1. Is Bivalirudin Monotherapy Sufficient for Diabetic Patients
with Acute Coronary Syndrome Undergoing PCI?
Frederick Feit, Steven Manoukian, Ramin Ebrahimi, Charles Pollack,
Magnus Ohman, Michael Attubato and Gregg Stone

2. Is Bivalirudin Monotherapy Sufficient for Diabetic Patients
with Acute Coronary Syndrome Undergoing PCI?
Conflicts:
Shareholder: Johnson and Johnson, Medicines Co.,
Millenium Pharmaceuticals; Consultant: Medicines Co.

3. PCI for ACS in Diabetics: Metabolic Abnormalities
Increased blood glucose causes coronary artery inflammation and is prothrombotic
Increased generation of thrombin, CRP, fibrinogen, von Willebrand factor, factors VII and VIII, and platelet factor 4
Increased expression of platelet activation markers including p-selectin, which mediates platelet-leukocyte interactions
Higher proportion of platelets expressing GPIIb/IIIa receptors

4. PCI for ACS in Diabetics: Background
Based on prior data including a meta-analysis of ACS trials current clinical guidelines recommend the use of GPIIb/IIIa inhibitors (GPI) in diabetic patients with ACS, especially those in whom PCI is planned1
In the ACUITY Trial 13,819 pts, including 3852 diabetics, with moderate or high risk ACS, undergoing an early invasive strategy were randomly assigned to either the standard of care: Heparin (UFH or enoxaparin) + GPI; or, Bivalirudin + GPI; or Bivalirudin with provisional GPI
1. Roffi et al. Circulation. 2001;104:

5. PCI for ACS in Diabetics: Methods
We compared adverse events: composite ischemia (death, nonfatal MI, unplanned ischemia driven revascularization), major bleeding and net clinical outcome (composite ischemia or bleeding) within the first 30 days in diabetic vs. nondiabetic pts
We compared the same 30-day end points in diabetic pts by treatment group

6. ACUITY Design ACS: Unstable angina or NSTEMI, N=13,819
Chest pain >10’ within 24 hours, plus
Biomarker +, or
Dynamic ECG changes, or
Documented CAD or all other TIMI risk criteria
Bivalirudin
+ IIb/IIIa inhibitor
Enoxaparin or UFH
Bivalirudin + IIb/IIIai
ASA
Clopidogrel
per local practice
Cath within 72 hours
PCI, CABG or medical management
30 day endpoints
Death, MI, IUR, ACUITY major bleeding
(net clinical outcome)
Prior UFH, LMWH (1 dose), eptifibatide and tirofiban were allowed
Stone et al. Presented 2006; ACC

7. Study Medications Anti-thrombin agents (started pre angiography)
UF Heparin
Enoxaparin
Bivalirudin
U/Kg
mg/Kg
mg/kg
Bolus 60
1.0 sc bid
0.1 iv
Infusion/h
121
0.25 iv
PCI
ACT s
0.30 iv bolus2
0.75 iv bolus3
0.50 bolus iv
1.75/h infusion iv4
CABG
Per institution
Per institution5
Medical mgt
None6
1 Target aPTT seconds
2 If last enoxaparin dose ≥8h - <16h before PCI; 3 If maintenance dose discontinued or ≥16h from last dose
4 Discontinued at end of PCI with option to continue at 0.25mg/kg for 4-12h if IIb/IIIa inhibitor not used
5 Bivalirudin option for off-pump same as PCI dose. For on-pump bivalirudin discontinued 2 hours before
6 Option to continue with pre-PCI anti-thrombotic regimen at physician discretion

8. PCI for ACS in Diabetics: Angiographic Triage
Diabetes
(N=3852) %
No Diabetes
(N=9857)
# pts with angiography
98.6
99.3
Triaged procedure results
PCI
55.9
57.1
CABG
14.4
11.1*
Medical management
29.8
31.8
Source standard tables run 08SEP06 table
* - p<0.001

9. PCI for ACS in Diabetics: Baseline Characteristics
Diabetes
(N=2137)
No Diabetes
(N=5604)
P-value
Age mean, (median, [range], yrs)
63.9 (64.0, [25-92])
62.2 (62.0, [21-95])
<0.001
Age > 75 yrs
19%
17.2%
0.07
Female
33.6%
24.4%
Weight mean, (median, [IQR], kg)
91.3 (89.0, [78-102])
83.9 (82.0, [73-94])
Caucasian
84.5%
91.7%
Diabetes – insulin requiring
29.8% -
Hypertension n/N
83.5%
58.7%
Hyperlipidemia n/N
70.2%
50.8%
Current smoker n/N
22.4%
34.1%
Prior MI n/N
36.0%
28.3%
Prior PCI n/N
48.1%
35.2%
Prior CABG n/N
24.0%
15.1%
Prior CVA n/N
7.6%
5.0%
Creatinine Clearance* n/N
20.7%
17.6%
0.002
[jad ] Slide with percentages only from previous slide? All denominators are different.
* CrCL <60 mL/min

10. PCI for ACS in Diabetics: 30-Day Outcomes
Diabetes vs. No Diabetes
P = 0.008
P = 0.15
P < 0.001
†Heparin=unfractionated or enoxaparin

11. Bivalirudin + GP IIb/IIIa
Diabetic ACS Patients Undergoing PCI Baseline Characteristics by Treatment Group
Heparin† +
GP IIb/IIIa
(N=703)
Bivalirudin + GP IIb/IIIa
(N=713)
Bivalirudin alone
(N=721)
Age mean (median [range], yrs)
64.6 (66, [25-87])
63.5 (64, [26-90])
63.4 (64, [33-92])
Age ≥75 yrs, %
20.2
19.5
17.2
Female, %
35.8
32.0
33.0
Weight mean (median [IQR]) kg
91.6 (89.9 [78-103])
90.5 (88 [77-100])
91.7 (89 [78-103])
Caucasian, %
85.1
83.4
Diabetes–Insulin req, %
29.2
31.1
Hypertension, %
85.3
83.1
82.2
Hyperlipidemia, %
69.4
71.4
70.0
Current smoker, %
22.5
23.0
21.7
Prior MI, %
36.1
33.9
38.0
Prior PCI, %
47.6
46.8
49.7
Prior CABG, %
24.8
22.1
25.0
Prior CVA, %
7.1
6.4
9.3
Creatinine Clearance*, %
23.3
19.2
19.6
[jad] PERCENTAGES SLIDE – all denominators are different how to handle (see previous slide)?
Source Standard Tables 08SEP Cr Cl Table
Diabetes Insulin requiring – no longer in standard tables. Source table diabete_PCI run date 09AUG06
* creatinine clearance <60 mL/min
†Heparin = unfractionated or enoxaparin

12. Bivalirudin + GP IIb/IIIa
Diabetic ACS Patients Undergoing PCI: Baseline High Risk Features by Treatment Group
Heparin†
+ GP IIb/IIIa %
Bivalirudin GP IIb/IIIa
Bivalirudin alone
Baseline cardiac biomarker 
60.9
56.5
60.5
- Troponin 
59.5
54.7
58.8
ST-segment  ≥1mm
35.4
32.8
32.5
Source standard Diabetes run date 08SEP06
ST-segment >1mm = Adding ST depression >1 and ST elevation >1 together
†Heparin = unfractionated or enoxaparin

13. Diabetic ACS Patients Undergoing PCI: Intervention Type
Heparin† +
GP IIb/IIIa
( N=692)
Bivalirudin GP IIb/IIIa
( N=706)
Bivalirudin alone
(N=717)
Drug-Eluting Stent
62.9%
66.0%
62.8%
Non-Drug-Eluting Stent
31.5%
32.0%
33.1%
Thrombectomy
1.3%
0.8%
Atherectomy
0.6%
0.7%
1.0%
Cutting Balloon
3.2%
4.0%
2.8%
Distal Protection
1.7%
2.4%
1.1%
Brachytherapy
0.0%
0.1%
0.3%
All comparisons p= NS
†Heparin = unfractionated or enoxaparin

14. Diabetic ACS Patients Undergoing PCI: GP IIb/IIIa Inhibitor Administration
Heparin
+ IIb/IIIa
(N=703)
Bivalirudin
(N=713)
Bivalirudin alone
(N=721)
GPI inhibitor during PCI
96.3%
97.1%
7.9%
- Eptifibatide
63.9%
67.0%
3.7%
- Tirofiban
16.2%
16.0%
0.4%
- Abciximab
14.0%
IIb/IIIa inhib

15. Heparin* + GP IIb/IIIa vs. Bivalirudin + GP IIb/IIIa
Diabetic ACS Patients Undergoing PCI: 30-Day Endpoints by Treatment Group
Heparin* + GP IIb/IIIa vs. Bivalirudin + GP IIb/IIIa
P = 0.27
P = 0.48
P = 0.51
*Heparin = unfractionated or enoxaparin

16. Diabetic ACS Patients Undergoing PCI: 30-Day Endpoints
Heparin* + GP IIb/IIIa vs. Bivalirudin alone
P = 0.08
P = 0.42
P = 0.003
*Heparin = unfractionated or enoxaparin

17. Diabetic ACS Patients Undergoing PCI: Components of Ischemic Endpoint
Heparin* + IIb/IIIa vs. Bivalirudin Alone
PSup = 0.42
PSup = 0.26
PSup = 0.57
PSup = 0.74
*Heparin=unfractionated or enoxaparin

18. Heparin† + IIb/IIIa vs. Bivalirudin Alone
Diabetic ACS Patients Undergoing PCI: Myocardial Infarction Classification*
Heparin† + IIb/IIIa vs. Bivalirudin Alone
p = 0.57
6.3%
5.6%
30 day events (%)
Q-wave 1.7%
p = 0.08
Q-wave 0.7%
Non Q-wave
Non Q-wave
p = 0.79
4.9%
4.6%
Heparin + IIb/IIIa
Bivalirudin alone
(N=703)
(N=721)
*CEC-adjudicated
†Heparin=unfractionated or enoxaparin

19. Diabetic ACS Patients Undergoing PCI: Bleeding Endpoints 30-days
Heparin† +GP IIb/IIIa
( N=703)
Bivalirudin alone
(N=721) p-
value
ACUITY Scale
- Major Bleed, all
9.2%
5.3%
0.004
- Major, non-CABG
8.5%
4.6%
0.003
- Minor, non-CABG
24%
14.1%
<0.001
TIMI Scale
- Any
8.7%
4.3%
- Major
3.1%
0.7%
- Minor
8.4%
4.0%
[jad] Table SEP06
*P value for bivalirudin alone vs. heparin + IIb/IIIa inhibitor
†Heparin=unfractionated or enoxaparin

20. Heparin† + GP IIb/IIIa vs. Bivalirudin alone
Insulin-dependent Diabetic ACS Patients Undergoing PCI: 30-Day Endpoints by Treatment Group
Heparin† + GP IIb/IIIa vs. Bivalirudin alone
P = 0.08
P = 0.42
P = 0.04
†Heparin=unfractionated or enoxaparin

21. Diabetic Patients with ACS Undergoing PCI: Conclusions
Compared with non-diabetics, diabetic patients have worse net clinical outcomes at 30 days (14.9% vs. 12.6%; p=0.008), resulting from similar rates of the composite ischemic end point (9.5% vs. 8.5%; p=0.15) and a significantly higher rate of major bleeding (7.5% vs. 5.3%; p=0.008)
In diabetic patients, compared with the standard of care, heparin (UFH or enoxaparin) + GPIIb/IIIa, bivalirudin + GPIIb/IIIa was not better for protection from ischemic events or bleeding and resulted in similar net clinical outcome

22. Diabetic Patients with ACS Undergoing PCI: Conclusions
Compared to those receiving the reference standard, diabetics receiving bivalirudin monotherapy, with provisional GPIIb/IIIa in 7.9%, had similar protection from ischemic events (8.3% vs. 9.5%; p=0.42) and a marked reduction in major bleeding (4.6% vs. 8.5%; p=0.003) with a trend towards improved net clinical outcome (12.1% vs. 15.2%; p=0.08)
These 30-day outcomes suggest that bivalirudin monotherapy is safe and effective for diabetic patients with ACS undergoing PCI, including those requiring insulin
One-year clinical and economic data will determine whether this regimen will become the standard of care for these patients.