 (39.9, 41.6) 40.2 (39.4, 41.0) 38.7 (37.6, 40.3)

Nadir HCT 36.5 (34.9, 37.7) 35.9 (35.0, 36.6) 34.7 (34.0, 35.8) 33.6 (31.3, 34.7)

Nadir HCT† 25.6 (24.4, 27.2) 25.7 (24.4, 26.6) 25.6 (24.9, 26.7) 25.5 (24.4, 26.4)

Age (y) 66.5 (60.5, 71.8) 66.8 (64.0, 70.5) 70.0 (65.0, 75.0) 74.0 (69.0, 79.0)

Female (%) 39.0 38.1 42.9 45.4

CrCl (mL/min) 55.9 (47.3, 63.0) 54.7 (51.3, 59.0) 50.2 (42.8, 55.6) 42.1 (32.9, 50.1)

Diabetes (%) 30.2 31.1 34.6 35.5

Signs of CHF (%) 17.6 20.6 26.8 33.3

Cardiac catherization (%) 94.3 94.6 91.9 82.8

Acute heparin (%)* 89.6 89.4 89.4 91.8

Acute GP IIb/IIIa (%)* 45.5 50.0 46.2 40.0

Major Bleeding (%) 3.9 8.7 12.5 18.8

P values <.001 except for (*). Values represent median (25th, 75th) or % as indicated.

39

Mortality and Blood Transfusions by Nadir

Hematocrit

Alexander KP, et al. Am H J. 2008;155:1047-1053. 230

Questions for DiscussionWhat practical steps can clinicians take

to reduce bleeding associated with acute ACS care?

-Therapeutic choices

- Dose considerations

- Special populations

The Future of ACS Treatment:

New Therapies in Development

E. Magnus Ohman, MDDirector, Program for

Advanced Coronary Disease Duke University Medical Center

Durham, NC

•Identify emerging pharmacotherapies for

the ACS patient

•Compare and contrast the roles of existing and

evolving therapies in different ACS patient

populations

Learning Objectives

In your view, what is the most important limitation of current antiplatelet therapies?

1. Variable treatment response2. Slow onset3. Limited efficacy4. Too long-acting/irreversible5. Cost6. Other7. Unsure

Platelet Activation

Multiple potential agonistsMajor agonists include collagen, ADP, thromboxane A2 (TxA2) and thrombinTissue factor (TF) released from damaged endothelial wall leads to generation of thrombinGenerated thrombin binds to the platelet PAR1 receptor and contributes heightened platelet response

Wu KK. J Intern Med. 1996;236:17-34. Ruggeri ZM, et al. J Thromb Haemost. 2003;1:1335-1342. Jackson SP, et al. J Thromb Haemost. 2003;1:1602-1612.

Brass LF. Chest. 2003;124(3 suppl):18S-25S. Dorsam RT, et al. J Thromb Haemost. 2004;2:804-812.

40

Platelet Activation Mechanisms

Adapted with permission from: Storey RF. Curr Pharm Des. 2006;12:1255-1259.

PLATELETACTIVATION

P2Y12

P2Y5HT2A

PAR1

PAR4

αIIbβ3

αIIbβ3

αIIbβ3

TPGPVI

P2X1a

1



PLATELETACTIVATION

P2Y12

P2Y5HT2A

PAR1

PAR4

αIIbβ3

αIIbβ3

αIIbβ3

TPGPVI

P2X1a

1

Thromboxane A2



PLATELETACTIVATION

P2Y12

P2Y5HT2A

PAR1

PAR4

αIIbβ3

αIIbβ3

αIIbβ3

TPGPVI

P2X1a

1

ThromboxaneA2

Coagulation factorsInflammatory mediators

Shapechange

Densegranule

Alphagranule

5HTADP ADPADP

5HT

ATPATP



PLATELETACTIVATION

P2Y12

P2Y5HT2A

PAR1

PAR4

αIIbβ3

αIIbβ3

αIIbβ3

TPGPVI

P2X1a

1

Thromboxane A2


Shapechange

Densegranule

Alphagranule

5HTADP ADPADP

5HT

ATPATPThrombin

Thrombingeneration

Coagulation

Fibrinogen

Aggregation

Amplification

Platelet AggregationSignals generated inside the activated platelet cause GPIIb/IIIa conformational changes that expose fibrinogen or vWF binding sites

Phosphoinositide hydrolysis

Protein phosphorylation

Increase in platelet intracellular free Ca2+

Binding of fibrinogen (dimeric) and vWF(multimeric) crosslinks adjacent platelets, promoting additional platelet activation and aggregate formation

Frojmovic MM. Am Heart J. 1998;135(Suppl 5):S119-131.Kulkarni S, et al. J Clin Invest. 2000;105:783-791.

Ruggeri ZM. J Clin Invest. 2000;105:699-701. Adapted with permission from: Kuwahara M, et al. Arterioscler Thromb Vasc Biol. 2002;22:329-334.

Platelet Aggregation

Scanning electron micrograph of discoid, dormant platelets

Activated, aggregating platelets illustrating fibrin strands

FIRM BUT REVERSIBLEADHESION

IRREVERSIBLEADHESION

Flowingdisc-

shapedplatelet

Rollingball-shaped

platelet

Hemisphere-shapedplatelet

Spreadingplatelet

41

Antiplatelet Agents

Thrombin

ThromboxaneA2

5HT

P2Y12

ADP ADPADP

5HT

PLATELETACTIVATION

P2Y15HT2A

PAR-1

PAR-4

Densegranule

Thrombingeneration

Shapechange

αIIb β3

αIIb β3

FibrinogenαIIb β3

Aggregation

AmplificationAlpha

granule


TPa

Coagulation

GPVI

CollagenATPATP

P2X1

ASPIRIN

xACTIVE

METABOLITE

x

GP IIb/IIIa ANTAGONISTS

xx


TICLOPIDINECLOPIDOGREL

Antiplatelet Agents

Thrombin

ThromboxaneA2

5HT

P2Y12

ADP ADPADP

5HT

PLATELETACTIVATION

P2Y15HT2A

PAR-1

PAR-4

Densegranule

Thrombingeneration

Shapechange

αIIb β3

αIIb β3

FibrinogenαIIb β3

Aggregation

AmplificationAlpha

granule


TPa

Coagulation

GPVI

CollagenATPATP

P2X1

ASPIRIN,

xACTIVE

METABOLITE

x


xx


TICLOPIDINECLOPIDOGRELPRASUGREL

AZD6140 CANGRELORPRT128BX667INS50589

NCX-4016, RIDOGREL, S18886

SCH530348E5555

Gurbel PA, et al. Circulation. 2003;107:2908-2913.

Responsiveness to 300 mg Clopidogrel in Patients Undergoing Coronary Stenting

2 hours 24 hours

5 days 30 days

5 μM ADP used as agonist; resistance defined as Δ aggregation ≤10%

24

12

0

20

10

0

22

11

0

28

14

0

Patie

nts

(%)

Patie

nts

(%)

Patie

nts

(%)

Patie

nts

(%)

-30 -10 0 10 30 50 >60∆ aggregation (%)

-10 0 10 20 30 40 50 60 >60∆ aggregation (%)

-30 -10 0 10 30 50 >60∆ aggregation (%)

-30 -10 0 10 30 50 >60∆ aggregation (%)

Clopidogrel “Nonresponsiveness”

SAT, stent thrombosis. Muller I, et al. Thromb Haemost. 2003;89:783-787.

Inhibition of ADP-induced aggregation 4 hours following a 600 mg clopidogrel loading dose in 105 patients

Nonresponder ResponderSemiresponder0

40

60

80

100

20

5 μM ADP20 μM ADP

Patie

nts

(%)

5 12 10 27 6690

< 10% inhibition > 30% inhibition

10–29% inhibition5 patients with SAT were determined to be nonresponders

Clinical Outcome at 6 MonthsStratified By Post-treatment Reactivity

N=317

Patie

nts

(%)

*ST: 3 sub-acute (definite) (0.8%); 3 late (1 definite, 2 possible) (0.8%).

Price MJ, et al. Eur Heart J. 2008;29:992-1000.

Patients on clopidogrel therapy through 6-month follow-up period

0

2

4

6

8

1.0%

0.0%

1.0%

2.8%

1.9%

4.6%

6.5%

0%

CV death Nonfatal MI ST * CV death/MI/ST

Low post-treatment reactivity High post-treatment reactivity

P=.04

P=.6

P=.008P=.004

CURRENT (OASIS-7): Study Design

ACS (NSTEMI) patients planned for early PCI within 24 hours

Clopidogrel 600 mgDays 1–7 150 mg

ASA low doseDays 8–3075–100 mg

ASA high doseDays 8–30

300–325 mg

Clopidogrel 300 mgDays 1–7

75 mg

ASA low doseDays 8–3075–100 mg

ASA high doseDays 8–30

300–325 mg

N=~13,000

ClinicalTrials.gov identifier: NCT00335452.

Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent EveNTs/ Optimal Antiplatelet Strategy for InterventionS

42

Prasugrel

Mechanism: inhibition of P2Y12

PharmacodynamicsRapid onset (within 2 hours)Irreversible binding

Different metabolic pathway of activation versus clopidogrel

More potent inhibition of ADP-induced platelet activation than clopidogrel

Prasugrel is an ivestigational agent; not yet approved by FDA.Farid NA. Clin Pharmacol Ther. 2007;81:735-741.

Active Metabolite Formation

Prasugrel

Herbert JM, et al. Sem Vasc Med. 2003;3:113-122.

Pro-drug

Oxidation(Cytochrome P450)

HOOC* HS

N

O

F

NS

O

FO

Hydrolysis(esterases)

NS

O

CH3

CO

FO

85% inactive

metabolitesesterases

NS

O

Cl

O CH3C

ON

S

O

Cl

O CH3C HOOC* HS

N

O

Cl

OCH3

NS

O

Cl

O CH3CClopidogrel

Active metabolite Active metabolite

Inhi

bitio

n of

pla

tele

t agg

rega

tion

(IPA

)(2

0 μM

AD

P) (%

)

Prasugrel 60 mgClopidogrel 300 mg

Clopidogrel responder*Clopidogrel nonresponder

n=66

Healthy volunteers

Prasugrel vs ClopidogrelCrossover Study

*Responder ≥ 25% IPA at 4 and 24 hours.Adapted with permission from: Brandt Jt, et al. Am Heart J. 2007;153:66e9-66e16.

-20

0

20

40

60

80

100

Prasugrel Compared with Clopidogrel: ADP-induced Platelet Aggregation

MP

A (%

)

0102030405060708090

100

Mean ± SD, excluding outliers†

20 µM ADP and 24 hr post-LD

†

†

Clopidogrel

59.6±20.1

(112)

BL 1

85.1±7.5

(111)

BL 2

84.1±7.8

(111)

Prasugrel

20.0±6.7

(91)(N)

MPA =

"Placebo"

Rel

ativ

e Fr

eque

ncy

0.0

0.1

0.2

0.3

0.4

Rel

ativ

e Fr

eque

ncy

0.0

0.1

0.2

0.3

0.4

IPA(%)-20 0 20 40 60 80 100

Rel

ativ

e Fr

eque

ncy

0.0

0.1

0.2

0.3

0.4

Clopidogrel

Prasugrel

Adapted with permission from: Weerakkody GJ, et al. Platelets. 2007;18:428-435.Stone GW. Abstract presented at the 2007 American College of Cardiology Scientific Sessions, New Orleans, LA.

BL=blood level; MPA= ean platelet aggregation

Prasugrel (40 mg LD/5 mg MD)Prasugrel (40 mg LD/7.5 mg MD)Prasugrel (60 mg LD/10 mg MD)Prasugrel (60 mg LD/15 mg MD)Clopidogrel (300 mg LD/75 mg MD)

Mea

n IP

A (%

)

-10

0

10

20

30

40

50

60

70

Day/hour post-dosing1/0 1/2 1/4 1/6 7/1 7/2 28/0 28/2 28/4 28/6

Loading dose (LD) Maintenance dose (MD)

Adapted with permission from: Jernberg T, et al. Eur Heart J. 2006;27:1166-1173.

Inhibition of Platelet Aggregation Induced by 20 μM ADP

Greater Platelet Inhibition in Prasugrel vsClopidogrel at Higher Loading Doses

LSM=least square mean; VASP PRI=vasodilator-stimulated phosphoprotein platelet reactivity index. Adapted with permission from: Wiviott SD, et al. Circulation. 2007:116;2923-2932.

20

40

60

80

100

0

20

40

60

80

100

00 4 8 12 16 20 24

Hours0 4 8 12 16 20 24

Hours

Clopidogrel 600 mg

Prasugrel 60 mg

4.920.3

31.8 32.630.8***

64.5***74.8*** 69.3***

*** P<.0001

IPA

(20μ

M A

DP,

%)

VASP

PR

I (%

)

21.5***7.4*** 10.3***

68.47564.3

*** P<.0001

0.5 hr 2 hr 6 hr 18–24 hr

n=70 n=74 n=72 Prasugrel n=39

n=73 n=78 n=77 Clopidogrel n=46

26.0 44.8 43.2 LSM 36.4(18.9– (38.4– (38.0– difference (29.0–33.2) 51.2) 48.4) (95% CI) 43.8)

0 2 hr 6 hr 18–24 hr

n=89 n=93 n=68 Prasugrel n=48

n=89 n=88 n=68 Clopidogrel n=54

54.3 60.5 LSM 56.2(47.4– (54.0– difference (49.2–61.2) 67.1) (95% CI) 63.2)

43

Greater Platelet Inhibition in Prasugrel vsClopidogrel at Higher Maintenance Doses

IPA

(20μ

M A

DP,

%)

VASP

PR

I (%

)20304050607080

203040506070

010Clopidogrel

150 mg

Prasugrel 10 mg Prasugrel 10 mg

Clopidogrel150 mg

Clopidogrel150 mg

Prasugrel 10 mg Prasugrel 10 mg

Clopidogrel150 mg

25.1

48

21.7

39.746.8

60.8

45.4

61.9

14 18 22 26 30Days

14 18 22 26 30Days

LSM difference 15 & 29 days: 14.9 (95% CI: 10.6, 19.3), P<.0001

LSM difference 15 & 29 days: 20.1 (95% CI: 14.5–25.7), P<.0001

15 d 29 d

n=40 Prasugrel n=40

n=46 Clopidogrel n=45

15.7 LSM 14.8(9.2– difference (7.1–22.2) (95% CI) 22.5)

<.0001 P value .0003

15 d 29 d

n=50 Prasugrel n=51

n=52 Clopidogrel n=50

17.9 LSM 21.7(9.1– difference (12.4–26.6) (95% CI) 31.0)

.0001 P value <.0001

LSM=least square mean; VASP PRI=vasodilator-stimulated phosphoprotein platelet reactivity index. Adapted with permission from: Wiviott SD, et al. Circulation. 2007;116:2923-2932.

TITAN

Double-blind

ACS (STEMI or UA/NSTEMI) and planned PCIASA

PRASUGREL CLOPIDOGREL

Primary endpoint: CV death, MI, strokeSecondary endpoints: CV death, MI, stroke, re-ischemia

CV death, MI, UTVR

Median duration of therapy: 12 months

N≈13,000

TRITON–TIMI 38Protocol Design

TRITON-TIMI 38, TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet InhibitioN with prasugrel-Thrombolysis In Myocardial Infarction 38; UTVR, urgent target vessel revascularization.

Wiviott SD, et al. Am Heart J. 2006;152:627-635.

TRITON-TIMI 38: Efficacy and Safetyof Prasugrel vs Clopidogrel with Planned PCI

10

240180120600

5

0420360300

15

End

Poin

t (%

)

Days after Randomization

Primary Efficacy End Point

Key Safety End Point

Clopidogrel

Clopidogrel

Prasugrel

Prasugrel

1.82.4

9.9

12.1 ↓ 138 EventsHazard Ratio, 0.81;95% CI, 0.73-0.90;P<.001

↑ 35 EventsHazard Ratio, 1.32;95% CI, 1.03-1.68;P=.03

No. at Risk

Clopidogrel 6795 6036 5835 5043 4369 3017

Prasugrel 6813 6177 5951 5119 4445 3085

N=13,608; 10,704 with UA/NSTEMI3534 with STEMI

Primary efficacy endpoint: CV death, nonfatal MI, or nonfatal stroke.Primary safety endpoint: TIMI major bleeding not related to CABG during follow-up.


TRITON-TIMI 38: TIMI Bleeding Endpoints in the Overall Cohort at 15 Months

TIMI=Thrombolysis in myocardial infarction.*Most frequent sites of life threatening bleeding: gastrointestinal, intracranial, the puncture site, and retroperitoneal sites.

%Total number of patients were all patients receiving at least one dose of study drugbefore undergoing CABG; ratio is odds ratio.


End Point Prasugrel(N=6741)

Clopidogrel(N=6716)

PrasugrelHR (95% CI)

P Value

no. of patients (%)


146 (2.4) 111 (1.8) 1.32(1.03-1.68)

.03

Life-threatening* 85 (1.4) 56 (0.9) 1.52(1.08-2.13)

.01

Major or minor TIMI bleeding

303 (5.0) 231 (3.8) 1.31 (1.11-1.56)

.002

Bleeding requiring transfusion

244 (4.0) 182 (3.0) 1.34(1.11-1.63)

<. 001

CABG-related TIMI major bleeding%

24 (13.4) 6 (3.2) 4.73(1.90-11.82)

<. 001

AZD6140

First reversible oral ADP antagonistNew class of P2Y12 inhibitors

Not a thienopyridineor ATP antagonistDirect-acting (not a pro-drug)

Rapid onset (2 hours)Plasma t1/2 ~12 hoursGreater and more consistent inhibition of ADP-induced platelet activation than clopidogrel

AZD6140 is an investigational agent not yet approved by the FDA.Peters G, Robbie G. Haematologica. 2004;89(suppl.7):14-15.

F

F

HN

N

N S

N

NNO

HO OH

HO

AZD6140 Compared with Clopidogrel: ADP-induced Aggregation

Clopidogrel

Time (hours)

20

40

60

80

100

Day 1 Day 14

AZD6140 100 mg BID

Time (hours)

20

40

60

80

100

2 4 8 12 2 4 8 12 24

Day 1 Day 14

2 4 8 12 2 4 8 12 24

Mea

n in

hibi

tion

(%)

Mea

n in

hibi

tion

(%)

Adapted with permission from: Husted S, et al. Eur Heart J. 2006;27:1038-1047.

44

RandomizationV1

Day 1

V2 V3 V4 Follow-up

Week 4 Week 8 Week 12 Final visit+7 days

AZD6140 90 mg bid (n=334)

AZD6140 180 mg bid (n=323)

Clopidogrel 75 mg qd (n=327)

Onset of chestpain and 48 h maximum torandomization

N=990

DISPERSE2 Main Study Design

All patients received aspirin (≤ 325 mg first dose, then 75–100 mg qd) and heparin/LMWH and/or a GPIIb/IIIa antagonist

50% of AZD6140 patients in each arm received a 270 mg loading doseIn the clopidogrel group, thienopyridine-naïve patients received a 300-mg loading dose

DISPERSE2=Dose confirmatIon Study assessing anti-Platelet Effects of AZD6140 vs clopidogRel in NSTEMI.Cannon CP, et al. J Am Coll Cardiol. 2007;50:1844-1851.

DISPERSE2Adjudicated bleeding rates within 48 hours

4

3

2

0

1

Tota

l ble

edin

g ra

te (%

)

AZD614090 mg bid

N=168

2.4%

AZD6140180 mg bid

N=159

1.3%

AZD6140270 mg**

N=330

3.6%

Clopidogrel75 mg qd

N=327

2.8%

Minor bleeds*Major bleeds

* Minor bleeding without major bleeding; ** loading dose.Adapted with permission from: Cannon CP, et al. J Am Coll Cardiol. 2007;50:1844-1851.

DISPERSE2Cumulative adjudicated clinical endpoint of CV death/MI/stroke

No significant differences were found between the groups for clinical endpoints

AZD6140 90 mg bid AZD6140 180 mg bid Clopidogrel 75 mg QD

Study day4131211 11 91817151 61

0.10

0.05

0.00

Cum

ulat

ive

risk

of a

n ev

ent

Primary endpoint of the DISPERSE-2 trial was the Kaplan-Meier rate of major or minor bleeding through 4 weeks.Adapted with permission from: Cannon CP, et al. J Am Coll Cardiol. 2007;50:1844-1851.

DISPERSE2Non-bleeding adverse events

Preferredterm

AZD614090 mg bid

n=334

AZD6140180 mg bid

n=323

Clopidogrel75 mg qd

n=327Dyspnea 10.5 15.8 6.4

Chest pain 7.5 7.4 8.9

Headache 9.6 6.5 8.6

Nausea 6.6 6.5 3.4

Dyspepsia 4.8 3.1 2.8

Insomnia 5.4 4.6 2.8

Diarrhea 3.0 7.4 3.4

Hypotension 4.2 3.7 0.6

Discontinuation rates due to adverse events were low and similar between the groups: 21 (6%), 23 (7%), and 19 (6%) discontinued in the AZD6140 90 mg bid, AZD6140 180 mg bid, and clopidogrel 75 mg qd groups, respectively.

Cannon CP, et al. J Am Coll Cardiol. 2007;50:1844-1851.

PLATOCan PLATelet Inhibition Be Optimized to Prevent

Vascular Events?~16,000 patients within 24 hours

of an index ACS (STEMI or NSTEMI)

At least 2 inclusion criteria:1. ST segment changes2. ↑ biomarkers3. At least 1:

- > 60 years old- Previous MI/CABG- Known > 1V CAD- AODM- PVD- Renal dysfunction

ASA 75–100 mg QD

AZD6140 BID

Clopidogrel75 mg QD

Primary endpoint: Time to first occurrence of the composite of death, MI or stroke

Primary safety endpoint: Major bleeding

Double-blind, double-dummyMean follow-up ~12.5 months

Range 6–24

ClinicalTrials.gov Identifier: NCT00391872.

Cangrelor

ATP analogue Immediate onset (within 5 minutes)Plasma half-life of 5–9 minutes 20–60 minutes for return to normal platelet function

N N

N N

NH

SCF3

OHOH

OOP

OO

PP

OO

OClCl

OO

O

S

4Na+

Cangrelor is an invesigational agent not yet approved by the FDA.Storey RF, et al. Thromb Haemost. 2001;85:401-407.

Greenbaum AB, et al. Am Heart J. 2006;151:689e1-689e10.

Parenteral ADP-P2Y12 receptor antagonist

45

200

6040

10080

200

6040

10080

200

6040

10080

0.5 1.5 2.5 3.5 5 24 48 72 20 m 1 h

post post

Inhi

bitio

n of

agg

rega

tion

(%)

Time after onset of cangrelorinfusion (hrs) and time post-infusion

Adapted with permission from: Storey RF, et al. Thromb Haemost. 2001;85:401-407.

Rapid, Dose-dependent Inhibition of Platelet Aggregation with Cangrelor

n=12

Infusion rates:0.05 μg/kg/min (0.5 hours)0.2 μg/kg/min (1.5 hours)0.5 μg/kg/min (2.5 hours)2.0 μg/kg/min (3.5–24 hours)

n=13


n=14


Improved ADP Blockade with Cangrelorin Clopidogrel-treated Patients

VASP=vasodilator-stimulated phosphoprotein.Adapted with permission from: Aleil B. J Thromb Haemost.

2005;3:85-92.

Platelet Reactivity Index (PRI) determined by the difference in VASP fluorescence intensity between resting and ADP-activated platelets.

33 clopidogrel treated patients with a mean PRI of 61% and decreased to close to zero with in vitro cangrelor.

-20

-10

0

20

10

40

30

50

70

60

90

80

Healthy + in vitro + in vitrodonors cangrelor cangrelor

Patients Patientsnot treated treatedwith clop with clop

P<.001

Plat

elet

reac

tivity

inde

x (%

)

Cangrelor Phase II Clinical Data: Compared with Abciximab in PCI

Double-blind randomized trial performed in US

5.7%5.4%

2.1%

1.0%

Death, MI, revascularization Major bleed (TIMI criteria)

Abciximab (n=94)Cangrelor (n=105)

Incidence of events up to 7 days

AR-C69931MX report number: SC931-5129 Part 2. Unpublished data.

CHAMPION–PCIPCI for ACS

(N~9,000)

Primary endpoint: death, MI, and UTVR at 48 hours

Secondary endpoints:Death, MI, uRevasc at 30 daysDeath at 6 months and 1 year

Index procedure and study drug infusion (for at least 2 hours or the duration of the procedure, whichever is longer)

Clopidogrel600 mg

Placebobolus and infusion

Placebocapsules

Cangrelor 30 μg/kg bolus4 μg/kg/min Infusion

Clopidogrel600 mg

Placebocapsules

CHAMPION-PCI Trial=A Clinical Trial Comparing Cangrelor to Clopidogrelin subjects who require percutaneous coronary intervention.

ClinicalTrials.gov Identifier: NCT00305162.

0

20

40

60

80

100

0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0Time (hours)

Ligh

t tra

nsm

ittan

ce (%

)

Clopidogrel 600mgClopidogrel 600mg at time of cangrelorbolus and 2hr infusion

Clopidogrel 600mg

Clopidogrel 600mg given at the end of a cangrelor infusion

Clopidogrel/Cangrelor Interaction

Adapted with permission from: Steinhubl SR, et al. Thromb Res. 2008;121:527-534.

Antiplatelet Agents

Thrombin

ThromboxaneA2

5HT

P2Y12

ADP ADPADP

5HT

PLATELETACTIVATION

P2Y15HT2A

PAR-1

PAR-4

Densegranule

Thrombingeneration

Shapechange

αIIb β3

αIIb β3

FibrinogenαIIb β3

Aggregation

AmplificationAlpha

granule


TPa

Coagulation

GPVI

CollagenATPATP

P2X1

ASPIRIN,

x PRASUGREL

ACTIVE METABOLITE

x AZD6140 CANGRELORPRT128BX667INS50589


xx


xSCH530348

E5555

TICLOPIDINECLOPIDOGREL

NCX-4016, RIDOGREL, S18886

46

Protease Activated Receptor (PAR)-1

LDPR SFLLRNP LDPRNRLLFS

Thrombin

Signal

CC CC CC CC

Vu TH, et al. Cell. 1991;64:1057-1066.

Thrombin Receptor Antagonist (TRA SCH 530348)

First of a new classOral administration, long-acting Blocks the platelet PAR-1 receptor, primary thrombin receptor in humansDoes not interfere with thrombin-mediated generation of fibrinNo effect on bleeding time or PT/aPTT

TRA SCH 530348 is an investigational agent not yet approved by FDA.Husted S. Eur Heart J Suppl. 2007;9:D20-27.

TRA-PCI: Study DesignNon-urgent PCI or catheter with possible PCI (all receive aspirin)

No PCI**

Maintenance therapy qd for ~60 daysPlacebo loading dose → placebo

SCH 530348 loading dose → SCH 530348

Safety: TIMI major plus minor bleedingEfficacy: death/MACE at 60 days

Primary evaluable cohort **Secondary evaluable cohort

Catheterization

CABG Medical management

0.5 mgn ~100

1 mgn ~100

2.5 mgn ~100

Placebon ~100

SCH 530348

Randomization #1— 3:1 SCH530348:Placebo Sequential groups (loading dose x 1: 10 mg; 20 mg; 40 mg)

Randomization #2

PCI

Safety: TIMI major plus minor bleeding

No additional study drug

N=1030

TRA-PCI=Thrombin Receptor Antagonist in Percutaneous Coronary Intervention trial. Adapted with permission from: Moliterno DJ, et al. J Am Coll Cardiol. 2007;49 [abstract 2402-9].

TIMI major/minor bleeding

2.8%

PCI Cohort

P=.77

P=.35

P=.70

P=.73

3.3%

1.6%

2.5%

4.0%4

0

2

All TRAn=422

1

3

5

Placebon=151

10 mgn=129

20 mgn=120

40 mgn=173

SCH 530348P value relative to placebo.

Adapted with permission from: Moliterno DJ, et al. J Am Coll Cardiol. 2007;49 [abstract 2402-9].

Patie

nts

(%)

60-day death or MI

8

0

4

All TRAn=422

4.5%

TRA-PCI Efficacy Outcomes

2

6

10

Placebon=151

7.3%

10 mgn=129

20 mgn=120

40 mgn=173

5.4%

4.2% 4.0%

SCH 530348

P=.19P=.53

P=.28P=.20

P value relative to placebo.Adapted with permission from: Moliterno DJ, et al. J Am Coll Cardiol. 2007;49 [abstract 2402-9].

Patie

nts

(%)

TRA (SCH 530348) program(29,500 patients)

Primary endpoint: composite of CV death, MI,

stroke, and urgent revascularization

TRA (SCH 530348) ProgramEvaluation of efficacy and safety in acute and chronic atherothrombosis

NSTEACS10,000 patients

Secondary prevention19,500 patients

SCH 530348 Placebo SCH 530348 Placebo

Follow-up: at 30 days; at 4, 8, and 12 months; and at 6 months thereafter (I year minimum)

Primary endpoint: composite of

CV death, MI, stroke, urgent revascularization, and

recurrent ischemia with rehospitalization

ClinicalTrials.gov Identifier: NCT00527943. ClinicalTrials.gov Identifier: NCT00526474.

TRA-CER TRA2°P - TIMI 50

47

PAR-1 Antagonist–E5555

600 patientsages 55–80 with known ASCAD,

on ASA +/-clopidogrel, with hs-CRP > 3mg/L

E5555 Outcomes• MACE• hs-CRP

E5555 is an investigational agent not yet approved by FDA.ClinicalTrials.gov Identifier: NCT00312052.

LANCELOT

Tissue factor

Factor Xa

Prothrombin

Thrombin

Fibrinogen Fibrin Thrombus Fibrin degradationPlasmin

Collagen Leukocytes

Platelets

vWF ADP

Activated platelets

Fibrinogen cross-linking

Platelet aggregation

Thromboxane A2

Coagulation Platelets

Direct thrombin inhibitors

LMWHUH

LMWHUH

TFPI

Antithrombin

Antithrombin

LMWH

ThrombolyticsAdapted with permission from: Selwyn AP. Am J Cardiol. 2003;91(Suppl):3H-11H.

New and Investigational Anticoagulants

TFPI (tifacogin)

FondaparinuxIdraparinux

RivaroxabanApixabanLY517717YM150DU-176bPRT-054021

XimelagatranDabigatran

ORAL PARENTERAL

DX-9065aOtamixaban

Xa

IIa

TF/VIIa

X IX

IXaVIIIa

Va

II

FibrinFibrinogen

AT

APC (drotrecogin alfa)sTM (ART-123)

Adapted from Weitz & Bates. J Thromb Haemost. 2005;3(8):1843-1853.

TTP889

Factor Xa inhibitors

• FXa may be a better target than thrombin• Has few functions outside coagulation (compared with

thrombin)• Has a wider therapeutic window than thrombin

(separation of efficacy and bleeding), in vitro• Thrombin inhibitors are associated with rebound

thrombin generation – no evidence with FXa inhibitors• Efficacy of heparin-based anticoagulants improves as

selectivity for FXa increases: UFH < LMWH < fondaparinux

IIaIIaIIII

FibrinogenFibrinogen Fibrin clotFibrin clot

Extrinsic Extrinsic pathwaypathway

IntrinsicIntrinsicpathwaypathway

ATAT XaXaATAT ATAT

Fondaparinux Fondaparinux

XaXa

AntithrombinAntithrombin

Fondaparinux:Targeted Mechanism of Action

Turpie AGG, et al. N Engl J Med. 2001;344:619.

RivaroxabanHuman Factor Xa/rivaroxaban complex

Rivaroxaban is an oral, direct Factor Xa inhibitor, with high selectivity for Factor Xa (Ki 0.4±0.02 nM) 50% inhibition (IC50) for Factor VIIa, Factor XIa, thrombin, activated protein C, plasmin, urokinase, trypsin: >20,000 nM

Rivaroxaban is an investigational agent not yet approved by FDA.Roehrig S, et al. J Med Chem. 2005;48(19):5900-5908.

Perzborn P, et al. J Thromb Haemost. 2005;3(3):514-521.

S4

S1

N N ONH

O

SC l

O

O

O Rivaroxaban

48

APPRAISE-1

• ISTH major or CRNM bleeding: 7.9% for 10 mg apixaban, 5.7% for 5 mg apixaban, 3% for placebo (p=0.005 for high dose vs. placebo and p=0.09 for low dose vs placebo)

• Death, MI, recurrent ischemia, or stroke: 6.0%, 7.6%, 8.7% (p=0.07 for high dose vs placebo and p=0.21 for low dose vs placebo), respectively

Trial design: Patients recovering from an ACS were randomized to apixaban 10 mg daily (n=318), apixaban 2.5 mg twice daily (n=317), or placebo (n=611). Study medications were administered for 6 months.

Results

Conclusions• This dose-finding study reveals that bleeding

is increased among patients with a recent ACS with higher doses of apixaban compared with placebo

• Although this study was not powered for efficacy, adverse events appeared to be lowest with 10 mg apixaban

ISTH=International Society of Thrombosis and HaemostasisCRNM=clinically relevant non-major

Apixaban is an investigational agent not yet approved by FDA.Presented by Dr. John Alexander at ESC 2008.

%

7.9

5.7

3

p=0.005 for high dose vs

placebo

p=0.09 for low dose vs

placebo

Apixaban 10 mg Apixaban 5 mg

Placebo

0

3

6

9

ISTH major or CRNM bleedingISTH major or clinically relevant nonmajor bleeding

Rivaroxaban-Clinical Studies

- VTE Treatment

- Atrial Fibrillation

ACS treatment

Recent ACS PatientsStabilized 1-7 Days Post-Index Event

STRATUM 1STRATUM 1 STRATUM 2STRATUM 2

Primary Endpoint: TIMI Significant Bleeding

MD Decision to Treat with ClopidogrelMD Decision to Treat with Clopidogrel

Dose Levels5, 10, & 20 mg

N ~ 1,350

RIVAQD

3 Dose Levels

RIVAQD

3 Dose Levels

PLACEBO PLACEBO RIVABID

3 Dose Levels

RIVABID

3 Dose Levels

RIVAQD

3 Dose Levels

RIVAQD

3 Dose Levels

PLACEBOPLACEBORIVABID

3 Dose Levels

RIVABID

3 Dose Levels

Treat for 6 MonthsTreat for 6 Months

YESNO

STAGE 1: Dose Escalation

RIVA Rivaroxaban

ATLAS – TIMI 46

This study sponsored by Bayer/Johnson & Johnson Pharmaceutical Research & Development, LLC.

Recent ACS PatientsStabilized 1-7 Days Post-Index Event

STRATUM 1STRATUM 1 STRATUM 2STRATUM 2

Primary Endpoint: Death, MI, Stroke, or Recurrent Ischemia Requiring Revascularization

MD Decision to Treat with ClopidogrelMD Decision to Treat with ClopidogrelN ~ 2,100

RIVAQD

RIVAQDPLACEBOPLACEBO RIVA

BIDRIVABID

RIVAQD

RIVAQDPLACEBOPLACEBO RIVA

BIDRIVABID

Treat for 6 MonthsTreat for 6 Months

NO YES

STAGE 2: Dose Confirmation

RIVA=Rivaroxaban

ATLAS – TIMI 46

This study sponsored by Bayer/Johnson & Johnson Pharmaceutical Research & Development, LLC.

Mod-to-High Risk NSTE ACS w/ Planned Early Inv Strategy

OtamixGroup 1(n=450)


RAspirin +clopidogrel

Bail-out eptifibatide in otamixaban

groups if rec. ischemia or thrombotic

complic. during PCI

Study druguntil end of PCI,

as clin. indicated, until Day 4 or hospital d/c,whichever comes first

1° EP: Death, MI, Urgent Revasc, Bail-out IIb/IIIa thru 7 d1° EP: Death, MI, Urgent Revasc, Bail-out IIb/IIIa thru 7 d

Coronary angiography ± PCI (Day 1-3)Coronary angiography ± PCI (Day 1-3)









UFH + Eptifi.(n=450)

UFH + Eptifi.(n=450)

at randomization

Day 30 Visit, Day 90 Tel f/up, Day 180 Tel. f/upDay 30 Visit, Day 90 Tel f/up, Day 180 Tel. f/up

Dose Ranging Study of Otomixaban - a Novel, Intravenous, Direct Xa Inhibitor

SEPIA-ACS 1 – TIMI 42

Otomixaban is an investigational agent not yet approved by FDA.This study sponsored by sanofi-aventis.

Factor Xa Inhibitors in DevelopmentIndicationIndication VTE prevention*VTE prevention* VTE treatmentVTE treatment Stroke

prevention in patients with AF

Other?Other?

IdraparinuxIdraparinux –– Phase III results Phase III results expected soonexpected soon

Long-term therapy caused

significantly more bleeding†

––

Rivaroxaban Rivaroxaban Phase IIIPhase III Phase IIIPhase III Phase III Phase II data in ACS to be presented at

AHA

LY517717LY517717 Phase IIb completedPhase IIb completed –– –– ––

YM150YM150 Phase IIa completedPhase IIa completed –– Planned ––

DUDU--176b176b Phase IIa completedPhase IIa completed –– Phase III planned ACS plannedACS planned

ApixabanApixaban Phase IIb Phase IIb completed; planned completed; planned in cancer patientsin cancer patients

Phase II Phase II underwayunderway

– Phase II data in ACS presented at ESC

PRTPRT--054021054021 Phase II plannedPhase II planned PlannedPlanned Planned Secondary Secondary prevention of stroke prevention of stroke

and MI plannedand MI planned

*Prevention of VTE after major orthopaedic surgery, unless indicated†The Amadeus Investigators. Lancet. 2008;371:315-321.

49

Factor Xa Inhibitors in Development

IndicationIndication VTE prevention*VTE prevention* VTE treatmentVTE treatment Stroke prevention in

patients with AF

Other?Other?

IdraparinuxIdraparinux –– Phase III results Phase III results expected soonexpected soon

Phase III halted ––

Rivaroxaban Rivaroxaban Phase IIIPhase III Phase IIIPhase III Phase III ACS ongoingACS ongoing

LY517717LY517717 Phase IIb completedPhase IIb completed –– – ––

YM150YM150 Phase IIa completedPhase IIa completed –– Planned ––

DUDU--176b176b Phase IIa completedPhase IIa completed –– Planned ACS plannedACS planned

ApixabanApixaban Phase IIb Phase IIb completed; planned completed; planned in cancer patientsin cancer patients

Phase II Phase II underwayunderway

– PostPost--ACS plannedACS planned

PRTPRT--054021054021 Phase II plannedPhase II planned PlannedPlanned Planned Secondary Secondary prevention of stroke prevention of stroke

and MI plannedand MI planned

*Prevention of VTE after major orthopaedic surgery, unless indicated

Questions for DiscussionWhat will optimal antiplatelet/antithrombin

therapy look like in 2015…

In PCI?

ACS medical management?

For patients who go onto CABG?

Long-term secondary prevention?

Among elderly patients?

Among patients with renal dysfunction?

Solutions for Toughest Cases •Apply evidence-based

ACS care to complex patient cases

•Probe difficult ACS issues in light of research

evidence and common medical practice

Learning Objectives

real-world practice files/syllabus... · michael bloch, md is a member of speakers bureaus for...

Documents