Transcript Baseline Characteristics

Baseline Characteristics
UFH/Enoxaparin
+ GP IIb/IIIa
(N=4,603)
Bivalirudin
+ GP IIb/IIIa
(N=4,604)
Bivalirudin
alone
(N=4,612)
63 [23-91]
63 [21-95]
63 [20-92]
Male
70.6%
69.9%
69.3%
Diabetes
28.4%
27.7%
28.1%
8.5%
8.6%
8.8%
Hypertension
66.8%
67.2%
67.1%
Hyperlipidemia
57.2%
57.4%
57.0%
Current smoker
29.0%
29.3%
29.0%
Prior MI
31.6%
30.5%
31.8%
Prior PCI
39.0%
37.8%
39.9%
Prior CABG
18.2%
17.4%
18.1%
Renal insufficiency
5.7%
6.0%
5.7%
Age (median [range], yrs)
- Insulin requiring
Baseline High Risk Features
UFH/Enoxaparin
+ GP IIb/IIIa
(N=4,603)
Bivalirudin
+ GP IIb/IIIa
(N=4,604)
Bivalirudin
alone
(N=4,612)
Biomarker or ST 
71.3%
70.1%
70.9%
- Biomarker +
58.1%
56.9%
58.5%
- ST-segment 
35.2%
35.4%
34.3%
Biomarker + ST 
21.9%
22.2%
21.9%
- Low (0-2)
16.1%
15.4%
15.6%
- Intermediate (3-4)
53.7%
55.5%
54.5%
- High (5-7)
30.3%
29.1%
29.9%
TIMI Risk Score
Invasive Management
UFH/Enoxaparin
+ GP IIb/IIIa
(N=4,603)
Bivalirudin
+ GP IIb/IIIa
(N=4,604)
Bivalirudin
alone
(N=4,612)
99.2%
98.8%
98.9%
Adm. to angio (h)
19.7 (7.0-29.3)†
19.5 (7.0-28.2)†
19.8 (7.3-29.0)†
Drug* to angio/interv (h)
5.6 (1.6-22.5)†
5.0 (1.4-21.4)†
5.2 (1.5-22.5)†
PCI
55.6%
56.7%
56.8%
CABG
11.9%
10.8%
10.6%
Medical therapy
32.4%
32.5%
32.6%
Angiography
Actual procedure
*In patients receiving study antithrombin pre angiography
†median (IQR)
Primary Endpoint Measures (ITT)
UFH/Enoxaparin + GPI vs. Bivalirudin + GPI
30 day events (%)
UFH/Enoxaparin+GPI (N=4603)
PNI <0.0001
PSup = 0.93
Bivalirudin+GPI (N=4604)
PNI = 0.007
PSup = 0.39
PNI =0.0001
PSup = 0.38
11.7% 11.8%
7.3%
7.7%
5.7%
Net clinical
outcome
Ischemic composite
5.3%
Major bleeding
Primary Endpoint Measures (ITT)
UFH/Enoxaparin + GPI vs. Bivalirudin + GPI
Risk ratio
±95% CI
Bival UFH/Enox
+ IIb/IIIa + IIb/IIIa
Upper boundary non-inferiority
Primary
endpoint
Net clinical
outcome
Ischemic
composite
Major bleeding
0
Bivalirudin + IIb/IIIa better
1
RR (95% CI)
p value
(non inferior)
(superior)
11.8%
11.7%
1.01 (0.90-1.12)
<0.001
0.93
7.7%
7.3%
1.07 (0.92-1.23)
0.015
0.39
5.3%
5.7%
0.93 (0.78-1.10)
<0.001
0.38
2
UFH/Enox + IIb/IIIa better
Primary Endpoint Measures (ITT)
UFH/Enoxaparin + GPI vs. Bivalirudin Alone
30 day events (%)
UFH/Enoxaparin+GPI (N=4603)
PNI <0.0001
PSup = 0.015
Bivalirudin alone (N=4612)
PNI = 0.011
PSup = 0.32
PNI <0.0001
PSup <0.0001
11.7%
10.1%
7.3%
7.8%
5.7%
3.0%
Net clinical
outcome
Ischemic composite
Major bleeding
Primary Endpoint Measures (ITT)
UFH/Enoxaparin + GPI vs. Bivalirudin Alone
Risk ratio
±95% CI
Bival UFH/Enox
alone + IIb/IIIa
Upper boundary non-inferiority
Primary
endpoint
Net clinical
outcome
Ischemic
composite
Major bleeding
0
Bivalirudin alone better
1
RR (95% CI)
p value
(non inferior)
(superior)
10.1%
11.7%
0.86 (0.77-0.97)
<0.001
0.015
7.8%
7.3%
1.08 (0.93-1.24)
0.02
0.32
3.0%
5.7%
0.53 (0.43-0.65)
<0.001
<0.001
2
UFH/Enox + IIb/IIIa better
Components of the Ischemic Composite
UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone
30 day events (%)
UFH/Enox+GPI (N=4603)
PSup = 0.32
Bivalirudin+GPI (N=4604)
PSup = 0.34
Bivalirudin alone (N=4612)
PSup = 0.35
PSup = 0.78
7.3% 7.7% 7.8%
4.9% 5.0% 5.4%
2.3% 2.7% 2.4%
1.3% 1.5% 1.6%
Ischemic
composite
Death
Myocardial
infarction
Unplanned
revasc for
ischemia
Major Bleeding Endpoints
UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone
Heparin+GPI (N=4603)
30 day events (%)
PSup=0.31
11.8%
Bivalirudin+GPI (N=4604)
PSup<.001
Bivalirudin alone (N=4612)
PSup=0.38
PSup<0.0001
11.1%
9.1%
5.7%
5.3%
3.0%
All major bleeding
Non CABG major bleeding
(primary endpoint)
Major Bleeding (Primary Endpoint)
UFH/Enoxaparin
+ GP IIb/IIIa
(N=4,603)
Bivalirudin
+ GP IIb/IIIa
(N=4,604)
Bivalirudin
alone
(N=4,612)
5.7%
5.3%
3.0%
0.07%
0.04%
0.07%
• Retroperitoneal
0.5%
0.6%
0.2%
• Access site
2.6%
2.6%
0.8%
- req interv/surgery
0.3%
0.5%
0.2%
- hematoma ≥5 cm
2.2%
2.2%
0.7%
2.2%
1.8%
1.0%
0.8%
0.7%
0.7%
2.7%
2.6%
1.6%
0.04%
0.1%
0.1%
Any major bleeding
• Intracranial
• Hgb  ≥3 g/dL with
overt source
• Hgb  ≥4 g/dL with
no overt source
• Blood transfusion
• Reoperation for bleed
Values in yellow = P<0.05
Minor Bleeding (Non CABG)
UFH/Enoxaparin
+ GP IIb/IIIa
(N=4,603)
Bivalirudin
+ GP IIb/IIIa
(N=4,604)
Bivalirudin
alone
(N=4,612)
21.6%
21.7%
12.8%
• Ecchymoses
5.6%
5.9%
3.6%
• Epistaxis
1.4%
1.9%
0.7%
• GI bleeding
2.8%
1.8%
1.1%
• GU bleeding
0.8%
1.1%
0.3%
• Puncture site
14.7%
14.3%
8.2%
• Hemopericardium
0.1%
0.1%
0.0%
• Pulmonary
0.3%
0.5%
0.1%
• Other
2.1%
2.6%
1.1%
Any minor bleeding
Values in yellow = P<0.05
Bleeding Endpoints (Non-CABG)
UFH/Enoxaparin Bivalirudin Bivalirudin
P1
+ GP IIb/IIIa
+ GP IIb/IIIa
alone
Value
(N=4,603)
(N=4,604) (N=4,612)
P2
Value
ACUITY Scale
- Any
23.9%
23.7%
14.2%
0.88
<0.001
- Major
5.7%
5.3%
3.0%
0.38
<0.001
- Minor
21.6%
21.7%
12.8%
0.84
<0.001
- Any
6.6%
6.4%
3.9%
0.67
<0.001
- Major
1.8%
1.6%
0.9%
0.42
<0.001
- Minor
6.4%
6.1%
3.7%
0.52
<0.001
2.7%
2.6%
1.6%
0.70
<0.001
TIMI Scale
Blood transfusion
P1 = Bivalirudin+GPI vs. UFH/Enox+GPI; P2 = Bivalirudin alone vs. UFH/Enox+GPI
Net Clinical Outcome Composite
UFH/Enoxaparin + IIb/IIIa vs. Bivalirudin Alone
Risk ratio
±95% CI
Bival UFH/Enox
Alone + IIb/IIIa
RR (95% CI)
P
Pint
Age <65 (n=5051)
Age ≥65 (n=4164)
7.8%
12.9%
9.2%
14.7%
0.86 (0.71-1.03)
0.88 (0.75-1.02)
0.09
0.09
0.89
Men (n=6444)
Women (n=2771)
9.5%
11.6%
10.9%
13.5%
0.87 (0.75-1.00)
0.86 (0.70-1.04)
0.05
0.12
0.91
Diabetes (n=2585)
No diabetes (n=6630)
10.8%
9.8%
13.7%
10.9%
0.79 (0.64-0.97)
0.90 (0.78-1.04)
0.02
0.16
0.28
CrCl ≥60 (n=6993)
CrCl <60 (n=1644)
8.9%
16.1%
10.4%
16.8%
0.86 (0.74-0.99)
0.96 (0.77-1.19)
0.03
0.71
0.43
US (n=5224)
OUS (n=3991)
10.6%
9.5%
11.8%
11.5%
0.90 (0.77-1.05)
0.82 (0.68-0.98)
0.16
0.03
0.47
0
Bivalirudin alone better
1
2
UFH/Enox + IIb/IIIa better
Net Clinical Outcome Composite
UFH/Enoxaparin + IIb/IIIa vs. Bivalirudin Alone
Risk ratio
±95% CI
Bival UFH/Enox
Alone + IIb/IIIa
RR (95% CI)
P
Pint
Biomarkers (CK/Trop)
Elevated (n=5368)
Normal (n=3841)
12.2%
7.1%
13.3%
9.4%
0.92 (0.80-1.06)
0.75 (0.61-0.93)
0.23
0.01
0.35
13.0%
8.6%
13.7%
10.6%
0.96 (0.80-1.14)
0.81 (0.69-0.95)
0.61
0.01
0.42
6.4%
9.4%
13.9%
10.2%
10.2%
15.2%
0.63 (0.43-0.91)
0.92 (0.77-1.10)
0.92 (0.76-1.11)
0.01
0.34
0.36
0.18
9.2%
11.3%
12.2%
11.1%
0.76 (0.65-0.89) <0.001
0.02
1.02 (0.86-1.21) 0.83
ST Deviation
Yes (n=3197)
No (n=6008)
TIMI Risk Score
Low (0-2) (n=1291)
Intermed (3-4) (n=4407)
High (5-7) (n=2449)
Pre Thienopyridine
Yes (n=5192)
No (n=4023)
0
Bivalirudin alone better
1
2
UFH/Enox + IIb/IIIa better
Net Clinical Outcome Composite
UFH/Enoxaparin + IIb/IIIa vs. Bivalirudin Alone
Risk ratio
±95% CI
Bival UFH/Enox
Alone + IIb/IIIa
RR (95% CI)
P
Pint
Actual treatment
PCI (n=5170)
11.6%
13.3%
0.87 (0.75-1.00)
0.09
CABG (n=1048)
Medical (n=2989)
10.6%
5.1%
18.2%
6.5%
0.97 (0.75-1.26)
0.78 (0.58-1.04)
0.84
0.09
Rand. to angio/interv.
tertiles Early (<3.0 h)
8.3%
9.8%
0.85 (0.67-1.06)
0.15
9.2%
12.5%
9.4%
14.4%
0.98 (0.78-1.23)
0.87 (0.73-1.05)
0.86
No prior AT (n=3290)
9.1%
10.0%
0.91 (0.73-1.12)
Consistent Rx (n=5519)
6.7%
7.1%
0.94 (0.80-1.10)
0.36
0.46
Crossover (n=3211)
10.6%
12.6%
0.84 (0.65-1.10)
0.21
Intermediate (3.0-19.7 h)
Late (≥19.7 h)
0.59
0.62
0.14
A-thrombin crossover
0
Bivalirudin alone better
1
2
UFH/Enox + IIb/IIIa better
0.56
Net Clinical Outcome Composite Endpoint
UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone
Cumulative Events (%)
15
10
Estimate
5
UFH/Enoxaparin + IIb/IIIa (N=4603)
Bivalirudin + IIb/IIIa (N=4604)
Bivalirudin alone (N=4612)
P
11.7% (log rank)
11.8% 0.89
10.1% 0.014
0
0
5
10
15
20
25
Days from Randomization
30
35
Ischemic Composite Endpoint
UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone
Cumulative Events (%)
15
Estimate
UFH/Enoxaparin + IIb/IIIa (N=4603)
Bivalirudin + IIb/IIIa (N=4604)
Bivalirudin alone (N=4612)
10
7.3%
7.7%
7.8%
P
(log rank)
0.37
0.30
5
0
0
5
10
15
20
25
Days from Randomization
30
35
Major Bleeding Endpoint
UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone
Cumulative Events (%)
15
Estimate
UFH/Enoxaparin + IIb/IIIa (N=4603)
Bivalirudin + IIb/IIIa (N=4604)
Bivalirudin alone (N=4612)
10
P
5.7% (log rank)
5.3% 0.41
3.0% <0.0001
5
0
0
5
10
15
20
25
Days from Randomization
30
35
Event Rates and Power Calculations
UFH/Enox +
GP IIb/IIIa
Predicted
Rate
Bivalirudin +
GP IIb/IIIa
Rate
Endpoint
Power
NI
Bivalirudin
alone
Rate
Sup
Power
NI
Sup
Net clinical
outcome
12.4%
10.3% 99%
88%
10.5%
99% 81%
Ischemic
events
6.5%
5.3%
99%
67%
6.5%
87%
Major
bleeding
9.0%
7.5%
99%
73%
6.0%
99% 99%
NI = non-inferiority; Sup = superiority
-
Summary Conclusions: Primary Results
UFH/Enox +
GP IIb/IIIa
Bivalirudin +
GP IIb/IIIa
Endpoint
Net clinical
outcome
Ischemic
events
Major
bleeding
NI = non-inferiority; Sup = superiority
Bivalirudin
alone
Summary Conclusions: Primary Results
UFH/Enox +
GP IIb/IIIa
Observed
Bivalirudin +
GP IIb/IIIa
Rate
Endpoint
Net clinical
outcome
11.7%
Ischemic
events
7.3%
Major
bleeding
5.7%
NI = non-inferiority; Sup = superiority
Bivalirudin
alone
Summary Conclusions: Primary Results
UFH/Enox +
GP IIb/IIIa
Observed
Bivalirudin +
GP IIb/IIIa
Rate
Rate
P
Value
Net clinical
outcome
11.7%
11.8%
<0.001 NI
Ischemic
events
7.3%
7.7%
0.007 NI
Major
bleeding
5.7%
5.3%
0.001 NI
Endpoint
NI = non-inferiority; Sup = superiority
Bivalirudin
alone
Conclusions: Primary Results
UFH/Enox +
GP IIb/IIIa
Observed
Bivalirudin +
GP IIb/IIIa
Bivalirudin
alone
Rate
Rate
P
Value
Rate
P
Value
Net clinical
outcome
11.7%
11.8%
<0.001 NI
10.1%
0.015 Sup
Ischemic
events
7.3%
7.7%
0.007 NI
7.8%
0.011 NI
Major
bleeding
5.7%
5.3%
0.001 NI
3.0%
<0.001 Sup
Endpoint
NI = non-inferiority; Sup = superiority
Clinical Implications
 In patients with moderate-high risk ACS undergoing
an early invasive strategy with use of GP IIb/IIIa
inhibitors
 Bivalirudin is an acceptable substitute for either
unfractionated heparin or enoxaparin
 However, compared to either UFH/enoxaparin with
GP IIb/IIIa inhibition or bivalirudin with GP IIb/IIIa
inhibition
 A bivalirudin alone strategy results in significantly
greater net clinical benefit and enhanced survival
free from adverse events at 30 days