1. Dr. Harvey White on behalf of the ACUITY investigators
ACUITY PCI
A Prospective Trial of Patients with ACS Undergoing PCI after Randomization to Heparin plus GP IIb/IIIa Inhibitors vs Bivalirudin With or Without GP IIb/IIIa Inhibitors
Dr. Harvey White on behalf of the ACUITY investigators

2. Disclosure Harvey D. White Research Grants:
Alexion, Fournier Laboratories, Sanofi Aventis, Johnson & Johnson, Eli Lilly, Proctor & Gamble, Merck Sharpe & Dohme, Schering Plough, Roche, The Medicines Company, Glaxo Smith Kline, Pfizer, Neuren Pharmaceuticals, NIH
Consultant:
Sanofi Aventis, The Medicines Company

3. Study Design – First Randomization
Moderate and high risk unstable angina or NSTEMI undergoing an invasive strategy (N=13,819)
UFH/Enox
+ GP IIb/IIIa
(n=4,603)
Medical
management
PCI
Moderate
and high
risk ACS
(n=13,819)
Bivalirudin
+ GP IIb/IIIa
(n=4,604)
Angiography within 72h R*
Aspirin in all
Clopidogrel
dosing and timing
per local practice
Bivalirudin
Alone
(n=4,612)
CABG
*Stratified by pre-angiography thienopyridine use or administration

4. Study Design – Second Randomization
Moderate and high risk unstable angina or NSTEMI undergoing an invasive strategy
UFH/Enox
+ GP IIb/IIIa
(n=4,603)
GP IIb/IIIa upstream (N=2294)
GP IIb/IIIa CCL for PCI (N=2309)
Moderate
and high
risk ACS
(n=13,819)
Bivalirudin
+ GP IIb/IIIa
(n=4,604)
GP IIb/IIIa upstream (N=2311) R*
GP IIb/IIIa CCL for PCI (N=2293)
Aspirin in all
Clopidogrel
dosing and timing
per local practice
Bivalirudin
Alone
(n=4,612)
*Stratified by pre-angiography thienopyridine use or administration

5. ACUITY Primary Endpoints
Net Clinical Outcome (Composite Ischemia, Non-CABG Major Bleeding)
Composite Ischemia:
Death from any cause
Myocardial infarction
During medical Rx: Any biomarker elevation >ULN
Post PCI: CKMB >ULN with new Q waves or >3x ULN w/o Q waves
Post CABG: CKMB >5x ULN with new Q waves, >10x ULN w/o Q waves
Unplanned revascularization for ischemia
Non-CABG Major Bleeding
Intracranial bleeding or intraocular bleeding
Retroperitoneal bleeding
Access site bleed requiring intervention/surgery
Hematoma ≥5 cm
Hgb  ≥ 3 g/dL with , or  ≥ 4 g/dL without overt source
Blood product transfusion
Reoperation for bleeding

6. ACUITY: Primary results – 30 days
UFH/Enox + GP IIb/IIIa vs. Bivalirudin + GP IIb/IIIa vs. Bivalirudin Alone
PNI <0.001
PSup = 0.015
PNI = 0.011
PSup = 0.32
PSup <0.001
Stone GW et al. NEJM 2006;355:

7. Ischemic Composite Endpoint (Death, MI, unplanned revascularization for ischemia)
UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone 25
Estimate P
(log rank)
30 day
7.4%
0.36
7.8%
0.34
7.9% —
Estimate P
(log rank)
16.3%
0.38
16.5%
0.31
16.4%
1 year — 20
UFH/Enoxaparin + IIb/IIIa
Bivalirudin + IIb/IIIa
Bivalirudin alone
p=0.55 15
Ischemic Composite (%) 10
Bivalirudin+GPI vs. Hep+GPI
HR [95% CI] = 1.05 ( ) 5
Bivalirudin alone vs. Hep+GPI
HR [95% CI] = 1.05 ( ) 30 60 90
120
150
180
210
240
270
300
330
360
390
Days from Randomization
Stone GW. ACC 2007 presentation

8. Mortality: 524 total deaths at 1-year
UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone 5
Bivalirudin+GPI vs. Hep+GPI
HR [95% CI] = 0.99 ( )
p=0.90 4
Bivalirudin alone vs. Hep+GPI
HR [95% CI] = 0.95 ( ) 3
Mortality (%) 2
Estimate P
(log rank)
1.4%
0.53
1.6%
0.39 —
30 day
Estimate P
(log rank)
4.4%
0.93
4.2%
0.66
3.8%
1 year — 1
UFH/Enoxaparin + IIb/IIIa
Bivalirudin + IIb/IIIa
Bivalirudin alone 30 60 90
120
150
180
210
240
270
300
330
360
390
Days from Randomization
Stone GW. ACC 2007 presentation

9. Goals of the present analysis
To examine the long-term outcomes of bivalirudin ± GP IIb/IIIa inhibition compared to UFH/Enoxaparin + GP IIb/IIIa inhibition in moderate and high risk ACS patients undergoing PCI
Overall primary clinical endpoints at 1 year
Outcomes in patients switched to bivalirudin monotherapy from UFH or enoxaparin
Analysis of the relative impact of iatrogenic bleeding complications on long-term outcome

10. Management Strategy (N=13,819)
Medical Rx (n=4,491)
CABG (n=1,539)
32.5%
11.1%
56.4%
PCI (n=7,789)
UFH/Enox + GP IIb/IIIa
N = 2,561
Bivalirudin + GP IIb/IIIa
N = 2,609
Bivalirudin alone
N = 2,619

11. ACUITY PCI: Baseline Characteristics
UFH/Enox
+ GP IIb/IIIa
(N=2561)
Bivalirudin GP IIb/IIIa
(N=2609)
Bivalirudin alone
(N=2619)
Age (median [range], yrs)
63 [25-91]
62 [21-95]
63 [30-92]
Male
73%
74%
Weight (median [IQR], kg)
84 [73,96]
84 [74,96]
84 [75,95]
Diabetes
28%
27%
- Insulin requiring 8% 9%
Hypertension
66%
65%
Hyperlipidemia
56%
Current smoker
31%
Prior MI
30%
Prior PCI
38%
40%
Prior CABG
17%
18%
Renal insufficiency*
19%
* creatinine clearance <60 mL/min
Stone GW et al. Lancet 2007;369:907-19

12. ACUITY PCI: Baseline High Risk Features
UFH/Enox
+ GP IIb/IIIa
(N=2561)
Bivalirudin GP IIb/IIIa
(N=2609)
Bivalirudin alone
(N=2619)
Cardiac biomarker  (CK-MB or trop)
65%
64%
66%
- Troponin 
63%
ST-segment  ≥1mm
35%
37%
Cardiac biomarker  or ST-segments 
77%
75%
TIMI Risk Score
0-2*
17%
15%
16%
3-4
52%
55%
53%
5-7
31%
30%
Non-ST-segment elevation MI (elevated baseline CKMB or troponin) was present in 59 percent of patients, whereas 41 percent had unstable angina.
Baseline ST-segment deviation or cardiac biomarker elevation
3171/4340 (73.1%)3119/4362 (71.5%)3173/4385 (72.4%)
* 84.0% had +biomarkers or baseline ST
97% of all pts had +biomarkers or baseline ST, or were TIMI Int/High risk
Stone GW et al. Lancet 2007;369:907-19

13. ACUITY PCI: Primary results – 30 days
UFH/Enox + GP IIb/IIIa vs. Bivalirudin + GP IIb/IIIa vs. Bivalirudin Alone
P=0.10
P=0.057
P=0.16
P=0.45
P=0.32
<0.0001
Stone GW et al. Lancet 2007;369:907-19

14. ACUITY PCI: Bleeding – 30 days
UFH/Enox + GP IIb/IIIa
(N=2561)
Bivalirudin GP IIb/IIIa
(N=2609)
Bivalirudin alone
(N=2619) P
Value*
ACUITY Scale
- Major Bleed, all
7.3%
8.0%
4.2%
<0.0001
- Major, non-CABG 7% 8% 4%
- Minor, non-CABG
26%
28%
15%
TIMI Scale
- Any 9% 5%
- Major 2%
0.8%
- Minor
Transfusions, non-CABG 3%
0.002
*P value for bivalirudin alone vs. heparin + IIb/IIIa inhibitor
Stone GW et al. Lancet 2007;369:907-19

15. ACUITY PCI: Primary Results – 1 Year
Hazard Ratio
±95% CI
HR (95% CI)
Composite Ischemia
1.09 ( )
Mortality
0.95 ( )
Bivalirudin Better
UFH/Enox+ IIb/IIIa Better

16. ACUITY PCI: Early and Late Mortality
UFH/Enox + GP IIb/IIIa vs. Bivalirudin + GP IIb/IIIa vs. Bivalirudin Alone
UFH/Enoxaparin + IIb/IIIa
Bivalirudin + IIb/IIIa
Bivalirudin alone
30 day
Estimate P
(log rank)
0.9%
0.45
1.2%
0.63
1.1% —
3.1%
0.70
2.4%
0.48
2.2%
1 year
Mortality (%)
p=0.78
Days from Randomization

17. ACUITY PCI: Influence of 30 day Major Bleeding and MI on Late Mortality
Hazard Ratio
±95% CI
HR (95% CI)
P-Value
30 Day Major Bleed
3.16 ( )
<0.0001
30 Day Myocardial Infarction
2.30 ( )
<0.0001
Cox model adjusted for baseline predictors, with non-CABG major bleeding and MI as time-updated covariates

18. ACUITY PCI: Impact of Bleeding on LOS
Patients with Bleeding Event
N=459
Patients without Bleeding Event
N=7318 P
Value
Hospital length of stay, median days
5.0
3.0
<0.0001

19. ACUITY PCI: High Risk* patients
30 day Results
1 year Results
Risk Ratio ±95% CI
Hazard Ratio ±95% CI
RR (95% CI)
HR (95% CI)
Composite ischemia
1.08 ( )
Major bleeding
0.55 ( )
Mortality
0.94 ( )
Bivalirudin better
UFH/Enox+ IIb/IIIa better
Bivalirudin better
UFH/Enox+ IIb/IIIa better
* High risk = ↑Tn, CKMB or ECG Δ’s

20. ACUITY PCI: Impact of clopidogrel
PCI patients
1-year Mortality Hazard Ratio ±95% CI
HR (95% CI)
Clopidogrel at any time prior to hospitalization, randomization or end of angiography (n=3,429)
1.02 ( )
Clopidogrel after end of angiography to 30’ post PCI (n=1,044)
1.14 ( )
Clopidogrel after 30’ post PCI (n=519)
0.43 ( )
No clopidogrel (n=88)
3.20 ( )
Bivalirudin better
UFH/Enox + IIb/IIIa better
Groups based on first exposure to clopidogrel; excludes patients who received ticlopidine

21. ACUITY PCI: Impact of clopidogrel
PCI troponin+ patients
1-year Mortality Hazard Ratio ±95% CI
HR (95% CI)
Clopidogrel at any time prior to hospitalization, randomization or end of angiography (n=1,891)
1.07 ( )
Clopidogrel after end of angiography to 30’ post PCI (n=649)
1.09 ( )
Clopidogrel after 30’ post PCI (n=307)
0.56 ( )
No clopidogrel (n=51)
3.07 ( )
Bivalirudin better
UFH/Enox + IIb/IIIa Better
Groups based on first exposure to clopidogrel; excludes patients who received ticlopidine

22. 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)
Composite ischemia
1.10 ( )
Major bleeding
0.52 ( )
PCI (n=2528)
Mortality
0.93 ( )
PCI HIGH RISK* (n=1988)
Composite ischemia
1.14 ( )
Major bleeding
0.56 ( )
PCI HIGH RISK* (n=1988)
Mortality
0.99 ( )
Switch to
Bivalirudin better
Switch to
Bivalirudin better
Consistent UFH/Enox
+ IIb/IIIa better
Consistent UFH/Enox
+ IIb/IIIa better
* High risk = ↑Tn, CKMB or ECG Δ’s

23. ACUITY PCI: Antithrombin Naïve Patients
30 day Results
1 year Results
Risk Ratio ±95% CI
Hazard Ratio ±95% CI
RR (95% CI)
HR (95% CI)
PCI (n=1639)
Composite ischemia
1.03 ( )
Major bleeding
0.46 ( )
PCI (n=1639)
Mortality
1.08 ( )
PCI HIGH RISK* (n=987)
Composite ischemia
1.06 ( )
Major bleeding
0.48 ( )
PCI HIGH RISK* (n=987)
Mortality
1.15 ( )
UFH/Enox
+ IIb/IIIa better
UFH/Enox
+ IIb/IIIa better
Bivalirudin better
Bivalirudin better
* High risk = ↑Tn, CKMB or ECG Δ’s

24. This analysis is of post-randomization outcomes
Study Limitations
This analysis is of post-randomization outcomes
The ACUITY PCI sub-study was under-powered for subgroup comparisons
All analyses should be considered hypothesis generating

25. Conclusions and Clinical Implications
In patients with moderate and high risk ACS undergoing PCI
Bivalirudin alone results in similar 1 year mortality to UFH/enoxaparin plus GP IIb/IIIa inhibition regardless of patient risk, prior antithrombin therapy and clopidogrel exposure
Switching from UFH or enoxaparin to bivalirudin enables patients to achieve significant reductions in bleeding at 30 days and similar mortality at 1 year
These results substantiate the strong relationship between bleeding complications and late mortality in PCI patients