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The Science and Medicine of STEMI and High

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The Science and Medicine of STEMI and High Powered By Docstoc
					                       A Year 2008 Update

              The Science and Medicine
             of Acute Coronary Syndrome
The Emergence of Consistent and Unified Management
          Strategies for STEMI and NSTEMI


                     Program Moderator
                   Sunil V. Rao, MD, FACC
Host, Duke University Medical Center Cardiac Catheterization Conference
                    Assistant Professor of Medicine
                    Duke University Medical Center
            Director, Cardiac Catheterization Laboratories
                      Durham VA 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 and related ischemic conditions, and their implications for invasive
    vascular management.

  ► Learn how recently issued AHA/ACC Guidelines for 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, STEMI, 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 Faculty
Program Moderator                               Harold L. Dauerman, MD
Sunil V. Rao, MD, FACC                          Director, Cardiovascular Catheterization
Host, Duke University Medical Center Cardiac    Laboratories | Professor of Medicine |
Catheterization Conference                      University of Vermont/Fletcher Allen Health
Assistant Professor of Medicine | Duke          Care | Burlington, VT
University Medical Center | Director, Cardiac
Catheterization Laboratories | Durham VA        Gregg W. Stone, MD
Medical Center | Durham, NC                     Professor of Medicine | Director of
                                                Cardiovascular Research and Education |
Distinguished Faculty Presenters                Center for Interventional Vascular Therapy |
Deepak L. Bhatt, MD, FACC, FSCAI,               Columbia University Medical Center |
FESC, FAHA                                      Chairman, The Cardiovascular Research
Associate Director, Cardiovascular              Foundation | New York, NY
Coordinating Center | Staff, Cardiac,
Peripheral, and Carotid Intervention |          Ron Waksman, MD, FACC
Associate Professor of Medicine | Department    Associate Director, Division of Cardiology |
of Cardiovascular Medicine | Cleveland Clinic   Washington Hospital Center | Director of
                                                Experimental Angioplasty and Vascular
                                                Brachytherapy | Cardiovascular Research
                                                Institute | Washington Hospital Center |
                                                Clinical Professor of Medicine |
                                                Georgetown University | Washington, DC
                          Faculty Disclosures
Sunil V. Rao, MD, FACC
Grant/Research Support: Cordis
Consultant: Sanofi-Aventis, The Medicines Company
Speaker’s Bureau: Sanofi-Aventis, The Medicines Company, Cordis

Deepak L. Bhatt, MD, FACC, FSCAI, FESC, FAHA
Grant/Research Support: The Medicines Co., BMS, Sanofi-Aventis, Eisai, Ethicon
Consultant: Astra Zeneca, BMS, Cardax, Centocor, Daiichi-Sankyo, Eisai, Eli Lilly, GSK,
Millennium, Otsuka, Paringenix, PDL, Sanofi-Aventis, Schering Plough, The Medicines Co.,
tns Healthcare
Speaker’s Bureau: BMS, Sanofi-Aventis, The Medicines Co

Harold L. Dauerman, MD
Consultant: The Medicines Company, Abbott Vascular
Research Grants: Abbott Vascular and Boston Scientific
Fellowship Support: Boston Scientific, Cordis/JNJ and Medtronic

Gregg W. Stone, MD
Grant/Research Support: The Medicines Co. and Boston Scientific

Ron Waksman, MD, FACC
Consultant and speaker or research grant support: Medtronic, Boston Scientific, Biotronik,
GSK, Sanofi, BMS
       The Science and Medicine of Acute Coronary Syndrome


    Challenges and Uncertainties in
Managing Acute Coronary Syndrome (ACS)

  Connecting Evidence Across All the Streams:
       How and Why Bleeding Matters

                       Program Moderator
                     Sunil V. Rao, MD, FACC
    Host, Duke University Medical Center Cardiac Catheterization Conference
                        Assistant Professor of Medicine
                        Duke University Medical Center
                Director, Cardiac Catheterization Laboratories
                          Durham VA Medical Center
                           Durham, North Carolina
    Questions We Will Illuminate and Debate

► Is there a consistent approach to care of STEMI and NSTEMI
  patients that can be use across the ACS risk spectrum? Across
  institutional needs in patients undergoing PCI?

► How should recent ACC/AHA 2007 NSTEMI Guidelines impact
  our choices for upstream antithrombotic therapy?

► What is the relationship between bleeding avoidance and
  mortality in ACS patents? Should bleeding avoidance be
  primary driver for selection of antithrombotic therapy? In all
  patients? In some?

► How should recent STEMI trials impact our approach
  to upstream care for STEMI? For NSTEMI?
   Questions We Will Illuminate and Debate
► What do know about changing anticoagulant
  therapy “midstream?” Problematic? Safe? Agent-
  specific?

► What is the ideal “alignment” between oral antiplatelet
  therapy and anticoagulation in STEMI and NSTEMI?

► What does a “consistent and unified” approach to
  upstream care look like in an institutional setting? A
  university-based case study.

► Doing the right thing: What do the trials tell us?
                                Acute Coronary Syndromes
                                  Clinical Spectrum and Presentation

 Presentation                            Ischemic Discomfort
                                               at Rest



Emergency               No ST-segment                     ST-segment
Department                Elevation                        Elevation

                                                                       +
                                                      +     +
 In-hospital
 6-24hrs                             NSTEMI
                       Unstable            Non-Q-wave MI          Q-wave MI
                        Angina
                                                 ( : positive cardiac biomarker)
Adapted from AHA/ACC NSTEMI Guidelines
                   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.
                      Algorithm for Patients With UA/NSTEMI Managed by
                     an Initial Invasive Strategy: ACC/AHA 2007 Guidelines

                              Diagnosis of UA/NSTEMI is Likely or Definite


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

                                                                                           Initial
                                        Select Management Strategy†                     Conservative
                                                                                          Strategy

                                            Invasive Strategy              B1
                            Initiate anticoagulant therapy (Class I, LOE: A):
                           Acceptable options*: enoxaparin or UFH (Class I,
                           LOE: A), bivalirudin or fondaparinux are preferable
                                            (Class I, LOE: B)




ACC/AHA 2007 Guidelines for the Management of UA/NSTEMI. August 6, 2007, Circulation.
                              Algorithm for Patients With UA/NSTEMI
                              Managed by an Initial Invasive Strategy

                                              Prior to Angiography            B2
                                   Initiate at least one (Class I, LOE: A) or
                                   Both (Class IIa, LOE: B) of the following:

                                                   Clopidogrel* ‡
                                               IV GP IIb/IIIa inhibitor* ‡

                             Factors favoring administration of both clopidogrel
                                      and GP IIb/IIIa inhibitor include:

                                              Delay to angiography
                                                High risk features
                                       Early recurrent ischemic discomfort


                                            Diagnostic Angiography


ACC/AHA 2007 Guidelines for the Management of UA/NSTEMI. August 6, 2007, Circulation.
        Considerations in the Modern Era of ACS/PCI


►   55-year-old male with 3        ►   86-year-old female with 3
    hours of chest pain                hours of chest pain
     ● Hx of HTN,  lipids              ● Hx of DM, HTN, 

     ● Marked ST-segment                  lipids
       depression leads II, III,        ● ECG non-specific (no
       aVL                                prior study for
     ● Elevated serum                     comparison)
       troponin T, CKMB 4 X             ● Elevated troponin,
       ULN                                normal CKMB
     ● Normal renal function            ● Est. GFR 45 ml/min
                                        Ischemia vs. Bleeding: NSTE ACS vs. STEMI
                                  3.5                        3.5          P=0.047
                                                                   3.1
                                   3                          3
                                                                                     Heparin +
30-Day Mortality (%)




                                  2.5
                                                P=NS         2.5
                                                                                     IIb/IIIa
                                                                              2.1
                                   2                          2
                                                       1.6                           Bivalirudin
                                         1.4
                                  1.5                        1.5

                                   1                          1

                                  0.5                        0.5

                                   0                          0




                                                                             41%
                                  10                          10
                                                                    8.6
                                                                                     Heparin +
                                   9                           9
                                                                                     IIb/IIIa
             Major Bleeding (%)




                                   8              47%          8
                                   7                           7
                                          5.7
                                   6                           6               5.1   Bivalirudin
                                   5                           5
                                   4                   3.0     4
                                   3                           3
                                   2                           2
                                   1                           1
                                   0                           0
                                          ACUITY                   HORIZONS AMI
Stone GW NEJM 2007
                    Is the Bleeding Issue Still Relevant in 2008?




Wiviott SD, et al. NEJM 2007 Nov 15;357(20):2001-15
                                             Is the Bleeding Issue Still Relevant in 2008?

                                        8
                                                                                                  6.9
                                        7
                                                                Clopidogrel
                                        6
       Primary Efficacy End Point (%)




                                        5
                                                                                                       5.6
                                        4

                                        3                                      Prasugrel     P=0.003

                                        2

                                        1

                                        0
                                            0 30   60 90 120 150 180 210 240 270 300 330 360 390 420 450

                                                              Days After Randomization

Wiviott SD, et al. NEJM 2007 Nov 15;357(20):2001-15
                                     Is the Bleeding Issue Still Relevant in 2008?


                                  Even in 2008, the balance between efficacy
                                           and safety is paramount
                                                                                        ↑ 35 Events
Key Safety End Point




                                                                                        Hazard ratio, 1.32;
                       4                                                                95% CI, 1/03-1.68;
                                                                     Prasugrel          P=0.03
                       3
                                                                                       2.4
                       2
                                                                                       1.8
                       1
                                                                         Clopidogrel
                       0

                           3 30    60 90 120 150 180 210 240 270 300 330 360 390 420 450


                                              Days After Randomization


Wiviott SD, et al. NEJM 2007 Nov 15;357(20):2001-15
                                 ISAR-REACT 3: Results

            Endpoint          Bivalirudin (%)   UFH (%)     p
               Primary                8.3         8.7      0.57

             Secondary                5.9         5.0      0.23

         Major bleeding*              3.1         4.6     0.008

         Minor bleeding*              6.8         9.9     0.0001

            Transfusion               1.3         1.8      0.15

             TIMI major               0.5         1.0      0.04

             TIMI minor               1.3         2.2      *p<0.0001
                                                           0.01

           * as per ISAR-REACT 3 definition


Kastrati A, et al. ACC 2008
ACS-related Bleeding—Relevant Questions


►   Who bleeds? Can we risk stratify?

►   Should bleeding risk affect upstream
    antithrombotic care? If so, how?

►   Is bleeding bad or a necessary evil?

►   Can blood transfusion “correct” risks associated
    with bleeding?

►   Does bleeding affect resource use?
                         Predictors of Major Bleeding in ACS



        ►   Older Age
                                                                  Independent
        ►   Female Gender                                         predictors of
        ►   Renal Failure                                         major bleeding
                                                                  in marker-
        ►   History of Bleeding                                   positive
        ►   Right Heart Catheterization                           acute coronary
                                                                  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.
     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
                               Bleeding and Outcomes in ACS
               Kaplan Meier Curves for 30-Day Death, Stratified by Bleed Severity
          N=26,452 ACS patients from GUSTO IIb, PARAGON A, PARAGON B, & PURSUIT
              1.00

              0.95

              0.90
                                                                                                     None
              0.85                                                                                   Mild
                                                                                                     Moderate
                                                                                                     Severe
              0.80

              0.75

              0.70
                     0           5         10         15          20          25          30
                                          Days to Death
                                                                       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
                                         30d Death                 30d Death/MI   6 mo. Death
              Severity
                  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.
                             Impact of MI and Major Bleeding (non-CABG) in
                              the First 30 Days on Risk of Death Over 1 Year

                                                                                 1 year
                                                                                Estimate       ACUITY
                                               Both MI and Major Bleed (N=94)    28.9%
                                       Major Bleed only (without MI) (N=551)     12.5%
                                       MI only (without Major Bleed) (N=611)         8.6%
                    30                      No MI or Major Bleed (N=12,557)          3.4%
                                                                                                     28.9%
                    25
    Mortality (%)




                    20

                    15
                                                                                                     12.5%
                    10
                                                                                                     8.6%
                     5
                                                                                                     3.4%
                     0
                         0   30   60    90    120 150     180 210 240 270        300 330 360   390
                                              Days from Randomization

Stone GW. TCT 2007
                      Impact of MI and Major Bleeding (non-CABG) in
                       the First 30 Days on Risk of Death Over 1 Year
   ACUITY TRIAL—Cox model adjusted for baseline predictors: Bleeding and MI as time updated covariates


                                  HR ± 95% CI                   HR (CI)        Deaths (n/%)   P-value
                   Day 0 – 2 after MI                        12.6 (7.8-20.4)      29 (37.6)   <0.0001
                   Day 3 – 7 after MI                         5.3 (2.7-10.4)      11 (14.3)   <0.0001

                  Day 8 – 35 after MI                          1.6 (0.8-3.1)      12 (15.6)    0.18
                    Day > 35 after MI                          1.2 (0.8-1.9)      25 (32.5)    0.34




         Day 0 – 2 after Major Bleed                           3.0 (1.6-5.6)      12 (12.9)   0.0009
         Day 3 – 7 after Major Bleed                           4.0 (2.1-7.5)      15 (16.1)   <0.0001
         Day 8 – 35 after Major Bleed                          4.5 (2.8-7.4)      25 (26.9)   <0.0001
           Day > 35 after Major Bleed                          2.2 (1.5-3.2)      41 (44.1)   <0.0001


                                    0.5   1   2   4   8 16



Stone, ACC 2007
     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
►   Worse bleeding associated with worse outcomes
►   This relationship is persistent after robust statistical
    adjustment for confounders
                                            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


        Adjusted for
        transfusion propensity                                     3.77 (3.13, 4.52

        Adjusted for
        baseline
        characteristics                                            3.54 (2.96, 4.23)

        Adjusted for baseline
        characteristics,
                                                                   3.94 (3.26, 4.75)
        bleeding propensity,
        transfusion propensity,
        and nadir HCT


                                            -4.0             1.0                           10.0
                     *Transfusion as a time-dependent covariate

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




                           Death




             Death or Re-MI




                                            1.0                    2.0
                   *Non-CABG patients only

Yang X, J Am Coll Cardiol 2005;46:1490–5.
                                      Transfusion, Ischemic Endpoints,
                                        and Mortality in ACUITY Trial
                                     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.
    Blood Transfusion — Conclusions


►   Blood transfusion is independently associated
    with death and recurrent MI
►   Transfusion does not correct the adverse
    impact bleeding and is not an “insurance
    policy” against adverse outcomes associated
    with bleeding
►   Blood transfusion is best avoided in ACS
    patients whenever possible
Bleeding in ACS—The Big Switch

►   What are the bleeding consequences of
    switching anticoagulation in midstream?
►   Are there switching strategies that mitigate
    against or reduce risk of bleeding in ACS
    patients? What are they?
►   Should routine switching be advocated as a
    strategy for bleeding minimization? In NSTE-
    ACS? In STEMI?
                                     In High-Risk Patient Subset, Switching to
                                    Bivalirudin Also Improves Bleeding Outcomes                                                     PCI Subgroup


  ►                     Ischemic suppression was maintained and major bleeding significantly reduced at 30 days
  ►                     Long-term efficacy in both groups was consistent at 1 year

                             Switch to bivalirudin* vs consistent heparin + GP IIb/IIIa outcomes†
                                                      Bivalirudin* (n=1,014)      UFH/enoxaparin + GP IIb/IIIa (n=974)
                        15                            switch arm                  consistent5arm
                                       P=.36                    P=.003                                      P=.97
                                                                                                            4




                                                                                       Adverse events (%)
   Adverse events (%)




                        10      9.3%                                                                            3.1%         3.1%
                                               8.1%                                                         3
                                                                      7.1%
                                                            45%
                                                                                                            2
                        5
                                                            3.9%
                                                                                                            1



                        0                                                                                   0
                             Composite ischemia         Non-CABG major bleeding                                        Mortality
                                                      30-day                                                           1-year
 *Bivalirudin monotherapy with GP IIb/IIIa reserved for severe breakthrough ischemia and procedural complications during PCI.
 †76% of ACUITY PCI patients had raised cardiac biomarkers and/or ST-segment deviation at baseline.



Data on file. The Medicines Company, Parsippany, NJ.
                                Bleeding and Resource Use
                                          Predictors of Total Costs
                                                                      Moderate/severe bleed
                                                                                  Per patient cost - $530
          14,000                                                      Transfusion - $2,080, P < 0.01
                                                         $12,409                  Per patient cost - $287
          12,000

          10,000

           8,000                                $7,188
      $
           6,000                                                               $5,255

           4,000     $3,370
                                       $2,164                       $2,488               $2,436
           2,000              $1,158                                                                $1,336

               0
                    Mod/Sev    UA       Cath     PCI      CABG     Pacemaker    IABP     ICU day    Non-ICU
                      Bld                                                                             day


                              N=1235 pts from GUSTO IIb                                 Model C-index=0.87
                                                                          Adjusted for patient characteristics
Rao SV, et. al. AHJ 2008.
                                         ACUITY: Hospital Index Costs

                                                                                         Hospital Index Costs
          $16,000
                                                          $14,925
                           $14,416
                                          $14,028                         $14,153
                                                                                         $13,844



                                                         p<0.001 for comparison
          $12,000                                                across
                                                             the five groups




             $8,000
                           Heparin +       Heparin +     Bivalirudin +   Bivalirudin +    Bivalirudin
                          Upstream GPI    Cath Lab GPI   Upstream GPI    Cath Lab GPI    Monotherapy


Pinto D et al. ACC 2008
     Bleeding and Costs — Conclusions



►   The available costs data clearly show that a
    balance must be struck between ischemia
    reduction and bleeding
    ●   Both ischemic complications and bleeding are
        associated with increased costs such that any cost
        savings realized by reducing one is offset by cost
        increases associated with the other
             Risk versus Benefit




Thrombosis




                              Bleeding
             Targets for Intervention
             Better Options, Worse Options




                                II
                   X
TF    VIIa              Va (Prothrombin)
                       Xa

     IX      IXa
                                 IIa

                             (Thrombin)

               Xa Inhibitors—            Direct Thrombin
                                          Direct Thrombin
               Fondaparinux            Inhibitors—Bivalirudin
                                       Inhibitors—Bivalirudin
                       Bivalirudin Pharmacology

Gly-Pro-Arg-Pro
(active site binding region)           • Bivalent direct thrombin
                                         inhibitor
                                       • High specificity and potency
       (Gly)4
                                       • Lack of dependence on
                                         antithrombin-III
                                       • Effect on clot-bound & free
                                         thrombin
                                       • No platelet activation
                                       • No inhibition by PF4 and
                                         others
          C-terminal dodecapeptide
          (exosite 1-binding region)   • Reversible
            Addressing the Challenges 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
Bleeding Among Patients with ACS—Conclusions

   ►   There are several therapeutic pathways for
       ACS care


   ►   Choices for therapy must take into account:
       ●   Ischemic complications
       ●   Bleeding complications


   ►   The risk for bleeding and ischemia increases
       from NSTE-ACS to STEMI
           Conclusions—Bleeding in ACS

►   Certain patient and PCI procedure characteristics
    predict bleeding
    ●   Age, female gender, CKD
    ●   Diabetes and anemia are newly identified risk factors for
        bleeding among ACS patients

► Bleeding is associated with worse short and long-
    term outcomes including death and MI
► Blood transfusion is associated with increased
    mortality in ACS patients
► In addition to an adverse impact on clinical
    outcomes, bleeding is associated with increased cost
    of care
    Conclusions — Bleeding in ACS

► ACC/AHA guidelines now recognize the value
  of bleeding reduction in ACS care

    Bivalirudin is a Class I (Level of evidence: B)
    recommended antithrombin agent for NSTE-ACS
    patients undergoing an invasive strategy


► We now have evidence for a bleeding
  reduction strategy with bivalirudin that is
  consistent across the spectrum of risk for
  NSTE-ACS and STEMI
       Getting in the Stream of Things

        Acute Coronary
   Syndromes — A Year 2008
         Status Report
The Guidelines: Many Streams Runs Through

    Deepak L. Bhatt MD, FACC, FSCAI, FESC,
               FACP, FCCP, FAHA
 Associate Director, Cleveland Clinic Cardiovascular Coordinating
    Center Staff, Cardiac, Peripheral, and Carotid Intervention
                 Associate Professor of Medicine
                         Mechanisms Behind Periprocedural MI

        Arterial Inflammation                     Aspirin Resistance        Interventional
                                                                                Device
      ↑ Atheroma Burden                          ↓ Antithrombotics
      ↑ Plaque                                     Clopidogrel          ↑ Atherectomy
        Vulnerability                              GP IIb/IIIa          ↓ EPD
      ↓ Statins                                    Enoxaparin
                                                   Bivalirudin




                                          Perioprocedural Myonecrosis


                                   Cardiovascular Morbidity and Mortality


Bhatt DL et al. Circulation 2005; 112:906-923.
                                   Potential 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.
                          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 Strategy Overview




                                     Pivotal Trials
                                 Focus on Anticoagulation




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

       Refract Isch               1.9                2.05

                                                             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                Enoxaparin             Fondaparinux    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
                                     1.3                 0.7        0.54 (0.41 – 0.73)   < 0.0001
       Bleed (%)

   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 ischemia                    13.2%       12.3%       0.06

                     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

             Events (30 Days)                        Enoxaparin   Fondaparinux   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, et al. 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, et al. 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
UA/NSTEMI Strategy Overview




 Antiplatelet Agents
Mechanisms and Current Trials
                            Platelet and Thrombus Formation
                                                      Vascular Injury




Meadows TA, Bhatt DL. Circ Res. 2007;100:1261-1275.
Meadows TA, Bhatt DL. Circ Res. 2007;100:1261-1275.
                                                   ADP Receptors




Bhatt DL et al. Nature Reviews Drug Discovery 2003; 2:15-28.
                          CURRENT OASIS 7 Study Design

                         Patients with UA/NSTEMI planned for early invasive
                    strategy, i.e. intend for PCI as early as possible within 24 hrs


                                                                                            N = ~14, 000
                                                 RANDOMIZE


          Clopidogrel High Dose Group                                   Clopidogrel Standard Dose Group
 Clopidogrel 600mg loading dose Day 1 followed by                   Clopidogrel 300mg (+placebo) Day 1 followed
            150mg from Day 2 to Day 7;                                by 75mg (+placebo) from Day 2 to Day 7;
               75mg from Day 8 to 30                                           75mg from Day 8 to 30



                    RANDOMIZE                                                   RANDOMIZE


   ASA low dose group           ASA high dose group             ASA low dose group        ASA high dose group
   At least 300mg Day1;         At least 300mg Day1;            At least 300mg Day1;      At least 300mg Day1;
          75–100mg                  300mg–325mg                        75–100mg               300mg–325mg
       from D2 to D30               from D2 to D30                  from D2 to D30            from D2 to D30

PCI: Percutaneous coronary intervention                                       Slide courtesy of Dr. Shamir Mehta
UA/NSTEMI: Unstable angina/non-ST-segment elevation myocardial infarction
                 Cangrelor (AR-C69931MX)

Parenteral ADP-P2Y12 receptor antagonist
  ●    ATP analogue
  ●    Molecular weight 800 Daltons
  ●    Plasma half-life of 5-9 minutes
  ●    20 minutes for return to normal platelet
       function
                                                            S
                                               HN

            4Na +                         N
                                                    N
       O         O       O                                      CF
   O                                      N                          3
                                                N       S
                 P       P            O
       P                     O
   O                 O
                 O       O
       Cl
            Cl
                                 HO       OH
                                CHAMPION — Platform Trial
                                                     PCI for ACS
                                                         (N~4400)

                                         1:1 Double -blind, double-dummy


                          Placebo            Cangrelor
                                                                         Clopidogrel          Placebo bolus
                        capsules (to     bolus (30 µg/kg) &
                                                                          capsules             and infusion
                          match)            infusion (4
                                                                          (600 mg)              (to match)
                                             µg/kg/min)

                                                         Index Procedure
                                            Study drug infusion (for at least 2 hours or
                                        the duration of the procedure, whichever is longer)


                                           Clopidogrel                Placebo
                                            capsules                capsules (to
                                            (600 mg)                  match)


                                    1º Endpoint: Death, MI, and UTVR at 48 hours

                                                    2 º Endpoints:
                                            Death, MI, uRevasc at 30 days
                                            Death at 6 months and 1 year
uRevasc, urgent revascularization
  NSTE-ACS Strategy Overview




The Inflammatory Interfaces
       Focus on Statins
                   Statins as Anti-Inflammatory Drugs?
                                              Statins
                                       Inhibit Isoprenylation
                                        Rac, Rho, RA 1
 ROS                                  Upregulate eNOS                       Inflammatory cells
 Oxidized LDL                         Activate AKT pathway                  Cytokines,  chemokines
 Angiotensin 1                                                              Vasoconstriction
                                       Inhibit caveolin
 Endothelin 1                                                               Cardiac remodeling
 Inflammatory cells                                                          Improve Autonomic Function
 CRP, IL-6
 Endothelial nitric oxide  Foam cell                        Matrix metalloproteinases
  production & improves  Inflammatory                        Platelet activation
  endothelial function       macrophages & T-cells            Tissue factor
                            Cytokines                        Plasminogen activator
                            Adhesion molecules                inhibitor-1
                            P- and C-selectin                CD40/CD40L
                            Smooth muscle cell               Platelet/thrombus
                             proliferation                     formation




                                                                                   Acute
               Patel T, Shishehbor MH, Bhatt DL. EHJ 2007.                         Coronary Syndrome
                         Baseline hs-CRP and Outcome in PCI




Chew DP, Bhatt DL, Robbins M, et al. Circulation 2001.
                                               Statin Pretreatment Prior to
                                                      PCI and CRP
                                                                                           P=0.009
                                   16
                                                                                                   14.8
                                   14                   Statin         No Statin
            1-Year Mortality (%)




                                   12
                                           3.4% vs. 6.9%, P=0.003
                                   10
                                                                              P=0.97
                                    8
                                                                                   6.3
                                                            P=0.69           5.6             5.7
                                    6    P=0.26
                                    4          3.1               2.8
                                                           1.8
                                    2    1.2

                                    0
                                        1st Quartile     2nd Quartile       3rd Quartile    4th Quartile

                                                       Preprocedural CRP (mg/dL)



Chan AW, Bhatt DL, Chew DP, et al. Circulation 2003.
                         Statin Pretreatment Early in ACS
                                                                           Mortality      Incidence (%)
      Study                                       Odds Ratio             Statin therapy   Less-intensive
      L-CAD                                                                      2.9           3.6
      PTT                                                                        2.5           8.1
      Florida                                                                    2.6           4.0
      Colivicchi                                                                 7.5           9.8
      PROVE-IT                                                                   2.2           3.2
      ESTABLISH                                                                  0.0           2.9
      A to Z                                                                     4.6           5.8

                       Overall OR (95% CI)                      0.74(0.61, 0.90)

                                           0.1            1.0         10.0
                                               Favors               Favors
                                           Statin Therapy       Less-intensive
                                                                Lipid Therapy

Bavry, Mood, Kumbhani, Borek, Askari, Bhatt. AJCD 2006.
                          Statin Pretreatment Prior to PCI and MI

                                                             Odds ratio
                      Study                             (95% Confidence         % Weight
                                                            Interval)


                  PREDICT                                   1.00 (0.25, 3.98)       3.9
                  FLARE                                     0.31 (0.09, 1.12)       9.5
                  GAIN                                      0.20 (0.01, 4.15)       2.4
                  LIPS                                      0.78 (0.49, 1.25)      36.9
                  ARMYDA                                    0.29 (0.10 0.84)       13.4
                  Briguori                                  0.51 (0.30, 0.88)      33.9


                  Overall (95% Confidence                   0.57 (0.42, 0.78)
                 Interval)
                                            .1    1        10

                                                      Odds ratio



Mood G, Bavry AA, Roukoz H, Bhatt DL. AJC 2007.
                  Summary 2007 Guidelines
              Upstream Management of Suspected ACS


► ECG and ASA within 10 minutes
    ●   STEMI patients directed to their pathway


►   Risk stratification
    ●   Focused history and physical, biomarkers, serial ECGs, risk
        score, and bleeding risk


► Patients with high ischemic risk should go for EIS
  (Class I) or, in a minority of cases, for ICS (Class
  IIa), but only after medical stabilization
                   Summary 2007 Guidelines
                      Upstream Medical Stabilization

► Anticoagulation       Strategies
  ●   EIS: Enoxaparin (I-A), UFH (I-A), or bivalirudin (I-B)
       • Strong support for bivalirudin when time to lab is quick and/or
         when bleeding risk is higher (screen for patients at higher risk for
         bleeding)


  ●    ECS: Enoxaparin (I-A), UFH (I-A), or fondaparinux
      (I-B)
       • Strong support for fondaparinux when bleeding risk is higher, but
         more problematic if catheterization later required


  ●   Individual patient characteristics (ischemic risk,
      bleeding risk, time to cath) should drive choices,
                      Year 2007 Guidelines:
                       Good News, Bad News
                  No (Up)Stream Strategy is Perfect



 Guideline Strategy              Possible Limitation
           ASA                            Allergy

       Clopidogrel             Resistance, CABG planned

           UFH                   Platelet activation, HIT

UFH + GP IIb/IIIa Inhibitor           Bleeding, cost

Enoxaparin + GP IIb/IIIa       Bleeding, renal dysfunction

        Bivalirudin               Clopidogrel exposure
                     Conclusions

►   New ACS guidelines provide considerable
    latitude as far as strategies of care
►   Need to minimize ischemia and bleeding
►   Anticoagulation remains important
►   Switching permitted with some agents
►   Early antiplatelet therapy upgraded
►   Early statin use probably a good idea
►   Early invasive remains preferred
A New Paradigm of Care for
 ST-Elevation Myocardial
    Infarction (STEMI)
       Gregg W. Stone MD
  Columbia University Medical Center
  Cardiovascular Research Foundation
                 FACT
Major bleeding (with or without
 blood product transfusions)
  has emerged as a powerful
independent predictor of early
 and late mortality in pts with
 NSTEMI, STEMI and in those
       undergoing PCI

         Ndrepepa et al. JACC 2008;51:690–7
Impact of 30 Day Adverse Events on 1-Year
             Mortality after PCI
 ISAR REACT-1, -2, -SWEET, -SMART-2 (n=5,384)
  30 day event rates: Death 0.8%, MI 5.8%, urgent revasc 1.0%,
TIMI major/minor bleed 4.0%; 1 year mortality: 3.6% (197 deaths)

    • 501 pts within 30-days had MI, urgent revasc
      or TIMI bleeding
    • 58/501 (11.6%) pts with a 30-day event died vs.
      139/4,883 (2.8%) pts without a 30-day event
      (OR [95% CI] = 4.46 [3.23-6.16], P<0.001)
    • 58 of 197 deaths (29.4%) at 1-year occurred in
      pts with one or more of these 30-day events

                    Ndrepepa et al. JACC 2008;51:690–7
Impact of 30 Day Adverse Events on 1-Year
             Mortality after PCI
 ISAR REACT-1, -2, -SWEET, -SMART-2 (n=5,384)
Cox model relating 30 day events to mortality at 1 year
    Variable                                HR (95% CI)        P
    Bleeding w/i 30 days                  2.96 (1.96–4.48)   0.001
    MI w/i 30 days                        2.29 (1.52–3.46)   0.001
    Urgent revasc w/i 30 days             2.49 (1.16–5.35)    0.02
    Age (per 10 yrs)                      2.27 (1.78–2.89)   0.001
    Diabetes                              1.47 (1.11–1.96)   0.008
    MVD                                   2.72 (1.58–4.67)   0.001
    ↑ Troponin                            1.77 (1.27–2.47)   0.001
    LVEF                                  0.71 (0.60–0.85)   0.001
    Creatinine (per 0.25 mg/dl ↑)         1.10 (1.06–1.14)   0.001

                    Ndrepepa et al. JACC 2008;51:690–7
                            Impact of Major Bleed and MI
                            after Elective and Urgent PCI
                                     1-Year Mortality (N=6,012)
Cumulative % Mortality




                                                                  With major bleed 8.8%



                                                                   With MI 5.7%



                                                                  Without major bleed 2.0%
                                                                  Without MI 1.9%



                         Time from Randomization in Days


                               Stone GW. J Inv Cardiol 2004;16(suppl G):12–17.
           Predictors of 1-year Mortality
           after Elective and Urgent PCI
Variable                 Groups         O.R.       (95% CI)      p-value
Creatinine clear.      <30 mL/min        7.21     (2.53–20.51)
                      30–60 mL/min       3.34     (1.92–5.78)    <0.0001
                      60–90 mL/min       1.57     (0.96–2.57)
CHF                        Yes           4.38     (2.83–6.78)    <0.0001
Major Bleeding             Yes           3.26     (1.78–5.96)    0.0001
MI @30day                  Yes           2.77     (1.62–4.75)    0.0002
Urg Revasc @30d            Yes           2.77     (1.15–6.71)     .024
Hx angina                  Yes           2.18     (1.25–3.81)     0.006
Prior MI                   Yes           1.81     (1.09–3.03)     0.023
Diabetes                   Yes           1.64     (1.10–2.44)     0.015


              Stone GW. J Inv Cardiol 2004;16(suppl G):12–17.
    30 Day Primary Endpoint
     6,012 Patients Undergoing PCI
p = 0.32

                             p = 0.23

                                                       p <0.001


                                            p = 0.44
              p = 0.26




                    Triple ischemic endpoint


           Lincoff AM et al. JAMA 2003;289:853–63
                                    1-year Mortality
                               All 6,012 Patients (ITT)
                    3.0       Heparin+GPllb/llla N=3008       Bivalirudin N=2994

                                                                                     2.5%
Cumulative Deaths




                    2.5
                                    P value = 0.16
                    2.0
                                                                                     1.9%
                    1.5

                    1.0

                    0.5

                    0.0
                          0   60          120       180        240           300   360
                                                   Days

                                   Lincoff AM et al. JAMA 2004;292:696–703
          ACUITY: First Randomization
Moderate and high risk unstable angina or NSTEMI
  undergoing an invasive strategy (N = 13,819)

                               UFH/Enox




                                                          Angiography 19.6° median
                                                                                       Medical
                              + GP IIb/IIIa                                                     33%
                                                                                     management
                               (n=4,603)
     Moderate
                              Bivalirudin
     and high
                       R*     + GP IIb/IIIa
     risk ACS                  (n=4,604)                                                PCI    56%
    (n=13,819)
    Aspirin in all             Bivalirudin
     Clopidogrel                  Alone
  dosing and timing                                                                    CABG    11%
                                (n=4,612)
  per local practice


*Stratified by pre-angiography thienopyridine use or administration

                            Stone GW et al. NEJM 2006;355:2203-16
Impact of MI and Major Bleeding (non-CABG) in
 the First 30 Days on Risk of Death Over 1 Year
                                                                               1 year
                                                                              Estimate
                                           Both MI and Major Bleed (N=94)      28.9%
                                      Major Bleed only (without MI) (N=551)    12.5%
                                      MI only (without Major Bleed) (N=611)     8.6%
                   30                      No MI or Major Bleed (N=12,557)      3.4%


                   25
   Mortality (%)




                   20

                   15

                   10

                    5

                    0
                        0   30   60    90    120 150      180 210 240 270      300 330 360   390
                                            Days from Randomization

                                              Stone GW. ACC 2007
    Influence of Major Bleeding and MI in the
First 30 Days on the Risk of Death within 30 Days
 Of 13,819 enrolled pts, 704 (5.1%) had a MI, 644 (4.7%) had a
 major bleed (non CABG), and 206 (1.5%) died within 30 days
         Cox model adjusted for baseline predictors, with MI and major
              bleeding (non-CABG) as time-updated covariates
                                                                                 Attributable
                                       HR ± 95% CI        HR (95% CI)    P-value   deaths

   Myocardial infarction                                 5.25 (3.72-7.43) <0.0001      42.0*

Major bleeding without
 or before transfusion                                   3.04 (1.66-5.55) <0.0001
                                                                                       38.2**
     Major bleeding after
             transfusion                                 5.45 (3.54-8.38) <0.0001

                                                                             *20.4% of all deaths
                                                                            **18.5% of all deaths
Attributable deaths = N deaths
among pts with the time updated
event (attribute) X (adj. HR – 1)/adj. HR    Stone GW. ACC 2008
      Influence of Major Bleeding and MI in the
     First 30 Days on Risk of Death Over 1 Year
          Of 13,819 enrolled pts, 524 (3.8%) died within 1 year
         Cox model adjusted for baseline predictors, with MI and major
              bleeding (non-CABG) as time-updated covariates
                                                                                    Attributable
                                       HR ± 95% CI           HR (95% CI)    P-value   deaths

   Myocardial infarction                                    2.51 (1.95-3.25) <0.0001      51.5*

Major bleeding without
 or before transfusion                                      2.00 (1.30-3.06) <0.0001
                                                                                          66.5**
     Major bleeding after
             transfusion                                    3.93 (2.95-5.24) <0.0001

                                                                                 *9.8% of all deaths
                                                                               **12.7% of all deaths
Attributable deaths = N deaths
among pts with the time updated
event (attribute) X (adj. HR – 1)/adj. HR   Mehran RM et al. Submitted
  Influence of MI, Major Bleed and Transfusion in the
     First 30 Days on the Risk of Death Over 1 Year
                                                                                                 Attributable
                                                                    HR (95% CI)        P-value
                                                                                                   deaths
                MI         Day 0-1                               17.6 (10.8 to 28.7)   <0.001         21
                          Days 2-7                                8.2 (5.0 to 13.6)    <0.001         19
                        Days 8-30                                 2.9 (1.6 to 5.3)      0.001        12
                         Days 31+                                 1.4 (0.9 to 2.1)      0.12         25


     Major bleed           Day 0-1                                5.5 (2.7 to 11.0)    <0.001         9
     (non CABG)           Days 2-7                                5.8 (3.5 to 9.7)     <0.001        18
                        Days 8-30                                 5.6 (3.5 to 8.8)     <0.001        24
                         Days 31+                                 2.4 (1.7 to 3.3)     <0.001        42


     Transfusion           Day 0-1                                6.7 (3.1 to 14.7)    <0.001         7
                          Days 2-7                                8.1 (4.6 to 14.1)    <0.001        15
                        Days 8-30                                 6.4 (3.7 to 10.9)    <0.001        17
                         Days 31+                                 3.1 (2.1 to 4.5)     <0.001        31

                                        0.5 1 2 4 8 16 32
                                         Hazard ratio (95% CI)
Attributable deaths = N deaths
among pts with the time updated
event (attribute) X (adj. HR – 1)/adj. HR   Mehran RM et al. Submitted
 ACUITY: Primary Endpoint Measures
      UFH/Enoxaparin + GPI vs. Bivalirudin Alone
      Primary         Risk ratio                                      Bival UFH/Enox                         p value
                                                                                          RR (95% CI)       (non inferior)
     endpoint          ±95% CI                                        alone + IIb/IIIa                        (superior)




                                 Upper boundary non-inferiority
   Net clinical                                                                                              <0.001
                                                                      10.1%    11.7%     0.86 (0.77-0.97)
     outcome                                                                                                  0.015

     Ischemic                                                                                                  0.02
                                                                       7.8%     7.3%     1.08 (0.93-1.24)
    composite                                                                                                  0.32

                                                                                                             <0.001
Major bleeding                                                         3.0%     5.7%     0.53 (0.43-0.65)
                                                                                                             <0.001


                  0         1                                     2
 Bivalirudin alone better       UFH/Enox + IIb/IIIa better



                       Stone GW et al. NEJM 2006;355:2203-16
ACUITY: Early and Late Mortality
      Landmark analysis
                 4
                                                               30 day       P         30d - 1 year P
                                                              Estimate   (log rank)    Estimate (log rank)
                              UFH/Enoxaparin + IIb/IIIa        1.4%        —              3.1%       —
                 3                Bivalirudin + IIb/IIIa       1.6%       0.53            2.7%      0.54
 Mortality (%)




                                    Bivalirudin alone          1.6%       0.39            2.3%      0.21


                 2


                 1


                 0
                     0   30    60     90    120 150        180 210 240 270               300 330 360         390

                                           Days from Randomization



                                 Stone GW. JAMA 2007;298:2497-506
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
       3000 pts eligible for stent randomization
                                                     R
                                                    1:3

            Bare metal stent                          TAXUS paclitaxel-eluting stent

                              Clinical FU at 30 days, 6 months,
*To rand 3000 stent pts    1 year, and then yearly through 5 years
Harmonizing Outcomes with Revascularization and Stents in AMI
                             3602 pts with STEMI
                                              R
                                             1:1

                       UFH +                               Bivalirudin
      Randomized      GP IIb/IIIa                         Monotherapy
                       N=1802                               N=1800
                                9     • • • Withdrew • • •    10
                                15   • • • Lost to FU • • •   13

                       N=1778                                  N=1777
         30 day FU*
                       (98.7%)                                 (98.7%)

   ITT population      N=1802                                  N=1800

* Range ±7 days       Stone GW et al. In press.
        Primary Outcome Measures (ITT)
            Diff = -2.9% [-4.9, -0.8]    Diff = -3.3% [-5.0, -1.6]   Diff = 0.0% [-1.6, 1.5]
            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 = 0.95
                 Psup = 0.005                 Psup ≤ 0.0001




                  1 endpoint                   1 endpoint




*Not related to CABG
**MACE = All cause death, reinfarction, ischemic TVR or stroke
            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%      0.009
TIMI Major                                      5.0%           3.1%      0.002
TIMI Minor                                      4.6%           2.8%      0.006
TIMI Major or Minor                             9.6%           5.9%     <0.0001
GUSTO LT*** or Severe                           0.6%           0.4%       0.49
GUSTO Moderate                                  5.0%           3.1%      0.002
GUSTO LT or Sev or Mod                          5.6%           3.5%      0.002
*CEC adjudicated, except protocol minor;
**Primary endpoint; ***Life threatening
      Thrombocytopenia


         P = 0.002




                           P = 0.04

                                              P = 0.02




<100,000 cells/mm3     <50,000 cells/mm3   <20,000 cells/mm3

              Stone GW et al. In press.
         30 Day MACE Components*
                          UFH + GP IIb/IIIa       Bivalirudin
                                                                P Value
                             (N=1802)              (N=1800)
Death                           3.1%                 2.1%        0.047
  - Cardiac                     2.9%                 1.8%        0.028
  - 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%        0.37
Ischemic TVR                    1.9%                 2.6%        0.18
  - Ischemic TLR                1.8%                 2.5%        0.13
  - Ischemic remote TVR         0.3%                 0.3%         1.0
Stroke                          0.6%                 0.7%        0.68

*CEC adjudicated
                      Stone GW et al. In press.
                                 30 Day Mortality
                                    Heparin + GPIIb/IIIa inhibitor (n=1802)
                                    Bivalirudin monotherapy (n=1800)
              Death (%)

                                                                                  3.1%

                                                                                  2.1%
                                                                     HR [95%CI] =
                                                                    0.66 [0.44, 1.00]
                                                                      P=0.048

                                              Time in Days
Number at risk
Bivalirudin               1800    1758     1751     1746     1742      1729     1666
Heparin + GPIIb/IIIa      1802    1764     1748     1736     1728      1707     1630


                                     Stone GW et al. In press.
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%

Number at risk                             Time in Days
Bivalirudin              1800   1758    1751      1746     1742    1729     1666
Heparin + GPIIb/IIIa     1802   1764    1748      1736     1728    1707     1630


                                   Stone GW et al. In press.
  30 Day Stent Thrombosis (N=3,124)
                                      UFH +
                                                 Bivalirudin P
                                     GP IIb/IIIa
                                                  (N=1571) Value
                                     (N=1553)
 ARC 30d definite or
                                        1.9%          2.5%    0.30
 probable stent thrombosis*

   - definite                           1.4%          2.2%    0.09

   - probable                           0.5%          0.3%    0.24

   - acute (≤24 hrs)                    0.3%          1.3%   0.0007

   - subacute (>24 hrs – 30d)           1.7%          1.2%    0.28

*Protocol definition of stent thrombosis, CEC adjudicated
          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 (%)


                        3
                                                  P=0.049                                2.8%
                                                                          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


                                     Stone GW et al. In press.
    Predictors of 30 Day Mortality
   32 Candidate Baseline Variables*
 Demographic: Age; sex; race; US vs. OUS; HTN, hyperlipidemia,
 smoking, diabetes, diabetes on insulin, MI, PCI, CABG, CAD,
 angina, CHF, major cardiac rhythm/rate disturbances, PVD
 Medication use at home previous 5 days: aspirin, beta blocker,
 thienopyridines, calcium channel blocker, ACE/ARB, diuretic
 Time from symptom onset to hospital ER
 Physical exam: BMI; KILLIP class
 Baseline labs: Estimated CrCl, anemia, platelet count
 Medications in hospital prior to angiography: Randomized
 treatment (bivalirudin vs. heparin + GPI; pre-procedure heparin;
 clopidogrel load

* Angiographic variables not yet available;
 - treatment related variables not used
Time-updated covariate adjusted Cox model relating
  single 30-day adverse events to 30-day mortality
                                                             Attributable
Ischemic Events              HR (95% CI)             P         deaths*    C-stat

Reinfarction                11.09 [5.44,22.59]    <0.001      9.1 [8.2,9.6]   0.83

Ischemic TVR                6.91 [3.36,14.18]     <0.001      7.7 [6.3,8.4]   0.83

Stent thrombosis, definite**

  - any                     10.71 [3.93,29.18]    <0.001      4.5 [3.7,4.8]   0.83

  - acute (<24 hours)       5.88 [0.78,44.30]      0.09       0.8 [-0.3,1]    0.82

Stroke                      5.44 [1.67,17.69]     0.005       2.4 [1.2,2.8]   0.82

* Of 93 total deaths; ** in 3,124 successfully stented pts
***Only 2 pts with acute stent thrombosis died within 30
days, 1 in each randomized group
Time-updated covariate adjusted Cox model relating
  single 30-day adverse events to 30-day mortality
                                                         Attributable
Bleeding Events              HR (95% CI)          P        deaths*    C-stat

Major bleed (non-CABG)      4.43 [2.67, 7.33]   <0.001   20.1 [16.3,22.5] 0.85

Major bleed (all)           5.92 [3.73, 9.41]   <0.001   29.1 [25.6,31.3] 0.86

Transfusion                 3.88 [2.09, 7.20]   <0.001   11.9 [8.4,13.8]   0.83

Thrombocytopenia**

  - <100,000 cells/mm3      3.89 [2.22, 6.84]   <0.001   11.1 [8.2,12.8]   0.78

  - <50,000 cells/mm3       6.44 [2.93,14.18]   <0.001    5.9 [4.6,6.5]    0.78

  - <20,000 cells/mm3       4.98 [1.20,20.66]    0.03     1.6 [0.3,1.9]    0.77

* Of 93 total deaths; ** 88 deaths in 3550 patients
Attributable deaths = N deaths among pts with the time
updated event (attribute) X (adj. HR – 1)/adj. HR
Time-updated covariate adjusted Cox model
 relating 30-day events to 30-day mortality
 - Complete model with MACE components and major bleeding -

  Risk Factor                                              HR [95% CI]     P-value

  Reinfarction                                                 9.75        <0.001
                                                            [2.72,34.91]

  Major bleeding (non CABG)                                    4.66        <0.001
                                                            [2.84, 7.63]

  Ischemic TVR                                                 1.11         0.88
                                                            [0.29, 4.21]

  Stroke                                                       2.64         0.15
                                                            [0.71, 9.75]

                      0.01    0.1     1      10      100
                             Hazard Ratio [95% CI]

C-statistic = 0.87.
Time-updated covariate adjusted Cox model
 relating 30-day events to 30-day mortality
- Complete model with MACE components and major bleeding -
                                                                        Attributable
 Risk Factor                               HR [95% CI]        P-value     Deaths

Reinfarction
Incidence 69 (2.2%)                               9.75        <0.001        9.0*
                                               [2.72,34.91]               [6.3, 9.7]
10 deaths with event

Major bleeding
(Non CABG)                                        4.66                     20.4**
                                                              <0.001
Incidence 238 (6.8%)                           [2.84, 7.63]              [16.8, 22.6]
26 deaths with event


         0.01    0.1      1      10      100               *9.7% of 93 total deaths
                Hazard Ratio [95% CI]                    **21.9% of 93 total deaths
C-statistic = 0.87. Attributable deaths = N deaths among pts
with the time updated event (attribute) X (adj. HR – 1)/adj. HR
Time-updated covariate adjusted Cox model
 relating 30-day events to 30-day mortality
 - Complete model in 3,124 pts with successfully implanted stents -
                                                                         Attributable
 Risk Factor                               HR [95% CI]         P-value     Deaths

Stent thrombosis
(definite)                                       10.62                       4.5*
                                                               <0.001
Incidence 57 (1.8%)                            [3.96, 28.48]               [3.7, 4.8]
5 deaths with event

Major bleeding
(non CABG)                                        6.22                      15.1**
                                                               <0.001
Incidence 195 (6.2%)                           [3.33, 11.60]              [12.6, 16.4]
18 deaths with event


         0.01    0.1      1      10      100                *8.3% of 54 total deaths
                Hazard Ratio [95% CI]                     **28.0% of 54 total deaths
C-statistic = 0.87. Attributable deaths = N deaths among pts
with the time updated event (attribute) X (adj. HR – 1)/adj. HR
                 Conclusions
1. Major bleeding is a powerful independent determinant
   of mortality in ACS, STEMI, and in pts undergoing PCI,
   at least as important as MI/reinfarction.
2. In high risk pts with STEMI undergoing primary PCI,
   treatment with bivalirudin compared to heparin + GPI
   results in a significant reduction in bleeding,
   thrombocytopenia and transfusions, with similar rates
   of reinfarction, stent thrombosis, iTVR and stroke.
3. This favorable balance of adverse events results in
   lower 30-day mortality in primary PCI pts treated with
   bivalirudin rather than heparin + GPI, representing a
   new standard of care for pts with STEMI.
         The Science and Medicine of Acute Coronary Syndrome



Getting in the Stream(s) of Antithrombotic
     Therapy for ACS—What Do The
               Data Tell Us?
             To Switch or Not to Switch —
              Why, When, How, To What?


               Ron Waksman, MD, FACC
              Associate Director, Division of Cardiology
      Washington Hospital Center, Washington Hospital Center
   Professor of Medicine - Georgetown University Washington, DC
           Overview of Presentation
►   Why should switching to bivalirudin for PCI be
    reasonable?
►   Mechanistic rationale for switching
►   Why is there a concern about switching
    antithrombins in patients with ACS (lessons from
    SYNERGY)
►   Clinical Evidence
    ● BAT

    ● 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
                                       An Alternative to UFH/LMWH
        ►    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.
                          Indirect vs Direct Thrombin Inhibition




        Indirect inhibition by heparin requires    Direct inhibition with bivalirudin
        the presence of antithrombin (AT),         inhibits thrombin directly with high
        the actual inhibitor.                      affinity and specificity.

        Heparin (long yellow strand) binds to      It requires no cofactor, and acts
        AT, causing a shape change that            alone.
        increases the ability of AT to inhibit
        thrombin.                                  Bivalirudin’s effectiveness is not
                                                   affected by variability in the
                                                   concentration of a co-factor like AT.
Hirsh J et al. Chest. 2001;119(1 suppl):64S-94S.
Weitz JI et al. Thromb Res. 2002;106:V275-V284.    Gibson CM, 2006.
                                               Bivalirudin Inhibits
                                              Clot-Bound Thrombin




          The heparin-AT complex “bounces”            Bivalirudin has a high affinity for and
          off and is not effective against clot-      “sticks” to thrombin, which displaces
          bound thrombin.                             thrombin from fibrin.

          This reservoir of active thrombin           Bivalirudin effectively inhibits both
          continues to activate platelets and         clot-bound and circulating thrombin.
          trigger further clotting.


Hirsh J et al. Chest. 2001;119(1 suppl):64S-94S.
Weitz JI et al. Thromb Res. 2002;106:V275-V284.        Gibson CM, 2006.
               Switching Antithrombins

►   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?
                                      B•A•T
    Bivalirudin Angioplasty Trial


    A double-blind randomized
  comparison of bivalirudin versus
heparin in 4312 patients undergoing
   PTCA for new onset of severe,
   accelerating or rest angina or
angina within 2 weeks of myocardial
              infarction
                                                                         B•A•T
                             Study Design

                              HIGH RISK PATIENTS
                   • New onset severe, accelerating or rest angina
                              • Symptoms in last month
                                 • Suitable for PTCA

                                        Stratify
Heparin
                       Primary                           Post-MI
pretreatment
                    Randomized                       Randomized

                 ASA             ASA               ASA             ASA
               Bivalirudin    Heparin          Bivalirudin     Heparin
                PTCA          PTCA                 PTCA        PTCA
                                                                         B•A•T
                     Primary Endpoints

                    Hemorrhage                 Death, MI, Revascularization



Bivalirudin                          3.5% 6.2%
n = 2,161


            62% reduction       43% reduction           22% reduction
            p-value <0.001          p-value <0.001       p-value 0.039



Heparin
n = 2,151                    9.7%                7.9%



                  % of patients with events at 7 days
                                                                                 B•A•T
                Net Benefit By Risk Strata

                         Hemorrhage               Death, MI, revasc
Unstable                        3.3%       Bivalirudin      5.8%
& post-MI
n = 241      16.5%                          Heparin                      14.0%


Unstable                       4.1%        Bivalirudin            7.4%
on heparin
                     11.9%                  Heparin              10.3%
n = 1,006

                                    2.4%   Bivalirudin     4.9%
Post-MI
n = 741              11.8%                  Heparin               9.9%


No risk                        3.6%        Bivalirudin          6.1%
factors
n = 2,806                    8.3%           Heparin      7.0%


                      % of patients with events at 7 days
                    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



                                              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                  BLEEDING
          PCI                            4-8 h before PCI
                                                                          bolus
            (3 US                                                      1.75 mg/kg/h
            sites)                           LMWH                       IV infusion
                             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
             Outcomes                         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

Waksman J Invasive Cardiol 2006;18:370-375.
             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: 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




Gibson CM, Am J Cardiol 2007.
                           REPLACE-2: SWITCH Analysis

                           Overall population: Urgent or elective PCI patients
                                               (N=6,002)1

                                                       Randomize

                        Bivalirudin                                             UFH
     0.75 mg/kg bolus/1.75 mg/kg/h infusion with                   65 U/kg with planned GP IIb/IIIa
          “provisional” GP IIb/IIIa (n=2,994)1                                (n=3,008)1


        Naïve – no                                 Prior       Naïve – no                        Prior
                              Prior UFH                                          Prior UFH
         prior AT                                 LMWH          prior AT                        LMWH
                               (n=287)2                                           (n=349)2
        (n=2,345)2                               (n=258)2      (n=2,325)2                      (n=313)2



               Protocol major/minor bleeding, TIMI bleeding, transfusion, mortality

AT=antithrombin.

1. Lincoff ML et al. JAMA. 2004;292:696-703.
2. Gibson CM et al. Am J Cardiol. 2007;99:1687-1690.
                                                  Protocol Major/Minor Bleed by
                                                SWITCH and Randomized Therapy
                                    ►    Regardless of prior heparin or not, patients administered bivalirudin
                                         had decreased bleeding
                                    ►    There was a significant increase in major/minor protocol bleeding
                                         in patients administered UFH with prior heparin therapy
                                   35%                                                                   33.8%          34.8%
                                                                                                 †
                                                                                         28.6%
      Protocol major/minor bleed




                                   30%

                                   25%

                                   20%
                                                                            16.7%
                                                15.6%*       15.3%
                                   15%

                                   10%

                                   5%

                                   0%
                                               Naïve→         UFH→         LMWH→         Naïve→        UFH→UFH LMWH→UFH
                                             Bivalirudin‡   Bivalirudin   Bivalirudin     UFH +        + GP IIb/IIIa + GP IIb/IIIa
                                              (n=2,345)      (n=287)       (n=258)      GP IIb/IIIa‡     (n=349)       (n=313)
                                                                                        (n=2,325)

 *P=NS for all 3-way comparisons versus bivalirudin alone; †P<.05 vs prior treatment with UFH or enoxaparin;
 ‡naïve=no prior AT therapy in preceding 48 hours.



Gibson CM et al. Am J Cardiol. 2007;99:1687-1690.
                                                 TIMI Major/Minor Bleed by
                                              SWITCH and Randomized Therapy
  ►   Patients switched from UFH or enoxaparin to bivalirudin had the lowest rates of TIMI bleeding
  ►   Patients administered UFH had higher rates of bleeding, with highest rates in patients
      switching between heparins
                                6%
                                                                                                                  5.4%
                                5%
       TIMI major/minor bleed




                                                                                                  4.3%
                                4%                                                  3.5%

                                3%

                                        1.9% *                      1.9%
                                2%
                                                      1.4%
                                1%

                                0%
                                       Naïve→         UFH→         LMWH →       Naïve→UFH UFH→UFH              LMWH→UFH
                                     Bivalirudin†   Bivalirudin   Bivalirudin   + GP IIb/IIIa† + GP IIb/IIIa    + GP IIb/IIIa
                                      (n=2,345)      (n=287)        (n=258)      (n=2,325)       (n=349)          (n=313)



 *P=NS for all 3-way comparisons versus bivalirudin alone; †naïve=no prior AT therapy in preceding 48 hours.


Gibson CM et al. Am J Cardiol. 2007;99:1687-1690.
                                                   Switching and 1-Year Mortality
                                     REPLACE-2 Subanalysis: 1-Year Mortality Results
                                          Consistent with Overall Trial Results
            Cumulative events (mortality), %




                                                   Bivalirudin with "provisional" GP IIb/IIIa   Heparin + GP IIb/IIIa

                                               6
                                                                                       4.9
                                               5
                                                                                                            3.8
                                               4              3.3
                                               3       2.2                      2.1                   2.1
                                               2
                                               1
                                               0
                                                        UFH                    LMWH               Any heparin
                                                    pretreatment            pretreatment          pretreatment


Gibson CM, Am J Cardiol 2007 in press.
                     ACUITY Study Design – First
                          Randomization
         Moderate and high risk unstable angina or NSTEMI
           undergoing an invasive strategy (N=13,819)


                             UFH/Enox                                                Medical
                            + GP IIb/IIIa




                                                          Angiography within 72h
                                                                                   management
                             (n=4,603)

  Moderate                   Bivalirudin
  and high                  + GP IIb/IIIa
                     R*
  risk ACS                   (n=4,604)                                                PCI
  (n=13,819)

  Aspirin in all              Bivalirudin
   Clopidogrel
dosing and timing               Alone
per local practice            (n=4,612)                                              CABG


         *Stratified by pre-angiography thienopyridine use or administration
                                          Scope of Analysis


                   This analysis will address the question of the
                   safety and efficacy of switching from indirect
                thrombin inhibition (UFH or enoxaparin) to direct
                 thrombin inhibition (bivalirudin) in high risk ACS

                          A protocol-driven activity of the ACUITY
                             study at the time of randomization




Harvey White. Presentation at AHA, 2006
                                               ACUITY: Primary Results
      ►                    Heparin* + IIb/IIIa vs. Bivalirudin + IIb/IIIa vs. Bivalirudin Alone

                              Heparin+IIb/IIIa (N=4603)   Bivalirudin+IIb/IIIa (N=4604)   Bivalirudin alone (N=4612)

                                PNI <0.001                   PNI = 0.011                   PNI <0.001
                               PSup = 0.015                  PSup = 0.32                   PSup <0.001
       30 day events (%)




                              11.7% 11.8%
                                              10.1%

                                                            7.3% 7.7% 7.8%
                                                                                           5.7% 5.3%

                                                                                                          3.0%




                             Net clinical outcome         Composite ischemia              Major bleeding (non-
                                   *Heparin=unfractionated or enoxaparin                         CABG)
Harvey White. Presentation at AHA, 2006
                          Current Analysis and Questions

          ► 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.


          ► Is  it better to switch to bivalirudin or
              remain on consistent therapy?


Harvey White. Presentation at AHA, 2006
                               ACUITY — Current 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

Harvey White. Presentation at AHA, 2006
                                               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. Presentation at AHA, 2006
                                          Consistent vs. Switch
                                          All Patients — Adjusted
                                              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
Harvey White. Presentation at AHA, 2006
                                          Consistent vs. Switch
                                              High Risk — Adjusted
                 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
Harvey White. Presentation at AHA, 2006
                                                     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
Harvey White. Presentation at AHA, 2006
                                                   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

Harvey White. Presentation at AHA, 2006
                       ACUITY PCI: Switch from Prior Antithrombin

                    30-Day Results                                                          1-Year Results
                           Risk Ratio                                                         Hazard Ratio
                            ±95% CI               RR (95% CI)                                   ±95% CI               HR (95% CI)

PCI                                                                          PCI
(n=2528)
                                                                             (n=2528)
    Composite
                                            1.10 (0.85-1.42)                            Mortality                   0.93 (0.58-1.48)
     ischemia

Major bleeding                              0.52 (0.36-0.74)




 PCI HIGH RISK*                                                            PCI HIGH RISK*
 (n=1988)                                                                  (n=1988)
      Composite                                                                       Mortality                   0.99 (0.60-1.63)
                                              1.14 (0.86-1.52)
       ischemia
  Major bleeding                              0.56 (0.38-0.81)



       0.1                     1                     10                        0.1 Switch to        1                 10
             Switch to                                                                                       Consistent UFH/Enox
                                   Consistent UFH/Enox                               Bivalirudin
             Bivalirudin              + IIb/IIIa better                                                         + IIb/IIIa better
                                                                                       better
               better
                                                  * High risk = ↑Tn, CKMB or ECG Δ’s
                  SWITCH III


(Switching from fondaparinux to bivalirudin or
 unfractionated heparin in patients with acute
  coronary syndromes without ST-segment
elevation undergoing percutaneous coronary
              intervention (PCI))


   Principal Investigator: Ron Waksman, MD
                          SWITCH III Study AIM


       ►    The primary objective of this clinical trial is to
            evaluate safety of switching from fondaparinux to
            either unfractionated heparin or bivalirudin for
            patients experiencing acute coronary syndrome
            undergoing percutaneous coronary angioplasty.




SWITCH III ver 1.7
                          SWITCH III Study Design

                                         Patient Presents to
                                           ED/Cath Lab

                                    Fondaparinux Administration
                                         2.5 mg SubQ QD

                                          Catheterization
                                    ≤ 24 hours of fondaparinux

                     No PCI                                                      300 patients will
                 “Screen Failure”                          Requires PCI          be randomized


            All patients are followed
          through the duration of the                                1:1
         hospitalization or until CABG           Bivalirudin     Randomization    UFH
SWITCH III ver 1.7
            Pre-Randomization Anticoagulant
                    Switching and Bleeding
                 Overall Conclusion

►   When switching to bivalirudin was undertaken
    across the risk spectrum of ACS, 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.
 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
                    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, while preserving anti-ischemic
      efficacy.
      The Science and Medicine of ACS



Translating Advances in NSTEMI
   and STEMI into Real World
      Institutional Practice


          Harold L. Dauerman, MD
 Director, Cardiovascular Catheterization Laboratories
                 Professor of Medicine
                 University of Vermont
              Fletcher Allen Health Care
                                 University of Vermont Post-PCI Bleeding
                                    and Vascular Complication Rates
                            4
                                                          Introduction of
                           3.5                        Bivalirudin to Cath Lab
Bleeding Complication, %




                            3
                                                                 NNE Rate: 2.0% in 2006
                           2.5
                            2

                           1.5

                            1
                           0.5                                                Introduction of
                                                                            Upstream Bivalirudin
                            0
                                 2001   2002   2003   2004      2005      2006     2007

                            Any Transfusion, RPH or Repair = Bleeding Complication
Incorporation of Bivalirudin in Cath Lab for
 NSTEMI in 2003—A Cautious Beginning




                            25%          33%
                                  42%




                        Bivalirudin
                        GP IIb/IIIa Inhibitor
                        UFH alone
                                                            Signs of Hope Since 2004
                                                4
                                                                                P < 0.001 for temporal trend
                                                     3.37
                                               3.5
                                                                    3.2
            Major Vascular Complications, %*




                                                3

                                                                                   2.51
                                               2.5
                                                                                                  2.11
                                                                                                                    1.96
                                                2


                                               1.5


                                                1


                                               0.5


                                                0
                                                     2002          2003           2004            2005              2006
                                                        • Arterial injury and/or arterial injury related bleeding
                                                        • N= 36,631 Patients Undergoing PCI, NNE Registry
Dauerman, Applegate and Cohen, JACC 2007
             How We Introduced Upstream and Downstream
                  Bivalirudin: The UVMC Time Line

►   2003: Put bivalirudin on the cath lab shelf as an option for
    NSTEMI
►   2007: Educational programs for fellows, floor staff and
    attendings
►   We did not remove GPI option
►   We did NOT involve community hospitals in this decision.
    They can do whatever they want as long as they transfer and
    don’t overdose patients.
►   2008: A standardized STEMI bivalirudin approach
►   For upstream AMI utilization, bivalirudin ordered from
    pharmacy
►   In collaboration with ED (EDICT for ACS Strategy)
   Non ST-Elevation Myocardial Infarction



             NSTEMI
Transfers, Upstream Strategies, and
      Results of Clinical Trials
               What We Really Do With Transfers?
                   September 24, 2007 email from me


To:            Sullivan, Claudia A.
Cc:            Ades, Philip A.
Subject:       Transfer of John XXXXX, DOB 11/08/25

81M with NSTEMI/old LBBB, Tn 3.0 Pain free, but with NSVT.
ASA/clopidogrel 300 po/enoxaparin. From Adirondack Medical
Center.

Class I transfer. Change to bivalirudin on arrival. DNR—reverse
POLST (wants a cath, but no CABG). Echo today, cath tomorrow
(or today if unstable).

Thanks,
Harry
                                              Protocol Major/Minor Bleed by
                                            SWITCH and Randomized Therapy

                             35%                                                                  33.8%           34.8%
Protocol major/minor bleed




                             30%                                                    28.6%   †

                             25%

                             20%
                                     15.6%                           16.7%
                                                       15.3%
                             15%
                                                  *

                             10%

                             5%

                             0%
                                     Naïve→             UFH→         LMWH→        Naïve→ UFH +    UFH→UFH LMWH→UFH
                                   Bivalirudin‡       Bivalirudin   Bivalirudin    GP IIb/IIIa‡   + GP IIb/IIIa + GP IIb/IIIa
                                    (n=2,345)          (n=287)       (n=258)        (n=2,325)       (n=349)       (n=313)


*P=NS for all 3-way comparisons versus bivalirudin alone; †P<.05 vs prior treatment with UFH or enoxaparin;
‡naïve=no prior AT therapy in preceding 48 hours.




Gibson CM et al. Am J Cardiol. 2007;99:1687-1690.
                           REPLACE-2 One-Year Cumulative Mortality in
                               Prespecified High-Risk Subgroups

                                                 Cumulative mortality at 1 year

                    8
                               6.8         6.9
                                                                                      Bivalirudin with
                    6                                                                 “provisional” GP IIb/IIIa
   Percentage (%)




                         4.1                               4.3                        Heparin + GP IIb/IIIa
                                                                       3.9
                    4                3.6
                                                     2.9                            3.0
                                                                 2.3                               2.6
                    2                                                         1.4            1.5            1.5 1.8


                    0
                        CrCl ≤60 Age >75            Age >65      Di abet es    UA*          UA* or            ACS†
                        (n=1,010)    (n=795)         (n=2,489)   (n=1,606)    (n=2,046)      ACS†           (n=1,330)
                                                                                            (n=2,553)


*UA at any time, within preceding 48 hours or before.
†ACS defined as UA within preceding 48 hours or MI within prior 7 days.

CrCl= creatinine clearance.
Lincoff AM et al. JAMA. 2004;292:696-703.
Stone GW. J Invasive Cardiol. 2004;16(suppl G):12-17.
                   Transfer to Cardiology Floor

►   Enoxaparin held—wait 8
    hours from community
    hospital last dose.
►   Then, start upstream
    bivalirudin
►   Patient pain free—1st
    case next A.M
►   DES, no eptifibatide,
    closure device, 150 mg
    clopidogrel
►   Ambulate at 6 hours
►   D/C following 0900 A.M.
                               The University of Vermont Experience—GPI Trigger Strategy
                                     Impact of REPLACE 2 and ACUITY Trials: 91% Bivalirudin Use


                           REPLACE 2         ACUITY              ►   Elective PCI—24%
                     100
                                                                 ►   Urgent PCI—30%
                     90
                              Eptifibatide
                                                                 ►   Emergent PCI—30%
                     80       Bivalirudin
                     70
                                                                 ►   Pre-Load Clopidgrel in
                                                                     60% and Switching in
   PCI Patients, %




                     60
                                                                     45% of Patients
                     50
                                                                 ►   Note: Increasing
                     40
                                                                     utilization of bivalirudin
                     30                                              but with maintained
                     20                                              trigger-induced
                     10
                                                                     adjunctive use of GP
                                                                     IIb/IIIa antagonist
                      0

                              2005               2007


Ahmed B and Dauerman HL, Submitted ESC 2008
                              If Patient is not Clopidogrel Exposed,
                               Do We Use Bivalirudin? Definitions?
            UFH/Enoxaparin + IIb/IIIa (N=1722)                          UFH/Enoxaparin + IIb/IIIa (N=811)
            Bivalirudin Alone (N=1789)                                  Bivalirudin Alone (N=804)


      RR [95%CI]         RR [95%CI]           RR [95%CI]           RR [95%CI]          RR [95%CI]            RR [95%CI]
    0.81 (0.68-0.96)   0.96 (0.77-1.20)     0.50 (0.37-0.67)     1.07 (0.83-1.39)    1.37 (1.00-1.88)      0.61 (0.39-0.97)

  13.8%
                                                                       12.7%
                                                               11.8%
          11.1%                                                                            10.3%
                       8.4%   8.1%
                                           7.2%                                     7.5%
                                                                                                         5.7%

                                                   3.6%                                                           3.5%




   Net clinical         Ischemic          Major bleeding       Net clinical          Ischemic           Major bleeding
   outcomes            composite                               outcomes             composite
                                                                        Not Thienopyridine Exposed
        Thienopyridine Exposed

Stone GW, McLaurin BT. NEJM. 2006 Nov 23;355(21):2203-16
                        Timing of Clopidogrel Administration and
                           30-Day Risk of Ischemic Outcomes

                   Risk ratio (RR) ±95% CI for the triple ischemic endpoint
                           (death, MI, unplanned revascularization)

           Pre-PCI clopidogrel
    N=3429, RR 0.92 [95% CI 0.74,1.15]


           Peri-PCI Clopidogrel
     N=1044, RR 1.26 [95% CI 0.82,1.92]                                     pinteraction = 0.35
          Post-PCI Clopidgrel
        (> 30 minutes After PCI)
     N=519 RR 1.48 [95% CI 0.89, 2.47]

               No Clopidogrel
      N=88 RR 2.62 [95% CI 0.89, 7.72]


                                            0      1   2   3     4     5      6      7    8
                        Bivalirudin alone better       Heparin + GPIIb/IIIa better


S. Steinhubl TCT 2007
                     ACUITY PCI: Impact of Clopidogrel
                                               1-year Mortality
 PCI troponin+ patients                      Hazard Ratio ±95% CI
                                                                                    HR (95% CI)



   Clopidogrel at any time prior to
   hospitalization, randomization or end
                                                                                1.07 (0.66-1.73)
   of angiography (n=1,891)

   Clopidogrel after end of angio-
                                                                                1.09 (0.46-2.58)
   graphy to 30’ post PCI (n=649)

   Clopidogrel after 30’                                                        0.56 (0.17-1.93)
   post PCI (n=307)

    No clopidogrel (n=51)                                                      3.07 (0.32-29.49)

                            0.1                    1                      10
                        Bivalirudin Alone Better       UFH/Enox + IIb/IIIa Better




H.White ESC 2007
                Does Periprocedural Infarct Increase With
               Upstream and Downstream Bivalirudin? No!


                                   2005            2007
        Outcome                  1st 6 months    1st 6 Months      P value
                                     N=373          N=361

    Any Transfusion (%)              2.0             1.0              NS

         Death (%)                   3.0             1.0              0.08

Urgent revascularization (%)         2.0             1.0              NS

  MI, 50% CK-MB Rise (%)             4.0             1.0              0.02

Mechanical Complication (%)          8.0             6.0              NS




             Clopidogrel preload in approx 60% of PCI patients
      CK-MB on all patients the day after PCI (University of Vermont data)
    ST-Elevation Myocardial Infarction



            STEMI
Switching, Clopidogrel and Stent
          Thrombosis
                    The Standard of Care for STEMI PCI in 2005:
                                    National Registry of Myocardial Infarction-5


                                                                         Primary PCI for STEMI N= 7,629



                                                                 Bivalirudin PCI
                                                                                                                No Bivalirudin PCI
                                                                  N=320 (4%)
                                                                                                                     N= 7,309



                                         Bivalirudin and GPIIbIIIa PCI               Bivalirudin Alone
                                                 N=177 (55%)                           N=143 (45%)

                                                                                                                                  Clopidogrel Prior
                                                                                                                                                           Clopidogrel
                                                                                                                                       to PCI
                      Clopidogrel     Prior to PCI         Not Prior to PCI            Clopidogrel                                                        N=6878 (94%)
                                                                                                                                   N=1466 (21%)
                     N=171 (97%)      N=37 (21%)           N= 140 (79%)               N=137 (96%)



                     Clopidogrel                                                       Prior to PCI                          GP IIbIIIa Inhibitor use
                     Prior to PCI                                                      N=31 (23%)                              N=6,873 (94%)
                     N=41 (24%)
                                           Abciximab N=64 (36%)
                                           Eptifibatide N=93 (52%)
                                                                                                              Prior to PCI                   Not Prior to PCI
                                           Tirofiban N=1 (1%)
                                                                                                              N=2,489 (36%)                  N= 4,384 (64%)
                                           Unkown N=19 (11%)


                                                                                                                       Abciximab N=2,283 (33%)
                             Abciximab N=8 (22%)           Abciximab N=56 (40%)                                        Eptifibatide N=3,551 (52%)
                             Eptifibatide N=27 (73%)       Eptifibatide N=66 (47%)
                                                                                                                       Tirofiban N=154 (2%)
                             Tirofiban N=1 (3%)            Tirofiban N=0 (0%)
                             Unknown N=1 (2%)              Unknown N=18 (13%)
                                                                                                                       Unknown N= 885 (13%)


                                                                                                      Abciximab N=622 (25%)          Abciximab N=1661 (38%)
                                                                                                      Eptifibatide N=1621 (65%)      Eptifibatide N=1930 (44%)
                                                                                                      Tirofiban N=99 (4%)            Tirofiban N=55 (1%)
                                                                                                      Unknown N=147 (6%)             Unknown N=738 (17%)




Dauerman and French, Coronary Artery Disease, 2006
                   Implementation of HORIZONS AMI PCI
                        Pharmacologic Aspects of Management
 ► 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            at the REPLACE-2 Dosing (NOT ACUITY)
     ●   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 (abciximab) or
         12-18 (eptifibatide)

* If pre randomization UFH administered, ACT is checked first
** If pre randomization UFH administered, started 30’ after last bolus
       Primary PCI for STEMI: Community Hospital Algorithm
       ASA, Clopidogrel and UFH and then Switch to Bivalirudin at UVM




                                  27 miles, on interstate highway




Time from ED Presentation at NWMC to Open Artery at FAHC:
                        88 Minutes
                   Do I Have to Load Bivalirudin in the ED or Can I Start in the
                     Cath Lab? The HORIZONS AMI Switching Perspective


                                         UFH + GP IIb/IIIa                    Bivalirudin
                                               (N=1802)                         (N=1800)
    UFH pre randomization                        65.6%                           65.6%
    Antithrombin in CCL
     ► UFH                                    98.9%                            4.1%
     ► Bivalirudin                             0.4%                           96.9%
     ► Peak ACT                            264 [228, 320]                  357 [300, 402]
    GP IIb/IIIa in CCL                        94.5%*                           7.2%*
     ► Bail-out per protocol**                   -                             4.4%
     ► Abciximab                              49.9%                            4.0%
     ► Eptifibatide                           44.4%                            3.1%
     ► Tirofiban                               0.2%                            0.1%


G Stone TCT 2007           *97.7% and 7.5% during PCI. ** For giant thrombus or refractory no reflow after
                           PCI. CCL = cardiac catheterization laboratory
                               Bivalirudin Improves Mortality in STEMI

                                      Heparin + GPIIb/IIIa inhibitor (n=1802)
                                      Bivalirudin monotherapy (n=1800)



                                                                                       3.1%
                   Death (%)




                                                                                       2.1%

                                                                        HR [95%CI] =
                                                                       0.66 [0.44, 1.00]
                                                                          P=0.048

                                                 Time in Days


G Stone TCT 2007
                             The UVM STEMI Order Sheet
                One Pathway for Primary PCI and ED Collaboration

                              TESTS AND MEDICATIONS
EKG: EKG for diagnosis performed within 10 minutes of ED arrival. No further EKG required.

LABORATORY:
7. CBC,lytes, BUN, CR, PT, PTT, Lipids, LFT’s, CK, CK-MB and TnI sent immediately
   on arrival: STAT
8. Other labs:

MEDICATIONS: Weight: __kg             Estimated / Actual (Circle one)
    Check patient not allergic to aspirin
9. Aspirin Non- Enteric Coated 325 mg PO Daily
10. Clopidogrel 600 mg PO x one
11. Bivalirudin bolus 0.75 mg/kg IV, then infusion 1.75 mg/kg/hr (STAT from
    Pharmacy)
12. Saline Lock with routine flushes every 8 hours

OPTIONAL:
13. Nitroglycerin infusion: 400 mcg/ml infusion at _______ mcg/kg/min IV
    Titrate to chest pain, keep systolic BP >90.
14. Lopressor 5 mg IVP x 1 if HR > 80 and SBP > 140
              The Bivalirudin Strategy for STEMI PCI




ASA, clopidogrel 600 po x 1, bivalirudin and stent
                        What About The Stent Thrombosis Risk?


                          UFH + GP IIb/IIIa       Bivalirudin               P
                              (N=1553)              (N=1571)              Value
        ARC definite
                                1.9%                 2.5%                  0.33
        or probable*

             Definite           1.4%                 2.2%                  0.11

            Probable            0.5%                 0.3%                  0.26

              Acute             0.3%                 1.3%                 0.0009
            (≤24 hrs)
            Subacute            1.7%                 1.2%                  0.30
        (>24 hrs – 30d)



G Stone TCT 2007
                                   *Protocol definition of stent thrombosis, CEC adjudicated
             Risk Stratification For STEMI Stent Thrombosis
                        The Importance of Thrombus Burden




                Sianos, G. et al. J Am Coll Cardiol 2007;50:573-583


Large thrombus burden (LTB), defined as thrombus burden > 2 vessel
                 diameters: Approx 25% of STEMI
                                                Drug Eluting Stent Thrombosis and Large Thrombus
                                                Burden: Modifying Strategy In Highest Risk Patients


                             15
                                                                                             ►   Large Thrombus
Cumulative IRA-ST Rate (%)




                             12                               LTB vs. STB, p<0.001
                                                                                             ►   Burden> 5 fold
                                                                                             ►   Increased Risk of
                                                                            LTB      8.2%
                             9                                                                   30 Day Stent
                                                      5.8%
                                                                                                 Thrombosis
                             6
                                              3.2%
                                   2.7%                           Total Population
                             3                        2.1%                            3.2%
                                   1.1% 1.4%                                STB              Thrombectomy
                                                                                      1.3%
                                                                                             Prolonged Bivalirudin
                             0     0.5%        0.7%       0.7%                               GPI
                                  0 1     3      6    9      12   15   18    21      24
                                                      Months of follow-up


Sianos, G. et al. J Am Coll Cardiol 2007;50:573-583
                            ACUITY and Large Thrombus Data
                            The Rationale for Selective Adjunctive GPI


                                Heparin      Bivalirudin   Bivalirudin   P value
            ACUITY              + IIb/IIIa    + IIb/IIIa     alone
                                               (N=241)       (N=249)
                                                                         3-way
                                 (N=222)


       Any thrombotic
                                  8.6%          3.7%          5.6%        0.09
    complication post PCI


        Final TIMI flow 3         90.5%        93.7%         90.7%        0.37


      Final blush grade 3         81.5%        79.0%         79.5%        0.78


       * New or ↑ thrombus, abrupt closure, no reflow, or distal embolization


G. Stone AHA 2006
                                 The Data on GPI and Bivalirudin for Large
                                 Thrombus Patients is Favorable (ACUITY)

                          Heparin+IIb/IIIa (N=222)   Bivalirudin+IIb/IIIa (N=241)   Bivalirudin alone (N=249)

                                p=0.37    p=0.58            p=0.22     p=0.61            p=0.67    p=0.03
      30 day events (%)




                          17.1%
                                          15.3%
                                  14.1%                               13.3%
                                                     11.7%

                                                              8.3%
                                                                                    7.2%
                                                                                            6.2%
                                                                                                    2.8%



                          Net clinical outcome       Composite ischemia             Major bleeding (non-
                                                                                          CABG)


G. Stone et al. Lancet 2007; 369: 907–19
                           Projecting What Happens if You Use GPI in
                            25% of Your Bivalirudin STEMI Patients


                    9                       Bival +
                                      8.3   UFH + GPI            8.3
                    8
                        P < 0.001
                    7
                                               Still P < 0.001
Major Bleeding, %




                    6
                               4.9                       5.2
                    5
                    4
                    3
                    2
                    1
                    0
                             HORIZONS 7%                UVM Implemented
                                                        HORIZONS—25%

Assumes Bival + GPI bleeding rate of 6.8%
            Incorporation of HORIZONS AMI and Large
              Thrombus Data—STEMI Algorithm

►   ED STEMI—25% of Patients
►   ASA/clopidogrel 600 mg po
    load and bivalirudin
►   Bolus and infusion of
    eptifibatide after wiring
    vessel shows Large
    Thrombus Burden
►   Angiojet and Bare Metal
    Stent
►   150 mg clopidogrel and 18
    hours of eptifibatide
►   No ambulation until
    eptifibatide off (18 hours)
►   D/C on Day 3 post MI
    PCI Capability or                           STEMI:
                                                                             No PCI Capability and
< 60 minute Transfer Time                 Within 24 Hours CP               > 60 minute Transfer Time

                                                   ASA
         UFH or Bivalirudin:
                                                  325 po                       UFH (60 U/Kg)
GPI Optional: Avoid if High Bleed Risk
     B Blockers ONLY if HTN                                               Beta Blockers only if HTN


  Clopidogrel                                                                               Clopidogrel
                         90 minutes                                                           300 po
    600 po
                          To Open
                           Artery             Emergent Transfer                Lytic
       Primary PCI with Stenting:                                         Contraindicated
  GPI/Thrombectomy if Large Thrombus
or as Bailout; Otherwise, Bivalirudin Alone                   Rescue
                                                                PCI:
  Continue bivalirudin for                                     Class I
    2 hours after PCI             If Reperfusion Fails,      Indication
                                                                               TNK and UFH
                                 Emergent PCI with stent
  ASA/Clopidogrel
       Statin                                                 Transfer
   Groin Closure               If no CP and less than 50%                           Transfer from
   Cardiac Rehab               ST Elevations, PCI at 12-24     The NSTEMI           Community ER
 Lopressor 12.5 bid                  Hours with Stent            Paradigm             To PCI Site
                                                               of 4-48 Hours
                            Conclusions
                    Key Implementation Points

► Bivalirudin can be safely instituted across the spectrum of
  PCI patients, including those with NSTE-ACS and STEMI.
► Clopidogrel 600 mg po load may be done in ED or
  immediately after PCI.
► Community referring hospitals may use antithrombotic
  therapy of choice—then switch to bivalirudin on arrival to PCI
  institution.
► STEMI requires an algorithm for care and bivalirudin is the
  baseline strategy. But, bivalirudin may be instituted in the ED
  or the cath lab, depending upon local issues.
► Enhanced management of large thrombus burden should be
  considered especially during the most “vulnerable” 2 hours
  after PCI.
                      Questions for the Panel

► Does a consistent, unified upstream strategy for anticoagulation
  across the STEMI and NSTE-ACS risk spectrum make sense?
  When does it? When doesn’t it?


► Given that bleeding appears to be a driver of MACE events,
  including mortality, in ACS and STEMI, and since switching to
  bivalirudin appears to decrease bleeding, should this switching
  strategy be promulgated in patients undergoing PCI?


► What are the best ways, from an institutional/process-of-care
  perspective, to establish a consistent antithrombotic strategy for
  this patient population?


► Other issues? We’ll answer your questions!

				
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