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					        Getting in the ACS (Up)Stream of Things


         Critical Challenges in
        Cardiovascular Medicine
Translating Landmark Trials and AHA/ACC Guidelines into
     the Front Lines of Cardiovascular Care for Acute,
                  Ischemic Heart Disease


         E. Magnus Ohman, MD, FRCPI, FACC
                 Program Chairman
                       Professor of Medicine
        Director, Program for Advanced Coronary Disease
                       Division of Cardiology
                  Duke University Medical Center
                      Durham, North Carolina
          Welcome and Program Overview

CME-accredited symposium jointly sponsored by the University of
Massachusetts Medical School and CMEducation Resources, LLC

Commercial Support: Sponsored by an independent educational grant
from The Medicines Company

Mission statement: Improve patient care through evidence-based
education, expert analysis, and case study-based management

Processes: Strives for fair balance, clinical relevance, on-label
indications for agents discussed, and emerging evidence and
information from recent studies

COI: Full faculty disclosures provided in syllabus and at the beginning
of the program
                Program Educational Objectives
As a result of this educational activity, physicians will:

    ►     Learn to identify signs, symptoms, and prognostic features of acute
          coronary syndrome (ACS) and related ischemic conditions, and their
          implications for invasive vascular management.
    ►     Learn how recently issued 2007 AHA/ACC Guidelines for UA/Non ST-
          Elevation Myocardial Infarction are best applied to appropriately risk-
          stratified patients with UA and NSTEMI.
    ►     Learn to assess and implement optimal pharmacologic interventions,
          especially antithrombotic therapy, in the upstream setting, for patients
          presenting with manifestations of UA, NSTEMI and related conditions.
    ►     Learn to understand the implications of recent clinical data, trials, and
          recommendations on switching antithrombotic therapy in patients who
          present with acute ischemic coronary syndromes, with an emphasis on
          determining when switching from one agent to another is appropriate,
          safe, and feasible; and, when switching among antithrombotic agents
          may be problematic.
                   Program Educational Objectives
As a result of this educational activity, physicians will:

    ►     Learn to characterize, identify, and evaluate the safety, efficacy, and
          side effects of myriad therapeutic options used for acute ischemic
          coronary syndromes including: Aspirin, antiplatelet agents, direct
          thrombin inhibitors, UFH, LMWHs, and factor Xa inhibitors.
    ►     Learn to understand the specific advantages and potential
          disadvantages of pharmacologic agents currently used to reduce
          ischemic and bleeding end points in the setting of cardiovascular
          emergencies.
    ►     Learn to identify the ideal properties of antithrombotic agents used in
          conjunction with stent insertion.
    ►     Learn to discuss and assess the impact that new trials and Year 2007
          AHA/ACC Guidelines are likely to have on future invasive management
          of patients with UA and NSTEMI.
    ►     Learn to apply national guidelines and expert, consensus-based
          recommendations in order to optimize invasive vascular management
          of patients with acute, ischemic heart disease.
                               Program Faculty

Program Chairman
E. Magnus Ohman, MD,                        A. Michael Lincoff, MD
                                            Vice Chairman for Research
FRCPI, FACC                                 Department of Cardiovascular Medicine
Professor of Medicine                       Director, Cleveland Clinic Cardiovascular
Director, Program for Advanced Coronary     Coordinating Center
  Disease                                   Professor of Medicine
Division of Cardiology                      Cleveland Clinic Lerner College of Medicine of
Duke University Medical Center                Case Western Reserve University
Durham, North Carolina                      The Cleveland Clinic Foundation
                                            Cleveland, Ohio
Distinguished Faculty
C. Michael Gibson, MS, MD
Director, TIMI Core Laboratories and Data   Charles V. Pollack Jr, MA, MD,
Coordinating Center
Associate Professor
                                            FACEP, FAAEM
Harvard Medical School                      Chairman, Department of Emergency Medicine
Boston, Massachusetts                       Pennsylvania Hospital
                                            Professor of Emergency Medicine
                                            University of Pennsylvania School of Medicine
                                            Philadelphia, Pennsylvania
                   Faculty COI Disclosures
E. Magnus Ohman, MD, FRCPI, FACC
Research Grants: Berlex, sanofi-aventis, Schering-Plough Corporation, Bristol
Meyer Squibb, and Millennium.
Stockholder: Medtronic. Consultant: Response Biomedical, Liposcience, and Inovise
Medical

C. Michael Gibson, MS, MD
Present Research/Grant Funding: CardioKinetix, Eli Lilly, KAI Pharmaceuticals,
Nuvelo, Schering Plough Corporation, Sanofi-Aventis, St. Jude Medical, Baxter,
Novartis, FoldRx, INO Therapeutics, LLC
Speakers Bureau: Genentech, Inc., GlaxoSmithKline, Schering Plough Corporation,
The Medicines Company
Consultant: Angel Medical Systems, The Medicines Company. HeartScape
Technologies, Inc., Ascenta Therapeutics, Inc., Archemix Corp., PDL
Pharmaceuticals, Atrium Medical Corporation, TIMI3 Systems, Biogen IDEC

Charles V. Pollack Jr, MA, MD, FACEP, FAAEM
Grant/Research Support: GlaxoSmithKline
Consultant: The Medicines Co., Schering-Plough, Sanofi-Aventis, BMS, Genentech
Speaker’s Bureau: Schering-Plough, Sanofi-Aventis, BMS, Genentech
                                   Faculty COI Disclosures
A. Michael Lincoff, MD Relationships with Industry Research Sponsors
                             C5Research
  ►

  ►
      Abraxis
      Alexion Pharma
                                         ►   Edwards Lifesciences   ►   Novartis
  ►

  ►
      AstraZeneca
      Atherogenics
                                         ►   Esperion               ►   Novo Nordisk
  ►

  ►
      Aventis
      Biosense Webster
                                         ►   GE Medical             ►   Orphan Therapeutics
  ►

  ►
      Biosite
      Boehringer Ingelheim
                                         ►   Genentech              ►   P&G Pharma
  ►

  ►
      Boston Scientific
      Bristol-Myers Squibb (BMS)
                                         ►   Gilford                ►   Pfizer
  ►

  ►
      Cardionet
      Centocor
                                         ►   GSK                    ►   Roche
  ►

  ►
      Converge Medical Inc.
      Cordis
                                         ►   Guidant                ►   Sankyo
  ►
  ►
      Dr. Reddy’s Laboratory
      Novartis
                                         ►   J&J                    ►   Sanofi-Aventis
  ►   Novo Nordisk
  ►   Orphan Therapeutics                ►   Kensey-Nash            ►   Schering-Plough
  ►   P&G Pharma
  ►

  ►
      Pfizer
      Roche                              ►   Lilly                  ►   Scios
  ►   Sankyo
  ►

  ►
      Sanofi-Aventis
      Schering-Plough
                                         ►   Medicines Company      ►   St. Jude Medical
  ►

  ►
      Scios
      St. Jude Medical                   ►   Medtronic              ►   Takeda
  ►   Takeda
  ►

  ►
      VasoGenix
      Viacor
                                         ►   Merck                  ►   VasoGenix
                                         ►   Mytogen                ►   Viacor
                                         ►   Novartis
              Getting in the ACS (Up)Stream of Things

          Critical Challenges in Acute
      Ischemic Heart Disease — Overview

   Where Metal Meets Thrombus, Drugs, and Vascular
     Endothelium: A State of the ―Union‖ Synthesis


             E. Magnus Ohman MD, FRCPI, FACC
                     Program Chairman
Professor of Medicine | Director, Program for Advanced Coronary Disease |
        Division of Cardiology | Duke University Medical Center |
                          Durham, North Carolina
                   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
                 Possible Relationship Between
                 Bleeding and Mortality in ACS
                                Major Bleeding



Hypotension                         Cessation of              Transfusion
                                   ASA/Clopidogrel




 Ischemia                         Stent Thrombosis            Inflammation




                                         Mortality

      Bhatt DL et al. In Braunwald: Harrison’s Online 2005.
         Getting in the ACS (Up)Stream of Things

       Issues We Will Address Tonight

• GUIDELINES — Do we need them? If so, why? In what
situations? And how do we adapt to new evidence presented
after guidelines are released?

• UPSTREAM THERAPY—How do we identify optimal
strategies?

• COLLABORATION—How do we facilitate collaboration
among ED physicians and CV specialists?

• CASE STUDIES—Translating science and evidence to
practice
                UA/NSTEMI Strategy Overview
                   THE BIG PICTURE: EARLY INVASIVE VS.
                     INITIAL CONSERVATIVE THERAPY

―An early invasive strategy (i.e., diagnostic angiography with intent to perform
revascularization) is indicated in initially stabilized UA/NSTEMI patients
(without serious comorbidities or contraindications to such procedures) who
have an elevated risk for clinical events.‖

―In initially stabilized patients, an initially conservative (i.e., a selectively
invasive) strategy may be considered as a treatment strategy for UA/NSTEMI
patients (without serious comorbidities or contraindications to such
procedures) who have an elevated risk for clinical events, including those who
are troponin positive.‖

―The decision to implement an initial conservative (vs. initial invasive) strategy
in these patients may be made by considering physician and patient
preference.‖

           ACC/AHA 2007 Guidelines for the Management of UA/NSTEMI. August 6, 2007, Circulation.
              UA/NSTEMI Strategy Overview
       BIG PICTURE: ANTIPLATELET AGENTS

―Support for thienopyridine use (primarily with clopidogrel)
continues to grow, including higher loading-dose options,
earlier (upstream) administration, and longer administration
(especially after drug-eluting stent placement).‖

―The question of how best to integrate thienopyridine use with
parenteral glycoprotein (GP) IIb/IIIa antagonists to provide
optimal antiplatelet therapy early in the course of UA/NSTEMI
therapy, including cardiac catheterization, is an evolving area.‖



          ACC/AHA 2007 Guidelines for the Management of UA/NSTEMI. August 6, 2007, Circulation.
            UA/NSTEMI Strategy Overview

        BIG PICTURE: ANTICOAGULANTS

―Two new anticoagulants, fondaparinux and bivalirudin,
have undergone favorable testing in clinical trials and
are recommended as alternatives to unfractionated
heparin (UFH) and low-molecular-weight heparins
(LMWHs) for specific or more general applications.‖




        ACC/AHA 2007 Guidelines for the Management of UA/NSTEMI. August 6, 2007, Circulation.
                 UA/NSTEMI Pivotal Trials




          PIVOTAL TRIALS
Snapshot of Trial Results that Supported Addition
 of Bivalirudin and Fondaparinux to Year 2007
       AHA/ACC UA/NSTEMI Guidelines




     ACC/AHA 2007 Guidelines for the Management of UA/NSTEMI. August 6, 2007, Circulation.
                            OASIS-5: Efficacy at Day 9
                                                                             Non-inferiority
                  Enox Fonda                                                 Margin = 1.185
                    ——%——
      Death/MI/RI 5.8   5.9

      Death/MI               4.1            4.1

      Death                  1.9            1.8

      MI                     2.7            2.7

      Refractory             1.9           2.05
      Ischemia
                                                       0.8           1           1.2
                                                     Fonda Better          Enox Better
Yusuf S, et al. N Engl J Med. 2006;354(14):1464-76              Hazard Ratio
                   OASIS-5: Bleeding Rates at Day 9

 Outcome                             Enox            Fonda     HR (95% CI)            P
 No. Randomized                     10,021           10,057
 Total Bleed (%)                       7.0            3.2     0.44 (0.39 – 0.51)   < 0.0001
 Major Bleed (%)                       4.0            2.1     0.53 (0.45 – 0.62)   < 0.0001
 TIMI Major Bleed (%)                  1.3            0.7     0.54 (0.41 – 0.73)   < 0.0001
 Minor Bleed (%)                       3.1            1.1     0.35 (0.28 – 0.43)   < 0.0001




Yusuf S, et al. N Engl J Med. 2006;354(14):1464-76
                                                 OASIS-5
                                      Efficacy End Points at 6 Months


  End point                                    Enoxaparin Fondaparinux   P value

  Death/MI/ refractory
                                                     13.2%   12.3%        0.06
  ischemia
  Death/MI                                           11.4%   10.5%        0.05

  Death                                              6.5%     5.8%        0.05

  MI                                                 6.6%     6.3%         NS

  Stroke                                             1.7%     1.3%        0.04

  Death/MI/stroke*                                   12.5%   11.3%       0.007


Yusuf S, et al. N Engl J Med. 2006;354(14):1464-76
                   PCI — Procedural Complications

                                           Enoxaparin   Fondaparinux
       Events (30 Days)                                                P value
                                             n=3089        n=3118

       Any UFH during PCI                      53.8%       18.8%
       Any procedural
                                                8.6%       9.6%         0.18
       complication
       Abrupt closure                           1.1%       1.5%         0.20
       Catheter thrombus                        0.5%       1.3%         0.001
       Vascular access                          8.1%       3.3%        <0.0001

       Pseudo-aneurysm                          1.6%       1.0%         0.39

       Large hematoma                           4.4%       1.6%        <0.0001

Yusuf S, et al. N Engl J Med. 2006;354(14):1464-76
                         ACUITY—Ischemic Composite Endpoint

                        15                                                                          P
                                                                                     Estimate
                                            UFH/Enoxaparin + IIb/IIIa (N=4603)         7.3%     (log rank)
Cumulative Events (%)




                                                Bivalirudin + IIb/IIIa (N=4604)        7.7%     0.37
                                                  Bivalirudin alone (N=4612)           7.8%     0.30
                        10



                         5



                         0
                             0          5          10          15          20         25          30         35

                                                      Days from Randomization



                         Stone GW, McLaurin BT. NEJM. 2006 Nov 23;355(21):2203-16.
                             ACUITY—Major Bleeding Endpoint

                        15
                                                                                     Estimate       P
                                            UFH/Enoxaparin + IIb/IIIa (N=4603)         5.7%     (log rank)
Cumulative Events (%)




                                                Bivalirudin + IIb/IIIa (N=4604)        5.3%     0.41
                                                  Bivalirudin alone (N=4612)           3.0% <0.0001
                        10



                         5



                         0
                             0          5           10          15          20         25          30        35

                                                      Days from Randomization



                         Stone GW, McLaurin BT. NEJM. 2006 Nov 23;355(21):2203-16.
                                 ACUITY — Net Clinical Outcome

                        15
Cumulative Events (%)




                        10



                                                                                           Estimate   P
                         5
                                                 UFH/Enoxaparin + IIb/IIIa (N=4603)                (log
                                                                                               11.7% rank)
                                                        Bivalirudin + IIb/IIIa (N=4604)        11.8% 0.89
                                                           Bivalirudin alone (N=4612)          10.1%0.014

                         0
                             0         5          10          15          20          25        30           35

                                                   Days from Randomization



                         Stone GW, McLaurin BT. NEJM. 2006 Nov 23;355(21):2203-16.
                               ACUITY Mortality at One Year

                5
                        Bivalirudin+GPI vs. Hep+GPI
                        HR [95% CI] = 0.99 (0.80-1.22)                                                            p=0.90
                4
                        Bivalirudin alone vs. Hep+GPI
Mortality (%)




                        HR [95% CI] = 0.95 (0.77-1.18)
                3

                2                                                  30 day       P          1 year       P
                                                                  Estimate   (log rank)   Estimate   (log rank)


                1                   UFH/Enoxaparin + IIb/IIIa        1.4%      —             4.4%      —
                                         Bivalirudin + IIb/IIIa      1.6%     0.53           4.2%     0.93
                                          Bivalirudin alone          1.6%     0.39           3.8%     0.66
                0
                    0     30   60    90    120 150       180 210 240 270            300 330 360             390

                                          Days from Randomization



                    Stone GW, ACC 2007
            Addressing the Challenge of
        Selecting an Anticoagulation Strategy

                Age          Renal function


Bleeding Risk                                 Cost



                                        Ease of use
Ischemic Risk



     PCI vs CABG vs Med Rx     Time to cath
          Sea and Stream Changes in ACS
►   The 2007 Guidelines have created a ―Sea Change‖ in
    the care of patients with UA/NSTEMI

       New “Streams” of care, with new anticoagulants,
        are in play

       Clopidogrel use has been liberalized

       Bleeding end points play a more important role in
        drug selection

       Dogmatism is out, customization is in

       Collaboration is emphasized
        Getting in the ACS Stream of Things

Getting in the Stream(s) of Antithrombotic
             Therapy for ACS:
       What Do The Trials Tell Us?

        To Switch or Not to Switch —
         If, When, How, To What?

      C. Michael Gibson, M.S., M.D., FACC
        Director, TIMI Core Laboratories and Data Coordinating Center
                  Associate Professor, Harvard Medical School
                            Boston, Massachusetts
                Overview of Presentation

►   Mechanistic rational for switching
►   Why is there a concern about switching
    antithrombins in patients with ACS (lessons from
    SYNERGY)
►   Why should switching to bivalirudin for PCI be
    reasonable?
►   Clinical evidence in support of switching
     SWITCH

     REPLACE 2

     ACUITY
                  Background — Issues and Concerns


► ACS         patients
     87% of patients receive either UFH, enoxaparin, or fondaparinux
      within 24 hours after admission1
     72% of patients in SYNERGY and 50 % of patients in OASIS- 5
      received prior antithrombin2,3


► Published                 studies and perceptions
     Patients in SYNERGY who crossed over between UFH and
      enoxaparin had an increase in bleeding complications2
       • This activity occurred at various times through the study period: At
         times in response to clinical or clinician perception
     Consistent therapy is better4


          1   CRUSADE( 1Q-2006 results); 2 SYNERGY results; JAMA 2004;   3   OASIS -5; Yusuf et al,NEJM 2006; 4 Cohen et al, JACC 2006.
                Bivalirudin: A Guidelines-Supported
                 Alternative to UFH/LMWH in ACS
► Advantages            of the direct thrombin inhibitor
    bivalirudin
       No requirement for antithrombin III
       Effective on clot-bound thrombin
       Inhibits thrombin-mediated platelet activation
       No interactions with PF- 4
       Plasma half-life 25 minutes
       No requirement for anticoagulant monitoring

► Clinical      results with bivalirudin in PCI
       Similar protection from ischemic events as UFH + GP IIb/IIIa
        inhibitors, with markedly reduced bleeding1

►   Not previously tested in contemporary ACS patients
                                             REPLACE 2. Lincoff AM et al. JAMA 2003;289:853-863.
             Switching Antithrombins: SYNERGY

►   The SYNERGY trial suggested a switch in
    anthithrombins (from heparin to LMWH) can lead
    to increase in bleeding.


►   What outcomes are observed when switching from
    heparin, LMWH, or fondaparinux to bivalirudin in
    PCI?


►   Is it better to switch or to stay on consistent
    therapy?
               The SWITCH Study

Switching from Enoxaparin to Bivalirudin in Patients
   with Acute Coronary Syndromes Without ST-
  segment Elevation Undergoing Percutaneous
            Coronary Intervention (PCI)

         Ron Waksman, MD, FACC, FSCAI
           Associate Director Division of Cardiology
                Washington Hospital Center
                      Washington, DC




               The study was sponsored in part by The Medicines Company
           SWITCH: Study Design
                Open-label, prospective, 3-arm study



                       LMWH
           30        1mg/kg SC
                  0-4 h before PCI                  Bivalirudin
  91 ACS                                                                  Primary
                                                    during PCI
 patients                                                                Endpoint —
undergoing             LMWH            Arms         0.75 mg/kg
           30        1mg/kg SC        Switched         bolus             BLEEDING
    PCI           4-8 h before PCI
  (3 US                                           1.75 mg/kg/h
  sites)                                           IV infusion
                       LMWH
           31        1mg/kg SC
                  8-12 h before PCI




                                             Waksman J Invasive Cardiol 2006;18:370-375.
                        Results: Study Drug-Related
                              Bleeding Events

                              All, %    Group 1,%   Group 2,%   Group 3,%     p
                              N=91        n=30        N=30        N=31      value
All Major Bleed               7.7 (7)    13.3 (4)     3.2 (1)     6.5 (2)   0.39

Transfusion ≥2 units          4.4 (4)     3.2 (1)     3.2 (1)     6.5 (2)    1.0

Intracranial Bleed             0 (0)       0 (0)       0 (0)       0 (0)     --

Retroperitoneal Bleed          0 (0)       0 (0)       0 (0)       0 (0)     --

Spontaneous Hematuria or      1.1 (1)     3.2 (1)      0 (0)       0 (0)    0.66
Hematemesis
Drop in Hg > 4g/dL, no site   2.2 (2)     6.7 (2)      0 (0)       0 (0)    0.21

Drop in Hg ≥ 3 g/dL            0 (0)       0 (0)       0 (0)       0 (0)     --

All Transfusions              4.4 (4)     6.7 (2)      0 (0)      6.5 (2)    1.0

Minor Bleed                   4.4 (4)     6.7 (2)     6.7 (2)      0 (0)    0.39
            SWITCH: Conclusions


► Switching from LMWH to bivalirudin during
  PCI for patients with ACS was safe
► Switching was not associated with major
  bleeding complications regardless of when
  LMWH was administered
► The use of bivalirudin as the sole antithrombin
  agent during PCI can be extended for patients
  who were pretreated with enoxaparin 8 hours
  post the last dose of LMWH
                   REPLACE-2 Trial: Impact of
                     Antithrombin Switching
  Association of Pre-Randomization Anticoagulant
Switching with Bleeding in the Setting of Percutaneous
   Coronary Intervention: A REPLACE-2 Analysis

    C. Michael Gibson, Yuli Ten, Sabina A. Murphy, Lauren N. Ciaglo,
      Matthew C. Southard, A. Michael Lincoff, and Ron Waksman


   The goal of this analysis was to evaluate whether a
     hazard existed when either UFH or LMWH were
       administered prior to study medication in the
                      REPLACE-2 trial


                                       Gibson CM, Am J Cardiol. 2007 Jun 15;99(12):1687-90.
       Pre-Randomization Anticoagulant
           Switching and Bleeding


The present study compared bleeding
 among patients treated either with
preceding antithrombin therapy or no
preceding antithrombin therapy in the
           prior 48 hours.




                    Gibson CM, Am J Cardiol. 2007 Jun 15;99(12):1687-90.
             Pre-Randomization Anticoagulant
                 Switching and Bleeding

The method of switching or transition involved
administration of bivalirudin as follows:
>8 hours after last low molecular weight heparin
 (LMWH) dose
                          OR
> 6 hours after unfractionated heparin, unless in the case
of UFH therapy the activated partial thromboplastin time
was ≤ 50 seconds or the activated clotting time was ≤
175 seconds


                               Gibson CM, Am J Cardiol. 2007 Jun 15;99(12):1687-90.
                      Bleeding and Switching in REPLACE-2

                                                                                            UFH→             LMWH→
                                                                          Naive→
                           Naive→           UFH→         LMWH→                               GP                GP
                                                                         GP IIbIIIa
     Variable                 BIV*           BIV           BIV                               IIbIIIa/U         IIbIIIa/U
                                                                           /UFH
                          (n=2,345)        (n=287)       (n=258)                                FH                FH
                                                                         (n=2,325)
                                                                                           (n=349)           (n=313)
Protocol Major
                            2.3%*           1.7%           2.7%             3.6%             4.9%              5.8%
    Bleed

Protocol Minor
                            13.4%*         13.6%          14.0%            25.0%            28.9%             29.1%
    Bleed

Protocol
    Major/Minor             15.6%*         15.3%          16.7%           28.6%**           33.8%             34.8%
    Bleed

TIMI Major/Minor
                            1.9%*           1.4%           1.9%             3.5%             4.3%              5.4%
    Bleed

≥2 Non-CABG
                            0.8%*           1.1%           1.2%           1.0%**             2.3%              2.9%
    Transfusions

   * p=NS for all 3-way comparisons vs BIV alone
   ** p<0.05 for 3-way comparison vs glycoprotein IIbIIIa (GP IIbIIIa), unfractionated heparin (UFH) naïve as well as 2-
   way comparisons of unfractionated heparin (UFH) naïve vs either preceding unfractionated heparin (UFH) or
   preceding low molecular weight heparin (LMWH)

                                                                   Gibson CM, Am J Cardiol. 2007 Jun 15;99(12):1687-90.
                                                     Time from Last Dose of LMWH to PCI in Bivalirudin
                                                     Patients by Presence of Protocol Major/Minor Bleed


                                          1.0       NO BLEED
                                                    Median = 18 hrs
Fraction of Patients with hours <X axis




                                                    IQ 14.5 – 24 hrs
                                                                                                                p = 0.91
                                                    N=228


                                                                                      BLEED
                                          0.5
                                                                                      Median = 18.5 hrs
                                                                                      IQ 12.6 – 24.5
                                                                                      N=51




                                          0.0
                                                0        6         12        18      24        30          36          42         48
                                                                       Time to PCI (hours)

                                                                                       Gibson CM, Am J Cardiol. 2007 Jun 15;99(12):1687-90.
                                   Switching and One Year Mortality
                         REPLACE-2 Subanalysis: 1-Year Mortality Results
                              Consistent with Overall Trial Results
Cumulative events (mortality), %




                                                   Gibson CM, Am J Cardiol. 2007 Jun 15;99(12):1687-90.
          Pre-Randomization Anticoagulant
              Switching and Bleeding


►When switching to bivalirudin was undertaken in
 this fashion, preceding therapy with either LMWH
 or UFH was not associated with an excess of
 bleeding or transfusions compared with bivalirudin
 therapy alone in the cardiac catheterization
 laboratory.




                           Gibson CM, Am J Cardiol. 2007 Jun 15;99(12):1687-90.
How to Switch — Science to Practice


From UFH to Bivalirudin —
• Discontinue UFH for 30 minutes before
  starting bivalirudin for PCI



From LMWH to Bivalirudin —
• Discontinue LMWH for 8 hours before
 starting bivalirudin for PCI



                         Gibson CM, Am J Cardiol. 2007 Jun 15;99(12):1687-90.
                           ACUITY: Study Medications

            Antithrombin Agents Started Pre-angiography

                       UF Heparin                    Enoxaparin                        Bivalirudin
                            U/Kg                         mg/Kg                             mg/kg
Bolus                          60                     1.0 sc bid                            0.1 iv
Infusion/h                    121                                                          0.25 iv
                             ACT                   0.30 iv bolus2                    0.50 bolus iv
PCI
                         200-250s                  0.75 iv bolus3                1.75/h infusion iv4

CABG                 Per institution               Per institution                 Per institution5
Medical mgt                None6                         None6                             None6

        1 Target aPTT 50-75 seconds.
        2 If last enoxaparin dose ≥8h - <16h before PCI.
        3 If maintenance dose discontinued or ≥16h from last dose.
        4 Discontinued at end of PCI with option to continue at 0.25mg/kg for 4-12h if GPIIb/IIIa inhibitor not used.
        5 Bivalirudin option for off-pump same as PCI dose. For on-pump bivalirudin discontinued 2 hours before.
        6 Option to continue with pre-PCI anti-thrombotic regimen at physician discretion.
        Switching Hypothesis and Question

► Hypothesis:
 Bivalirudin improves bleeding outcomes while
 preserving ischemic protection for ACS patients
 even if the patients are switched from either UFH
 or enoxaparin to bivalirudin (monotherapy) at the
 time of presentation.


► Question:

 Is it better to switch to bivalirudin or remain on
 consistent therapy with the antithrombin
 originally started?
                ACUITY: ―Switching‖ Analysis

►   Study Methods
     Patients on prior antithrombin therapy
        • Consistent: No switching from pre-randomization
          antithrombin agent to randomized therapy:
             – Enoxaparin →Enoxaparin or UFH → UFH
        • Switch: Single switch to bivalirudin determined by
          randomization code
             – from Enoxaparin → Bivalirudin or UFH → Bivalirudin

       Event rates at 30-days
        • Net clinical outcome
        • Ischemic composite
        • Major bleeding
            ACUITY Primary Endpoints at 30 Days

►   Net Clinical Endpoint
       Composite ischemic and non-CABG major bleeding
        endpoints
►   Ischemic Endpoint
       Death, MI, or unplanned revascularization
►   Non-CABG Major Bleeding Endpoint
       Intracranial, intraocular, or retroperitoneal bleeding
       Access site bleed requiring intervention/surgery
       Hematoma ≥5 cm
       Hgb ≥3g/dL with an overt source or ≥4g/dL w/o overt
        source
       Blood transfusion
                       ―Switching‖ Consort Diagram

                                            ACUITY
                                                13819

                                     Patients on Prior AT
                                         N = 6606 ╪



     CONSISTENT                                                                  SWITCH
       UFH/Enox                                                                  Bivalirudin*
       N = 2223                                                                   N = 2237


UFH→UFH          Enox→Enox                                            UFH→Biv             Enox→Biv
 N = 1294          N = 929                                            N = 1313             N = 857

            • * Includes 67 pts. who had UFH and Enox
            • ╪ excludes Arm B and pts. with multiple crossovers, missing data
                                Baseline Characteristics
                 Consistent UFH/Enox vs. Switch to Bivalirudin
                                               Consistent              Switch
                                               UFH/Enox              Bivalirudin         P-value
                                                N = 2223              N = 2237
Age (median [range], yrs)                      63 [23, 91]           62 [20, 92]           0.02
Male (%)                                          71.6                  70.0               NS
Weight (median [IQR], kg)                      83 [73, 96]           84 [73, 96]           NS
Diabetes(%)                                       27.6                  25.0               0.05
Hypertension (%)                                  64.5                  63.8               NS
Hyperlipidemia (%)                                54.6                  54.0               NS
Current smoker (%)                                29.5                  30.7               NS
Prior MI (%)                                      31.0                  30.4               NS
Prior PCI (%)                                     36.8                  36.8               NS
Prior CABG (%)                                    18.4                  18.1               NS
Thienopyridine exposure                           63.8                  66.1               NS
Renal insufficiency* (%)                          19.6                  17.4               NS
High Risk* (%)                                    77.6                  74.6               0.02
Troponin + (%)                                    65.4                  63.6               NS

           * creatinine clearance <60 mL/min     *Elevated cardiac markers and/or ST changes
                                  Results: Consistent vs. Switch

Comparison of Consistent therapy on UFH/Enox
       vs. Switch to Bivalirudin Alone
                                            Consistent UFH/Enox (N = 2223 )
                                            Switch to Bivalirudin (N= 2237)
30 day events (%)




                         11.9%

                                     9.1%
                                                   7.3%        6.9%
                                                                              5.8%

                                                                                        2.8%



                      Net Clinical Outcome       Ischemic composite           Major bleeding

                    0.77 [0.63 – 0.91]         0.95 [0.76 – 1.17]        0.47 [0.35 – 0.64]

                        P=0.002                     P=0.601                   P<0.001         Harvey White, ESC 2007
             Consistent vs. Switch MV Adjusted
                   Results in all Patients

                                   Odds ratio ±95% CI                OR (95% CI)        P-value




             Ischemia                                                1.10 (0.86-1.41)   0.464




      Major Bleeding                                                 0.47 (0.34-0.65)   <0.001



Net Clinical Outcome                                                 0.83 (0.67-1.02)   0.073




                               0                1                2
       Switch to Bivalirudin alone better           Consistent UFH/Enox better

         * Comparing consistent UFH/Enox vs Switch Bivalirudin
                  Consistent vs. Switch
         High Risk Patients — Adjusted Analysis
      Comparing Consistent UFH/Enox vs Switch Bivalirudin

                               Odds ratio±95% CI             OR (95% CI)        P-value




            Ischemia                                         1.11 (0.85-1.46)   0.445




      Major Bleeding                                         0.51 (0.36-0.72)   <0.001



Net Clinical Outcome                                         0.86 (0.68-1.07)   0.177




                           0                1            2
       Switch to Bivalirudin alone better       Consistent UFH/Enox better
                                   Consistent vs. Switch
Comparing Consistent therapy on Enoxaparin vs. Switch from
            Enoxaparin to Bivalirudin Alone

                                     Consistent Enox (N = 929 )
                                     Switch from Enox to Bivalirudin (N= 857)
 30 day events (%)




                       11.2%
                                  9.1%
                                                7.0%
                                                          6.4%
                                                                         5.2%

                                                                                   2.8%



                     Net Clinical Outcome    Ischemic composite          Major bleeding

 0.81 [0.61 – 1.07]                          0.92 [0.65 – 1.30]           0.54 [0.34 – 0.88]

                     P=0.145                      P=0.626                       P=0.013
                                        Consistent vs. Switch
                              Comparing Consistent therapy on UFH vs.
                                Switch from UFH to Bivalirudin Alone
                                           ) UFH+ GP IIb/IIIa (N = 1294
                                           )UFH to Bivalirudin (N= 1313
30 day events (%)




                      12.4%

                                  9.4%
                                                7.6%      7.4%
                                                                          6.3%


                                                                                     2.8%



                    Net Clinical Outcome     Ischemic composite           Major bleeding
                    0.75[0.60 – 0.94]        0.98[0.74 – 1.28]            0.44[0.30 – 0.65]

                        P=0.012                   P=0.857                     P<0.001
              Conclusions

► Switching    to bivalirudin is safe
     Switching from any heparin (either enoxaparin
      or UFH) to bivalirudin monotherapy is not
      associated with an increased risk for ischemic
      events.


► Furthermore
     Switching to bivalirudin provides patients the
      50% bleeding advantage of bivalirudin
      compared with consistent therapy on UFH or
      enoxaparin.
         Getting in the ACS (Up)Stream of Things


  NSTE Acute Coronary Syndromes
    The Year 2007 ACC/AHA Guidelines
         and Upstream Therapy —
How Do We Collaborate Across Best Evidence?




  Charles V. Pollack, Jr., M.A., M.D., FACEP, FAHA
                Professor and Chairman
      Emergency Medicine, Pennsylvania Hospital
       University of Pennsylvania Health System
                      Philadelphia
         NSTE ACS: Optimal Therapy, 8/6/07

► Anderson JL, Adams CD, Antman EM, et al. 2007
 guidelines for the management of patients with unstable
 angina/non-ST-segment-elevation myocardial infarction: a
 report of the American College of Cardiology/American
 Heart Association Task Force on Practice Guidelines. J Am
 Coll Cardiol 2007;50:e1-e157, and Circulation
 2007;116:e148-e304, and at www.acc.org and at
 www.americanheart.org.

► Pollack CV, Braunwald E: 2007 Update to the ACC/AHA
 guidelines for the management of patients with unstable
 angina and non-ST-segment elevation myocardial infarction:
 Implications for emergency department practice. Ann
 Emerg Med 2007, in press.
         The Role of the Emergency Physician in the
                Management of Chest Pain

► Stabilization
     When required
► Recognition
     ―Atypical is the new typical‖
► Prompt    STEMI management
     ~ 15% of our ACS population—new data to follow
► Risk   Stratification of the rest
     > 50% don’t have ACS
     Of those who do, fewer than 30% are high
      (ischemic) risk in the ED
            The Role of the Emergency Physician in the
                   Management of Chest Pain

►   Communication with Cardiology
       Often hospital medicine, PCP, and noninterventionalists as part
        of process-of-care in ACS

►   Confluent Therapeutic Choices — Considerations Include:
       Ischemic risk
       Bleeding risk
       Choice of upstream therapy
       Reversibility of upstream therapy—re CABG and bleeding
       Likely duration of upstream therapy

►   Transition of care
       If patient going to cath, time frame increasingly compressed
       If to tele/CCU, emergency physician has more impact
                         Risk Stratification
    Patients with Chest Pain Syndrome Must Be Risk-
                     Stratified in ED

►   Three levels of risk stratification are pertinent to the
    ED:
    Low, intermediate, or high risk that ischemic symptoms
      are a result of CAD

    Low, intermediate, or high risk of short-term death or
      nonfatal MI from ACS

       Dynamic, ongoing risk-oriented evaluation of low- or
       intermediate-risk patients for ―conversion‖ to high-risk
            status that is linked to intensity of treatment
       ―Dynamic Risk Stratification‖ Tools

► History and Physical
► Standard EKG and Non-standard EKG leads
     15-lead ECGs should perhaps be ―standard‖ in all
      but very-low-risk patients
► Markers
    CPK-MB, Troponins I and T, Myoglobin
    Markers of inflammation and ischemia
    BNP
► Non-Invasive Imaging
    Echocardiogram
    Stress testing
    Technetium-99m-sestamibi
    CT coronary angiography
► Predictive Indices/Schemes
    TIMI, GRACE, PURSUIT
           The CRUSADE Experience

           CRUSADE: A National
         Quality Improvement Initiative

Can Rapid Risk Stratification of Unstable Angina Patients
Suppress ADverse Outcomes with Early Implementation
               of the ACC/AHA Guidelines



                    2002-2007
                                    The CRUSADE Experience
                                                                          443 Participating Sites
                                                                            205,528 Patients
                              WA                                                                                                                                          ME
                              (5)                                                                                                                               VT (1)
                                                                                                                                                                          (0)
                                                   MT                      ND
                                                                           (1)                                      MI                                                            NH (1)
                                                   (0)
                                                                                              MN
                        OR                                                                    (3)                                                            NY                     MA (10)
                        (5)                                                SD                                 WI                                            (34)
                                      ID                                                                                   MI                                                       RI (1)
                                                                           (3)                                (5)
                                      (0)            WY                                                                   (20)
                                                                                                                                                      PA                        CT (7)
                                                     (0)                                        IA                                                   (36)                 NJ (12)
                                                                            NE                  (6)                                 OH                                   DE (3)
                                NV                                          (3)                                  IL       IN        (35)
                                (2)                                                                             (17)                         WV                             MD (13)
                                                                                                                          (7)                         VA
                                             UT                                                                                              (2)
                                                           CO                                                                                        (17)
                                             (1)                                  KS                  MO                          KY                                       DC (1)
                      CA                                   (9)
                                                                                  (3)                 (8)                         (8)
                     (34)                                                                                                                                NC
                                                                                                                           TN                            (14)
                                                                                                                           (9)
                                                                                        OK                                                         SC
                                                                                        (7)            AR                                          (7)
                                       AZ                NM                                            (2)
                                       (8)               (1)                                                                AL             GA
                                                                                                                    MS      (9)            (14)
                                                                                                                    (6)
                                                                                                        LA
                                                                                  TX                    (6)
                                                                                 (13)
                                                                                                                                                      FL
                        AK                                                                                                                           (31)
                        (0)



                                                                 HI (0)




                                                                                                                                 January 2007
Data on file, Duke Clinical Research Institute.
Quality and Outcomes
      Invasive Procedures 2006
(Among Patients Without Contraindications to Cath



                                      Median Times
                                      • Cath - 22 hrs
                                      • PCI - 21 hrs
                                      • CABG - 69 hrs
                Management Strategies: 2007
             Early Invasive versus Selectively Invasive


►   Early Invasive: Diagnostic angiography with intent
    to perform revascularization
      Cath anticipated within 4-24 hours

      Follows a foundation of risk-directed medical
       therapy
►   Selectively Invasive (or Early Conservative):
    Invasive evaluation only if optimal medical
    management fails
►   Note: From the ED perspective, both strategies
    involve risk-directed, evidence-based medical
    therapy
                        What Is ―Risk-Directed‖
                        Medical Management?


             ►   ASA
             ►   Antithrombin therapy
                    I-A: Enoxaparin or UFH
                    I-B: Bivalirudin or
                     fondaparinux
             ►   Antiplatelet therapy
                    Oral anti-activation therapy
                    Parenteral anti-aggregation
                     therapy
As number of therapies increases, bleeding risk generally increases
                      The Upstream Antithrombin Challenge:
                             Collaboration Across Many Choices
             Elderly: ???   Age                 Renal function
                                                          Normal: Enox, Bival, Fonda, UFH
                                                          CKD: Bival, UFH

 Bleeding Risk                                                          Cost
 Low: Enox, UFH, Bival
 Mod: Bival, Fonda, UFH                                              Enox, UFH
 High: Bival, Fonda, UFH                                             Fonda? Bival?


                                                                   Ease of use
Ischemic Risk
                                                                    Enox, Bival, Fonda
Low: Enox, Bival, UFH
Mod: Enox, Bival, UFH
High: Enox, Fonda, Bival?


           PCI vs CABG vs Med Rx                  Time to Cath
                  PCI: Enox, Bival, UFH
                  CABG: UFH                       Rapid: Bival, UFH
                  Med Rx: Enox, Fonda, Bival?     Early: Enox, UFH, Bival?
                                                  Delayed: Enox
                                                                  Courtesy Dr. Sunil Rao, DCRI
 Recent ACS Trials — Forging A New
 Paradigm for Upstream Management

              ISCHEMIA: The traditional, primary
              concern of the emergency physician
ISCHEMIA




           BLEEDING: Newer, important
           concern for the cardiologist — A novel
           issue for the emergency physician


             BLEEDING
              Possible Relationship Between
                 Bleeding and Mortality
                   Major Bleeding



Hypotension          Cessation of                       Transfusion
                    ASA/Clopidogrel




 Ischemia          Stent Thrombosis                    Inflammation




                       Mortality

                                   Bhatt DL et al. In Braunwald: Harrison’s Online 2005.
 Recent ACS Trials — Forging A New
 Paradigm for Upstream Management

ISCHEMIA




           BLEEDING
      Invasive Procedures 2006
(Among Patients Without Contraindications to Cath



                                      Median Times
                                      • Cath - 22 hrs
                                      • PCI - 21 hrs
                                      • CABG - 69 hrs
                Management Strategies: 2007
             Early Invasive versus Selectively Invasive


►   Early Invasive: Diagnostic angiography with intent
    to perform revascularization
      Cath anticipated within 4-24 hours

      Follows a foundation of risk-directed medical
       therapy
►   Selectively Invasive (or Early Conservative):
    Invasive evaluation only if optimal medical
    management fails
►   Note: From the ED perspective, both strategies
    involve risk-directed, evidence-based medical
    therapy
               Case Studies in Upstream Management
                  How Many Ways Can We Cut the Cake?

►   Consider Case Scenario 1:
       55 year-old man with chest pain syndrome for 4
        hours
       Smoker, diabetic, normal renal function
       Troponin not elevated; nonspecific ST-T wave
        changes
       Unless he deteriorates, not likely to go to cath before
        tomorrow
►   Optimal Upstream Therapy in Emergency Department:
     Enoxaparin or UFH

     Strongly consider clopidogrel

     GPI if troponin ↑ overnight
            Case Studies in Upstream Management
              How Many Ways Can We Cut the Cake?



►   Consider Case Scenario 2:
     55 year-old man with chest pain syndrome for 4
      hours
     Smoker, diabetic, normal renal function

     Troponin not elevated; Non-specific ST-T wave
      changes
     Going to cath later today

►   Optimal Upstream Therapy in Emergency Department:
     Bivalirudin or UFH

     Stronger support for clopidogrel
              Case Studies in Upstream Management
                How Many Ways Can We Cut the Cake?


►   Consider Case Scenario 3:
►   80 year-old woman with chest pain syndrome for 4
    hours
      Smoker, diabetic, Cr Cl 40 ml/min

      Troponin elevated; ST-T Wave changes

      Going to cath later today

►   Optimal Upstream Therapy in Emergency Department:
     Bivalirudin

     Consider clopidogrel, but CABG risk may be higher
      here
           Case Studies in Upstream Management
              How Many Ways Can We Cut the Cake?


►   Consider Case Scenario 4:
     80 year-old woman with chest pain syndrome for 4
      hours
     Smoker, diabetic, Cr Cl 40 ml/min

     Troponin elevated, NSSTTΔs

     No catheterization lab in hospital; transfer time
      uncertain
►   Optimal Upstream Therapy:
     Enoxaparin or fondaparinux

     Strongly consider clopidogrel

     Consider renal-adjusted small-molecule GPI
       Recent ACS Trials — Forging A New
       Paradigm for Upstream Management

ISCHEMIA




               BLEEDING
                   Optimal Upstream Management
                         Ischemic Risk Assessment

►   Basis for Assessment:
       ―Pain story‖
       Background ASCVD risk
       ECG
       Troponin in pertinent time frame
       Predictive score
►   Options:
     UFH and enoxaparin established

     Bivalirudin and fondaparinux: New options that are
      non-inferior
     Antiplatelet therapy increasingly more important as
      ischemic risk increases
       Recent ACS Trials — Forging A New
       Paradigm for Upstream Management

ISCHEMIA




               BLEEDING
                   Optimal Upstream Management
                        Bleeding Risk Assessment

►   Basis for Assessment:
       Female > male
       Old > young
       CKD > normal renal function
       Anemic > normal H/H
       Diabetic > nondiabetic
►   Options:
     Bivalirudin and fondaparinux associated with less
      bleeding than UFH and enoxaparin
     Clopidogrel not reversible

     GPIs increase bleeding risk but with renal-adjusted
      doses seem to have reasonable safety margin
           A New Paradigm in Upstream
                  Management

ISCHEMIA




                BLEEDING
                     Optimal Upstream Management
                              Time to Catheterization

►   Basis for Assessment:
       Time to catheterization is frequently an unknown variable in the
        ED for UA/NSTEMI patients: May have impact on initial
        antithrombin selection
       Improved collaboration among CV specialists and ED physicians—
        and perhaps, development of EDICT for ACS therapeutic teams—
        would lead to more consistent management of ACS and
        predictability of time to catheterization
►   Options:
       With shorter times to catheterization, increasing support for
        bivalirudin
       With longer times to catheterization or medical management,
        increasing support for enoxaparin and UFH
       Role of fondaparinux in patients going to cath may be problematic
        and not adequately tested
       Note Dr. Gibson’s ―switch‖ data re: bivalirudin
            Optimal Management of NSTE ACS:
           ED to Cardiology — A Functional Model


► Chest Pain or ACS Committee


► Meets quarterly or PRN
     PRN means after . . .
       • Pertinent, “practice-changing” new study
         published
       • ACC / AHA / TCT meetings
       • M & M or sentinel event
       • New guidelines published
          Optimal Management of NSTE ACS
         ED to Cardiology — A Functional Model

► Chest Pain or ACS Committee comprised of:
   Emergency physicians

   Interventional cardiologists

   Medical cardiologists

   Hospitalists

   CT surgeons

   ED nursing

   Cath lab nursing

   CCU nursing

   Lab

   Imaging
               Optimal Management of NSTE ACS
              ED to Cardiology — A Functional Model


►   Chest Pain or ACS Committee discusses:
        Protocols and standing orders
        Practice variations versus evidence
        Time to catheterization predictability
        Reduction of medical errors in ACS care
        DTB times
        QI issues (CRUSADE / NRMI / ACTION)
        Transfers in, transfers out
        New data: How should it impact our protocols?
             Optimal Management of NSTE ACS
        ED to Cardiology — Summary and Game Plan

►   ED physicians should be using optimal, evidence-
    based, guideline-consistent medical therapy for NSTE
    ACS
►   ED physicians must work with their colleagues in
    cardiology to develop pathways and approaches
    (EDICT for ACS) for proper use of antithrombotic and
    antiplatelet therapy at all levels
►   ED physicians should facilitate early invasive
    management of ACS whenever feasible and
    appropriate
►   ED physicians should address issues related to
    bleeding risk as well as ischemic risk.
►   A seamless transition of care is most likely to result in
    good outcomes.
                    The Mandate to Cooperate
                         and Collaborate

   ED                  IC                  T
Emergency     +   Interventional   +   Therapeutic   for   ACS
Department          Cardiology           Teams




                   UPSTREAM ACS CARE
             Collaborations, Models, and Protocols
                   The Mandate to Cooperate
                        and Collaborate

   ED                 IC                  T
Emergency    +   Interventional   +   Therapeutic   for   ACS
Department         Cardiology           Teams




               UPSTREAM ACS CARE
         Collaborations, Models, and Protocols
                  HORIZONS AMI


  A Prospective, Randomized Comparison of
   Bivalirudin vs. Heparin Plus Glycoprotein
IIb/IIIa Inhibitors During Primary Angioplasty in
            Acute Myocardial Infarction
              – 30 Day Results –

             Gregg W. Stone MD
    For the HORIZONS AMI Investigators
                 TCT 2007
                                     HORIZONS AMI
              Harmonizing Outcomes with Revascularization and Stents in AMI


      ≥3400* pts with STEMI with symptom onset ≤12 hours
                        Aspirin, thienopyridine
                                                   R
                                                  1:1

     UFH + GP IIb/IIIa inhibitor                        Bivalirudin monotherapy
     (abciximab or eptifibatide)                        (± provisional GP IIb/IIIa)

Emergent angiography, followed by triage to…

                       CABG – Primary PCI – Medical Rx
                             Pharmacology Arm
                             Primary Endpoints*
                                    30 Day
                        Intention to Treat Population
* All stent randomization results are still blinded
                        Inclusion Criteria

►   STEMI >20 mins and <12 hours in duration
       ST-segment elevation of 1 mm in 2 contiguous leads;
        or
       Presumably new left bundle branch block; or
       True posterior MI with ST depression of 1 mm in 2
        contiguous anterior leads
       Patients with cardiogenic shock, left main disease, etc.,
        were not excluded
►   Age ≥18 years
►   Written, informed consent
                  Principal Exclusion Criteria
►   Contraindication to any of the study medications
►   Prior administration of thrombolytic therapy, bivalirudin, GP
    IIb/IIIa inhibitors, LMWH or fondaparinux for the present
    admission (prior UFH allowed)
►   Current use of coumadin
►   History of bleeding diathesis or known coagulopathy (including
    HIT), or will refuse blood transfusions
►   History of intracerebral mass, aneurysm, AVM, or hemorrhagic
    stroke; stroke or TIA within 6 months or any permanent
    neurologic deficit; GI or GU bleed within 2 months, or major
    surgery within 6 weeks; recent or known platelet count
    <100,000 cells/mm3 or hgb <10 g/dL
►   Planned elective surgical procedure that would necessitate
    interruption of thienopyridines during the first 6 months post
    enrollment
                          Study Medications (i)
 ►   Unfractionated heparin
      60 U/kg IV*; subsequent boluses titrated by nomogram to
        ACT 200-250 secs; terminated at procedure end unless
        prolonged antithrombin needed
 ►   Bivalirudin
      Bolus 0.75 mg/kg IV**, infusion 1.75 mg/kg/h, not titrated to
        ACT; terminated at procedure end unless prolonged
        antithrombin needed (0.25 mg/kg/hr infusion)
 ►   Glycoprotein IIb/IIIa inhibitors
      Routine use in UFH arm; recommended only for giant
        thrombus or refractory no reflow in bivalirudin arm
      Abciximab or double bolus eptifibatide as per investigator
        discretion – dosing per FDA label, renal adjusted; continued
        for 12 (abcx) or 12-18 (eptif)
* If pre randomization UFH administered, ACT is checked first
** If pre randomization UFH administered, started 30’ after last bolus
                           Study Medications (ii)
►   Aspirin
       324 mg chewed non enteric coated or 500 mg IV in the ER, followed
        by 300-325 mg/day in-hospital and 75-81 mg/day as out patient
        indefinitely
►   Thienopyridines
       Clopidogrel 300 mg or 600 mg loading dose (per investigator
        discretion) in the ER followed by 75 mg PO QD for at least 6 months
        (1 year or longer recommended)
        • Ticlopidine load + daily dose permissible if clopiodgrel is unavailable or
          patient is allergic
►   Other
       Beta blockers: IV pre procedure followed by PO QD in the absence
        of contraindications; ACE inhibitors for HTN, CHF or LVEF <40%;
        Statin if LDL >100 mg/dl
2 Primary Endpoints (at 30 Days)

1) Net Adverse Clinical Events
                   and
2) Major Bleeding (non CABG)
             • Intracranial bleeding
              • intraocular bleeding
           • Retroperitoneal bleeding
         • Access site bleed requiring
                intervention/surgery
               • Hematoma ≥5 cm
     • Hgb ≥3g/dL with an overt source
       • Hgb ≥4g/dL w/o overt source
           • Reoperation for bleeding
          • Blood product transfusion
2 Primary Endpoints (at 30 Days)

1) Net Adverse Clinical Events
                  =
2) Major Bleeding (non CABG)
                 or
         Major adverse
     cardiovascular events
      (major secondary endpoint)
           • All cause death
             • Reinfarction
            • Ischemic TVR
                 • Stroke
                Baseline Characteristics

                    UFH + GP IIb/IIIa          Bivalirudin
                       (N=1802)                (N=1800)
 Age (years)        60.7 [52.9, 70.1]       59.8 [51.9, 69.5]
 Male                    76.1%                   77.1%
 Diabetes                17.3%                   15.6%
 Hypertension            55.2%          *        51.8%
 Hyperlipidemia          42.7%                   43.4%
 Current smoking         45.0%                   47.2%
 Prior MI                11.4%                   10.4%
 Prior PCI               11.0%                   10.5%
 Prior CABG               2.6%                   3.3%
*P=0.04
                                      Primary Outcome Measures (ITT)
                         Heparin + GPIIb/IIIa inhibitor (N=1802)       Bivalirudin monotherapy (N=1800)
                                  Diff = -2.9% [-4.9, -0.8]   Diff = -3.3% [-5.0, -1.6]   Diff = 0.0% [-1.6, 1.5]
                         20       RR = 0.76 [0.63, 0.92]      RR = 0.60 [0.46, 0.77]      RR = 0.99 [0.76, 1.30]
                                      PNI ≤ 0.0001               PNI ≤ 0.0001                 Psup = 1.00
30 day event rates (%)




                                      Psup = 0.006               Psup ≤ 0.0001
                         15
                                   12.1

                         10                   9.2
                                                                8.3

                                                                          4.9               5.5      5.4
                          5

                                       1 endpoint                 1 endpoint

                          0
                                Net adverse clinical          Major bleeding*                 MACE**
                                      events
            *Not related to CABG
            **MACE = All cause death, reinfarction, ischemic TVR or stroke
                                                                30 Day Net Adverse Clinical Events
                                                                          Heparin + GPIIb/IIIa inhibitor (n=1802)

                             Net adverse clinical events (%)*
                                                                          Bivalirudin monotherapy (n=1800)
                                                                                                                            12.2%
          Primary Endpoint



                                                                                                                              9.3%

                                                                                                         HR [95%CI] =
                                                                                                        0.75 [0.62, 0.92]
                                                                                                             P=0.006


                                                                                       Time in Days
 Number at risk
 Bivalirudin                                                    1800   1660     1633       1626       1620     1607    1544
 Heparin + GPIIb/IIIa                                           1802   1635     1591       1578       1569     1552    1482



*MACE or major bleeding (non CABG)
                            30 Day Major Bleeding (non-CABG)
                                     Heparin + GPIIb/IIIa inhibitor (n=1802)
                                     Bivalirudin monotherapy (n=1800)
       Major Bleeding (%)
       Primary Endpoint


                                                                                       8.4%


                                                                                       5.0%
                                                                    HR [95%CI] =
                                                                   0.59 [0.45, 0.76]
                                                                     P<0.0001

                                                   Time in Days
Number at risk
Bivalirudin                 1800   1697     1675       1668       1664    1653     1590
Heparin + GPIIb/IIIa        1802   1651     1617       1606       1598    1581     1511
                      30 Day Bleeding Endpoints
                                        UFH + GP IIb/IIIa Bivalirudin
                                                                        P Value
                                           (N=1802)       (N=1800)
Protocol Major, non CABG*                    8.3%            4.9%       <0.0001
Protocol Major, All                          10.8%           6.8%       <0.0001
Protocol Minor                               15.4%           8.6%       <0.0001
Blood transfusion                            3.5%            2.1%        0.01
TIMI Major                                   5.0%            3.1%        0.003
TIMI Minor                                   4.6%            2.8%        0.008
TIMI Major or Minor                          9.6%            5.9%       <0.0001
GUSTO LT** or Severe                         0.6%            0.4%        0.65
GUSTO Moderate                               5.0%            3.1%        0.003
GUSTO LT or Sev or Mod                       5.6%            3.5%        0.003
*Primary endpoint; **Life threatening
                             30 Day Major Adverse CV Events
                                                       Heparin + GPIIb/IIIa inhibitor (n=1802)

               Major adverse CV events (%)*
                                                       Bivalirudin monotherapy (n=1800)


                                                                                                          5.5%
                                                                                                          5.5%


                                                                                       HR [95%CI] =
                                                                                      1.00 [0.75, 1.32]
                                                                                           P=0.98



                                                                     Time in Days
Number at risk
Bivalirudin                                   1800   1716     1701       1695       1689     1673     1608
Heparin + GPIIb/IIIa                          1802   1744     1712       1699       1688     1668     1590


*MACE = All cause death, reinfarction, ischemic TVR or stroke
                   30 Day MACE Components*
                          UFH + GP IIb/IIIa   Bivalirudin
                                                            P Value
                             (N=1802)         (N=1800)
Death                          3.1%             2.1%        0.058
  - Cardiac                    2.9%             1.8%        0.035
  - Non cardiac                0.2%             0.3%         0.75
Reinfarction                   1.8%             1.8%         0.90
  - Q-wave                     1.2%             1.4%         0.66
  - Non Q-wave                 0.7%             0.4%         0.50
Ischemic TVR                   1.9%             2.6%         0.18
  - Ischemic TLR               1.8%             2.5%         0.14
  - Ischemic remote TVR        0.3%             0.3%          1.0
Stroke                         0.6%             0.7%         0.69
*CEC adjudicated
                                      30 Day Mortality:
                                   Cardiac and Non Cardiac
                                          Heparin + GPIIb/IIIa inhibitor (n=1802)
                                          Bivalirudin monotherapy (n=1800)


                                                        HR [95%CI] =
                                                       0.62 [0.40, 0.96]
                Death (%)


                                                          P=0.029                          2.9%
                                                                           Cardiac
                                                                                       1.8%


                                                                       Non cardiac     0.3%
                                                                                       0.2%

                                                     Time in Days
Number at risk
Bivalirudin                 1800   1758       1751       1746       1742   1729     1666
Heparin + GPIIb/IIIa        1802   1764       1748       1736       1728   1707     1630
               Primary Management Strategy*
   UFH + GP IIb/IIIa Inhibitor                 Bivalirudin Monotherapy
          N=1802                                        N=1800

         Primary PCI           Deferred PCI           CABG       Medical Rx




*Primary ITT analysis includes all pts regardless of treatment
                                                       Primary PCI Cohort
                                                                (N=3,340; 92.7%)

                       Heparin + GPIIb/IIIa inhibitors (N=1662)            Bivalirudin monotherapy (N=1678)

                           20   Diff = -3.0% [-5.2, -2.9]   Diff = -3.5% [-5.2, -1.7]   Diff = -0.1% [-1.6, 1.5]
                                RR = 0.75 [0.62, 0.92]      RR = 0.59 [0.46, 0.77]      RR = 0.99 [0.75, 1.32]
                                    PNI ≤ 0.0001               PNI ≤ 0.0001                  Psup = 1.00
  30 day event rates (%)




                                    Psup = 0.005               Psup ≤ 0.0001
                           15
                                     12.2

                           10                   9.2               8.5

                                                                            5.1               5.4      5.4
                           5


                           0
                                 Net adverse clinical           Major bleeding*                 MACE**
                                       events
*Not related to CABG
**MACE = All cause death, reinfarction, ischemic TVR or stroke
              30 Day Net Clinical Events: PCI Cohort

              Net Adverse Clinical Events (%)*
                                                    Heparin + GPIIb/IIIa inhibitor (n=1662)
                                                    Bivalirudin monotherapy (n=1678)
                                                                                                  12.3%

                                                                                                       9.2%

                                                                             HR [95%CI] =
                                                                            0.74 [0.60, 0.92]
                                                                                 P=0.005



                                                                 Time in Days
Number at risk
Bivalirudin          1678                        1554     1528       1521       1516   1505     1448
Heparin + GPIIb/IIIa 1662                        1510     1467       1456       1448   1436     1372


*MACE or major bleeding (non CABG)
                                               30 Day Major Bleeding: PCI Cohort
                                                        Heparin + GPIIb/IIIa inhibitor (n=1662)

               Major Bleeding (Non-CABG) (%)
                                                        Bivalirudin monotherapy (n=1678)


                                                                                                          8.6%


                                                                                                          5.1%
                                                                                       HR [95%CI] =
                                                                                      0.58 [0.44, 0.76]
                                                                                           P<0.0001


Number at risk
                                                                     Time in Days
Bivalirudin                                    1678   1590    1568       1561       1558      1548    1490
Heparin + GPIIb/IIIa                           1662   1525    1492       1482       1475      1463    1399
                                             30 Day Major Adverse CV Events:
                                                       PCI Cohort
                                                 Heparin + GPIIb/IIIa inhibitor (n=1662)

              Major Adverse CV Events (%)*
                                                 Bivalirudin monotherapy (n=1678)


                                                                                                     5.5%
                                                                                                     5.4%

                                                                               HR [95%CI] =
                                                                              1.00 [0.74, 1.33]
                                                                                 P=0.98


                                                               Time in Days
Number at risk
Bivalirudin          1678                      1606     1592       1585       1581     1567       1509
Heparin + GPIIb/IIIa 1662                      1613     1581       1570       1561     1546       1474


      *MACE = All cause death, reinfarction, ischemic TVR or stroke
                            30 Day Mortality: PCI Cohort
                                     Heparin + GPIIb/IIIa inhibitor (n=1662)
                        5            Bivalirudin monotherapy (n=1678)

                                               HR [95%CI] =
                        4
                                              0.63 [0.40, 0.99]
            Death (%)


                                                  P=0.049                            2.8%
                        3
                                                                          Cardiac
                        2                                                            1.8%

                        1
                                                                      Non cardiac        0.2%
                        0                                                                0.1%
                            0    5          10        15         20       25        30
                                                  Time in days
Number at risk
Bivalirudin          1678       1647       1640       1635       1632    1620   1563
Heparin + GPIIb/IIIa 1662       1631       1615       1604       1598    1583   1512
               30 Day Stent Thrombosis (N=3,124)

                                          UFH +
                                                            Bivalirudin     P
                                         GP IIb/IIIa
                                                            (N=1571)      Value
                                         (N=1553)

    ARC definite or probable*                1.9%              2.5%        0.33

      - definite                             1.4%              2.2%        0.11

      - probable                             0.5%              0.3%        0.26

      - acute )≤24 hrs)                      0.3%              1.3%       0.0009

      - subacute (>24 hrs – 30d)             1.7%              1.2%        0.30

*Protocol definition of stent thrombosis, CEC adjudicated
                            Conclusions
► In this large scale, prospective, randomized trial of
  pts with STEMI undergoing a primary PCI
  management strategy, compared to UFH plus the
  routine use of GP IIb/IIIa inhibitors, bivalirudin
  monotherapy with GP IIb/IIIa inhibitors reserved for
  suboptimal PCI outcomes resulted in:
      A significant 24% reduction in the 30 day primary
       endpoint of net adverse clinical events

      A significant 40% reduction in the 30 day primary
       endpoint of major bleeding
                Optimal Management of ACS
        ED to Cardiology — Summary and Game Plan

►   Risk Stratification is an essential function of the ED
    evaluation.
►   ―Treatment stratification‖ must be coupled to risk
    stratification.
►   Risk stratification must be considered for bleeding as
    well as ischemia.
►   Time issues also direct therapeutic choices, but
    management of these issues must be multidisciplinary.
►   We now have evidence across the ACS spectrum that
    bivalirudin is associated with superior bleeding
    outcomes.
►   A seamless transition of care is most likely to result in
    good outcomes.
       Getting in the ACS Stream of Things


  Where Metal Meets Thrombus and
       Vascular Endothelium
A Case Study Analysis of Upstream Interventions




          Chairman and Distinguished Faculty
         ACS Case Presentation #1
►   77 year old female presents to ED with 2 weeks of
    progressive angina, one episode lasting 90 minutes
      History of Type 2 DM, HTN, cigarette smoking

      Weight 65 kg

►   ECG non-specific, POS TnI 0.79 (ULN 0.5), nl CKMB,
    CrCL 40 ml/min, Hgb 9.7 g/dl
►   Given ASA, 300 mg clopidogrel, 5 mg IV metoprolol, IV
    NTG
►   Continued chest pain
      Anticoagulation options in the ED?

      Risk stratification strategy?

      Which upstream strategy makes most sense?

      Collaboration with cardiology colleagues?
                 ACS Case Presentation #1

►   Decision made to pursue rapid invasive risk
    stratification
       High-risk features
        • Elevated troponin
        • Ongoing chest pain despite
          medical therapy

►   Antithrombin therapy choices
       Risk for bleeding
        • Age, Female sex, renal
          insufficiency, anemia
       Bivalirudin bolus and drip initiated
►   Angiography
               ACS Case Presentation #2

►   A 76 year-old white male with h/o stent to LAD 1 year
    ago
►   Presents with multiple episodes of recurrent chest
    pain including rest pain over 2 days
►   Pain similar to time of PCI in past
►   Symptoms relieved in ED with sl NTG
►   PMH: IDDM, HTN, CHOL elevation
►   PE: benign (weight 84 kg).
►   Labs: Hgb 10.7, Cr 1.9, CK 173/2, Tr <0.03.
►   ECG (next slide)
             Case #2: ECG




New anterior and lateral ST / T changes.
            ACS Case Presentation #2

Based on your clinical assessment, this patient’s risk of
       short-term (30-Day) ischemic events is:


      A.   Low
      B.   Moderate
      C.   High
      D.   Very high
              ACS Case Presentation #2

Which of this patient’s baseline factors do you consider most
   important for determining this patient’s ischemic risk?



         A. Advanced age
         B. Anginal pattern
         C. ECG findings
         D. Biomarkers




     *
                 ACS Case Presentation #2

Based on your clinical assessment, this patient’s risk of incurring
  a short-term (30-Day) hemorrhagic event related to PCI is:


          A. Low
          B. Moderate
          C. High
          D. Very high
               ACS Case Presentation #2

Which of this patient’s baseline factors do you consider most
       important for determining hemorrhagic risk?


         A. Advanced age
         B. Hypertension
         C. Impaired creatinine clearance
         D. Anemia




     *
              ACS Case Presentation #2

In ACS patients, do you alter your choice of anticoagulant/
antithrombotic therapy based upon an assessment of the
  individual patient’s risk of hemorrhagic complications?




        A. Yes
        B. No




    *
              ACS Case Presentation #2

     Among those of you who would alter or customize
 antithrombotic therapy based on an ACS patient’s risk for
  hemorrhage in the setting of PCI, which of the following
baseline characteristics would you consider most important
    in supporting the use of a ―hemorrhage-minimizing‖
                   anithrombotic regimen:


        A. Elderly and female
        B. Renal insufficiency and positive biomarkers
        C. Anemia and high risk ischemic features


    *
               ACS Case Presentation #2

What would you likely use for anticoagulation in this patient,
 prior to catheterization, if you anticipated catheterization
              would occur in 4 hours or less?

         A. Unfractionated heparin alone
         B. Enoxaparin alone
         C. Bivalirudin alone
         D. A heparin with a GP IIb/IIIa inhibitor
         E. Fondaparinux


     *
               ACS Case Presentation #2

What would your choice of upstream anticoagulation therapy
 be, if you anticipated cardiac catheterization the same day
                       (within 12 hours)?

         A. Unfractionated heparin alone
         B. Enoxaparin alone
         C. Bivalirudin alone
         D. A heparin with a GP IIb/IIIa inhibitor
         E. Fondaparinux


     *
               ACS Case Presentation #2

What would your choice of upstream anticoagulation therapy
 be, if you anticipated cardiac catheterization the next day
                      (within 24 hours)?

         A. Unfractionated heparin alone
         B. Enoxaparin alone
         C. Bivalirudin alone
         D. A heparin with a GP IIb/IIIa inhibitor
         E. Fondaparinux


     *
             ACS Case Presentation #2

At this point, your anticoagulation regimen for PCI in this
                     patient would be?


       A. Additional heparin
       B. Switch to enoxaparin
       C. Switch to bivalirudin
       D. Additional heparin plus GP IIb/IIIa inhibitor




   *

				
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