Accreditation Information Jointly Sponsored by the University of Massachusetts Medical School Office of Continuing Educati...
Program Requirements Instructions for Receiving Category 1 AMA Credit Participants: This SlideCAST is a CME-certified prog...
Accreditation Information Intended Audience:  This SlideCAST is designed for interventional cardiologists, cardiologists, ...
Accreditation Information Accreditation Statement for Jointly-Sponsored Programs This activity has been planned and implem...
Policy on Faculty And Provider Disclosure It is the policy of the University of Massachusetts Medical School to ensure fai...
ACS Forum Leadership Panel Deepak L. Bhatt, MD, FACC, FSCAI, FESC, FACP Associate Director, Cleveland  Clinic Cardiovascul...
ACS Forum Leadership Panel Judd E. Hollander, MD Professor Clinical Research Director Department of Emergency Medicine Uni...
ACS Forum Leadership Panel Charles Pollack, MD, FACEP Chairman, Department of Emergency Medicine Pennsylvania Hospital Pro...
ACS Leadership Panel Financial Disclosures Deepak L. Bhatt, MD:  Consultant/H onoraria or Grant/Research Support: Astra Ze...
ACS Leadership Panel Financial Disclosures Christopher Granger, MD:  Educational Grants and/or Research Support: Alexion, ...
ACS Faculty Review Committee Thomas Amidon, MD The Hope Heart Institute Atul Aggarwal, MD Nebraska Heart Institute Himansh...
ACS Faculty Review Committee Tim Henry, MD Minneapolis Heart Institute  Kurt Kleinschmidt, MD UT Southwestern Medical Cent...
ACS Faculty Review Committee Robert N. Piana, MD Vanderbilt University  Vincent J. Pompili, MD, FACC Case School of Medici...
Educational Objectives <ul><li>Physicians will learn about the impact that bleeding has on outcomes in patients with acute...
A  Science-to-Strategy Analysis of Bleeding Issues in Acute Coronary Syndromes BLEEDING IN THE SETTING OF ACUTE CORONARY S...
Medical Rx (cath) Time PCI Surgery Medical Rx (no cath) Medical Rx No disease (82 % of total) (18 % of total) (52% of tota...
SYNERGY 1994 1995 1996 1997 1998 1999 2000 2002 2003 2004 2005 2006 2001 Bleeding risk Ischemic risk ACUITY ISAR-REACT 2 M...
Evolving Paradigm for Evaluating ACS Management Strategies Ischemic Complications <ul><li>Death </li></ul><ul><li>MI </li>...
Evolving Paradigm for Evaluating ACS Management Strategies Ischemic Complications Hemorrhage HIT <ul><li>Death </li></ul><...
Evolving Paradigm for Evaluating ACS Management Strategies Periprocedural  Complications Clinical Benefit <ul><li>Death </...
Balancing Events and Bleeding Risk of events Risk of bleeding Thrombosis Hemostasis Two sides of the same coin Degree of A...
<ul><li>Death 4.3%   </li></ul><ul><li>(Re)-Infarction 2.5% </li></ul><ul><li>CHF 8.0% </li></ul><ul><li>Cardiogenic Shock...
Bleeding in ACS - Agenda <ul><li>Predictors of bleeding in ACS </li></ul><ul><li>Outcomes associated with bleeding </li></...
<ul><li>What predicts bleeding among patients with ACS ? </li></ul>Bleeding in ACS Question to be answered:
Predictors of Major Bleeding in ACS <ul><li>Older Age </li></ul><ul><li>Female Gender </li></ul><ul><li>Renal Failure </li...
Predictors of Major Bleeding P-value RR (95% CI) Risk ratio ± 95% CI Manoukian SV, Voeltz MD, Feit F et al.  TCT 2006. Res...
P-value RR (95% CI) Predictors of Transfusion Risk ratio ± 95% CI Manoukian SV, Voeltz MD, Feit F et al.  TCT 2006. Result...
REPLACE-2 Multivariate Predictors of Major Bleeding Feit F et al. Unpublished (in manuscript)  <0.0001 3.433 to 22.072 8.7...
<ul><li>Older age, chronic kidney disease, female gender are consistently associated with bleeding and blood transfusion <...
<ul><li>Does bleeding influence the prognosis of ACS patients ? </li></ul>Bleeding in ACS Question to be answered:
Moscucci M et al.  Eur Heart J  2003;24:1815-23. P<0.001 Overall  Unstable  NSTEMI  STEMI ACS  Angina Patients (%) Major B...
Bleeding & Outcomes log rank p-value for all four categories <0.0001 log-rank p-value for no bleeding vs. mild bleeding = ...
Bleeding and Outcomes in NSTE ACS  26,452 patients from PURSUIT, PARAGON A,  PARAGON B, GUSTO IIb NST Bleeding severity an...
Major Bleeding, Ischemic Endpoints,  and Mortality P <0.0001 for all Manoukian SV, Voeltz MD, Feit F et al.  TCT 2006. Res...
Major Bleeding and Myocardial Infarction P <0.0001 for all Manoukian SV, Voeltz MD, Feit F et al.  TCT 2006. Results: The ...
Major and Minor Bleeding in PCI Bleeding Increases Mortality and Events Kinnaird TD et al.  AM J Cardiol  2003;92:930-5. 1...
<ul><li>Bleeding is associated with adverse short- and long-term outcomes among patients with ACS and those undergoing PCI...
<ul><li>How does one assess bleeding severity? </li></ul>Bleeding in ACS Question to be answered:
Bleeding Incidence in ACS Clinical Trials Rao SV, et al.  J Am Coll Cardiol . 2006 Feb 21;47(4):809-16. Epub 2006 Jan 26
Bleeding Definitions <ul><li>TIMI Definition </li></ul><ul><ul><li>Major </li></ul></ul><ul><ul><ul><li>ICH </li></ul></ul...
Bleeding Definitions <ul><li>GUSTO Definition </li></ul><ul><ul><li>Severe or life threatening </li></ul></ul><ul><ul><ul>...
Bleeding Incidence Among 15,858 NSTE ACS Patients: Impact of Definition Rao SV, et al.  J Am Coll Cardiol . 2006 Feb 21;47...
Bleeding Scales Among  NSTE ACS Patients Rao SV, et al.  J Am Coll Cardiol . 2006 Feb 21;47(4):809-16. Epub 2006 Jan 26  T...
<ul><li>Clearly defining bleeding severity can be difficult, but there are definitions that have been used in clinical tri...
<ul><li>Do blood transfusions have predictive value? </li></ul><ul><li>Do blood transfusions correct negative impact of bl...
Transfusion in ACS 30-Day Survival By Transfusion Group Rao SV, et. al.,  JAMA  2004;292:1555–1562 N=24,111
PRBC Transfusion Among NSTE ACS Patients: Cox Model for 30-day Death *Transfusion as a time-dependent covariate Rao SV, et...
Adjusted Risk of In-Hospital Outcomes  By Transfusion Status* *Non-CABG patients only Yang X,  J Am Coll Cardiol  2005;46:...
Transfusion, Ischemic Endpoints, and Mortality P <0.0001 for all Manoukian SV, Voeltz MD, Feit F et al.  TCT 2006. Results...
Transfusion and Myocardial Infarction P <0.0001 for all Manoukian SV, Voeltz MD, Feit F et al.  TCT 2006. Results: The ACU...
Transfusion Post PCI: REPLACE 2 One Year Mortality Increased 1-year mortality in transfused patients Adjusted Odds Ratio 4...
<ul><li>Although there has never been a randomized trial of blood transfusion in patients with ACS, the available observat...
<ul><li>Are there certain ACS subpopulations at especially high risk for bleeding, transfusion, and morbidity/mortality? <...
Bleeding Risks—Transfusions by Age Alexander KA,  JAMA  2005;294:3108–16.
REPLACE-2: Elderly Patients Have Increased Major Bleeding and Transfusions 6,002 patients in REPLACE-2 806 patients (13.4%...
Elderly Patients in REPLACE-2: Increased 30-Day Mortality With Major Bleeding and Transfusions p<0.0001 p=0.0001 6,002 pat...
Excessive Dosing of Anticoagulants by Age Alexander KA,  JAMA  2005;294:3108–16.   12.5 28.7 8.5 33.1 37 12.5 64.5 38.5 16...
RBC Transfusions by Excess Dosing Alexander KA,  JAMA  2005;294:3108–16.
Cumulative Effects of Dosing Errors:  Combined Use of Heparin and GP IIb-IIIa Alexander KA,  JAMA  2005;294:3108–16.
Excess Dosing of Gp IIb/IIIa  and Bleeding in Women Alexander KP, et. al.  Circulation  2006 N=32,601 patients from CRUSAD...
Bleeding is Increased in Patients With Impaired Renal Function Undergoing PCI Creatinine Clearance Chew DP et al.  Am J Ca...
Anemia Identifies High-Risk The Unrecognized Risk Factor <ul><li>Older </li></ul><ul><li>Female </li></ul><ul><li>Lower BM...
Major Bleeding is Increased in Anemic Patients Undergoing PCI 6,010 patients in REPLACE-2. 1,362 patients (22.7%) classifi...
NSTE-ACS Mortality Stratified by Hemoglobin Sabatine MS.  Circulation  2005 Unadjusted <ul><ul><li>Hb (g/dL) n OR (95% Cl)...
<ul><li>Certain ACS patient populations are at especially high risk for bleeding and mortality </li></ul><ul><ul><li>Elder...
<ul><li>Does bleeding influence the cost of care for patients with ischemic heart disease? </li></ul>Bleeding in ACS Quest...
Calculating Costs of Ischemia and Bleeding: EPIC EQOL Study (Abciximab in PCI) Abciximab versus Placebo    ischemic costs...
<ul><li>The available costs data confirms that a balance must be struck between ischemia reduction and bleeding. </li></ul...
Bleeding Among Patients with ACS Conclusions <ul><li>Antithrombotic therapies are cornerstone Rx </li></ul><ul><ul><li>Mus...
Conclusions—Bleeding  <ul><li>Bleeding is associated with worse short and long-term outcomes including death and MI </li><...
Conclusions—Bleeding  <ul><li>In addition to clinical outcomes, bleeding is associated with increased cost of care </li></...
CME Test Complimentary CME Test:   To access the complimentary CME test, program participants must have internet access. P...
ACS Faculty Review Committee Thomas Amidon, MD Medical Director The Hope Heart Institute Overlake Internal Medicine Associ...
ACS Faculty Review Committee Harold Dauerman, MD Director, Cardiovascular Catheterization Laboratory Professor of Medicine...
ACS Faculty Review Committee James Leggett, MD Associate Medical Director Hope Heart Institute Seattle, WA Glen Levine, MD...
ACS Faculty Review Committee Robert N. Piana, MD Associate Professor of Medicine Vanderbilt University School of Medicine ...
ACS Faculty Review Committee Lowell H. Steen, Jr., MD Associate Professor of Medicine, Cardiology Loyoyla University Chica...
ACS Review Committee Financial Disclosures Thomas Amidon, MD:  Nothing to disclose. Atul Aggarwal, MD:  Grant/Research Sup...
ACS Review Committee Financial Disclosures Tim Henry, MD:  Nothing to disclose.   Kurt Kleinschmidt, MD:  Consultant:   Th...
ACS Review Committee Financial Disclosures Paul E. Pepe, MD, MPH :  Nothing to disclose. Robert N. Piana, MD:  Speaker’s B...
CME Test Complimentary CME Test:   To access the complimentary CME test, program participants must have internet access. P...
 
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  • The following presentation is designed to highlight recent major studies that have the potential to significantly affect the standard of care for patients with acute coronary syndromes. Our standards are constantly evolving, and these studies have only recently come forward. The challenge we face is how to use the information from these new studies to improve the care of our patients.
  • Listed here are the participating faculty who helped develop this program.
  • Listed here are the participating faculty who helped develop this program.
  • Listed here are the participating faculty who helped develop this program.
  • Listed here are the financial disclosures for the participating faculty who helped develop this program.
  • Listed here are the financial disclosures for the participating faculty who helped develop this program.
  • Listed here are the participating faculty who reviewed this program.
  • Listed here are the participating faculty who reviewed this program.
  • Listed here are the participating faculty who reviewed this program.
  • The modern-day management of ACS patients is complicated. As one looks across the time course of hospitalization, there are multiple possible pathways. The problem is, that at time zero, the time at which the patient first presents, you do not necessarily know exactly what is going to happen, or what route the patient will follow. According to data from the CRUSADE Registry from a 1 year period, approximately 18% of ACS patients did not come forward to the cath lab, and were managed medically throughout their hospital course; 82% of patients did come to the cath lab – 63% within the first 48 hours of admission. This means that there is an additional period of medical management prior to catheterization that must be considered, but it varies tremendously from patient to patient and from institution to institution. Following catheterization, 12% of the total patients went to bypass surgery, and 52% of the total patient s underwent PCI (40% within the first 48 hours of admission), leaving approximately 18% of the total patients who were not revascularized (and continued medical management) or had no significant disease. These numbers highlight the necessity of choosing therapies that do not restrict your therapeutic options.
  • The treatment of UA/NSTEMI has evolved considerably over the last decade. In the early 1990s, the “standard” of care was aspirin, unfractionated heparin, a conservative management strategy, and, if done, PCI involved primarily balloon angioplasty. Subsequently a number of management options (upper portion of the slide) as well as major trials (middle portion of the slide) have come forward. The clinical availability of GP IIb/IIIa blockers (green) in 1995, with trials such as PRISM-PLUS and PURSUIT (also in green) showing their efficacy in UA/NSTEMI patients, particularly those undergoing coronary intervention. The LMWH enoxaparin was studied in the mid-1990s in ESSENCE (in dark blue), and was released for use in unstable angina in 1997. Clopidogrel (in orange) released in 1998, was a mainstay of therapy for coronary intervention (particularly the rapidly-growing world of stents). It’s utility in UA/NSTEMI was confirmed in the large scale CURE trial. Bivalirudin also was approved (based on the REPLACE 2 trial) for use as procedural anticoagulation for PCI in about 2001. Finally, on the basis of trials such as TACTICS, the rapid invasive management strategy began to predominate, particularly in the US, in the late 1990s. Newer data (gray boxes) have come forward (the trial names are color-coded to correspond to the agent and prior trials) that need to be assimilated into modern-day practice. Trials such as SYNERGY ( enoxaparin vs UFH in high-risk ACS patients managed with a rapid invasive management strategy), OASIS 5 (fondaparinux vs enoxaparin in higher-risk ACS), ICTUS (testing a rapid invasive strategy versus a selective invasive strategy in troponin (+) patients). ISAR-REACT 2 (assessing the utility of abciximab in ACS patients already pre-loaded with high doses of clopidogrel), and ACUITY(evaluating bivalirudin in rapidly invasively managed UA/NSTEMI) are going to help define the practice standards for the future. In the bottom of the slide are schematic graphs of the general trends in bleeding and thrombotic (ischemic) events over this same period. The arrival of GP IIb/IIIa antagonists brought with it substantial increases in bleeding. Thienopyridines both reduced this rate (by substituting for IIb/IIIa antagonists in lower-risk patients) and worsened it (by further adding to the antithrombotic milieu. Enoxaparin had some issues in that it did not fit well with anticoagulation management (traditionally done with ACTs and UFH in the cath lab). The emerging early invasive strategy served to further highlight the importance of the transition to the cath lab. The arrival of bivalirudin brought with it an option for reducing the risk of bleeding complications. With time, better technologies, and better adjunctive therapies the clinical events rates have continued to fall, but this is to a large extent somewhat balanced by the emerging use of more sensitive markers for myocardial damage (such as troponin).
  • As one considers clinical outcomes in patients with ACS, a number of outcomes must be balanced. As far as ischemic complications, one has to consider death, MI and urgent TVR
  • As far as bleeding/hemorrhagic outcomes, one must consider major and minor bleeding, as well as thrombocytopenia (and HIT). In modern-day treatment one most consider both sides of the scale, and the fact that as more aggressive antithrombotic therapies are used to reduce ischemic complications, the frequency of adverse bleeding outcomes rises.
  • Two different issues that also have to be balanced are periprocedural complications (such as death and MI) and the clinical benefit that the patient derives from the procedure. One pays a price for long term benefit in terms of acute procedural risks. The overall clinical benefit has to be considered in terms of the cost of the therapies involved, how easy or hard those therapies are to use, how long therapy must be administered for, and the final balance struck between bleeding and ischemic endpoints.
  • Put a slightly different way, physiologic hemostasis and pathological thrombosis are two sides of the same coin. As the degree of anticoagulation increases, the risk of bleeding increases, but the risk of ischemic clinical events goes down. A balance must be struck between freely flowing blood (that doesn’t clot and cause events) and TOO-freely flowing blood (as at the site of bleeding, where physiologic hemostasis is impaired.
  • Data from the CRUSADE Registry demonstrate that the most common adverse in-hospital outcome among patients with ACS is bleeding.
  • The profile of the patient at high risk for bleeding is characterized by older age, renal failure, often female, with a prior history of bleeding.
  • These data from patients undergoing PCI in the ACUITY randomized trial confirm the findings from the GRACE Registry and also identify “novel” risk factors such as diabetes and anemia.
  • Similar risk factors are associated with the occurrence of blood transfusion, which is an important marker for bleeding. As shown here, age, CKD, and anemia are also risk factors for transfusion
  • Characteristics of the PCI procedure itself are also associated with bleeding complications. An analysis of the REPLACE-2 trial finds not only the expected patient characteristics, such as age, CKD, and anemia, but also finds that long procedures and, importantly, sheath dwell time, also place patients at risk for bleeding. Therapies that minimize sheath dwell time can reduce the risk for periprocedural bleeding.
  • The last point is an area where clinicians can intervene to potentially reduce the risk for bleeding.
  • Does bleeding influence the prognosis of ACS patients or is it a necessary evil of ACS therapy?
  • These data form the GRACE registry show that there is an association between bleeding and morality across the spectrum of unstable ischemic syndromes.
  • Data from clinical trial populations corroborates findings from the GRACE Registry. This analysis of 26,452 NSTEACS patients from 4 large international randomized clinical trials shows a relationship between bleeding severity and worsening 30day mortality; however, this is a post-hoc analysis and could be confounded by differences among patients that suffered varying bleed severity.
  • After adjustment for all potential confounders and accounting for the timing of bleeding relative to outcome, there is a highly significant stepwise increase in the risk for short and intermediate-term adverse outcomes.
  • Patients with ACS undergoing PCI, which accounts for 50-60% of the ACS population in the United States, are also at risk for death, recurrent MI, and unplanned revascularization if they develop bleeding complications.
  • This relationship between bleeding and MI appears to hold for both large infarctions (Q-wave MI) and smaller non Q-wave MIs.
  • Bleeding also is associated with a worse prognosis in the broader population of patients undergoing PCI. This analysis of 10,974 real-world patients undergoing PCI demonstrates this consistent stepwise increase in major adverse cardiac events as bleeding severity worsens.
  • The last point is an area where clinicians can intervene to potentially reduce the risk for bleeding.
  • For clinical care and for research purposes, determining the severity of a bleeding event is important. This begs the question: How does one define or assess bleeding severity?
  • Different definitions have been used across major clinical trials and registries. This influences the incidence of bleeding that is reported. Based on the definition used, the incidence of “major” or “severe” bleeding can be as high as 10% or as low as 0.4%.
  • The TIMI definition is one of the most common ones used to grade the severity of a bleeding complication. It was developed in the context of fibrinolytic therapy for STEMI; however, it has been used in studies of NSTE ACS and PCI as well. There are three categories based on the decrease in hemoglobin or hematocrit corrected for transfusion.
  • The GUSTO definition is another bleeding scale that is used commonly. It, too, was developed in the context of fibrinolytic therapy for STEMI and also has three categories. Rather than hemoglobin or HCT values, the GUSTO scale uses clinical events to define bleeding severity.
  • In this study that examined 15,858 NSTE ACS patients from PURSUIT and PARAGON B (2 studies that used both the TIMI and GUSTO definitions to grade the severity of bleeding complications) the incidence of bleeding depended on the definition used. This is significant because both definitions were applied to the same patient population of patients, and the incidence of “severe” bleeding could be as low as 1.2% or as high as 8.2%
  • In separate models, both bleeding definitions are associated with adverse outcomes; however, only the GUSTO scale is associated with a stepwise increase in the adjusted risk. In addition, when both scales are included in the same model, only the GUSTO scale was associated with worse outcomes.
  • Several bleeding definitions have been used in studies over the years; however, relatively few have been validated in terms of predicting outcomes. Definitions that include clinical events like the GUSTO definition are better at predicting outcomes that definitions that rely solely on laboratory values.
  • Blood transfusion is one of the most readily available treatments for bleeding. While it is logical to assume that this may correct the negative impact of bleeding, it is important to review the available evidence on transfusion and outcomes in ACS patients.
  • In this study of 24,111 ACS patients taken from 4 large randomized clinical trials, patients who received a blood transfusion had markedly worse 30-day mortality compared with those who did not receive a transfusion.
  • After comprehensive adjustment for all potential confounders, as well as accounting for the temporal relationship between transfusion and outcomes, blood transfusion was associated with a significantly higher risk for 30-day mortality. While this study is not definitive, it does underscore the importance of avoiding blood transfusion when necessary.
  • 17 The association between transfusion and adverse outcomes in patients with NSTEACS is corroborated by a study of 74,271 ACS patients from the CRUSADE Registry. Transfusion was associated with an increased risk for in-hospital death and in-hospital death or MI.
  • Among ACS patients undergoing PCI, the association between transfusion and ischemic outcomes is consistent, with an increased for not only death and MI, but also unplanned revascularization.
  • Transfusion is associated with an increased risk for both large Q-wave infarctions and non Q-wave infarctions.
  • Even in lower risk patients, such as those undergoing elective PCI, there is a relationship between transfusion and long-term mortality that persists after adjustment for confounders.
  • The available data find a strong consistent relationship between blood transfusion and adverse outcomes. It is probably best to avoid blood transfusion in ACS patients when possible.
  • The CRUSADE shows the significant impact of age on bleeding risk.
  • Elderly patients undergoing urgent or elective PCI are at increased risk for both major bleeding and transfusion.
  • In the elderly population undergoing PCI, the occurrence of major bleeding or transfusion increases the risk for 30-day mortality.
  • As these data from CRUSADE demonstrate, one risk factor for bleeding is the excessive dosing of indirect thrombin inhibitors (“heparins”) and glycoprotein IIb/IIIa inhibitors, which is particularly frequent in the elderly population.
  • Clearly, excessive dosing of antithrombins, glycoprotein IIb/IIIa inhibitors, or both increases the risk for transfusion.
  • If both unfractionated heparin and glycoprotein Iib/IIIa inhibitors are excessively dosed, the risk of transfusion increases almost 5-fold.
  • Females are at higher risk for bleeding than males and one reason may be the overdosing of glycoprotein IIb/IIIa inhibitors in women. In this study from CRUSADE, the attributable risk for bleeding due to excess dosing was 25% in women vs. 4.4% in men
  • Yet another group of patients at risk are those with chronic kidney disease. This study from the REPLACE-2 trial examined the risk of ischemic and bleeding complications by renal function. Patients with reduced kidney function were at risk for both ischemic and bleeding complications.
  • One unrecognized risk factor for adverse outcomes is anemia. Anemic patients are older, more often female, and more often have a history of diabetes mellitus, CHF, prior PCI, and prior CABG.
  • Interestingly, bleeding is increased among anemic patients. This may be due to bleeding definitions that include transfusion, the underlying disease state that causes gradual bleeding and makes patients anemic, or some other as yet undefined process.
  • In the broad population of patients with ACS, anemia is a predictor for mortality among patients with NSTE ACS.
  • In addition to clinical outcomes, bleeding is also associated with increased cost of care among patients with CAD.
  • Among patients undergoing PCI, savings from reduced ischemia associated with the combination of unfractionated heparin and abciximab is offset almost completely by the increased costs of bleeding.
  • Listed here are the participating faculty who reviewed this program.
  • Listed here are the participating faculty who reviewed this program.
  • Listed here are the participating faculty who reviewed this program.
  • Listed here are the participating faculty who reviewed this program.
  • Listed here are the participating faculty who reviewed this program.
  • Listed here are the participating faculty who reviewed this program.
  • Listed here are the participating faculty who reviewed this program.
  • Listed here are the participating faculty who reviewed this program.
  • Jointly Sponsored by the University of Massachusetts Medical ...

    1. 2. Accreditation Information Jointly Sponsored by the University of Massachusetts Medical School Office of Continuing Education and CMEducation Resources, LLC. Funded by an Independent Educational Grant from The Medicines Company
    2. 3. Program Requirements Instructions for Receiving Category 1 AMA Credit Participants: This SlideCAST is a CME-certified program that must be viewed in its entirety to receive CME credit. You should view the slides in their original order, and then access the online CME test as directed at the end of the program. If program content or total number of slides are expanded, reduced, or modified in any way, the program no longer qualifies for CME. Presenters: This SlideCAST is a CME-certified program that must be presented in its entirety for your audience to receive CME credit. You should present the slides in their original order, either as a PowerPoint presentation or in print form, and then instruct your audience how to access the test online. If program content or total number of slides are expanded, reduced, or modified in any way, the program no longer qualifies for CME and must be reviewed and certified by your own institution.
    3. 4. Accreditation Information Intended Audience: This SlideCAST is designed for interventional cardiologists, cardiologists, and emergency medicine physicians, and other healthcare providers caring for patients with acute cardiovascular disease. Registration: Enrollment for this SlideCAST is complimentary, and clinicians are invited to participate in this CME-certified program and/or share this invitation with other colleagues, departmental staff members, and healthcare professionals. Grantor Support: Supported by an independent educational grant from The Medicines Company, Inc.
    4. 5. Accreditation Information Accreditation Statement for Jointly-Sponsored Programs This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of The University of Massachusetts Medical School and CMEducation Resources, LLC. The University of Massachusetts Medical School is accredited by the ACCME to provide continuing medical education for physicians. Credit Designation Statement The University of Massachusetts Medical School designates this educational activity for a maximum of 1.5 AMA PRA Category 1 Credit(s)™.  Physicians should only claim credit commensurate with the extent of their participation in the activity. Accreditation Information
    5. 6. Policy on Faculty And Provider Disclosure It is the policy of the University of Massachusetts Medical School to ensure fair balance, independence, objectivity and scientific rigor in all activities.  All faculty participating in CME activities sponsored by the University of Massachusetts Medical School are required to present evidence-based data, identify and reference off-label product use and disclose all relevant financial relationships with those supporting the activity or others whose products or services are discussed.  Faculty disclosure will be provided in the activity materials. For additional CME-certified programs in cardiovascular health: Please visit us at www.EDICTforACS.com (click anywhere on banner below) Accreditation Information
    6. 7. ACS Forum Leadership Panel Deepak L. Bhatt, MD, FACC, FSCAI, FESC, FACP Associate Director, Cleveland Clinic Cardiovascular Coordinating Center Staff, Cardiac, Peripheral, and Carotid Intervention Associate Professor of Medicine Department of Cardiovascular Medicine Cleveland Clinic Foundation Frederick Feit, MD, FACC Director Cardiac Catheterization and Interventional Cardiology Bellevue Hospital Center Associate Professor of Medicine New York University School of Medicine New York, NY Deborah Diercks, MD Assistant Professor of Medicine Department of Emergency Medicine University of California Davis, California James Ferguson III, MD Associate Director, Cardiology Research Texas Heart Institute at St. Luke's Episcopal Hospital Associate Professor Baylor College of Medicine Clinical Assistant Professor University of Texas Health Science Center at Houston Christopher Granger, MD Associate Professor of Medicine Director of Cardiac Care Unit Division of Cardiovascular Medicine Duke University Medical Center
    7. 8. ACS Forum Leadership Panel Judd E. Hollander, MD Professor Clinical Research Director Department of Emergency Medicine University of Pennsylvania Philadelphia, PA David M. Lang, DO, FACOEP, FACEP Chief Emergency Medicine Mount Sinai Medical Center Miami Beach, FL Steven V. Manoukian, MD, FACC Director, Interventional Cardiology Emory-Crawford Long Hospital Emory University School of Medicine President American Heart Association, Atlanta Division Atlanta, GA Ralph G. Nader, MD, FACC, FACP, FSCAI Co-Medical Director Cardiovascular Labs at Mount-Sinai/Miami Heart Miami, FL E. Magnus Ohman, MD, FRCPI, FACC Professor of Medicine Director, Program for Advanced Coronary Disease Division of Cardiology Duke University Medical Center Durham, NC
    8. 9. ACS Forum Leadership Panel Charles Pollack, MD, FACEP Chairman, Department of Emergency Medicine Pennsylvania Hospital Professor of Emergency Medicine University of Pennsylvania School of Medicine Philadelphia, PA Sunil V. Rao MD Assistant Professor of Medicine Duke University Medical Center Director, Cardiac Catheterization Laboratories Durham VA Medical Center Durham, NC
    9. 10. ACS Leadership Panel Financial Disclosures Deepak L. Bhatt, MD: Consultant/H onoraria or Grant/Research Support: Astra Zeneca, Bristol-Myers Squibb, Eli Lilly, Eisai, Glaxo Smith Kline, Millennium, Paringenix, PDL, Schering Plough, sanofi-aventis, The Medicines Company. Deborah Diercks, MD: Grants/Research Support: Invoice Technology, The Medicines Company. Consultant: Invoice Technology, sanofi-aventis U.S., Astellas. Speaker’s Bureau: Bristol-Myers Squibb, Schering-Plough, sanofi-aventis U.S Frederick Feit, MD: Consultant: The Medicines Company James Ferguson III, MD : Grant/Research Support: Eisai Pharmaceuticals, The Medicines Company. Vitatron/Medtronic. Consulting/Honoraria: Bristol Myers-Squibb, Eisai Pharmaceuticals, GlaxoSmithKline, Prism Pharmaceuticals, sanofi-aventis, Schering-Plough, Takeda, The Medicines Company, Therox. Speaker’s Bureau: Bristol Myers-Squibb, sanofi-aventis, Schering-Plough Ralph G. Nader, MD: Nothing to disclose. E. Magnus Ohman, MD: Research Grants: Berlex, sanofi-aventis, Schering-Plough Corporation, Bristol Meyer Squibb, Millennium. Stockholder: Medtronic. Consultant: Response Biomedical, Liposcience, Inovise Medical
    10. 11. ACS Leadership Panel Financial Disclosures Christopher Granger, MD: Educational Grants and/or Research Support: Alexion, Astra Zeneca, Procter and Gamble, sanofi-aventis, Novartis, Boehringer Ingelheim, Genentech, and Berlex Judd E. Hollander, MD : Grant/Research Support: sanofi-aventis, Biosite, Scios, The Medicines Company. Consultant: sanofi-aventis, Biosite, Scios, The Medicines Company. Speaker’s Bureau: sanofi-aventis, Biosite, Scios, The Medicines Company David Lang, DO: H onoraria: Roche and Pfizer. Consultant: Aventis Steven V. Manoukian, MD : Grant/ Research Support: The Medicines Company Speaker’s Bureau: The Medicines Company Charles Pollack, MD : Grant/Research Support: GlaxoSmithKline. Consultant: The Medicines Company, Schering-Plough, sanofi-aventis, BMS, Genentech. Speaker’s Bureau: Schering-Plough, sanofi-aventis, BMS, Genentech Sunil V. Rao, MD: Consultant: sanofi-aventis, The Medicines Company, Pfizer, Cordis. Research funding: Agency for Healthcare Research & Quality, National Institute for Aging, American College of Cardiology
    11. 12. ACS Faculty Review Committee Thomas Amidon, MD The Hope Heart Institute Atul Aggarwal, MD Nebraska Heart Institute Himanshu Aggarwal, MD Nebraska Heart Institute Keith Benzuly, MD, FACC Northwestern University Joseph J. Brennan Jr., MD Yale University School of Medicine Carl Chudnofsky, MD Albert Einstein Medical Center Michael J. Cowley, MD Medical College of Virginia Harold Dauerman, MD University of Vermont William J. French, MD UCLA Medical Center Satyendra Giri, MD Baystate Health Systems Paul A. Gurbel, MD Johns Hopkins University * Complete affiliations and financial disclosures for Review Committee members are listed at end of slide deck.
    12. 13. ACS Faculty Review Committee Tim Henry, MD Minneapolis Heart Institute Kurt Kleinschmidt, MD UT Southwestern Medical Center James Leggett, MD Hope Heart Institute Glenn Levine, MD Baylor College of Medicine John J. Lopez, MD University of Chicago Reginald Low, MD University of California, Davis Roberto Medina, MD Florida Medical Clinic Barry L. Molk, MD, FACC University of Colorado Reynaldo Mulingtapang, MD University of South Florida Robert A. Mulliken, MD University of Chicago Hospitals Sandeep Nathan, MD, FACC Rush Medical College Paul E. Pepe, MD, MPH UT Southwestern Medical Center * Complete affiliations and financial disclosures for Review Committee members are listed at end of slide deck.
    13. 14. ACS Faculty Review Committee Robert N. Piana, MD Vanderbilt University Vincent J. Pompili, MD, FACC Case School of Medicine Matthew J. Price, MD Scripps Clinic Douglas J. Spriggs, MD, FACC University of South Florida Lowell H. Steen, Jr., MD Loyoyla University Chicago David J. Robinson, MD, MS, FACEP UT Health Sciences Center Joseph F. Stella, DO, FACC Heart Care Centers of Illinois Rex J. Winters, MD Long Beach Memorial Heart Institute * Complete affiliations and financial disclosures for Review Committee members are listed at end of slide deck.
    14. 15. Educational Objectives <ul><li>Physicians will learn about the impact that bleeding has on outcomes in patients with acute coronary ischemic syndromes (ACS) </li></ul><ul><li>Physicians will learn what factors predict bleeding in patients with ACS </li></ul><ul><li>Physicians will learn what predictive value different bleeding scales have on outcomes in patients with ACS </li></ul><ul><li>Physicians will learn how to implement strategies that balance risk of bleeding and ischemia. </li></ul><ul><li>Physicians will learn how to apply landmark trials and analyses of bleeding and ACS to clinical situations. </li></ul>
    15. 16. A Science-to-Strategy Analysis of Bleeding Issues in Acute Coronary Syndromes BLEEDING IN THE SETTING OF ACUTE CORONARY SYNDROMES (ACS) Clinical Implications and Effects on Mortality and Resource Utilization A CME-Certified Activity Developed by the National Experts' Educational Forum in Cardiovascular Disease
    16. 17. Medical Rx (cath) Time PCI Surgery Medical Rx (no cath) Medical Rx No disease (82 % of total) (18 % of total) (52% of total, 63% of those undergoing cath) (12% of total, 15% of those undergoing cath) CRUSADE Registry 10/04-9/05 n=35,897 Patient X ACS Management Pathways Cath Medical Rx Admission Cath Discharge No Cath Cath 40 % < 48 hrs 12 % > 48 hrs 63 % < 48 hrs 19 % > 48 hrs
    17. 18. SYNERGY 1994 1995 1996 1997 1998 1999 2000 2002 2003 2004 2005 2006 2001 Bleeding risk Ischemic risk ACUITY ISAR-REACT 2 Milestones in ACS Management ICTUS Adapted from and with the courtesy of Steven Manoukian, MD. LMWH ESSENCE CURE Clopidogrel GP IIb/IIIa blockers PRISM-PLUS PURSUIT TACTICS TIMI-18 Early invasive PCI ~ 5% stents ~85% stents Drug-eluting stents OASIS-5 [ Fondaparinux ] Anti-Thrombin Rx Anti-Platelet Rx Treatment Strategy Heparin Aspirin Conservative Bivalirudin REPLACE 2
    18. 19. Evolving Paradigm for Evaluating ACS Management Strategies Ischemic Complications <ul><li>Death </li></ul><ul><li>MI </li></ul><ul><li>Urgent TVR </li></ul>Composite Adverse Event Endpoints
    19. 20. Evolving Paradigm for Evaluating ACS Management Strategies Ischemic Complications Hemorrhage HIT <ul><li>Death </li></ul><ul><li>MI </li></ul><ul><li>Urgent TVR </li></ul><ul><li>Major Bleeding </li></ul><ul><li>Minor Bleeding </li></ul><ul><li>Thrombocytopenia </li></ul>Composite Adverse Event Endpoints
    20. 21. Evolving Paradigm for Evaluating ACS Management Strategies Periprocedural Complications Clinical Benefit <ul><li>Death </li></ul><ul><li>Major Disability </li></ul><ul><li>Cost </li></ul><ul><li>Ease of Use </li></ul><ul><li>Duration of Therapy </li></ul><ul><li>Accounting for Bleeding and Ischemic Endpoints </li></ul>Composite Adverse Event Endpoints
    21. 22. Balancing Events and Bleeding Risk of events Risk of bleeding Thrombosis Hemostasis Two sides of the same coin Degree of Anticoagulation Risk
    22. 23. <ul><li>Death 4.3% </li></ul><ul><li>(Re)-Infarction 2.5% </li></ul><ul><li>CHF 8.0% </li></ul><ul><li>Cardiogenic Shock 2.6% </li></ul><ul><li>Stroke 0.8% </li></ul><ul><li>Non-CABG Transfusion 9.9% </li></ul>CRUSADE In-Hospital Outcomes Bhatt DL, et al. JAMA . 2004 Nov 3;292(17):2096-104.
    23. 24. Bleeding in ACS - Agenda <ul><li>Predictors of bleeding in ACS </li></ul><ul><li>Outcomes associated with bleeding </li></ul><ul><ul><li>Impact of definition on outcomes </li></ul></ul><ul><li>Outcomes associated with blood transfusion </li></ul><ul><li>Special populations at risk </li></ul><ul><ul><li>Elderly </li></ul></ul><ul><ul><li>Chronic kidney disease </li></ul></ul><ul><ul><li>Anemia </li></ul></ul><ul><li>Cost implications of bleeding </li></ul>
    24. 25. <ul><li>What predicts bleeding among patients with ACS ? </li></ul>Bleeding in ACS Question to be answered:
    25. 26. Predictors of Major Bleeding in ACS <ul><li>Older Age </li></ul><ul><li>Female Gender </li></ul><ul><li>Renal Failure </li></ul><ul><li>History of Bleeding </li></ul><ul><li>Right Heart Catheterization </li></ul><ul><li>GPIIb-IIIa antagonists </li></ul>Independent Predictors of Major Bleeding in Marker Positive Acute Coronary Syndromes Moscucci, GRACE Registry, Eur Heart J . 2003 Oct;24(20):1815-23.
    26. 27. Predictors of Major Bleeding P-value RR (95% CI) Risk ratio ± 95% CI Manoukian SV, Voeltz MD, Feit F et al. TCT 2006. Results: The ACUITY Trial PCI Population Heparin(s) + GPI (vs. Bivalirudin) Prior antithrombotic therapy No prior PCI Hypertension High-risk (ST / biomarkers) Female gender Diabetes CrCl <60mL/min Anemia Age > 75 (vs. 55-75) <0.0001 0.0768 0.0019 0.0287 0.0178 <0.0001 0.0248 <0.0001 <0.0001 0.0009 2.08 (1.56-2.76) 1.23 (0.98-1.55) 1.47 (1.15-1.88) 1.33 (1.03-1.70) 1.42 (1.06-1.90) 2.08 (1.68-2.57) 1.30 (1.03-1.63) 1.68 (1.29-2.18) 1.89 (1.48-2.41) 1.56 (1.19-2.04)
    27. 28. P-value RR (95% CI) Predictors of Transfusion Risk ratio ± 95% CI Manoukian SV, Voeltz MD, Feit F et al. TCT 2006. Results: The ACUITY Trial Heparin (s) + GPI (vs. Bivalirudin) Hypertension High-risk (ST / biomarkers) Female gender Diabetes CrCl <60mL/min Anemia Age > 75 (vs. 55-75) 0.0007 0.0241 0.0003 <0.0001 0.0060 <0.0001 <0.0001 0.0060 1.728 (1.256-2.379) 1.457 (1.051-2.020) 1.754 (1.297-2.372) 2.233 (1.739-2.867) 1.560 (1.209-2.014) 2.097 (1.568-2.803) 3.764 (2.919-4.855) 1.420 (1.055-1.910)
    28. 29. REPLACE-2 Multivariate Predictors of Major Bleeding Feit F et al. Unpublished (in manuscript) <0.0001 3.433 to 22.072 8.705 IABP <0.0001 1.183 to 1.321 1.25 ICU stay (days)† 0.0244 1.064 to 2.448 1.614 Time to Sheath Removal >6h 0.0069 1.217 to 3.449 2.049 Procedure Duration >1h 0.0002 1.591 to 4.512 2.679 Provisional GPI received 0.0003 0.352 to 0.733 0.508 Treatment Group (BIV vs. H+GPI) Peri-procedural risk factors 0.0401 1.015 to 1.939 1.403 Anemia 0.0061 0.987 to 0.998 0.993 Creatinine clearance* 0.0197 1.077 to 2.345 1.589 Prior Angina 0.0072 0.477 to 0.890 0.652 Gender (M vs. F) 0.045 1.009 to 2.176 1.482 Age > 75 Baseline risk factors p-value 95% CI Odds Ratio RISK FACTORS
    29. 30. <ul><li>Older age, chronic kidney disease, female gender are consistently associated with bleeding and blood transfusion </li></ul><ul><li>Analysis of large randomized trials have also identified novel risk factors for bleeding such as diabetes and anemia </li></ul><ul><li>Procedural characteristics such as procedure duration and sheath dwell time also predict bleeding complications </li></ul>Bleeding Predictors—Conclusions
    30. 31. <ul><li>Does bleeding influence the prognosis of ACS patients ? </li></ul>Bleeding in ACS Question to be answered:
    31. 32. Moscucci M et al. Eur Heart J 2003;24:1815-23. P<0.001 Overall Unstable NSTEMI STEMI ACS Angina Patients (%) Major Bleeding Predicts Mortality in ACS 24,045 ACS patients in the GRACE registry, in-hospital death
    32. 33. Bleeding & Outcomes log rank p-value for all four categories <0.0001 log-rank p-value for no bleeding vs. mild bleeding = 0.02 log-rank p-value for mild vs. moderate bleeding <0.0001 log-rank p-value for moderate vs. severe <0.001 Rao SV, et al. Am J Cardiol . 2005 Nov 1;96(9):1200-6. Epub 2005 Sep 12 Kaplan Meier Curves for 30-Day Death, Stratified by Bleed Severity N=26,452 ACS patients from GUSTO IIb, PARAGON A, PARAGON B, & PURSUIT
    33. 34. Bleeding and Outcomes in NSTE ACS 26,452 patients from PURSUIT, PARAGON A, PARAGON B, GUSTO IIb NST Bleeding severity and adjusted hazard of death *p<0.0001 Bleeding Severity 30d Death 30d Death/MI 6 mo. Death Mild* 1.6 1.3 1.4 Moderate* 2.7 3.3 2.1 Severe* 10.6 5.6 7.5 *Bleeding as a time-dependent covariate Rao SV, et al. Am J Cardiol . 2005 Nov 1;96(9):1200-6. Epub 2005 Sep 12
    34. 35. Major Bleeding, Ischemic Endpoints, and Mortality P <0.0001 for all Manoukian SV, Voeltz MD, Feit F et al. TCT 2006. Results: The ACUITY Trial PCI Population (N=7,789)
    35. 36. Major Bleeding and Myocardial Infarction P <0.0001 for all Manoukian SV, Voeltz MD, Feit F et al. TCT 2006. Results: The ACUITY Trial PCI Population (N=7,789)
    36. 37. Major and Minor Bleeding in PCI Bleeding Increases Mortality and Events Kinnaird TD et al. AM J Cardiol 2003;92:930-5. 10,974 patients undergoing PCI, Washington Hospital Center, 1991-2000. Bleeding Complication * p<0.001 versus none † p<0.001 versus minor ‡ p<0.01 versus none § p<0.05 versus minor None (n=8,992) Minor (n=1,394) Major (n=588) In-Hospital Clinical Events 0.6% 2.2%* 6.6%* † Major adverse cardiac event 0.3% 0.8% ‡ 1.9%* § Repeat lesion angioplasty 11.8% 16.8%* 30.7%* † Non-Q-wave myocardial infarction 0.2% 0.7% ‡ 1.2%* Q-wave myocardial infarction 0.6% 1.8%* 7.5%* † Death
    37. 38. <ul><li>Bleeding is associated with adverse short- and long-term outcomes among patients with ACS and those undergoing PCI </li></ul><ul><ul><li>Mortality rates are higher among those who bleed </li></ul></ul><ul><ul><li>MI rates are higher among those who bleed </li></ul></ul><ul><li>The risk is “loss-dependent” with worse bleeding associated with worse outcomes </li></ul><ul><li>This relationship is persistent after robust statistical adjustment for confounders </li></ul>Bleeding and Outcomes—Conclusions
    38. 39. <ul><li>How does one assess bleeding severity? </li></ul>Bleeding in ACS Question to be answered:
    39. 40. Bleeding Incidence in ACS Clinical Trials Rao SV, et al. J Am Coll Cardiol . 2006 Feb 21;47(4):809-16. Epub 2006 Jan 26
    40. 41. Bleeding Definitions <ul><li>TIMI Definition </li></ul><ul><ul><li>Major </li></ul></ul><ul><ul><ul><li>ICH </li></ul></ul></ul><ul><ul><ul><li>Associated with Hgb decrease ≥ 5 g/dl or HCT decrease ≥ 15% </li></ul></ul></ul><ul><ul><li>Minor </li></ul></ul><ul><ul><ul><li>Observed blood loss associated with Hgb decrease ≥ 3 g/dl or HCT decrease ≥ 10% </li></ul></ul></ul><ul><ul><ul><li>No identifiable source but Hgb decrease ≥ 4 g/dl or HCT decrease ≥ 12% </li></ul></ul></ul><ul><ul><li>Minimal </li></ul></ul><ul><ul><ul><li>Overt hemorrhage with Hgb drop < 3 g/dl or HCT drop < 9% </li></ul></ul></ul>Chesebro JH. Circulation 1987. Jul;76(1):142-54.
    41. 42. Bleeding Definitions <ul><li>GUSTO Definition </li></ul><ul><ul><li>Severe or life threatening </li></ul></ul><ul><ul><ul><li>ICH or hemodynamic compromise requiring treatment </li></ul></ul></ul><ul><ul><li>Moderate </li></ul></ul><ul><ul><ul><li>Requiring transfusion </li></ul></ul></ul><ul><ul><li>Mild </li></ul></ul><ul><ul><ul><li>Not meeting criteria for Severe or Moderate </li></ul></ul></ul>N Engl J Med . 1993 Nov 25;329(22):1615-22. Erratum in: N Engl J Med 1994 Feb 17;330(7):516
    42. 43. Bleeding Incidence Among 15,858 NSTE ACS Patients: Impact of Definition Rao SV, et al. J Am Coll Cardiol . 2006 Feb 21;47(4):809-16. Epub 2006 Jan 26
    43. 44. Bleeding Scales Among NSTE ACS Patients Rao SV, et al. J Am Coll Cardiol . 2006 Feb 21;47(4):809-16. Epub 2006 Jan 26 TIMI and GUSTO – Adjusted Hazard of 30 d Death/MI N=15,858
    44. 45. <ul><li>Clearly defining bleeding severity can be difficult, but there are definitions that have been used in clinical trials and registries </li></ul><ul><li>Not all of these definitions have been validated in terms of prognosis </li></ul><ul><li>TIMI and GUSTO are 2 of the most commonly used definitions </li></ul><ul><li>Bleeding definitions that include clinical events (e.g. GUSTO) are better at predicting outcomes </li></ul>Bleeding Definitions—Conclusions
    45. 46. <ul><li>Do blood transfusions have predictive value? </li></ul><ul><li>Do blood transfusions correct negative impact of bleeding? </li></ul>Bleeding in ACS Questions to be answered:
    46. 47. Transfusion in ACS 30-Day Survival By Transfusion Group Rao SV, et. al., JAMA 2004;292:1555–1562 N=24,111
    47. 48. PRBC Transfusion Among NSTE ACS Patients: Cox Model for 30-day Death *Transfusion as a time-dependent covariate Rao SV, et. al., JAMA 2004;292:1555–1562 N=24,111
    48. 49. Adjusted Risk of In-Hospital Outcomes By Transfusion Status* *Non-CABG patients only Yang X, J Am Coll Cardiol 2005;46:1490–5. N=74,271 ACS patients from CRUSADE
    49. 50. Transfusion, Ischemic Endpoints, and Mortality P <0.0001 for all Manoukian SV, Voeltz MD, Feit F et al. TCT 2006. Results: The ACUITY Trial (N=13,819)
    50. 51. Transfusion and Myocardial Infarction P <0.0001 for all Manoukian SV, Voeltz MD, Feit F et al. TCT 2006. Results: The ACUITY Trial (N=13,819)
    51. 52. Transfusion Post PCI: REPLACE 2 One Year Mortality Increased 1-year mortality in transfused patients Adjusted Odds Ratio 4.26 (2.25–8.08) P<0.0001 Manoukian SV, Voeltz MD, Attubato MJ, Bittl JA, Feit F, Lincoff AM. CRT 2005. Abstract.
    52. 53. <ul><li>Although there has never been a randomized trial of blood transfusion in patients with ACS, the available observational data consistently supports a relationship between blood transfusion and increased adverse outcomes, including death, MI, and unplanned revascularization </li></ul><ul><li>Blood transfusion is best avoided in ACS patients whenever possible </li></ul>Blood Transfusion—Conclusions
    53. 54. <ul><li>Are there certain ACS subpopulations at especially high risk for bleeding, transfusion, and morbidity/mortality? </li></ul>Bleeding in ACS Question to be answered:
    54. 55. Bleeding Risks—Transfusions by Age Alexander KA, JAMA 2005;294:3108–16.
    55. 56. REPLACE-2: Elderly Patients Have Increased Major Bleeding and Transfusions 6,002 patients in REPLACE-2 806 patients (13.4%) classified as elderly, >75 years of age p<0.0001 p=0.0001 Voeltz MD, Lincoff AM, Feit F, Manoukian SV. Circulation 2005;112(17):II-613. Abstract. = Not Elderly, < 75 = Elderly, >75
    56. 57. Elderly Patients in REPLACE-2: Increased 30-Day Mortality With Major Bleeding and Transfusions p<0.0001 p=0.0001 6,002 patients in REPLACE-2. 806 patients (13.4%) classified as elderly, >75 years of age. Voeltz MD, Lincoff AM, Feit F, Manoukian SV. Circulation 2005;112(17):II-613. Abstract.
    57. 58. Excessive Dosing of Anticoagulants by Age Alexander KA, JAMA 2005;294:3108–16. 12.5 28.7 8.5 33.1 37 12.5 64.5 38.5 16.5 0 10 20 30 40 50 60 70 LMW Heparin UF Heparin GP Iib/IIIa % RBC Transfusion <65 yrs 65Š75 yrs >75 yrs
    58. 59. RBC Transfusions by Excess Dosing Alexander KA, JAMA 2005;294:3108–16.
    59. 60. Cumulative Effects of Dosing Errors: Combined Use of Heparin and GP IIb-IIIa Alexander KA, JAMA 2005;294:3108–16.
    60. 61. Excess Dosing of Gp IIb/IIIa and Bleeding in Women Alexander KP, et. al. Circulation 2006 N=32,601 patients from CRUSADE Overall Women Men 1.46 (1.22, 1.73) 1.72 (1.30, 2.28) 1.27 (0.97, 1.66) 0.5 1.0 1.5 2.0 2.5 Excess Dosing More Likely to Bleed
    61. 62. Bleeding is Increased in Patients With Impaired Renal Function Undergoing PCI Creatinine Clearance Chew DP et al. Am J Cardiol 2005;95:581–585 . < 0.001 46 (5.2%) 114 (2.4%) TIMI major + minor bleeding < 0.001 0.010 0.738 0.018 < 0.001 p value 54 (6.1%) 123 (2.5%) In-hospital protocol major bleeding 84 (9.5%) 338 (7.0%) Triple ischemic endpoint 10 (1.1%) 61 (1.3%) 30-d urgent revascularization 75 (8.5%) 305 (6.3%) 30-d Myocardial infarction 14 (1.6%) 5 (0.1%) 30-d Death < 60 ml/min N=886 ≥ 60 ml/min N=4824
    62. 63. Anemia Identifies High-Risk The Unrecognized Risk Factor <ul><li>Older </li></ul><ul><li>Female </li></ul><ul><li>Lower BMI </li></ul><ul><li>Fewer Caucasians </li></ul><ul><li>Lower Hemoglobin (11.7 vs. 14.3 g/dL) </li></ul><ul><li>Lower Hematocrit (34.6 vs. 41.8%) </li></ul><ul><li>Less Tobacco use </li></ul><ul><li>More Diabetes Mellitus </li></ul><ul><li>More history of CHF, MI, PCI, CABG </li></ul>REPLACE-2 Anemic Patient Baseline Characteristics: (Anemia in 22.7%) Voeltz MD, Attubato MJ, Feit F, Lincoff AM, Manoukian SV. J Am Coll Cardiol 2005;45(3)[Suppl A]:1037-13-31A. Abstract.
    63. 64. Major Bleeding is Increased in Anemic Patients Undergoing PCI 6,010 patients in REPLACE-2. 1,362 patients (22.7%) classified as anemic based upon WHO definition. Major bleeding = 3.2% Major Bleeding 2.8% 4.9% P=0.0001 Protocol definition: >3g/dL drop in HgB, intracranial, retroperitoneal, 2U transfusion Voeltz MD, Attubato MJ, Feit F, Lincoff AM, Manoukian SV. J Am Coll Cardiol 2005;45(3)[Suppl A]:1037-13-31A. Abstract.
    64. 65. NSTE-ACS Mortality Stratified by Hemoglobin Sabatine MS. Circulation 2005 Unadjusted <ul><ul><li>Hb (g/dL) n OR (95% Cl) OR (95% Cl) P value </li></ul></ul><ul><ul><li>>17 216 1.47 (1.03–2.10) 1.45 (0.94–2.23) 0.093 </li></ul></ul><ul><ul><li>16–17 812 1.21 (0.97–1.51) 1.27 (0.98–1.65) 0.066 </li></ul></ul><ul><ul><li>15–16 2130 1.0 reference 1.0 reference </li></ul></ul><ul><ul><li>14–15 3390 1.06 (0.89–1.22) 1.11 (0.93–1.33) 0.251 </li></ul></ul><ul><ul><li>13–14 3520 1.02 (0.88–1.19) 1.04 (0.86–1.24) 0.709 </li></ul></ul><ul><ul><li>12–13 2331 1.09 (0.92–1.28) 1.07 (0.88–1.30) 0.514 </li></ul></ul><ul><ul><li>11–12 976 1.20 (0.97–1.47) 1.04 (0.81–1.34) 0.755 </li></ul></ul><ul><ul><li>10–11 343 1.41 (1.05–1.89) 1.29 (0.92–1.82) 0.145 </li></ul></ul><ul><ul><li> 9–10 342 2.44 (1.88–3.18) 2.69 (2.01–3.60) <0.001 </li></ul></ul><ul><ul><li>8–9 306 2.24 (1.69–2.96) 2.45 (1.80–3.33) <0.001 </li></ul></ul><ul><ul><li><8 137 3.97 (2.76–5.70) 3.49 (2.35–5.20) <0.001 </li></ul></ul><ul><li>Abbreviations: CI, confidence interval; Hb, hemoglobin; OR, odds ration. Adapted with permission. </li></ul>Unadjusted and adjusted odds ratios for cardiovascular mortality in patients with non-ST elevation acute coronary syndromes at 30 days stratefied by hemoglobin Adjusted for baseline characteristics
    65. 66. <ul><li>Certain ACS patient populations are at especially high risk for bleeding and mortality </li></ul><ul><ul><li>Elderly, females, CKD, anemia </li></ul></ul><ul><li>Improper dosing of anticoagulants is a common error and is associated with bleeding risk in the elderly, females, and those with CKD </li></ul><ul><li>Anemia places patients at risk for both bleeding and mortality </li></ul>High-Risk Populations—Conclusions
    66. 67. <ul><li>Does bleeding influence the cost of care for patients with ischemic heart disease? </li></ul>Bleeding in ACS Question to be answered:
    67. 68. Calculating Costs of Ischemia and Bleeding: EPIC EQOL Study (Abciximab in PCI) Abciximab versus Placebo  ischemic costs: $523  major bleed costs: $458 Mark DB, et al. Circulation . 2000 Feb 1;101(4):366-71
    68. 69. <ul><li>The available costs data confirms that a balance must be struck between ischemia reduction and bleeding. </li></ul><ul><li>Both ischemic complications and bleeding are associated with increased costs. </li></ul>Bleeding and Costs—Conclusions
    69. 70. Bleeding Among Patients with ACS Conclusions <ul><li>Antithrombotic therapies are cornerstone Rx </li></ul><ul><ul><li>Must balance thrombosis and hemostasis </li></ul></ul><ul><li>Certain patient and PCI procedure characteristics predict bleeding </li></ul><ul><ul><li>Age, female gender, CKD, procedure time, sheath dwell time </li></ul></ul><ul><li>Diabetes and anemia are newly identified risk factors for bleeding among ACS patients </li></ul>
    70. 71. Conclusions—Bleeding <ul><li>Bleeding is associated with worse short and long-term outcomes including death and MI </li></ul><ul><li>Assessing bleeding severity is important </li></ul><ul><ul><li>Many definitions have been used </li></ul></ul><ul><ul><li>Definitions that include clinical events appear to be more useful than those that include only laboratory parameters </li></ul></ul><ul><li>Blood transfusion is associated with increased mortality in ACS patients </li></ul>
    71. 72. Conclusions—Bleeding <ul><li>In addition to clinical outcomes, bleeding is associated with increased cost of care </li></ul><ul><ul><li>Bleeding costs can offset the savings realized by reduced ischemic complications </li></ul></ul><ul><li>Given the body of evidence related to bleeding and transfusion, therapies that can reduce ischemia while minimizing the risk for bleeding have the potential to further improve outcomes among patients with ACS </li></ul>
    72. 73. CME Test Complimentary CME Test: To access the complimentary CME test, program participants must have internet access. Participants can access the on-line evaluation form and receive instant online notification of credit by clicking on the program icon below. Click Here for CME
    73. 74. ACS Faculty Review Committee Thomas Amidon, MD Medical Director The Hope Heart Institute Overlake Internal Medicine Associates Seattle, WA Atul Aggarwal, MD Nebraska Heart Institute Lincoln, NE Himanshu Aggarwal, MD Nebraska Heart Institute St. Frances Med Center Grand Island, NE Keith Benzuly, MD, FACC Assistant Professor of Medicine Bluhm Cardiovascular Institute Northwestern University Feinberg School of Medicine Chicago, IL Joseph J. Brennan Jr., MD Associate Professor of Medicine, Cardiology Director, Interventional Fellowship Program Yale University School of Medicine New Haven, CT Carl Chudnofsky, MD Chairman Department of Emergency Medicine Albert Einstein Medical Center Philadelphia, PA Michael J. Cowley, MD Professor Department of Internal Medicine Division of Cardiology Medical College of Virginia Virginia Commonwealth University Richmond, VA
    74. 75. ACS Faculty Review Committee Harold Dauerman, MD Director, Cardiovascular Catheterization Laboratory Professor of Medicine Fletcher Allen Health Care University of Vermont College of Medicine Burlington, VT William J. French, MD Medical Director Catheterization Laboratory UCLA Medical Center Los Angeles, CA Satyendra Giri, MD Section Chief Vascular Medicine Program Baystate Health Systems Springfield, MA Paul A. Gurbel, MD Helen Dalsheimer Director of the Division of Cardiology at Sinai Hospital of Baltimore Associate Professor of Medicine Division of Cardiology Johns Hopkins University School of Medicine Baltimore, MD Tim Henry, MD Minneapolis Heart Institute Foundation Associate Professor University of Minnesota School of Medicine Minneapolis, MD Kurt Kleinschmidt, MD Associate Professor Director of Toxicology Fellowship Program UT Southwestern Medical Center Dallas, TX
    75. 76. ACS Faculty Review Committee James Leggett, MD Associate Medical Director Hope Heart Institute Seattle, WA Glen Levine, MD Director, Cardiac Catheterization Lab Associate Professor of Medicine Baylor College of Medicine Chief, Critical Cardiac Care Houston VA Medical Center Houston, TX John J. Lopez, MD Associate Professor of Medicine Director Cardiac Catheterization and Interventional Cardiology University of Chicago Chicago, IL Reginald Low, MD Chief, Division of Cardiovascular Medicine University of California, Davis Davis, CA Barry L. Molk, MD, FACC Associate Clinical Professor University of Colorado Health Science Center Aurora Denver Cardiology Associates Denver, CO Reynaldo Mulingtapang, MD Assistant Professor of Medicine Director, University of South Florida Interventional Cardiology Program Tampa, FL Robert A. Mulliken, MD Medical Director, Emergency Department University of Chicago Hospitals Associate Professor University of Chicago School of Medicine Chicago, IL Sandeep Nathan, MD, FACC Assistant Professor of Medicine Rush Medical College, Section of Cardiology Rush University Medical Center Director, Cardiovascular Intervention Chicago, IL
    76. 77. ACS Faculty Review Committee Robert N. Piana, MD Associate Professor of Medicine Vanderbilt University School of Medicine Director, Cardiac Catheterization Laboratories Nashville, TN Vincent J. Pompili, MD, FACC Director of Interventional Cardiology University Hospitals Associate Professor of Medicine Case School of Medicine Cleveland, OH Matthew J. Price, MD Director Cardiac Catheterization Laboratory Scripps Clinic Division of Cardiovascular Diseases La Jolla, CA David J. Robinson, MD, MS, FACEP Associate Professor, Research Director and Vice-Chair Dept. of Emergency Medicine University of Texas Health Sciences Center Houston, TX Joseph F. Stella, DO, FACC Heart Care Centers of Illinois Clinical Assistant Professor Loyola University Medical Center Chicago, IL Paul E. Pepe, MD, MPH Riggs Family Chair in Emergency Medicine Professor and Division Chairman Emergency Medicine University of Texas Southwestern Medical Center Dallas, TX Douglas J. Spriggs, MD, FACC Clinical Assistant Professor Depts. of Internal Medicine and Family Practice University of South Florida College of Medicine Clearwater Cardiovascular and Interventional Consultants Clearwater, FL
    77. 78. ACS Faculty Review Committee Lowell H. Steen, Jr., MD Associate Professor of Medicine, Cardiology Loyoyla University Chicago Stritch School of Medicine Rex J. Winters, MD Director of Invasive Cardiology Long Beach Memorial Heart Institute
    78. 79. ACS Review Committee Financial Disclosures Thomas Amidon, MD: Nothing to disclose. Atul Aggarwal, MD: Grant/Research Support: Aventis, Schering-Plough Himanshu Aggarwal, MD: Nothing to disclose. Keith Benzuly, MD, FACC: Speaker’s Bureau: The Medicines Company Joseph J. Brennan Jr., MD: Nothing to disclose. Carl Chudnofsky, MD: Nothing to disclose . Michael J. Cowley, MD: Nothing to disclose. Harold Dauerman, MD: Grant/Research Support: Boston Scientific, Guidant. Consultant: The Medicines Company, Arginox. William J. French, MD: Nothing to disclose. Satyendra Giri, MD: Nothing to disclose. Paul A. Gurbel, MD: Grant/Research Support: Schering-Plough, Millennium, AstraZeneca, Bayer, Haemoscope, NIH, Medtronic, Boston Scientific
    79. 80. ACS Review Committee Financial Disclosures Tim Henry, MD: Nothing to disclose. Kurt Kleinschmidt, MD: Consultant: The Medicines Company. Speaker’s Bureau: sanofi-aventis. James Leggett, MD: Grant/Research Support: The Medicines Company, sanofi-aventis Glenn Levine, MD: Speaker’s Bureau: sanofi-aventis John J. Lopez, MD: Nothing to disclose. Reginald Low, MD: Nothing to disclose. Roberto Medina, MD: Speaker’s Bureau: The Medicines Company Barry L. Molk, MD, FACC: Nothing to disclose. Reynaldo Mulingtapang, MD: Grant/Research Support: GlaxoSmithKline. Consultant: Medtronic AAA, Abbott. Speaker’s Bureau: Pfizer. Major Shareholder: Vascular Architects. Robert A. Mulliken, MD: Nothing to disclose. Sandeep Nathan, MD, FACC: Research Support: Guilford. Speaker’s Bureau: The Medicines Company, sanofi-aventis.
    80. 81. ACS Review Committee Financial Disclosures Paul E. Pepe, MD, MPH : Nothing to disclose. Robert N. Piana, MD: Speaker’s Bureau: sanofi-aventis Vincent J. Pompili, MD, FACC: Major Shareholder: Arteriocyte, Inc. Matthew J. Price, MD: Nothing to disclose. Douglas J. Spriggs, MD, FACC: Nothing to disclose. Lowell H. Steen, Jr., MD: Nothing to disclose. David J. Robinson, MD, MS, FACEP : Nothing to disclose. Joseph F. Stella, DO, FACC: Nothing to disclose. Rex J. Winters, MD: Consultant: Cordis, Johnson & Johnson, Guidant. Speaker’s Bureau: The Medicines Company.
    81. 82. CME Test Complimentary CME Test: To access the complimentary CME test, program participants must have internet access. Participants can access the on-line evaluation form and receive instant online notification of credit by clicking on the program icon below. Click Here for CME

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