2. Introduction and Objectives Issues and challenges in ACS
High Risk Patients with ACS —
EuroPCR 2008, Barcelona, Spain
Introduction and Objectives Issues and challenges in ACS
Philippe Gabriel Steg
INSERM U-698
Hôpital Bichat – Claude Bernard
Université Paris VII – Denis Diderot

3. Disclosures Speaker’s name: Philippe Gabriel Steg
 I have the following potential conflicts of interest to report:
 Consulting/Advisory Board: AstraZeneca, Boehringer-Ingelheim, BMS, GSK, MSD, Nycomed, sanofi-aventis, Servier, Takeda, The Medicines Company
 Research Grant: sanofi-aventis
 Speaker’s Bureau: Boehringer-Ingelheim, BMS, GSK, Nycomed,
sanofi-aventis, Servier, ZLB-Behring
 I do not have any potential conflict of interest

4. The Landscape
A changing pattern of care for all high-risk ACS

5. Trends in Management of STEMI in the GRACE Registry
Fox KAA et al. JAMA 2007;297:

6. The Landscape A changing pattern of care for all high-risk ACS
…and outcomes which are improving

7. In-Hospital and 6-Month Outcomes in Patients With STEMI or LBBB
Fox KAA et al. JAMA 2007;297:

8. CRUSADE In-Hospital Outcomes: Data from 2006
Death %
(Re)-Infarction %
CHF %
Cardiogenic Shock %
Stroke %
RBC Transfusion* %
*Excluding CABG-related transfusions
CRUSADE DATA: January 1, 2006 – December 31, 2006 (n= 29,825)

9. The Landscape A changing pattern of care for all high-risk ACS
…and outcomes which are improving
A growing level of complexity

10. Antithrombotics for ACS More and More Choices (and Combinations)
Fonda
Direct TIs
Lytics
Clopidogrel
GP IIb/IIIa inhibitors
LMWH
Heparin
Aspirin

11. Choices Impacting Antithrombotic Therapy
Anticoagulants: UFH LMWH Fonda Bival
Antiplatelets: ASA (dose) Clopidogrel (time/dose)
IV antiplatelets: None Abcix Ept/Tiro (timing)
Cath strategy: Early Delayed Never
72 Different Combinations!

12. Treatment of ACS is a Jungle !
Anticoagulant Rx
UFH
Enoxaparin
Bivalirudin
Fondaparinux
Warfarin
? Anti X
? Anti II
Timing
Antiplatelet Rx
ASA
Clopidogrel
? Prasugrel
? AZD 6140
GpIIb/IIIA IV blockers
? Cangrelor
? TRA
Revascularization
PCI BMS
DES
CABG
Patient
Bleeding risk
Comorbidities
Risk of thrombotic event

13. The Landscape A changing pattern of care for all high-risk ACS
…and outcomes which are improving
A growing level of complexity
Use and timing of interventions impact therapeutic choices

14. The Landscape A changing pattern of care for all high-risk ACS
…and outcomes which are improving
A growing level of complexity
Use and timing of interventions impact therapeutic choices
Fortunately, we have guidelines to assist us !

15. Objectives
Know the current guidelines for the management of STEMI and NSTE ACS
Understand their implications for patient management

16. New Horizons for Patients with ST-Elevation Myocardial Infarction
Gregg W. Stone MD
Columbia University Medical Center Cardiovascular Research Foundation 16

17. Potential Conflicts of Interest
Speaker’s name: Gregg W. Stone, MD
 I have the following potential conflicts of interest to report:
 Consulting
 Employment in industry
 Stockholder of a healthcare company
 Owner of a healthcare company
 Grant/Research Support: The Medicines Company and Boston Scientific
 I do not have any potential conflict of interest 17

18. 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

19. Cumulative % Mortality Time from Randomization in Days
Impact of Major Bleed and MI after Elective and Urgent PCI 1-Year Mortality (N=6,012)
With major bleed
8.8%
With MI
5.7%
Cumulative % Mortality
Without major bleed
2.0%
1.9%
Without MI
Time from Randomization in Days
Stone GW. J Inv Cardiol 2004;16(suppl G):12–17.

20. 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)
<0.0001
30–60 mL/min
3.34
(1.92–5.78)
60–90 mL/min
1.57
(0.96–2.57)
CHF
Yes
4.38
(2.83–6.78)
Major Bleeding
3.26
(1.78–5.96)
0.0001
2.77
(1.62–4.75)
0.0002
Urg
(1.15–6.71)
.024
Hx angina
2.18
(1.25–3.81)
0.006
Prior MI
1.81
(1.09–3.03)
0.023
Diabetes
1.64
(1.10–2.44)
0.015
Stone GW. J Inv Cardiol 2004;16(suppl G):12–17. 20

21. 1-year Mortality All 6,012 Patients (ITT)
2.5%
P value = 0.16
1.9%
Cumulative Deaths
Days
Lincoff AM et al. JAMA 2004;292:696–703

22. Days from Randomization
Impact of MI and Major Bleeding (non-CABG) in the First 30 Days on Risk of Death Over 1 Year
1 year Estimate
28.9%
Both MI and Major Bleed (N=94)
Major Bleed only (without MI) (N=551)
12.5%
MI only (without Major Bleed) (N=611)
8.6% 30
3.4%
No MI or Major Bleed (N=12,557) 25 20
Mortality (%) 15 10 5 30 60 90
120
150
180
210
240
270
300
330
360
390
Days from Randomization
Stone GW. ACC 2007

23. 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
deaths
HR ± 95% CI
HR (95% CI)
P-value
Myocardial infarction
5.25 ( )
<0.0001
Major bleeding without or before transfusion
3.04 ( )
Major bleeding after transfusion
5.45 ( )
42.0*
38.2**
*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

24. Of 13,819 enrolled pts, 524 (3.8%) died within 1 year
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
deaths
HR ± 95% CI
HR (95% CI)
P-value
Myocardial infarction
2.51 ( )
<0.0001
Major bleeding without or before transfusion
2.00 ( )
Major bleeding after transfusion
3.93 ( )
51.5*
66.5**
*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

25. ACUITY: Early and Late Mortality Landmark analysis4
30 day
Estimate P
(log rank)
1.4%
0.53
1.6%
0.39 —
Estimate P
(log rank)
3.1%
0.54
2.7%
0.21
2.3%
30d - 1 year —
UFH/Enoxaparin + IIb/IIIa
Bivalirudin + IIb/IIIa
Bivalirudin alone 3
Mortality (%) 2 1 30 60 90
120
150
180
210
240
270
300
330
360
390
Days from Randomization
Stone GW. JAMA 2007;298:

26. Harmonizing Outcomes with Revascularization and Stents in AMI
≥3400* pts with STEMI with symptom onset ≤12 hours
UFH + GP IIb/IIIa inhibitor
(abciximab or eptifibatide)
Bivalirudin monotherapy
(± provisional GP IIb/IIIa)
Aspirin, thienopyridine R
1:1
Emergent angiography, followed by triage to…
Primary PCI
CABG –
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,
1 year, and then yearly through 5 years
*To rand 3000 stent pts

27. Harmonizing Outcomes with Revascularization and Stents in AMI
3602 pts with STEMI R
1:1
UFH +
GP IIb/IIIa
N=1802
Bivalirudin
Monotherapy
N=1800
Randomized 9 15
• • • Withdrew • • •
• • • Lost to FU • • • 10 13
N=1778
(98.7%)
N=1777
(98.7%)
30 day FU*
ITT population
N=1802
N=1800
* Range ±7 days
Stone GW et al. In press.

28. Primary Outcome Measures (ITT)
Diff = -2.9% [-4.9, -0.8]
RR = 0.76 [0.63, 0.92]
PNI ≤
Psup = 0.005
Diff = -3.3% [-5.0, -1.6]
RR = 0.60 [0.46, 0.77]
PNI ≤
Psup ≤
Diff = 0.0% [-1.6, 1.5]
RR = 0.99 [0.76, 1.30]
Psup = 0.95
1 endpoint
1 endpoint
*Not related to CABG
**MACE = All cause death, reinfarction, ischemic TVR or stroke

29. 30 Day Bleeding Endpoints*
UFH + GP IIb/IIIa
(N=1802)
Bivalirudin
(N=1800)
P Value
Protocol Major, non CABG**
8.3%
4.9%
<0.0001
Protocol Major, All
10.8%
6.8%
Protocol Minor
15.4%
8.6%
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%
GUSTO LT*** or Severe
0.6%
0.4%
0.49
GUSTO Moderate
GUSTO LT or Sev or Mod
5.6%
*CEC adjudicated, except protocol minor;
**Primary endpoint; ***Life threatening

30. Thrombocytopenia P = 0.002 P = 0.04 P = 0.02 <100,000 cells/mm3
Stone GW et al. In press.

31. 30 Day MACE Components* UFH + GP IIb/IIIa (N=1802) Bivalirudin
P Value
Death
3.1%
2.1%
0.047
- Cardiac
2.9%
1.8%
0.028
- Non cardiac
0.2%
0.3%
0.75
Reinfarction
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
2.5%
0.13
- Ischemic remote TVR
1.0
Stroke
0.6%
0.68
*CEC adjudicated
Stone GW et al. In press.

32. 30 Day Mortality 3.1% Death (%) 2.1% P=0.048 Time in Days
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
Number at risk
Bivalirudin
Heparin + GPIIb/IIIa
Stone GW et al. In press.

33. 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]
P=0.029
2.9%
Death (%)
Cardiac
1.8%
Non cardiac
0.3%
0.2%
Time in Days
Number at risk
Bivalirudin
Heparin + GPIIb/IIIa
Stone GW et al. In press.

34. 30 Day Stent Thrombosis (N=3,124)
UFH + GP IIb/IIIa
(N=1553)
Bivalirudin
(N=1571) P
Value
ARC 30d definite or probable stent thrombosis*
1.9%
2.5%
0.30
- definite
1.4%
2.2%
0.09
- probable
0.5%
0.3%
0.24
- acute (≤24 hrs)
1.3%
0.0007
- subacute (>24 hrs – 30d)
1.7%
1.2%
0.28
*Protocol definition of stent thrombosis, CEC adjudicated

35. 30 Day Mortality: PCI Cohort
Heparin + GPIIb/IIIa inhibitor (n=1662)
Bivalirudin monotherapy (n=1678)
HR [95%CI] =
0.63 [0.40, 0.99]
P=0.049
2.8%
Death (%)
Cardiac
1.8%
Non cardiac
0.2%
0.1%
Time in days
Number at risk
Bivalirudin
Heparin + GPIIb/IIIa
Stone GW et al. In press.

36. 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

37. 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 [5.44,22.59] < [8.2,9.6] 0.83
Ischemic TVR [3.36,14.18] < [6.3,8.4] 0.83
Stent thrombosis, definite**
- any [3.93,29.18] < [3.7,4.8] 0.83
- acute (<24 hours) [0.78,44.30] [-0.3,1] 0.82
Stroke [1.67,17.69] [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

38. 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) [2.67, 7.33] < [16.3,22.5] 0.85
Major bleed (all) [3.73, 9.41] < [25.6,31.3] 0.86
Transfusion [2.09, 7.20] < [8.4,13.8] 0.83
Thrombocytopenia**
- <100,000 cells/mm [2.22, 6.84] < [8.2,12.8] 0.78
- <50,000 cells/mm [2.93,14.18] < [4.6,6.5] 0.78
- <20,000 cells/mm [1.20,20.66] [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

39. 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
[2.72,34.91]
<0.001
Major bleeding (non CABG)
4.66
[2.84, 7.63]
<0.001
Ischemic TVR
1.11
[0.29, 4.21]
0.88
Stroke
2.64
[0.71, 9.75]
0.15
Hazard Ratio [95% CI]
0.01
0.1 1 10
100
C-statistic = 0.87.

40. Time-updated covariate adjusted Cox model relating 30-day events to 30-day mortality - Complete model with MACE components and major bleeding -
Attributable
Deaths
Risk Factor
HR [95% CI]
P-value
Reinfarction
Incidence 69 (2.2%)
10 deaths with event
9.75
[2.72,34.91]
9.0*
[6.3, 9.7]
<0.001
Major bleeding
(Non CABG)
Incidence 238 (6.8%)
26 deaths with event
4.66
[2.84, 7.63]
20.4**
[16.8, 22.6]
<0.001
Hazard Ratio [95% CI]
0.01
0.1 1 10
100
*9.7% of 93 total deaths
**21.9% of 93 total deaths
C-statistic = Attributable deaths = N deaths among pts with the time updated event (attribute) X (adj. HR – 1)/adj. HR

41. 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
Deaths
Risk Factor
HR [95% CI]
P-value
Stent thrombosis
(definite)
Incidence 57 (1.8%)
5 deaths with event
10.62
[3.96, 28.48]
4.5*
[3.7, 4.8]
<0.001
Major bleeding
(non CABG)
Incidence 195 (6.2%)
18 deaths with event
6.22
[3.33, 11.60]
15.1**
[12.6, 16.4]
<0.001
Hazard Ratio [95% CI]
0.01
0.1 1 10
100
*8.3% of 54 total deaths
**28.0% of 54 total deaths
C-statistic = Attributable deaths = N deaths among pts with the time updated event (attribute) X (adj. HR – 1)/adj. HR

42. 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.

43. SWITCH
Changing Anticoagulants in Midstream — What Are the Benefits and Risks?
Harvey White
Green Lane Cardiovascular Service and
Cardiovascular Research Unit
Auckland City Hospital; Auckland, New Zealand
Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ

44. Potential conflicts of interest
Speaker’s name: Harvey D. White
 I have the following potential conflicts of interest to report:
 Research Grants: Sanofi Aventis, The Medicines company, Eli Lilly, Roche,Schering Plough, Pfizer, Johnson and Johnson, Astra Zenica, Merck Sharpe and Dohme and NIH
 Consulting Fees: The Medicines Company
 Employment in industry
 Stockholder of a healthcare company
 Owner of a healthcare company
 I do not have any potential conflict of interest

45. Background ACS patients Published studies and perceptions
87% of patients receive either UFH or Enox 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 Enox 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
Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ
1 CRUSADE( 1Q-2006 results); 2 Synergy results; JAMA 2004;
3 OASIS -5; Yusuf et al, NEJM 2006; 4 Cohen et al, JACC 2006;

46. Switching
Concern about switching antithrombins in patients with ACS (lessons from SYNERGY)
European guidelines
Why should switching to bivalirudin monotherapy be reasonable?
Mechanistic rationale for switching
SWITCH
REPLACE 2
ACUITY
Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ 46

47. ESC Non-STEACS Guidelines
At PCI procedures, the initial anticoagulant should also be maintained during the procedure regardless of whether this treatment is UFH (I-C), enoxaparin (IIb-B), or bivalirudin (I-B)
Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ
EHJ 2007;28:

48. SWITCH
Definitions
Switch: Protocol mandated change in antithrombotic therapy at randomization
Crossover : Post randomization change in antithrombotic therapy due to physician choice
Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ

49. Is it better to switch to bivalirudin or remain on consistent therapy?
ACUITY — SWITCH
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?
Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ
White HD. In Press JACC 49

50. ACUITY – Primary Results
UFH/Enoxaparin + GPI vs. Bivalirudin Alone
UFH/Enoxaparin+GPI (N=4603)
Bivalirudin alone (N=4612)
PNI <0.0001
PSup = 0.015
PNI = 0.011
PSup = 0.32
PNI <0.0001
PSup <0.0001
30 day events (%)
11.7%
10.1%
7.3%
7.8%
5.7%
3.0%
Net clinical outcome
Ischemic composite
Major bleeding

51. ACUITY — Switch 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
White HD, et al. J Am Coll Cardiol 2008;51:1734–41 51

52. ACUITY – Switch Consort
CONSISTENT UFH/Enox N = 2137
SWITCH Bivalirudin N = 2078
UFH→UFH N = 1294
Enox→Enox N = 843
UFH→Biv N = 1313
Enox→Biv N = 765
Pts on Prior AT N = 4215 ╪
╪ excludes Arm B and pts. with multiple crossovers, missing data
Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ

53. Consistent vs. Switch
Comparing Consistent therapy on Enox + GPIIb/IIIa Inhibition vs. Switch to Bivalirudin Alone
Consistent Enox + GPIIb/IIIa Inhibition (N = 843)
Switch to Bivalirudin alone (N = 765)
P=0.15
0.80 [0.60 – 1.81]
P=0.43
0.86 [0.60 – 1.25]
P=0.03
0.58 [0.35 – 0.96]
11.0%
8.9%
7.0%
6.1%
5.0%
2.9% 20 15
30 day events (%) 10 5
Net clinical outcome
Ischemic composite
Major bleeding
Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ
White HD, et al. J Am Coll Cardiol 2008;51:1734–41

54. ACUITY – Switch Consistent vs. Switch High Risk
High Risk Patients
Comparing Consistent UFH/Enox vs Switch Bivalirudin
Consistent
UFH/Enox
N = 1581
Switch
Bivalirudin
N = 1496 RR
Net Clinical Outcome
13.0%
10.6%
0.82 [ ]
Ischemia
8.2%
7.7%
0.94 [ ]
Major Bleeding
6.5%
3.5%
0.51 [ ]
Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ

55. ACUITY – SWITCH Consistent vs. Switch Patients Undergoing PCI
PCI Patients
Comparing Consistent UFH/Enox vs Switch Bivalirudin
Consistent
UFH/Enox
N = 1236
Switch
Bivalirudin
N = 1292 RR
Net Clinical Outcome
13.2%
11.8%
0.90 [ ]
Ischemia
8.2%
9.0%
1.10 [ ]
Major Bleeding
6.7%
3.5%
0.52 [ ]
Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ

56. Prior Antithrombin Therapy
ACUITY: Switch
30 Days
Prior Antithrombin Therapy
Relative Risk ± 95% CI
RR (95% CI)
Composite Ischemia
0.93 ( )
Major Bleeding
0.49 ( )
Net Clinical Outcome
0.77 ( ) 1 2
Switch to Bivalirudin Better
Consistent UFH/Enox + IIb/IIIa Better
Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ
White HD, et al. J Am Coll Cardiol 2008;51:1734–41

57. Naïve to Antithrombin Therapy
ACUITY — Switch
30 Days
Naïve to Antithrombin Therapy
Relative Risk ± 95% CI
RR (95% CI)
Composite Ischemia
1.11 ( )
Major Bleeding
0.52 ( )
Net Clinical Outcome
0.85 ( ) 1 2
Randomization to Bivalirudin Better
Randomization to UFH/Enox + IIb/IIIa Better
Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ
White HD, et al. J Am Coll Cardiol 2008;51:1734–41

58. ACUITY – Switch ACUITY PCI: Switch from Prior Antithrombin
30-Day Results
1-Year Results
Risk Ratio ± 95% CI
Hazard Ratio ± 95% CI
RR (95% CI)
HR (95% CI)
PCI (n=2528)
PCI (n=2528)
Composite ischemia
1.10 ( )
Mortality
0.93 ( )
Major bleeding
0.52 ( )
PCI HIGH RISK* (n=1988)
PCI HIGH RISK* (n=1988)
Composite ischemia
1.14 ( )
Mortality
0.99 ( )
Major bleeding
0.56 ( )
Switch to
Bivalirudin better
Consistent UFH/Enox
+ IIb/IIIa better
* High risk = ↑Tn, CKMB or ECG Δ’s
0.1 1 10
0.1 1 10
White HD. In Press JACC 58

59. Naïve to Antithrombin Therapy
Randomized to Enox + GPIIb/IIIa Inhibition (N = 842)
Randomized to Bivalirudin (N = 1427)
P=0.18
0.83 [0.63 – 1.09
P=0.74
1.06 [0.76 – 1.49]
P<0.01
0.51 [0.33 – 0.78] 20
9.5%
8.0%
5.8%
6.2%
5.0%
2.5% 15
30 day events (%) 10 5
Net clinical
Ischemic
Major
outcome
composite
bleeding
Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ

60. ACUITY – Switch Limitations
Post-hoc subgroup analysis
Pre-randomization use of anti-thrombin was not stratified
Timing and dose of last UFH and Enox was not collected in the CRF
Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ

61. REPLACE-2: SWITCH Analysis
Overall population: Urgent or elective PCI patients
(N=6,002)1
Randomize
Bivalirudin
0.75 mg/kg bolus/1.75 mg/kg/h infusion with “provisional” GP IIb/IIIa (n=2,994)1
UFH 65 U/kg with planned GP IIb/IIIa
(n=3,008)1
Naïve – no prior AT
(n=2,345)2
Prior UFH
(n=287)2
Prior LMWH
(n=258)2
Naïve – no prior AT
(n=2,325)2
Prior UFH
(n=349)2
Prior LMWH
(n=313)2
Key Message: SWITCH Retrospective Post-hoc Analysis:
Among the patients who received ANGIOMAX, 2,345 patients had not received an AT agent during that hospitalization before randomization, 287 had received UFH, and 258 patients had received LMWH. Of the patients who received GP IIb/IIIa and UFH during PCI, 2,325 patients were AT-naïve, 349 had received UFH, and 313 had received LMWH.
Outcomes for patients in each randomized arm were analyzed according to whether they had received UFH, LMWH within 48 hours of randomization or no AT (naïve) before randomization.
Reference
Gibson CM, Ten Y, Murphy SA. Association of prerandomization anticoagulant switching with bleeding in the setting of percutaneous coronary intervention (a REPLACE-2 analysis). Am J Cardiol. 2007;99:
Protocol major/minor bleeding, TIMI bleeding, transfusion, mortality
AT=antithrombin.
Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ
1. Lincoff ML et al. JAMA. 2004;292:
2. Gibson CM et al. Am J Cardiol. 2007;99: 61

62. Protocol Major/Minor Bleeding 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
34.8%
35%
33.8% †
30%
28.6%
25% *
Protocol major/minor bleed
20%
16.7%
15.6%
15.3%
15%
Key Message: Regardless of receiving prior heparin or not, patients administered ANGIOMAX experienced fewer bleeding events.
In contrast, there was a significant increase in major/minor protocol bleeding in patients administered UFH with prior heparin therapy.
Reference
Gibson CM, Ten Y, Murphy SA. Association of prerandomization anticoagulant switching with bleeding in the setting of percutaneous coronary intervention (a REPLACE-2 analysis). Am J Cardiol. 2007;99:
10% 5% 0%
Naïve→ Bivalirudin‡
(n=2,345)
LMWH→ Bivalirudin
(n=258)
UFH→ Bivalirudin
(n=287)
LMWH→UFH + GP IIb/IIIa
(n=313)
Naïve→ UFH + GP IIb/IIIa‡ (n=2,325)
UFH→UFH + GP IIb/IIIa (n=349)
*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.
Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ
Gibson CM et al. Am J Cardiol. 2007;99:

63. TIMI Major/Minor Bleeding 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%
4.3% 4%
3.5%
TIMI major/minor bleed 3% *
1.9%
1.9% 2%
1.4%
Key Message: Patients switched from UFH or LMWH 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.
Reference
Gibson CM, Ten Y, Murphy SA. Association of prerandomization anticoagulant switching with bleeding in the setting of percutaneous coronary intervention (a REPLACE-2 analysis). Am J Cardiol. 2007;99: 1% 0%
Naïve→ Bivalirudin† (n=2,345)
LMWH → Bivalirudin (n=258)
UFH→ Bivalirudin
(n=287)
LMWH→UFH+ GP IIb/IIIa
(n=313)
Naïve→UFH + GP IIb/IIIa† (n=2,325)
UFH→UFH + GP IIb/IIIa
(n=349)
*P=NS for all 3-way comparisons versus bivalirudin alone; †naïve=no prior AT therapy in preceding 48 hours.
Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ
Gibson CM et al. Am J Cardiol. 2007;99:

64. SWITCH p = 0.39 n = 30 n = 30 n = 31 GPI (0 - 4 hr) GPII (4 - 8 hr)
15%
13%
p = 0.39
10% 7%
Major Bleeding % 5% 3%
n = 30
n = 30
n = 31 0%
GPI (0 - 4 hr)
GPII (4 - 8 hr)
GPIII ( hr)
Time from last enoxaparin dose
Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ
Waksman et al. J Invasive Cardiol 2006;18:370

65. HORIZONS AMI Switching Data
UFH pre-procedure was administered to 65.8% of bivalirudin pts and 76.3% of heparin + GPIIb/IIIa pts
Bivalirudin with "provisional" GP IIb/IIIa
Heparin + GP IIb/IIIa
Pint=0.47
10%
10%
Pint=0.08
8.5%
7.5% 8%
7.2% 8%
5.6%
5.2% 6% 6%
5.2%
4.8%
4.6%
30-Day MACE
30-Day Major Bleeding 4% 4% 2%
RR [95%CI]=
0.81 [0.58,1.14]
RR [95%CI]=
1.39 [0.85,2.28] 2%
RR [95%CI]=
0.57 [0.42,0.77]
RR [95%CI]=
0.69 [0.43,1.12] 0% 0%
UFH pretreatment
No UFH
UFH pretreatment
No UFH
(n=2,553)
pretreatment
(n=2,553)
pretreatment
(n=1,042)
(n=1,042)
Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ

66. From UFH to Bivalirudin
How to Switch
From UFH to Bivalirudin
Discontinue UFH for 30 minutes before
starting bivalirudin
From LMWH to Bivalirudin
• Discontinue LMWH for 8 hours before
starting bivalirudin
Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ 66

67. Conclusions Switching to bivalirudin is safe Furthermore
Switching from any heparin to bivalirudin monotherapy is not associated with an increased risk for ischemic events
Furthermore
Switch to bivalirudin provides patients the 50% bleeding advantage of bivalirudin
Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ

68. Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ

69. Role of Bleeding Reduction in ACS
The Role and Implications of Bleeding in ACS
Role of Bleeding Reduction in ACS
Impact on Outcomes and Costs
Keith A A Fox
Edinburgh Centre for Cardiovascular Science

70. Potential conflicts of interest
Speaker’s name: Keith A A Fox
 I have the following potential conflicts of interest to report:
 Consulting
 Research grants/speaker honoraria: sanofi-aventis, Bristol-Myers Squibb, and GlaxoSmithKline
 Stockholder of a healthcare company
 Owner of a healthcare company
 Other(s)
 I do not have any potential conflict of interest .

71. How common is major bleeding in ACS?
What are the risk factors for bleeding?
The impact of anti-thrombotic therapy?
What are the consequences of bleeding?
Net clinical outcome
Costs

72. Factors Contributing to the Balance of Risks
Reduced Thrombotic and Embolic Events
Cerebral and Systemic
Bleeding Events
Anticoagulants
Anti-platelets
Anti-thrombins
ACE / ARB
Hypertension &
lipid control
Smoking cessation
Anticoagulants
Anti-platelets
Anti-thrombins
Renal dysfunction
Poor hypertension
control

73. Hierarchy of Bleeding Risk
A consistent definition
of bleeding is required
Fatal bleed
Intra-cerebral bleed
Life-threatening bleed
Bleed with hemodynamic disturbance
or requiring transfusion
or prolonging hospital stay
Minor bleeds
TIMI “ Major Bleed”: >5gm Hb drop or 5U transfusion or ICH
GUSTO “ severe/life threatening”: ICH or
hemodynamic compromise requiring treatment

74. Major Bleeding in ACS: GRACE Registry6
3.9
2.3
4.7
4.8 5 4
Overall ACS
Unstable angina
Patients % 3
Non-ST MI 2
ST-MI 1
Major bleeding
Life threatening bleeding requiring a transfusion of 2+ units
Bleeding resulting in an absolute decrease in hematocrit of ≥ 10%
Bleeding resulting in death
n= 24,045 patients
Definition
of bleeding:
European Heart Journal (2003) 24, 1815–1823

75. Multivariate Risk (Non-ST MI)
Major Bleeding (1)
Hosomer-Lemeshow p value 0.70, C statistic 0.73
Odds Ratio
(95% CI)
Thrombolytic + IIb/IIIa
4.19
IIb/IIIa
1.86
History of Bleeding
2.18
Renal Insufficiency
1.53
Moscucci et al Eur Heart J 2003

76. Multivariate Risk (Non-ST MI)
Major Bleeding
Hosomer-Lemeshow p value 0.70, C statistic 0.73
Odds Ratio
(95% CI)
Age (10yr)
1.22
Female
1.36
Inotropes (iv)
1.88
Renal Insufficiency
2.01
Diuretics
1.91
Mean Arterial Pressure (20mm )
1.04
Moscucci et al Eur Heart J 2003

77. GUSTO I Predictors of Bleeding
Variable
Odds Ratio
95% CI 2
Patients treated in US
1.76
(1.08, 2.85)
521
Age (60 v 50y)
1.30
(1.26, 1.35)
222
Weight (75 v 85kg)
1.23
(1.18, 1.28)
164
Female
1.42
(1.31, 1.53) 73
African Ancestry
1.33
(1.12, 1.57) 10
Berkowitz, Circulation 1997;95:

78. The Role and Implications of Bleeding in ACS
Bleeding and Outcome?

79. 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
0.85
0.80
0.75
0.70
None
Mild
Moderate
Severe
Data from clinical trial populations corroborates findings from the GRACE Registry. This analysis of 26,452 NSTEACS patients from 4 large international randomized clinical trials shows a relationship between bleeding severity and worsening 30day mortality; however, this is a post-hoc analysis and could be confounded by differences among patients that suffered varying bleed severity.
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 Nov 1;96(9):

80. 6-month Death/MI (Adjusted) According to Severity of Bleeding
1.3
GUSTO Mild
2.0
GUSTO Moderate
5.1
GUSTO Severe
1.0
5.0
Odds ratio
Rao SV, et. al., ACC 2005

81. 30 Day Death According to Bleeding OASIS Registry, OASIS-2, CURE14 12 10
Bleeding
Cumulative Events, % 8 6 4 2
No Bleeding 5 10 15 20 25 30
Days
No. at Risk
No Bleeding
33676
33419
33157
32990
32879
32769
32710
Bleeding
470
459
440
430
420
410
408
J Eikelboom et al Circulation 2006

82. The impact of renal dysfunction
The Role and Implications of Bleeding in ACS
The impact of renal dysfunction

83. SYNERGY: Clinical Outcomes and Procedures Creatinine Clearance (CrCl)
p-value
30-Day Outcomes
Death/MI
24.4%
17.3%
12.7%
<0.0001
Death
15.4%
5.7%
1.8%
Cardiac Cath
80.1%
88.8%
93.7%
PCI
35.0%
42.4%
51.5%
CSBG
17.1%
20.0%
20.2%
0.84
In-Hospital Bleeding
GUSTO Severe
7.7%
3.7%
P-value from logistic regression with CrCl as continuous variable
* in-hospital

84. Increased Risks Associated with Transfusion
The Role and Implications of Bleeding in ACS
Increased Risks Associated with Transfusion

85. CRUSADE Bleeding Risks Transfusion by Age
14.9% overall
10.3% non-CABG 20
18.5
17.9
14.1 15
10.3
9.7
% RBC Transfusion 10
4.5 5
<65 yrs
65-75 yrs
> 75 yrs
Through Q (n=74,271)
Non-CABG
Overall
-- Yang, J Am Coll Cardiol 2005;46:1490-5

86. Transfusion and 30-day Mortality
3.8
Adjusted for transfusion
propensity
3.5
Adjusted for baseline
characteristics
Adjusted for baseline
characteristics, bleeding
propensity, transfusion
propensity, & nadir HCT
3.9
0.1
1.0 10
Odds Ratio
Cox model, transfusion = time-dependent covariate
-- Rao SV, et. al., JAMA 2004

87. Does Prevention of Bleeding Improve Long-term Outcome?
The Role and Implications of Bleeding in ACS
Does Prevention of Bleeding Improve Long-term Outcome?

88. Multivariate Logistic Model
1-Year Mortality
Multivariate Logistic Model
Predictor
Odds
Ratio
95%Confidence
Interval
p-value
CrCl <30 ml/min
7.9
<0.001
CrCl ml/min
3.8
CrCl ml/min
1.7
Major Bleed
3.67
Non-Q MI
2.58
0.004
Diabetes
1.74
0.005

89. 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
deaths
HR ± 95% CI
HR (95% CI)
P-value
Myocardial infarction
2.51 ( )
<0.0001
Major bleeding without or before transfusion
2.00 ( )
Major bleeding after transfusion
3.93 ( )
51.5*
66.5**
*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

90. Predictors of Major Bleeding
Results: The ACUITY Trial — PCI Population
Risk ratio ± 95% CI
RR (95% CI)
P-value 1 2 3
Age >75 (vs )
Anemia
CrCl <60mL/min
Diabetes
Female gender
High-risk (ST / biomarkers)
Hypertension
No prior PCI
Prior antithrombotic therapy
Heparin(s) + GPI (vs. Bivalirudin)
1.56 ( )
0.0009
1.89 ( )
<0.0001
1.68 ( )
1.30 ( )
0.0248
2.08 ( )
1.42 ( )
0.0178
1.33 ( )
0.0287
1.47 ( )
0.0019
1.23 ( )
0.0768
2.08 ( )
These data from patients undergoing PCI in the ACUITY randomized trial confirm the findings from the GRACE Registry and also identify “novel” risk factors such as diabetes and anemia.
Manoukian SV, Voeltz MD, Feit F et al. TCT 2006.

91. UFH/Enox versus Fondaparinux
Major Bleeding at 30 Days
UFH/Enox versus Fondaparinux
OASIS 5 & 6
UFH/Enoxaparin
0.04
0.03
Fondaparinux
Cumulative Hazard
0.02
HR 0.67
95% CI
P<
0.01
0.0 5 10 15 20 25 30
Days

92. Mortality: Day 30 Enoxaparin Fondaparinux OASIS 5 HR 0.83
0.03
Fondaparinux
0.02
Cumulative Hazard
HR 0.83
95% CI
P=0.022
0.01
0.0 3 6 9 12 15 18 21 24 27 30
Yusuf et al NEJM 2006
Days

93. Relative Impact of MI, Refractory Ischemia or Bleeding on Mortality
OASIS 5
Crude Odds Ratio for Death
(95% CI)
30 Days
30 to 180 Days
180 Days
Nonfatal MI
9.9 ( )
2.3 ( )
5.7 ( )
Refractory Ischemia
4.1 ( )
1.4 ( )
2.7 ( )
Major Bleeds
6.6 ( )
2.2 ( )
4.2 ( )
Minor Bleeds
3.0 ( )
1.6 ( )
2.2 ( )

94. Minimizing the Risks of Bleeding?
The Role and Implications of Bleeding in ACS
Minimizing the Risks of Bleeding?

95. Excessive Dosing of Anticoagulants by Age70
64.5 60 50
38.5 40 37
% Excessive Dose
33.1
28.7 30 20
16.5
12.5
12.5
8.5 10
LMW Heparin
UF Heparin
GP IIb/IIIa
< 65 yrs
65-75 yrs
>75 yrs

96. Dosing Combinations and Transfusions Heparin + GP IIb-IIIa Inhibitors*20
18.5 18 16 14 12
% RBC Transfusions 10 9 8 6
4.1 4 2
Both Right
1 Excessive
Both Excessive
* Among patients receiving both Heparin (UFH or LMWH) and GP IIb-IIIa Inhibitors

97. Bleeding and Resource Use Predictors of Total Costs
14,000
$12,409
12,000
10,000
8,000
$7,188 $
6,000
$5,255
4,000
$3,370
$2,488
$2,436
$2,164
2,000
$1,158
$1,336
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.

98. Conclusions
In ACS bleeding is important as it is a harbinger of adverse outcomes, including death
Major bleeding and recurrent MI have a similar risk of death
Older age, chronic kidney disease, female gender, anemia, diabetes: consistently associated with bleeding and blood transfusion
Major bleeding is associated with adverse outcomes and increased costs
Both ESC and ACC/AHA Guidelines in ACS highlight the importance of bleeding reduction in ACS care

99. 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 99

100. Potential conflicts of interest
Speaker’s name: Harold L. Dauerman, MD
 I have the following potential conflicts of interest to report:
 Consulting: The Medicines Company, Abbott Vascular
 Employment in industry
 Stockholder of a healthcare company
 Owner of a healthcare company
 Other(s)
 I do not have any potential conflict of interest

101. University of Vermont Post-PCI Bleeding and Vascular Complication Rates4
Introduction of
Bivalirudin to Cath Lab
3.5 3
NNE Rate: 2.0% in 2006
2.5
Bleeding Complication, % 2
1.5
Introduction of Upstream Bivalirudin 1
0.5
2001
2002
2003
2004
2005
2006
2007
Any Transfusion, RPH or Repair = Bleeding Complication
101

102. Incorporation of Bivalirudin in Cath Lab for NSTEMI in 2003—A Cautious Beginning
GP IIb/IIIa Inhibitor
UFH alone

103. Signs of Hope Since 2004 P < 0.001 for temporal trend
3.37
3.5
3.2 3
2.51
2.5
2.11
1.96
Major Vascular Complications, %* 2
1.5 1
0.5
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
103

104. 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)

105. NSTEMI Transfers, Upstream Strategies, and Results of Clinical Trials
Non ST-Elevation Myocardial Infarction
NSTEMI Transfers, Upstream Strategies, and Results of Clinical Trials
105

106. 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

107. Protocol Major/Minor Bleed by SWITCH and Randomized Therapy
15.6%
15.3%
16.7%
28.6%
33.8%
34.8% 0% 5%
10%
15%
20%
25%
30%
35% †
Protocol major/minor bleed *
Key Message: Regardless of receiving prior heparin or not, patients administered bivalirudin experienced fewer bleeding events.
In contrast, there was a significant increase in major/minor protocol bleeding in patients administered UFH with prior heparin therapy.
Reference
Gibson CM, Ten Y, Murphy SA. Association of prerandomization anticoagulant switching with bleeding in the setting of percutaneous coronary intervention (a REPLACE-2 analysis). Am J Cardiol. 2007;99:
Naïve→ Bivalirudin‡
(n=2,345)
UFH→ Bivalirudin
(n=287)
LMWH→ Bivalirudin
(n=258)
Naïve→ UFH + GP IIb/IIIa‡ (n=2,325)
UFH→UFH + GP IIb/IIIa (n=349)
LMWH→UFH + GP IIb/IIIa
(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:

108. 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.

109. If Patient is not Clopidogrel Exposed,
Do We Use Bivalirudin? Definitions?
11.8%
7.5%
5.7%
3.5%
12.7%
10.3%
Net clinical
outcomes
Ischemic
composite
Major bleeding
UFH/Enoxaparin + IIb/IIIa (N=1722)
UFH/Enoxaparin + IIb/IIIa (N=811)
Bivalirudin Alone (N=1789)
Bivalirudin Alone (N=804)
RR [95%CI]
0.81 ( )
RR [95%CI]
0.96 ( )
RR [95%CI]
0.50 ( )
RR [95%CI]
1.07 ( )
RR [95%CI]
1.37 ( )
RR [95%CI]
0.61 ( )
13.8%
11.1%
8.4%
8.1%
7.2%
One of the most hotly debated aspects of the study is the potential interaction with clopidogrel. In patients who were not exposed to clopidogrel before PCI (defined as any pre-procedural exposure, regardless of dose or timing) there was a significantly higher incidence of ischemic composite events in patients in the bivalirudin monotherapy group, in contrast to patients who had been exposed to clopidogrel, where no such difference existed. A number of issues are worth noting. The differences in ischemic events in the patients not treated with clopidogrel stem not only from worse outcomes with bivalirudin, but BETTER outcomes in the heparin group, at least in comparison to the thienopyridine exposed patients.
Mechanistically, this COULD relate to the fact that patients undergoing PCI may benefit from more than just ASA as an antiplatelet foundation, and that in patients not pre-loaded with clopidogrel, that critical time window may not be covered in patients not treated with a IIb/IIIa antagonist, and that what you are really comparing is potent early platelet inhibition with no potent early platelet inhibition, emphasizing the need for clopidogrel pretreatment in ACS patients coming forward to intervention.
It could, always represent the play of chance as well, given the multiple comparisons and subgroups involved in the study. Nevertheless, the observation is there, and for now reinforces the need for more than ASA therapy in ACS patients coming forward to PCI - in clopidogrel-loaded patients, incremental Iib/IIIa provides no additional benefit, and bivalirudin alone provides comparable (identical, actually) ischemic outcomes, and significantly less major bleeding.
3.6%
Net clinical
Ischemic
Major bleeding
outcomes
composite
Not Thienopyridine Exposed
Thienopyridine Exposed
Stone GW, McLaurin BT. NEJM Nov 23;355(21):
109

110. 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]
Angiomax was found to be superior to heparin and as effective as heparin plus GP IIb/IIIa with respect to the quadruple endpoint of death, MI, urgent revascularization and major bleeding.
No Clopidogrel
N=88 RR 2.62 [95% CI 0.89, 7.72] 1 2 3 4 5 6 7 8
Bivalirudin alone better
Heparin + GPIIb/IIIa better
S. Steinhubl TCT 2007

111. Does Periprocedural Infarct Increase With Upstream and Downstream Bivalirudin? No!
ACS PCI Outcomes
2005
Bival 61%
N=373
2007
Bival 91%
N=361
P value
Any Transfusion (%)
2.0
1.0 NS
Death (%)
3.0
0.08
Urgent revascularization (%)
MI, 50% CK-MB Rise (%)
4.0
0.02
Mechanical Complication (%)
8.0
6.0
Submitted, TCT 2008
Clopidogrel preload in approx 60% of PCI patients
CK-MB on all patients the day after PCI (University of Vermont data)

112. STEMI Switching, Clopidogrel and Stent Thrombosis
ST-Elevation Myocardial Infarction
STEMI Switching, Clopidogrel and Stent Thrombosis
112

113. The Standard of Care for STEMI PCI in 2005:
National Registry of Myocardial Infarction-5
Primary PCI for STEMI N= 7,629
Bivalirudin
and
GPIIbIIIa
PCI
N=177 (55%) No
N= 7,309
Clopidogrel
N=171 (97%) GP
IIbIIIa
Inhibitor use
N=6,873 (94%)
Prior to PCI
N=37 (21%)
Not Prior to PCI
N= 140 (79%)
N=2,489 (36%)
N= 4,384 (64%)
Abciximab
N=64 (36%)
Eptifibatide
N=93 (52%)
Tirofiban
N=1 (1%)
Unkown
N=19 (11%)
N=2,283 (33%)
N=3,551 (52%)
N=154 (2%)
Unknown N= 885 (13%)
N=8 (22%)
N=27 (73%)
N=1 (3%)
Unknown N=1 (2%)
N=622 (25%)
N=1621 (65%)
N=99 (4%)
Unknown N=147 (6%)
N=56 (40%)
N=66 (47%)
N=0 (0%)
Unknown N=18 (13%)
N=1661 (38%)
N=1930 (44%)
N=55 (1%)
Unknown N=738 (17%)
Alone
N=143 (45%)
N=41 (24%)
N=137 (96%)
N=31 (23%)
N=6878 (94%)
Prior
to PCI
N=1466 (21%)
N=320 (4%)
Dauerman and French, Coronary Artery Disease, 2006
113

114. Implementation of HORIZONS AMI PCI Pharmacologic Aspects of Management
Unfractionated heparin
60 U/kg IV*; subsequent boluses titrated by nomogram to ACT 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  (eptifibatide)
* If pre randomization UFH administered, ACT is checked first
** If pre randomization UFH administered, started 30’ after last bolus

115. 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

116. Do I Have to Load Bivalirudin in the ED or Can I Start in the Cath Lab
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
(N=1802)
Bivalirudin
(N=1800)
UFH pre randomization
65.6%
Antithrombin in CCL
UFH
98.9%
4.1%
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%
*97.7% and 7.5% during PCI. ** For giant thrombus or refractory no reflow after PCI. CCL = cardiac catheterization laboratory
G Stone TCT 2007

117. 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

118. 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

119. The Bivalirudin Strategy for STEMI PCI
ASA, clopidogrel 600 po x 1, bivalirudin and stent

120. What About The Stent Thrombosis Risk?
UFH + GP IIb/IIIa
(N=1553)
Bivalirudin
(N=1571) P
Value
ARC definite or probable*
1.9%
2.5%
0.33
Definite
1.4%
2.2%
0.11
Probable
0.5%
0.3%
0.26
Acute (≤24 hrs)
1.3%
0.0009
Subacute (>24 hrs – 30d)
1.7%
1.2%
0.30
G Stone TCT 2007
*Protocol definition of stent thrombosis, CEC adjudicated

121. Risk Stratification For STEMI Stent Thrombosis
The Importance of Thrombus Burden
Sianos, G. et al. J Am Coll Cardiol 2007;50:
Large thrombus burden (LTB), defined as thrombus burden >  2 vessel diameters: Approx 25% of STEMI

122. Increased Risk of 30 Day Stent Thrombosis
Drug Eluting Stent Thrombosis and Large Thrombus Burden: Modifying Strategy In Highest Risk Patients 15 12 9 6 3
Large Thrombus
Burden> 5 fold
Increased Risk of 30 Day Stent Thrombosis
LTB vs. STB, p<0.001
8.2%
LTB
Cumulative IRA-ST Rate (%)
5.8%
3.2%
Total Population
2.7%
2.1%
3.2%
Thrombectomy
Prolonged Bivalirudin
GPI
1.1%
1.4%
STB
1.3%
0.7%
0.5%
0.7%
Months of follow-up
Sianos, G. et al. J Am Coll Cardiol 2007;50:

123. ACUITY and Large Thrombus Data The Rationale for Selective Adjunctive GPI
Heparin
+ IIb/IIIa
(N=222)
Bivalirudin IIb/IIIa
(N=241)
Bivalirudin alone
(N=249)
P value
3-way
Any thrombotic complication post PCI
8.6%
3.7%
5.6%
0.09
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

124. Projecting What Happens if You Use GPI in 25% of Your Bivalirudin STEMI Patients
4.9
5.2
8.3 1 2 3 4 5 6 7 8 9
Major Bleeding, %
Bival +
UFH + GPI
P < 0.001
Still P < 0.001
UVM Implemented
HORIZONS—25%
HORIZONS 7%
Assumes Bival + GPI bleeding rate of 6.8%

125. 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

126. STEMI: Within 24 Hours CP Transfer PCI Capability or
< 60 minute Transfer Time
No PCI Capability and
> 60 minute Transfer Time
ASA
325 po
UFH or Bivalirudin:
GPI Optional: Avoid if High Bleed Risk
B Blockers ONLY if HTN
UFH (60 U/Kg)
Beta Blockers only if HTN
Clopidogrel
600 po
Clopidogrel
300 po
90 minutes
To Open
Artery
Emergent Transfer
Lytic
Contraindicated
Primary PCI with Stenting:
GPI/Thrombectomy if Large Thrombus
or as Bailout; Otherwise, Bivalirudin Alone
Rescue PCI:
Class I Indication
Continue bivalirudin for 2 hours after PCI
If Reperfusion Fails,
Emergent PCI with stent
TNK and UFH
ASA/Clopidogrel
Statin
Groin Closure
Cardiac Rehab
Lopressor 12.5 bid
Transfer
If no CP and less than 50%
ST Elevations, PCI at 12-24
Hours with Stent
Transfer from
Community ER
To PCI Site
The NSTEMI Paradigm
of 4-48 Hours

127. 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.
127

128. 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!
128