1. Gregg W. Stone MD for 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
Gregg W. Stone MD
for the ACUITY Investigators

2. Disclosure Gregg W. Stone
Consultant to The Medicines Company and Bristol Myers Squibb Imaging
Lecture fees from The Medicines Company and Nycomed

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)
Bivalirudin
(n=4,604)
Alone
(n=4,612) R*
Angiography within 72h
Medical
management
PCI
CABG
Moderate
and high
risk ACS
(n=13,819)
Aspirin in all
Clopidogrel
dosing and timing
per local practice
*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)
Bivalirudin
(N=4,604)
Alone
(N=4,612) R*
GPI upstream (N=2294)
GPI CCL for PCI (N=2309)
GPI upstream (N=2311)
GPI CCL for PCI (N=2293)
Moderate
and high
risk ACS
(n=13,819
Aspirin in all
Clopidogrel
dosing and timing
per local practice
*Stratified by pre-angiography thienopyridine use or administration

5. 3 Primary Endpoints (at 30 Days)
1. Composite net clinical benefit =
2. Ischemic composite or
3. Major bleeding
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

6. 3 Primary Endpoints (at 30 Days)
1. Composite net clinical benefit =
2. Ischemic composite or
3. Major bleeding
Non CABG related bleeding
- Intracranial bleeding or intraocular bleeding
- Retroperitoneal bleeding
Access site bleed requiring intervention/surgery
Hematoma ≥5 cm
- Hgb ≥3g/dL with an overt source or ≥4g/dL w/o overt source
- Blood product transfusion
- Reoperation for bleeding

7. Composite Ischemia – All pts
UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone 15
Estimate P
(log rank)
UFH/Enoxaparin + IIb/IIIa (N=4603)
7.4%
Bivalirudin + IIb/IIIa (N=4604)
7.9%
0.37 10
Bivalirudin alone (N=4612)
8.0%
0.30
Cumulative Events (%) 5 5 10 15 20 25 30 35
Days from Randomization

8. Major Bleeding (Non CABG) – All pts
UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone 5 10 15 20 25 30 35
Estimate P
(log rank)
5.7%
UFH/Enoxaparin + IIb/IIIa (N=4603)
Bivalirudin + IIb/IIIa (N=4604)
5.3%
0.41
Bivalirudin alone (N=4612)
3.1%
<0.0001
Cumulative Events (%)
Days from Randomization

9. Net Clinical Outcomes – All pts
UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone 15 10
Cumulative Events (%)
Estimate P
(log rank)
11.9%
UFH/Enoxaparin + IIb/IIIa (N=4603)
Bivalirudin + IIb/IIIa (N=4604)
0.89
Bivalirudin alone (N=4612)
0.014
10.3% 5 5 10 15 20 25 30 35
Days from Randomization

10. Goals of the ACUITY PCI Sub-study
To examine the outcomes of bivalirudin ± GPIIb/IIIa inhibitors compared to heparin (unfractionated or enoxaparin) + GPIIb/IIIa inhibitors in pts with moderate and high risk ACS undergoing PCI
3 primary clinical endpoints at 30 days
Angiographic outcomes from a large independent blinded core lab analysis
Specific subgroups and analyses of interest:
Troponin positive pts
Impact of pre-PCI thienopyridine use
“ISAR-REACT-2 like” cohort
Angiographic thrombus

11. Management Strategy (N=13,819)
Medical Rx (n=4,491)
CABG (n=1,539)
32.2%
11.4%
56.4%
PCI (n=7,789)
Heparin + IIb/IIIa
N = 2,561
Bivalirudin + IIb/IIIa
N = 2,609
Bivalirudin alone
N = 2,619

12. Baseline Characteristics – PCI pts
Heparin
+ IIb/IIIa
(N=2561)
Bivalirudin IIb/IIIa
(N=2609)
Bivalirudin alone
(N=2619)
Age (median [range], yrs)
63 [25-91]
62 [21-95]
63 [30-92]
Male
72.6%
73.6%
73.3%
Weight (median [IQR], kg)
84 [73,96]
84 [74,96]
84 [75,95]
Diabetes
27.5%
27.3%
- Insulin requiring
8.0%
8.6%
Hypertension
65.3%
64.8%
65.4%
Hyperlipidemia
55.0%
55.2%
54.9%
Current smoker
30.1%
30.6%
30.4%
Prior MI
29.7%
29.1%
30.5%
Prior PCI
38.2%
37.5%
39.3%
Prior CABG
17.3%
17.9%
Renal insufficiency*
19.0%
18.4%
17.8%
* creatinine clearance <60 mL/min

13. Baseline High Risk Features – PCI pts
Heparin
+ IIb/IIIa
(N=2561)
Bivalirudin IIb/IIIa
(N=2609)
Bivalirudin alone
(N=2619)
Cardiac biomarker  (MB or trop)
65.1%
63.7%
66.4%
- Troponin 
64.8%
62.6%
66.2%
ST-segment  ≥1mm
35.4%
36.7%
35.3%
Cardiac biomarker  or ST-segments 
76.8%
75.3%
77.0%
TIMI Risk Score
0-2*
16.7%
15.3%
16.0%
3-4
52.1%
54.6%
53.2%
5-7
31.2%
30.0%
30.8%
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

14. Antiplatelet Medications – PCI pts
Heparin
+ IIb/IIIa
(N=2561)
Bivalirudin IIb/IIIa
(N=2609)
Bivalirudin alone
(N=2619)
Aspirin use or administration pre-angiography or PCI
- Yes
98.0%
97.7%
Thienopyridine use or administration pre PCI
68.0%
67.4%
69.0%
- Clopidogrel
67.5%
67.7%
68.7%
- Ticlopidine
1.0%
0.7% -

15. GP IIb/IIIa Inhibitor Administration – PCI pts
Heparin
+ IIb/IIIa
(N=2561)
Bivalirudin
(N=2609)
Bivalirudin alone
(N=2619)
GPI initiated pre angio
50.7%
50.9%
0.7%
- Eptifibatide
31.8%
32.2%
0.4%
- Tirofiban
18.5%
18.2%
0.2%
- Abciximab
0.5%
0.1%
GPI inhibitor during PCI
96.6%
96.7%
9.1%*
59.6%
60.9%
4.5%
19.2%
19.7%
0.8%
17.8%
16.3%
3.8%
IIb/IIIa inhib
* For ischemic complications per protocol in 6.5% of pts

16. Procedural Characteristics – PCI pts
Heparin
+ IIb/IIIa
(N=2561)
Bivalirudin IIb/IIIa
(N=2609)
Bivalirudin alone
(N=2619)
Attempted lesions per pt
1.50 ± 0.83
1.49 ± 0.82
1.51 ± 1.93
- 1
65.2%
64.7%
66.3%
- 2
24.4%
25.3%
23.2%
- ≥3
10.4%
10.0%
10.6%
Attempted vessels per pt
1.18 ± 0.44
1.18 ± 0.43
1.18 ± 0.42
- ≥2
16.3%
16.9%
16.0%
Target Vessel
- Left main
1.7%
1.5%
- LAD
41.2%
44.0%
43.5%
- LCX
34.7%
34.4%
35.7%
- RCA
38.4%
36.7%
35.4%
- Bypass graft conduit
7.2%
7.5%
7.0%
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%)

17. Bivalirudin + IIb/IIIa
Device Use – PCI pts
Heparin
+ IIb/IIIa
(N=2561)
Bivalirudin IIb/IIIa
(N=2609)
Bivalirudin alone
(N=2619)
Stent implanted
92.7%
93.1%
Drug-eluting stents
60.9%
59.7%
59.6%
- ≥1 Cypher implanted
26.5%
25.8%
24.8%
- ≥1 Taxus implanted
31.3%
30.4%
31.1%
- ≥1 other DES implanted
5.4%
5.1%
5.6%
Non-drug-eluting stent
36.2%
37.6%
37.7%
Thrombectomy
1.7%
1.5%
1.8%
Distal Protection
1.3%
Atherectomy
0.7%
0.6%
0.5%
Cutting Balloon
2.9%
3.2%

18. Composite Ischemia – PCI pts
Heparin* + IIb/IIIa vs. Bivalirudin + IIb/IIIa vs. Bivalirudin Alone 15 10
P=0.36
Event Rate (%) 5
Estimate P
(log rank)
8.4%
Heparin* + IIb/IIIa (N=2561)
Bivalirudin + IIb/IIIa (N=2609)
0.15
9.4%
Bivalirudin alone (N=2619)
0.45
8.9% 5 10 15 20 25 30 35
Days from Randomization
*Heparin=unfractionated or enoxaparin

19. Components of Ischemia – PCI pts
Heparin* + IIb/IIIa vs. Bivalirudin + IIb/IIIa vs. Bivalirudin Alone
p=0.16
p=0.45
p=0.37
p=0.53
p=0.19
p=0.31
P=0.87
*Heparin=unfractionated or enoxaparin

20. Adjudicated Stent Thrombosis PCI Patients With ≥1 Stent Implanted (N=7,211)
RR 1.00 [ ] p=0.99
RR 0.82 [ ] p=0.39
RR 1.23 [ ] p=0.39

21. Major Bleeding (Non-CABG) – PCI pts
Heparin* + IIb/IIIa vs. Bivalirudin + IIb/IIIa vs. Bivalirudin Alone 15
Estimate P
(log rank)
6.8%
Heparin* + IIb/IIIa (N=2561)
Bivalirudin + IIb/IIIa (N=2609)
0.31
7.6%
Bivalirudin alone (N=2619)
<0.001
3.5% 10
Event Rate (%)
P<0.0001 5 5 10 15 20 25 30 35
Days from Randomization
*Heparin=unfractionated or enoxaparin

22. Major Bleeding (non-CABG) – PCI pts
Heparin
+ IIb/IIIa
(N=2561)
Bivalirudin IIb/IIIa
(N=2609)
Bivalirudin alone
(N=2619)
P value*
Major bleeding
6.8%
7.5%
3.5%
<0.001
Intracranial
0% (1)
1.00
Retroperitoneal
0.7%
0.9%
0.2%
0.006
Access site
3.3%
3.6%
1.0%
- req interv/surgery
0.6%
0.8%
0.3%
0.13
- hematoma ≥5 cm
2.9%
3.1%
Hgb  ≥3 g/dL with overt source
2.8%
1.2%
Hgb  ≥4 g/dL with no overt source
1.1%
0.82
Blood transfusion
3.0%
3.9%
1.7%
0.002
Reoperation for bleed
0.2% (5)
0.1% (3)
0.33
*P value for bivalirudin alone vs. heparin + IIb/IIIa inhibitor

23. Bleeding Endpoints – PCI pts
Heparin + IIb/IIIa
(N=2561)
Bivalirudin IIb/IIIa
(N=2609)
Bivalirudin alone
(N=2619) P
Value
ACUITY Scale
- Major Bleed, all
7.3%
8.0%
4.2%
<0.001
- Major, non-CABG
6.8%
7.5%
3.5%
- Minor, non-CABG
26.0%
28.4%
14.9%
TIMI Scale
- Any
7.8%
8.5%
4.5%
- Major
2.3%
2.4%
0.8%
- Minor
8.2%
Transfusions, non-CABG
3.0%
3.9%
1.7%
0.002
*P value for bivalirudin alone vs. heparin + IIb/IIIa inhibitor

24. Net Clinical Outcomes – PCI pts
Heparin* + IIb/IIIa vs. Bivalirudin + IIb/IIIa vs. Bivalirudin Alone 15
P=0.001 10
Event Rate (%) 5
Estimate P
(log rank)
13.5%
Heparin* + IIb/IIIa (N=2561)
Bivalirudin + IIb/IIIa (N=2609)
0.10
15.1%
Bivalirudin alone (N=2619)
0.049
11.7% 5 10 15 20 25 30 35
Days from Randomization
*Heparin=unfractionated or enoxaparin

25. Impact of Baseline Troponins – PCI pts
UFH/Enoxaparin + IIb/IIIa vs. Bivalirudin Alone
RR [95%CI]
0.93 [ ]
RR [95%CI]
1.12 [ ]
RR [95%CI]
0.59 [ ]
RR [95%CI]
0.75 [ ]
RR [95%CI]
1.02 [0.74—1.42]
RR [95%CI]
0.36 [ ]
Troponin +
Troponin -
Interaction P values = 0.46, 0.86 and 0.28 respectively

26. Thienopyridine Exposed* Not Thienopyridine Exposed
Influence of Thienopyridine Exposure – PCI pts
30 Day Primary Endpoint Adverse Events
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 ( )
Thienopyridine Exposed*
Not Thienopyridine Exposed
*Thienopyridine at any time, any dose, up to time of PCI
Interaction P values = 0.17, 0.19 and 0.65 respectively

27. “ISAR-REACT-2 Like” Patients (N=1,358) Troponin+ PCI pts, Thienopyridine use prior to PCI, GPI started after angiography but before PCI
RR [95%CI]
0.84 [ ]
RR [95%CI]
1.00 [ ]
RR [95%CI]
0.53 [ ]

28. Core Lab Analysis: Patient Flow
All patients
N = 13,819
US patients, total and PCI
N = 7,851 and 4,254
Goals:
7,000 acquired
6,300 interpretable
US core lab analysis, total and PCI
N = 6,921 (88.2%) and 3,664 (86.1%)
PCI core lab analysis
Heparin + IIb/IIIa
1,190 pts, 1,616 lsns
Bivalirudin + IIb/IIIa
1,254 pts, 1,680 lsns
Bivalirudin alone
1,220 pts, 1,617 lsns

29. Procedural Events – PCI pts Any adverse angiographic event (core lab)
Heparin
+ IIb/IIIa
(N=1190)
Bivalirudin IIb/IIIa
(N=1254)
Bivalirudin alone
(N=1220)
P value
3-way
New or ↑ thrombus
13.7%
13.6%
16.2%
0.12
Abrupt closure
1.1%
0.6%
0.28
No reflow
0.3%
0.7%
0.24
Distal embolization
1.3%
1.2%
0.26
Spasm
2.8%
2.4%
2.9%
0.74
Dissection
5.1%
5.6%
4.3%
0.36
Perforation
0.2%
0.1%
0.39

30. Bivalirudin + IIb/IIIa
Procedural Events – PCI pts Final adverse angiographic events (core lab)
Heparin
+ IIb/IIIa
(N=1190)
Bivalirudin IIb/IIIa
(N=1254)
Bivalirudin alone
(N=1220)
P value
3-way
New or ↑ thrombus
1.5%
0.9%
0.7%
0.13
Abrupt closure
0.2%
0.1%
0.62
No reflow 0%
0.25
Distal embolization
0.8%
0.4%
1.0%
0.21
Spasm
0.5%
0.6%
1.1%
0.19
Dissection
0.84
Perforation
0.61

31. TIMI Flows – PCI pts Core lab vessel analysis
Heparin
+ IIb/IIIa
Bivalirudin IIb/IIIa
Bivalirudin alone P1
value P2
Baseline TIMI Flow
(N=1389)
(N=1467)
(N=1421)
- 0/1
13.3%
12.4%
13.6%
0.47
0.84
- 2
9.6%
9.5%
10.1%
0.92
0.71
- 3
77.0%
78.1%
76.4%
0.52
0.67
Final TIMI Flow
(N=1384)
(N=1461)
(N=1419)
1.5%
1.0%
2.0%
0.24
0.29
1.7%
1.4%
2.6%
0.53
0.11
96.7%
97.5%
95.3%
0.21
0.06
P1 = H+GPI vs. Biv+GPI; P2 = H+GPI vs. Biv alone

32. Myocardial Blush – PCI pts Core lab vessel analysis
Heparin
+ IIb/IIIa
Bivalirudin IIb/IIIa
Bivalirudin alone P1
value P2
Baseline Blush
(N=1211)
(N=1304)
(N=1239)
- 0/1
17.0%
15.0%
16.9%
0.18
0.93
- 2
15.4%
16.8%
0.97
0.34
- 3
67.6%
69.6%
66.3%
0.30
0.50
Final Blush
(N=1145)
(N=1252)
(N=1168)
2.8%
1.8%
2.7%
0.12
0.84
10.0%
10.8%
12.0%
0.51
87.2%
87.4%
85.4%
0.92
0.19
P1 = H+GPI vs. Biv+GPI; P2 = H+GPI vs. Biv alone

33. Primary Endpoint Measures Patients with ≥1 PCI Thrombotic Lesion at Baseline (n=712)
*Heparin=unfractionated or enoxaparin

34. Bivalirudin + IIb/IIIa
Angiographic Outcomes (core lab analysis) Pts with ≥1 PCI Thrombotic Lesions at Baseline (n=712)
Heparin
+ IIb/IIIa
(N=222)
Bivalirudin IIb/IIIa
(N=241)
Bivalirudin alone
(N=249)
P value
3-way
Any thrombotic compl* 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

35. Composite Ischemia – PCI pts
All sub randomized groups
8.5%
Bivalirudin + IIb/IIIa Upstream (N=1341)
Bivalirudin + IIb/IIIa CCL for PCI (N=1268)
10.4%
Bivalirudin alone (N=2619)
9.0%
9.1%
UFH/Enox + IIb/IIIa CCl for PCI (N=1289)
7.7%
UFH/Enox + IIb/IIIa Upstream (N=1272) KM
Estimate
P value
(vs Biv)
0.71
0.14
0.97
0.20 5 10 15 20 25 30 35
Cumulative Events (%)
Days from Randomization
P=0.20
*Heparin=unfractionated or enoxaparin

36. Major Bleeding (Non-CABG) – PCI pts
All sub randomized groups 5 10 15 20 25 30 35
Cumulative Events (%)
Days from Randomization KM
Estimate
P value
(vs Biv)
Bivalirudin + IIb/IIIa Upstream (N=1341)
8.5%
<0.001
UFH/Enox + IIb/IIIa CCl for PCI (N=1289)
6.6%
<0.001
UFH/Enox + IIb/IIIa Upstream (N=1272)
7.0%
<0.001
Bivalirudin + IIb/IIIa CCL for PCI (N=1268)
6.5%
<0.001
Bivalirudin alone (N=2619)
3.5%
P<0.0001
*Heparin=unfractionated or enoxaparin

37. Net Clinical Outcomes – PCI pts
All sub randomized groups 15
P=0.006 10
Cumulative Events (%)
Bivalirudin + IIb/IIIa Upstream (N=1341)
Bivalirudin + IIb/IIIa CCL for PCI (N=1268)
Bivalirudin alone (N=2619)
UFH/Enox + IIb/IIIa CCl for PCI (N=1289)
UFH/Enox + IIb/IIIa Upstream (N=1272) KM
Estimate
P value
(vs Biv)
0.003
0.002
0.03
0.31 5
14.9%
15.3%
11.7%
14.2%
12.7% 5 10 15 20 25 30 35
Days from Randomization
*Heparin=unfractionated or enoxaparin

38. REPLACE-2 vs. ACUITY PCI REPLACE-2 (PCI) ACUITY PCI p = 0.40
* R2 major bleeding definition applied to both

39. Study Limitations
Even though the baseline characteristics of the 3 groups were well matched, the ACUITY PCI sub-study is not technically a randomized trial
The ACUITY PCI sub-study was under-powered for non-inferiority testing and subgroups
All analyses should be considered hypothesis generating
Given the complexity of the trial, the study design was open label, and as such bias cannot be excluded
The rate of provisional IIb/IIIa inhibitor use for ischemic complications was almost identical to that in the blinded REPLACE-2 trial
Use of blinded CECs and core labs reduces but does not eliminate the potential for bias

40. Conclusions and Clinical Implications
In patients with moderate and high risk ACS undergoing PCI
Replacing upstream heparin with bivalirudin in pts treated with GP IIb/IIIa inhibitors provides similar clinical and angiographic outcomes
Replacing heparin and GP IIb/IIIa inhibitors with bivalirudin alone (with provisional IIb/IIIa inhibitor use in <10% of pts) results in similar rates of ischemia with markedly reduced hemorrhagic complications, thereby improving overall event-free survival