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

Is Bivalirudin Monotherapy Sufficient for Diabetic Patients

with Acute Coronary Syndrome Undergoing PCI?

Shareholder: Johnson and Johnson, Medicines Co., Millenium Pharmaceuticals; Consultant: Medicines Co.

Conflicts:

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

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;104:2767-71

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

ACUITY Design

ACS: Unstable angina or NSTEMI, N=13,819Chest pain >10’ within 24 hours, plus

Biomarker +, orDynamic ECG changes, or

Documented CAD or all other TIMI risk criteria

Bivalirudin+ IIb/IIIa inhibitor

Enoxaparin or UFH+ IIb/IIIa inhibitor

Bivalirudin + IIb/IIIai

ASAClopidogrel

per local practice

Cath within 72 hoursPCI, CABG or medical management

30 day endpointsDeath, MI, IUR, ACUITY major bleeding

(net clinical outcome)

Prior UFH, LMWH (1 dose), eptifibatide and tirofiban were

allowed

Stone et al. Presented 2006; ACC

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

PCIACT

200-250s

0.30 iv bolus2

0.75 iv bolus3

0.50 bolus iv

1.75/h infusion iv4

CABG Per institution Per institution Per institution5

Medical mgt None6 None6 None6

Study Medications Anti-thrombin agents (started pre angiography)

1 Target aPTT 50-75 seconds2 If last enoxaparin dose ≥8h - <16h before PCI; 3 If maintenance dose discontinued or ≥16h from last dose4 Discontinued at end of PCI with option to continue at 0.25mg/kg for 4-12h if IIb/IIIa inhibitor not used5 Bivalirudin option for off-pump same as PCI dose. For on-pump bivalirudin discontinued 2 hours before6 Option to continue with pre-PCI anti-thrombotic regimen at physician discretion

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

* - p<0.001

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% 0.07Female 33.6% 24.4% <0.001Weight mean, (median, [IQR], kg)

91.3 (89.0, [78-102]) 83.9 (82.0, [73-94]) <0.001

Caucasian 84.5% 91.7% <0.001Diabetes – insulin requiring 29.8% -

Hypertension n/N 83.5% 58.7% <0.001

Hyperlipidemia n/N 70.2% 50.8% <0.001Current smoker n/N 22.4% 34.1% <0.001Prior MI n/N 36.0% 28.3% <0.001Prior PCI n/N 48.1% 35.2% <0.001Prior CABG n/N 24.0% 15.1% <0.001Prior CVA n/N 7.6% 5.0% <0.001Creatinine Clearance* n/N 20.7% 17.6% 0.002

* CrCL <60 mL/min

14.9%

9.5%7.5%

5.3%

12.6%

8.5%

Net clinical outcome Composite ischemia Major bleeding (non-CABG)

30 d

ay e

ven

ts (

%)

Diabetes (n=2137) No Diabetes (n=5604)

Diabetes vs. No DiabetesDiabetes vs. No Diabetes

P = 0.008 P = 0.15 P < 0.001

†Heparin=unfractionated or enoxaparin†Heparin=unfractionated or enoxaparin

PCI for ACS in Diabetics: 30-Day Outcomes

Diabetic ACS Patients Undergoing PCIBaseline 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 17.2Female, % 35.8 32.0 33.0Weight 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 85.1Diabetes–Insulin req, % 29.2 29.2 31.1Hypertension, % 85.3 83.1 82.2Hyperlipidemia, % 69.4 71.4 70.0Current smoker, % 22.5 23.0 21.7Prior MI, % 36.1 33.9 38.0Prior PCI, % 47.6 46.8 49.7Prior CABG, % 24.8 22.1 25.0Prior CVA, % 7.1 6.4 9.3Creatinine Clearance*, % 23.3 19.2 19.6

* creatinine clearance <60 mL/min †Heparin = unfractionated or enoxaparin†Heparin = unfractionated or enoxaparin

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

†Heparin = unfractionated or enoxaparin†Heparin = unfractionated or enoxaparin

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% 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†Heparin = unfractionated or enoxaparin

Diabetic ACS Patients Undergoing PCI: GP IIb/IIIa Inhibitor Administration

Heparin + IIb/IIIa(N=703)

Bivalirudin + IIb/IIIa(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 16.2% 14.0% 3.7%

Diabetic ACS Patients Undergoing PCI: 30-Day Endpoints by Treatment Group

15.2%

9.5%8.5%

10.7%

17.4%

9.5%

Net clinical outcome Composite ischemia Major bleeding (non-CABG)

30 d

ay e

ven

ts (

%)

Heparin+IIb/IIIa (N=703) Bivalirudin+IIb/IIIa (N=713)

Heparin* + GP IIb/IIIa vs. Bivalirudin + GP IIb/IIIaHeparin* + GP IIb/IIIa vs. Bivalirudin + GP IIb/IIIa

*Heparin = unfractionated or enoxaparin*Heparin = unfractionated or enoxaparin

P = 0.51 P = 0.48P = 0.27

Diabetic ACS Patients Undergoing PCI: 30-Day Endpoints

15.2%

9.5%8.5%

4.6%

12.1%

8.3%

Net clinical outcome Composite ischemia Major bleeding (non-CABG)

30 d

ay e

ven

ts (

%)

Heparin+IIb/IIIa (N=703) Bivalirudin alone (N=721)

Heparin* + GP IIb/IIIa vs. Bivalirudin aloneHeparin* + GP IIb/IIIa vs. Bivalirudin alone

*Heparin = unfractionated or enoxaparin*Heparin = unfractionated or enoxaparin

P = 0.08 P = 0.42 P = 0.003

22

Diabetic ACS Patients Undergoing PCI: Components of Ischemic Endpoint

9.5%

1.3%

6.3%

3.6% 3.9%

0.7%

8.3%

5.5%

Compositeischemia

Death Myocardialinfarction

Unplannedrevasc forischemia

30

da

y e

ve

nts

(%

)

Heparin+IIb/IIIa (N= 703) Bivalirudin alone (N=721)

Heparin* + IIb/IIIa vs. Bivalirudin AloneHeparin* + IIb/IIIa vs. Bivalirudin Alone

PSup = 0.42 PSup = 0.26 PSup = 0.57 PSup = 0.74

*Heparin=unfractionated or enoxaparin*Heparin=unfractionated or enoxaparin

30 d

ay e

ven

ts (

%)

Diabetic ACS Patients Undergoing PCI: Myocardial Infarction Classification*

6.3% 5.6%

Heparin† + IIb/IIIa vs. Bivalirudin AloneHeparin† + IIb/IIIa vs. Bivalirudin Alone

*CEC-adjudicated*CEC-adjudicated †Heparin=unfractionated or enoxaparin†Heparin=unfractionated or enoxaparin

Heparin + IIb/IIIa

Q-wave 1.7%

(N=703)Bivalirudin alone

(N=721)

Non Q-wave

4.9%

Q-wave 0.7%

Non Q-wave

4.6%

p = 0.57

p = 0.08

p = 0.79

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% <0.001

- Major 3.1% 0.7% <0.001

- Minor 8.4% 4.0% <0.001

*P value for bivalirudin alone vs. heparin + IIb/IIIa inhibitor*P value for bivalirudin alone vs. heparin + IIb/IIIa inhibitor †Heparin=unfractionated or enoxaparin†Heparin=unfractionated or enoxaparin

Insulin-dependent Diabetic ACS Patients Undergoing PCI: 30-Day Endpoints by Treatment Group

17.6%

9.3%11.2%

5.8%

11.6%

7.1%

Net clinical outcome Composite ischemia Major bleeding (non-CABG)

30 d

ay e

ven

ts (

%)

Heparin+IIb/IIIa (N=205) Bivalirudin alone (N=224)

Heparin† + GP IIb/IIIa vs. Bivalirudin aloneHeparin† + GP IIb/IIIa vs. Bivalirudin alone

P = 0.08 P = 0.42 P = 0.04

†Heparin=unfractionated or enoxaparin†Heparin=unfractionated or enoxaparin

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

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.