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School Office of Continuing Education and CMEducation
Resources, LLC.




Funded by an Independent Educational Grant from The Medicines
Company
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 This SlideCAST is designed for interventional cardiologists, cardiologists, and
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Registration:

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Grantor Support:

 Supported by an independent educational grant from The Medicines Company, Inc.
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Credit Designation Statement

 The University of Massachusetts Medical School designates this educational
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 should only claim credit commensurate with the extent of their participation in
 the activity.
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Policy on Faculty And Provider Disclosure

 It is the policy of the University of Massachusetts Medical School to ensure fair
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For additional CME-certified programs in cardiovascular health:

 Please visit us at www.EDICTforACS.com (click anywhere on banner below)
                              ACS Forum Leadership Panel

                                             Deborah Diercks, MD
Deepak L. Bhatt, MD, FACC,                   Assistant Professor of Medicine
                                             Department of Emergency Medicine
 FSCAI, FESC, FACP                           University of California
Associate Director, Cleveland                Davis, California
 Clinic Cardiovascular Coordinating Center
Staff, Cardiac, Peripheral, and
 Carotid Intervention
                                             James Ferguson III, MD
                                             Associate Director, Cardiology Research
Associate Professor of Medicine
                                             Texas Heart Institute at St. Luke's Episcopal
Department of Cardiovascular Medicine
                                                Hospital
Cleveland Clinic Foundation
                                             Associate Professor
                                             Baylor College of Medicine
Frederick Feit, MD, FACC                     Clinical Assistant Professor
Director                                     University of Texas Health Science Center at
Cardiac Catheterization and Interventional      Houston
   Cardiology
Bellevue Hospital Center
Associate Professor of Medicine
                                             Christopher Granger, MD
                                             Associate Professor of Medicine
New York University School of Medicine
                                             Director of Cardiac Care Unit
New York, NY
                                             Division of Cardiovascular Medicine
                                             Duke University Medical Center
                             ACS Forum Leadership Panel

Judd E. Hollander, MD                 Ralph G. Nader, MD, FACC, FACP,
Professor                              FSCAI
Clinical Research Director            Co-Medical Director Cardiovascular Labs at
Department of Emergency Medicine       Mount-Sinai/Miami Heart
University of Pennsylvania            Miami, FL
Philadelphia, PA

David M. Lang, DO, FACOEP,            E. Magnus Ohman, MD, FRCPI,
 FACEP                                  FACC
Chief                                 Professor of Medicine
Emergency Medicine                    Director, Program for Advanced Coronary
Mount Sinai Medical Center             Disease
Miami Beach, FL                       Division of Cardiology
                                      Duke University Medical Center
                                      Durham, NC
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
                        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
 ACS Leadership Panel Financial Disclosures
Deepak L. Bhatt, MD: Consultant/Honoraria 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
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: Honoraria: 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
                              ACS Faculty Review Committee

   Thomas Amidon, MD                             Michael J. Cowley, MD
   The Hope Heart Institute                      Medical College of Virginia

   Atul Aggarwal, MD                             Harold Dauerman, MD
   Nebraska Heart Institute                      University of Vermont

   Himanshu Aggarwal, MD                         William J. French, MD
   Nebraska Heart Institute                      UCLA Medical Center

   Keith Benzuly, MD, FACC                       Satyendra Giri, MD
   Northwestern University                       Baystate Health Systems

   Joseph J. Brennan Jr., MD                     Paul A. Gurbel, MD
   Yale University School of Medicine            Johns Hopkins University

   Carl Chudnofsky, MD
   Albert Einstein Medical Center



* Complete affiliations and financial disclosures for Review Committee members are listed
 at end of slide deck.
                             ACS Faculty Review Committee

   Tim Henry, MD                                 Roberto Medina, MD
   Minneapolis Heart Institute                   Florida Medical Clinic

   Kurt Kleinschmidt, MD                         Barry L. Molk, MD, FACC
   UT Southwestern Medical Center                University of Colorado

   James Leggett, MD                             Reynaldo Mulingtapang, MD
   Hope Heart Institute                          University of South Florida

   Glenn Levine, MD                              Robert A. Mulliken, MD
   Baylor College of Medicine                    University of Chicago Hospitals

   John J. Lopez, MD                             Sandeep Nathan, MD, FACC
   University of Chicago                         Rush Medical College

   Reginald Low, MD                              Paul E. Pepe, MD, MPH
   University of California, Davis               UT Southwestern Medical Center



* Complete affiliations and financial disclosures for Review Committee members are listed
at end of slide deck.
                             ACS Faculty Review Committee

   Robert N. Piana, MD
   Vanderbilt University                         David J. Robinson, MD, MS, FACEP
                                                 UT Health Sciences Center
   Vincent J. Pompili, MD, FACC
   Case School of Medicine                       Joseph F. Stella, DO, FACC
                                                 Heart Care Centers of Illinois
   Matthew J. Price, MD
   Scripps Clinic                                Rex J. Winters, MD
                                                 Long Beach Memorial Heart Institute
   Douglas J. Spriggs, MD, FACC
   University of South Florida

   Lowell H. Steen, Jr., MD
   Loyoyla University Chicago




* Complete affiliations and financial disclosures for Review Committee members are listed
at end of slide deck.
              Educational Objectives

►Physicians will learn about the impact that bleeding has on
 outcomes in patients with acute coronary ischemic syndromes
 (ACS)

►Physicians will learn what factors predict bleeding in patients
 with ACS

►Physicians will learn what predictive value different bleeding
 scales have on outcomes in patients with ACS

►Physicians will learn how to implement strategies that balance
 risk of bleeding and ischemia.

►Physicians will learn how to apply landmark trials and analyses
 of bleeding and ACS to clinical situations.
        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
                                                           (12% of total, 15% of those
  CRUSADE                                    Surgery       undergoing cath)
   Registry
                                                           No disease
  10/04-9/05
   n=35,897                                                Medical Rx



    Cath              Medical Rx                       (52% of total, 63% of
                                                 PCI   those undergoing cath)
(82 % of total)         (cath)
  63 % < 48 hrs
                                                          40 % < 48 hrs
  19 % > 48 hrs
                                          Cath            12 % > 48 hrs



      Patient X

  No Cath                               Medical Rx (no cath)
(18 % of total)
               Admission                  Cath                                   Discharge
                           Medical Rx


 ACS Management Pathways                               Time
                   Milestones in ACS Management
 Anti-Thrombin Rx
  Heparin                        LMWH                         Bivalirudin                             [ Fondaparinux ]

Anti-Platelet Rx
                GP IIb/IIIa
  Aspirin                              Clopidogrel
                blockers
Treatment Strategy
  Conservative                               Early invasive


                   PRISM-PLUS                      REPLACE 2                                        ICTUS

                           PURSUIT                CURE                               OASIS-5                ISAR-REACT 2

              ESSENCE           TACTICS TIMI-18                             SYNERGY                          ACUITY

            1994     1995 1996       1997   1998 1999    2000 2001     2002 2003             2004    2005      2006

   PCI      ~ 5% stents                              ~85% stents            Drug-eluting stents




Ischemic risk


Bleeding risk
                          Adapted from and with the courtesy of Steven Manoukian, MD.
                 Evolving Paradigm for Evaluating ACS
                        Management Strategies

             Composite Adverse Event Endpoints
►   Death

►   MI

►   Urgent TVR

               Ischemic
             Complications
                  Evolving Paradigm for Evaluating ACS
                         Management Strategies

                 Composite Adverse Event Endpoints
►   Death                                   ►   Major Bleeding

►   MI                                      ►   Minor Bleeding

►   Urgent TVR                              ►   Thrombocytopenia


                   Ischemic
                 Complications      Hemorrhage
                                       HIT
                Evolving Paradigm for Evaluating ACS
                       Management Strategies

              Composite Adverse Event Endpoints
                                             ►   Cost
►   Death
                                             ►   Ease of Use
►   Major Disability
                                             ►   Duration of
                                                 Therapy
              Periprocedural      Clinical
                                             ►   Accounting for
              Complications       Benefit        Bleeding and
                                                 Ischemic
                                                 Endpoints
          Balancing Events and Bleeding


           Risk of events
                                Risk of bleeding
Risk




                 Degree of Anticoagulation


       Hemostasis                         Thrombosis

                 Two sides of the same coin
                          CRUSADE In-Hospital Outcomes




              Death                                   4.3%
              (Re)-Infarction                         2.5%
              CHF                                     8.0%
              Cardiogenic Shock                       2.6%
              Stroke                                  0.8%
              Non-CABG Transfusion                    9.9%




Bhatt DL, et al. JAMA. 2004 Nov 3;292(17):2096-104.
              Bleeding in ACS - Agenda


►   Predictors of bleeding in ACS
►   Outcomes associated with bleeding
     Impact of definition on outcomes

►   Outcomes associated with blood
    transfusion
►   Special populations at risk
      Elderly

      Chronic kidney disease

      Anemia

►   Cost implications of bleeding
      Bleeding in ACS

      Question to be answered:
What predicts bleeding among patients
with ACS ?
                      Predictors of Major Bleeding in ACS



          ►   Older Age
          ►   Female Gender                                       Independent
                                                                  Predictors of
          ►   Renal Failure                                       Major Bleeding
                                                                  in Marker Positive
          ►   History of Bleeding                                 Acute Coronary
          ►   Right Heart Catheterization                         Syndromes

          ►   GPIIb-IIIa antagonists




Moscucci, GRACE Registry, Eur Heart J. 2003 Oct;24(20):1815-23.
                                  Predictors of Major Bleeding

                        Results: The ACUITY Trial PCI Population

                                                Risk ratio ± 95% CI       RR (95% CI)        P-value

                     Age >75 (vs. 55-75)                                  1.56 (1.19-2.04)    0.0009

                                 Anemia                                   1.89 (1.48-2.41)   <0.0001

                        CrCl <60mL/min                                    1.68 (1.29-2.18)   <0.0001

                               Diabetes                                   1.30 (1.03-1.63)    0.0248

                         Female gender                                    2.08 (1.68-2.57)   <0.0001

             High-risk (ST / biomarkers)                                  1.42 (1.06-1.90)    0.0178

                          Hypertension                                    1.33 (1.03-1.70)    0.0287

                            No prior PCI                                  1.47 (1.15-1.88)    0.0019

           Prior antithrombotic therapy                                   1.23 (0.98-1.55)    0.0768

       Heparin(s) + GPI (vs. Bivalirudin)                                 2.08 (1.56-2.76)   <0.0001

                                            0        1      2         3


Manoukian SV, Voeltz MD, Feit F et al. TCT 2006.
                                        Predictors of Transfusion

                                      Results: The ACUITY Trial
                                                Risk ratio ± 95% CI       RR (95% CI)           P-value

                  Age >75 (vs. 55-75)                                     1.420 (1.055-1.910)   0.0060
                               Anemia                                     3.764 (2.919-4.855)   <0.0001
                     CrCl <60mL/min                                       2.097 (1.568-2.803)   <0.0001
                              Diabetes                                    1.560 (1.209-2.014)   0.0060
                       Female gender                                      2.233 (1.739-2.867)   <0.0001
         High-risk (ST / biomarkers)                                      1.754 (1.297-2.372)   0.0003
                        Hypertension                                      1.457 (1.051-2.020)   0.0241
       Heparin(s) + GPI (vs. Bivalirudin)                                 1.728 (1.256-2.379)   0.0007




                                            0     1    2   3   4      5



Manoukian SV, Voeltz MD, Feit F et al. TCT 2006.
                                            REPLACE-2
                             Multivariate Predictors of Major Bleeding

                RISK FACTORS                Odds Ratio       95% CI        p-value
             Baseline risk factors
                      Age > 75                1.482      1.009 to 2.176     0.045
                Gender (M vs. F)              0.652      0.477 to 0.890    0.0072
                   Prior Angina               1.589      1.077 to 2.345    0.0197
            Creatinine clearance*             0.993      0.987 to 0.998    0.0061
                       Anemia                 1.403      1.015 to 1.939    0.0401


     Peri-procedural risk factors
    Treatment Group (BIV vs. H+GPI)           0.508      0.352 to 0.733    0.0003
          Provisional GPI received            2.679      1.591 to 4.512    0.0002
           Procedure Duration >1h             2.049      1.217 to 3.449    0.0069
       Time to Sheath Removal >6h             1.614      1.064 to 2.448    0.0244
                ICU stay (days)†               1.25      1.183 to 1.321    <0.0001
                         IABP                 8.705      3.433 to 22.072   <0.0001
Feit F et al. Unpublished (in manuscript)
  Bleeding Predictors—Conclusions



► Older age, chronic kidney disease, female
   gender are consistently associated with
   bleeding and blood transfusion
► Analysis of large randomized trials have
   also identified novel risk factors for bleeding
   such as diabetes and anemia
► Procedural characteristics such as
   procedure duration and sheath dwell time
   also predict bleeding complications
      Bleeding in ACS

      Question to be answered:
Does bleeding influence the prognosis
of ACS patients ?
                        Major Bleeding Predicts Mortality in ACS

                24,045 ACS patients in the GRACE registry, in-hospital death


                40.0

                                     P<0.001
                30.0
                                                            22.8
 Patients (%)




                           18.6                                    No Bleed
                20.0
                                     16.1          15.3            Bleed

                10.0                                      7.0
                         5.1                     5.3
                                   3.0

                 0.0
                  Overall          Unstable      NSTEMI   STEMI
                    ACS              Angina
Moscucci M et al. Eur Heart J 2003;24:1815-23.
                                        Bleeding & Outcomes
          Kaplan Meier Curves for 30-Day Death, Stratified by Bleed Severity
 N=26,452 ACS patients from GUSTO IIb, PARAGON A, PARAGON B, & PURSUIT




                           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
                     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

      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                               *p<0.0001




Rao SV, et al. Am J Cardiol. 2005 Nov 1;96(9):1200-6. Epub 2005 Sep 12
                                   Major Bleeding, Ischemic Endpoints,
                                              and Mortality
                              Results: The ACUITY Trial PCI Population (N=7,789)

                           Major Bleeding (N=462, 5.9%)             No Major Bleeding (N=7327, 94.1%)

                          24.2%                           P<0.0001 for all
      30 day events (%)




                                                                     17.1%



                                                                                         9.3%
                                  7.8%
                                             5.4%                            5.5%
                                                                                                3.0%
                                                     0.8%

                           Ischemic             Death                   MI (all)        Unplanned
                          Composite                                                      Revasc

Manoukian SV, Voeltz MD, Feit F et al. TCT 2006.
                             Major Bleeding and Myocardial Infarction

                              Results: The ACUITY Trial PCI Population (N=7,789)

                           Major Bleeding (N=462,
                           Major Bleeding (N=462, 5.9%)          No Major Bleeding (N=7327, 94.1%)
                                                                 No Major Bleeding (N=7327, 94.1%)

                                                      P<0.0001 for all
       30 day events (%)
       30 day events (%)




                           17.1%
                           17.1%

                                                     12.6%



                                     5.5%
                                     5.5%                       4.8%
                                                                4.8%            4.8%
                                                                                4.8%

                                                                                           0.8%
                                                                                          0.8%

                               MI (all)
                               MI (all)                         MI
                                                          Non-Q MI                   Q-MI
                                                                                     Q-MI

Manoukian SV, Voeltz MD, Feit F et al. TCT 2006.
                     Major and Minor Bleeding in PCI
                 Bleeding Increases Mortality and Events


      10,974 patients undergoing PCI, Washington Hospital Center, 1991-2000.

                                                              Bleeding Complication

                                                    Major               Minor          None
                                                   (n=588)            (n=1,394)      (n=8,992)
  In-Hospital Clinical Events
  Death                                             7.5%*†              1.8%*            0.6%
  Q-wave myocardial infarction                       1.2%*              0.7%‡            0.2%
  Non-Q-wave myocardial infarction                 30.7%*†             16.8%*            11.8%
  Repeat lesion angioplasty                         1.9%*§              0.8%‡            0.3%

  Major adverse cardiac event                       6.6%*†              2.2%*            0.6%

          * p<0.001 versus none    †   p<0.001 versus minor     ‡   p<0.01 versus none    §   p<0.05 versus minor




Kinnaird TD et al. AM J Cardiol 2003;92:930-5.
Bleeding and Outcomes—Conclusions



► Bleeding is associated with adverse short-
   and long-term outcomes among patients
   with ACS and those undergoing PCI
     Mortality rates are higher among those who
    bleed
       MI rates are higher among those who bleed
► The risk is ―loss-dependent‖ with worse
   bleeding associated with worse outcomes
► This relationship is persistent after robust
   statistical adjustment for confounders
      Bleeding in ACS

     Question to be answered:
How does one assess bleeding
severity?
                Bleeding Incidence in ACS Clinical Trials


      12
               10
      10                                                                            9.1


       8


   % 6
                                        4
                                                                           3.7
       4

                           1.2                     1.5
       2
                                                               0.4

       0
            GUSTO IIb    OASIS-2   PRISM-PLUS    PURSUIT      PRISM        CURE   SYNERGY




Rao SV, et al. J Am Coll Cardiol. 2006 Feb 21;47(4):809-16. Epub 2006 Jan 26
                           Bleeding Definitions

      ►   TIMI Definition
               Major
                • ICH
                • Associated with Hgb decrease ≥ 5 g/dl or
                  HCT decrease ≥ 15%
               Minor
                • Observed blood loss associated with Hgb
                  decrease ≥ 3 g/dl or HCT decrease ≥ 10%
                • No identifiable source but Hgb decrease
                  ≥ 4 g/dl or HCT decrease ≥ 12%
               Minimal
                • Overt hemorrhage with Hgb drop < 3 g/dl or
                  HCT drop < 9%

Chesebro JH. Circulation 1987. Jul;76(1):142-54.
                             Bleeding Definitions

           ►   GUSTO Definition
                Severe or life threatening
                  • ICH or hemodynamic compromise
                    requiring treatment
                Moderate
                  • Requiring transfusion
                Mild
                  • Not meeting criteria for Severe or
                    Moderate



N Engl J Med. 1993 Nov 25;329(22):1615-22. Erratum in: N Engl J Med 1994 Feb 17;330(7):516
                Bleeding Incidence Among 15,858 NSTE
                   ACS Patients: Impact of Definition

       25

               19.2
       20


       15                                                12.7
                             11.4
   %
                                                                        8.5       8.2
       10


        5
                                            1.2

        0
             GUSTO         GUSTO       GUSTO Sev       TIMI Mini     TIMI Min   TIMI Maj
              Mild          Mod




Rao SV, et al. J Am Coll Cardiol. 2006 Feb 21;47(4):809-16. Epub 2006 Jan 26
                                     Bleeding Scales Among
                                      NSTE ACS Patients
   TIMI and GUSTO – Adjusted Hazard of 30 d Death/MI                           N=15,858




Rao SV, et al. J Am Coll Cardiol. 2006 Feb 21;47(4):809-16. Epub 2006 Jan 26
  Bleeding Definitions—Conclusions


► Clearly defining bleeding severity can be
   difficult, but there are definitions that have
   been used in clinical trials and registries
► Not all of these definitions have been
   validated in terms of prognosis
► TIMI and GUSTO are 2 of the most
   commonly used definitions
► Bleeding definitions that include clinical
   events (e.g. GUSTO) are better at predicting
   outcomes
          Bleeding in ACS

       Questions to be answered:
► Do blood transfusions have predictive
 value?


► Do blood transfusions correct negative
 impact of bleeding?
                                    Transfusion in ACS

                     30-Day Survival By Transfusion Group   N=24,111




Rao SV, et. al., JAMA 2004;292:1555–1562
                    PRBC Transfusion Among NSTE ACS Patients:
                           Cox Model for 30-day Death
                                                          N=24,111




Rao SV, et. al., JAMA 2004;292:1555–1562   *Transfusion as a time-dependent covariate
                 Adjusted Risk of In-Hospital Outcomes
                        By Transfusion Status*
                         N=74,271 ACS patients from CRUSADE




Yang X, J Am Coll Cardiol 2005;46:1490–5.       *Non-CABG patients only
                                   Transfusion, Ischemic Endpoints, and
                                                  Mortality

                                   Results: The ACUITY Trial (N=13,819)

                            Transfusion (N=319, 2.3%)              No Transfusion (N=13500, 97.7%)

                          29.2%
                                                        P<0.0001 for all
      30 day events (%)




                                                                   18.8%


                                            11.0%
                                                                                       9.4%
                                  7.1%
                                                                           4.8%
                                                                                              2.3%
                                                    1.3%

                           Ischemic             Death                 MI (all)         Unplanned
                          Composite                                                     Revasc

Manoukian SV, Voeltz MD, Feit F et al. TCT 2006.
                                Transfusion and Myocardial Infarction

                                   Results: The ACUITY Trial (N=13,819)

                            Transfusion (N=319, 2.3%)
                           Transfusion (N=319, 2.3%)               No Transfusion (N=13500, 97.7%)
                                                                   No Transfusion (N=13500, 97.7%)

                                                        P<0.0001 for all
       30 day events (%)
       30 day events (%)




                           18.8%
                           18.8%


                                                        13.8%




                                    4.8%
                                    4.8%                                          5.3%
                                                                                  5.3%
                                                                  3.8%
                                                                  3.8%
                                                                                            0.9%
                                                                                           0.9%

                              MI (all)
                              MI (all)                          MI
                                                          Non-Q MI                    Q-MI
                                                                                      Q-MI

Manoukian SV, Voeltz MD, Feit F et al. TCT 2006.
                             Transfusion Post PCI:
                          REPLACE 2 One Year Mortality

                 Increased 1-year mortality in transfused patients
                       Adjusted Odds Ratio 4.26 (2.25–8.08)
             16.0%                                                    13.9%
             14.0%
             12.0%
             10.0%
                                               P<0.0001
              8.0%

              6.0%
              4.0%                   1.9%
              2.0%
              0.0%
                             Non-Transfused                      Transfused

Manoukian SV, Voeltz MD, Attubato MJ, Bittl JA, Feit F, Lincoff AM. CRT 2005. Abstract.
   Blood Transfusion—Conclusions



► 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
► Blood transfusion is best avoided in ACS
   patients whenever possible
      Bleeding in ACS

      Question to be answered:
Are there certain ACS subpopulations
at especially high risk for bleeding,
transfusion, and morbidity/mortality?
                                  Bleeding Risks—Transfusions by Age


                             20                          17.9                    18.5


                                                                          14.1
         % RBC Transfusion




                             15

                                          9.7     10.3
                             10


                                    4.5
                              5



                              0
                                     <65 yrs       65–75 yrs               > 75 yrs

                                                Non-CABG        Overall



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%) classified as elderly, >75 years of age
                               p<0.0001                    p=0.0001
      8.0%
                                  6.7%
      7.0%

      6.0%                                                          5.0%
      5.0%

      4.0%                                                                                = Not Elderly, <75
                     2.7%                                                                 = Elderly, >75
      3.0%
                                                        1.7%
      2.0%

      1.0%

      0.0%
                      Major Bleeding                     Transfusions

Voeltz MD, Lincoff AM, Feit F, Manoukian SV. Circulation 2005;112(17):II-613. Abstract.
                                          Elderly Patients in REPLACE-2:
                                  Increased 30-Day Mortality With Major Bleeding and Transfusions


                         6,002 patients in REPLACE-2.
          806 patients (13.4%) classified as elderly, >75 years of age.
                                  18.0%
                                               p<0.0001            p=0.0001 15.0%
                                  16.0%
                                                      13.0%
                                  14.0%
               30-Day Mortality




                                  12.0%

                                  10.0%                                                   No
                                   8.0%                                                   Yes

                                   6.0%

                                   4.0%

                                   2.0%        0.4%                  0.5%

                                   0.0%
                                              Major Bleeding         Transfusions

Voeltz MD, Lincoff AM, Feit F, Manoukian SV. Circulation 2005;112(17):II-613. Abstract.
                                          Excessive Dosing of
                                         Anticoagulants by Age

                              70                                                           64.5

                              60
          % RBC Transfusion




                              50
                                                                37 38.5
                              40                                                    33.1
                                                        28.7
                              30
                                               16.5
                              20   12.5 12.5
                                                                              8.5
                              10

                               0
                                   LMW Heparin            UF Heparin            GP Iib/IIIa

                                                      <65 yrs    65Š75 yrs   >75 yrs


Alexander KA, JAMA 2005;294:3108–16.
                                  RBC Transfusions by Excess Dosing


                             15                                                 13.3


                             12
         % RBC Transfusion




                                          10.4
                                                          8.8
                                     8
                              9
                                                    6.7

                              6                                      4.4


                              3


                              0
                                    UF Heparin       LMWH                GP llb-llla

                                                 Recommended    Excess


Alexander KA, JAMA 2005;294:3108–16.
                                  Cumulative Effects of Dosing Errors:
                                   Combined Use of Heparin and GP IIb-IIIa


                             20                                     18.5
         % RBC Transfusion




                             15


                                                      9
                             10


                                        4.1
                              5



                              0
                                    Both Right   1 Excessive   Both Excessive




Alexander KA, JAMA 2005;294:3108–16.
                                     Excess Dosing of Gp IIb/IIIa
                                      and Bleeding in Women
                                     N=32,601 patients from CRUSADE




                Overall      1.46 (1.22, 1.73)



              Women          1.72 (1.30, 2.28)



                   Men       1.27 (0.97, 1.66)




                                     0.5         1.0          1.5       2.0       2.5

                                                       Excess Dosing More Likely to Bleed


Alexander KP, et. al. Circulation 2006
                    Bleeding is Increased in Patients With
                   Impaired Renal Function Undergoing PCI
                                               Creatinine Clearance

                                           ≥ 60 ml/min     < 60 ml/min    p value
                                             N=4824           N=886

 30-d Death                                    5 (0.1%)     14 (1.6%)    < 0.001

 30-d Myocardial infarction                305 (6.3%)       75 (8.5%)     0.018

 30-d urgent revascularization                 61 (1.3%)    10 (1.1%)     0.738

 Triple ischemic endpoint                  338 (7.0%)       84 (9.5%)     0.010
 In-hospital protocol major                123 (2.5%)       54 (6.1%)    < 0.001
 bleeding

 TIMI major + minor bleeding               114 (2.4%)       46 (5.2%)    < 0.001



Chew DP et al. Am J Cardiol 2005;95:581–585.
                                Anemia Identifies High-Risk
                               The Unrecognized Risk Factor

             REPLACE-2 Anemic Patient Baseline Characteristics:
                           (Anemia in 22.7%)
                           ►   Older
                           ►   Female
                           ►   Lower BMI
                           ►   Fewer Caucasians
                           ►   Lower Hemoglobin (11.7 vs. 14.3 g/dL)
                           ►   Lower Hematocrit (34.6 vs. 41.8%)
                           ►   Less Tobacco use
                           ►   More Diabetes Mellitus
                           ►   More history of CHF, MI, PCI, CABG



Voeltz MD, Attubato MJ, Feit F, Lincoff AM, Manoukian SV. J Am Coll Cardiol 2005;45(3)[Suppl A]:1037-13-
31A. Abstract.
                             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%

                          6.0%
                                                          4.9%
                          5.0%
                                                                                P=0.0001
                          4.0%          2.8%
                                                                            Protocol definition:
                                                                            >3g/dL drop in HgB,
                          3.0%                                                  intracranial,
       Major Bleeding                                                         retroperitoneal,
                                                                              2U transfusion
                          2.0%

                          1.0%

                          0.0%
                                   Non-Anemic           Anemic
Voeltz MD, Attubato MJ, Feit F, Lincoff AM, Manoukian SV. J Am Coll Cardiol 2005;45(3)[Suppl A]:1037-
13-31A. Abstract.
                                           NSTE-ACS Mortality
                                         Stratified by Hemoglobin
         Unadjusted and adjusted odds ratios for cardiovascular mortality in patients
    with non-ST elevation acute coronary syndromes at 30 days stratefied by hemoglobin
                             Unadjusted                                           Adjusted for baseline characteristics
      Hb (g/dL)      n      OR    (95% Cl)                                             OR       (95% Cl) P value

         >17        216    1.47      (1.03–2.10)                                        1.45      (0.94–2.23)   0.093
        16–17       812    1.21      (0.97–1.51)                                        1.27      (0.98–1.65)   0.066
        15–16     2130      1.0       reference                                          1.0       reference
        14–15     3390     1.06      (0.89–1.22)                                        1.11      (0.93–1.33)   0.251
        13–14     3520     1.02      (0.88–1.19)                                        1.04      (0.86–1.24)   0.709
        12–13     2331     1.09      (0.92–1.28)                                        1.07      (0.88–1.30)   0.514
        11–12       976    1.20      (0.97–1.47)                                        1.04      (0.81–1.34)   0.755
        10–11       343    1.41      (1.05–1.89)                                        1.29      (0.92–1.82)   0.145
         9–10       342    2.44      (1.88–3.18)                                        2.69      (2.01–3.60)   <0.001
         8–9        306    2.24      (1.69–2.96)                                        2.45      (1.80–3.33)   <0.001
          <8        137    3.97      (2.76–5.70)                                        3.49      (2.35–5.20)   <0.001


     Abbreviations: CI, confidence interval; Hb, hemoglobin; OR, odds ration. Adapted with permission.

Sabatine MS. Circulation 2005
 High-Risk Populations—Conclusions


► Certain ACS patient populations are at
   especially high risk for bleeding and
   mortality
      Elderly, females, CKD, anemia
► Improper dosing of anticoagulants is a
   common error and is associated with
   bleeding risk in the elderly, females, and
   those with CKD
► Anemia places patients at risk for both
   bleeding and mortality
      Bleeding in ACS

      Question to be answered:
Does bleeding influence the cost of
care for patients with ischemic heart
disease?
                    Calculating Costs of Ischemia and Bleeding:
                              EPIC EQOL Study (Abciximab in PCI)


           30000                          27349

                            Costs                             Abciximab versus Placebo

           20000                                               ischemic costs:      $523
                                                               major bleed costs:   $458
     $$$




                         8800
           10000
                                                                         5900

                                                            1300

               0
                    Urgent PCI          Urgent          Minor bleed Major bleed
                                        CABG


Mark DB, et al. Circulation. 2000 Feb 1;101(4):366-71
   Bleeding and Costs—Conclusions


► The available costs data confirms that a
   balance must be struck between ischemia
   reduction and bleeding.


► Both ischemic complications and bleeding
   are associated with increased costs.
         Bleeding Among Patients with ACS
                   Conclusions

►   Antithrombotic therapies are cornerstone Rx
      Must balance thrombosis and hemostasis

►   Certain patient and PCI procedure
    characteristics predict bleeding
      Age, female gender, CKD, procedure time,
       sheath dwell time
►   Diabetes and anemia are newly identified risk
    factors for bleeding among ACS patients
            Conclusions—Bleeding


►Bleeding is associated with worse short and
 long-term outcomes including death and MI
►Assessing bleeding severity is important

   ► Many definitions have been used

   ► Definitions that include clinical events
     appear to be more useful than those that
     include only laboratory parameters
►Blood transfusion is associated with increased
 mortality in ACS patients
            Conclusions—Bleeding


►In addition to clinical outcomes, bleeding is
 associated with increased cost of care
   ► Bleeding costs can offset the savings
      realized by reduced ischemic
      complications
►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
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                           ACS Faculty Review Committee

Thomas Amidon, MD                       Joseph J. Brennan Jr., MD
Medical Director                        Associate Professor of Medicine, Cardiology
The Hope Heart Institute                Director, Interventional Fellowship Program
Overlake Internal Medicine Associates   Yale University School of Medicine
Seattle, WA                             New Haven, CT

Atul Aggarwal, MD                       Carl Chudnofsky, MD
Nebraska Heart Institute                Chairman
Lincoln, NE                             Department of Emergency Medicine
                                        Albert Einstein Medical Center
Himanshu Aggarwal, MD                   Philadelphia, PA
Nebraska Heart Institute
St. Frances Med Center                  Michael J. Cowley, MD
Grand Island, NE                        Professor
                                        Department of Internal Medicine
Keith Benzuly, MD, FACC                 Division of Cardiology
Assistant Professor of Medicine         Medical College of Virginia
Bluhm Cardiovascular Institute          Virginia Commonwealth University
Northwestern University                 Richmond, VA
Feinberg School of Medicine
Chicago, IL
                             ACS Faculty Review Committee

Harold Dauerman, MD                         Paul A. Gurbel, MD
Director, Cardiovascular Catheterization    Helen Dalsheimer Director of the Division of
   Laboratory                                  Cardiology
Professor of Medicine                       at Sinai Hospital of Baltimore
Fletcher Allen Health Care                  Associate Professor of Medicine
University of Vermont College of Medicine   Division of Cardiology
Burlington, VT                              Johns Hopkins University School of Medicine
                                            Baltimore, MD
William J. French, MD
Medical Director                            Tim Henry, MD
Catheterization Laboratory                  Minneapolis Heart Institute Foundation
UCLA Medical Center                         Associate Professor
Los Angeles, CA                             University of Minnesota School of Medicine
                                            Minneapolis, MD
Satyendra Giri, MD
Section Chief                               Kurt Kleinschmidt, MD
Vascular Medicine Program                   Associate Professor
Baystate Health Systems                     Director of Toxicology Fellowship Program
Springfield, MA                             UT Southwestern Medical Center
                                            Dallas, TX
                             ACS Faculty Review Committee

James Leggett, MD                            Barry L. Molk, MD, FACC
Associate Medical Director                   Associate Clinical Professor
Hope Heart Institute                         University of Colorado Health Science Center
Seattle, WA                                  Aurora Denver Cardiology Associates
                                             Denver, CO
Glen Levine, MD
Director, Cardiac Catheterization Lab        Reynaldo Mulingtapang, MD
Associate Professor of Medicine              Assistant Professor of Medicine
Baylor College of Medicine                   Director, University of South Florida
Chief, Critical Cardiac Care                    Interventional Cardiology Program
Houston VA Medical Center                    Tampa, FL
Houston, TX
                                             Robert A. Mulliken, MD
John J. Lopez, MD                            Medical Director, Emergency Department
Associate Professor of Medicine              University of Chicago Hospitals
Director                                     Associate Professor
Cardiac Catheterization and Interventional   University of Chicago School of Medicine
 Cardiology                                  Chicago, IL
University of Chicago
Chicago, IL                                  Sandeep Nathan, MD, FACC
                                             Assistant Professor of Medicine
Reginald Low, MD                             Rush Medical College, Section of Cardiology
Chief, Division of Cardiovascular Medicine   Rush University Medical Center
University of California, Davis              Director, Cardiovascular Intervention
Davis, CA                                    Chicago, IL
                             ACS Faculty Review Committee

Robert N. Piana, MD
Associate Professor of Medicine                  Joseph F. Stella, DO, FACC
Vanderbilt University School of Medicine         Heart Care Centers of Illinois
Director, Cardiac Catheterization Laboratories   Clinical Assistant Professor
Nashville, TN                                    Loyola University Medical Center
                                                 Chicago, IL
Vincent J. Pompili, MD, FACC
Director of Interventional Cardiology            Paul E. Pepe, MD, MPH
University Hospitals                             Riggs Family Chair in Emergency Medicine
Associate Professor of Medicine
Case School of Medicine                          Professor and Division Chairman
Cleveland, OH                                    Emergency Medicine
                                                 University of Texas Southwestern Medical
Matthew J. Price, MD                                Center
Director                                         Dallas, TX
Cardiac Catheterization Laboratory
Scripps Clinic                                   Douglas J. Spriggs, MD, FACC
Division of Cardiovascular Diseases              Clinical Assistant Professor
La Jolla, CA                                     Depts. of Internal Medicine and Family Practice
                                                 University of South Florida College of Medicine
David J. Robinson, MD, MS, FACEP                 Clearwater Cardiovascular and Interventional
Associate Professor, Research Director and
                                                  Consultants
  Vice-Chair
Dept. of Emergency Medicine                      Clearwater, FL
University of Texas Health Sciences Center
Houston, TX
                          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
  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
   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.
   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.
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