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 planned 1  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:

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=13,819 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 + IIb/IIIa inhibitor 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

UF HeparinEnoxaparinBivalirudin U/Kgmg/Kgmg/kg Bolus601.0 sc bid0.1 iv Infusion/h iv PCI ACT s 0.30 iv bolus iv bolus bolus iv 1.75/h infusion iv 4 CABGPer institution Per institution 5 Medical mgtNone 6 Study Medications  Anti-thrombin agents (started pre angiography) 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

PCI for ACS in Diabetics: Angiographic Triage Diabetes (N=3797) % No Diabetes (N=9723) % PCI CABG * Medical management * - p<0.001

PCI for ACS in Diabetics: Angiographic Triage Diabetes (N=3852) % No Diabetes (N=9857) % # pts with angiography Triaged procedure results PCI CABG * Medical management * - 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 yrs19%17.2%0.07 Female33.6%24.4%<0.001 Weight mean, (median, [IQR], kg) 91.3 (89.0, [78-102])83.9 (82.0, [73-94])<0.001 Caucasian84.5%91.7%<0.001 Diabetes – insulin requiring 29.8%- Hypertension n/N83.5%58.7%<0.001 Hyperlipidemia n/N70.2%50.8%<0.001 Current smoker n/N22.4%34.1%<0.001 Prior MI n/N36.0%28.3%<0.001 Prior PCI n/N48.1%35.2%<0.001 Prior CABG n/N24.0%15.1%<0.001 Prior CVA n/N7.6%5.0%<0.001 Creatinine Clearance* n/N20.7%17.6%0.002 * CrCL <60 mL/min

PCI for ACS in Diabetics: Baseline High Risk Features Diabetes % No Diabetes % p-value  Baseline cardiac biomarker  <0.001  - Troponin  <0.001 ST-segment  ≥1mm  Baseline cardiac biomarker  or ST-segment  <0.001

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

Diabetes % No Diabetes % P-value Net clinical outcome Composite ischemia Death/MI Death MI Q-wave MI Non Q-wave MI Unplanned revasc Bleeding (non CABG)7.55.3<0.001

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, % Female, % Weight mean (median [IQR]) kg 91.6 (89.9 [ ]) 90.5 (88 [77-100])91.7 (89 [78-103]) Caucasian, % Diabetes–Insulin req, % Hypertension, % Hyperlipidemia, % Current smoker, % Prior MI, % Prior PCI, % Prior CABG, % Prior CVA, % Creatinine Clearance*, % * creatinine clearance <60 mL/min † 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   - Troponin  ST-segment  ≥1mm † 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   - Troponin  ST-segment  ≥1mm  Baseline cardiac biomarker  or ST-segments  *71.7 * p<0.05 for comparison with H + GP IIb/IIIa † Heparin = unfractionated or enoxaparin

Diabetic ACS Patients Undergoing PCI: Procedural Characteristics Heparin † + GP IIb/IIIa (N=703) Bivalirudin + GP IIb/IIIa (N=713) Bivalirudin alone (N=721) PCI immediately after angiography Attempted vessels per patient >= Target Vessel per patient Native Bypass graft LAD LCX RCA Left Main All comparisons p= NS † 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 Stent62.9%66.0%62.8% Non-Drug-Eluting Stent 31.5%32.0%33.1% Thrombectomy1.3% 0.8% Atherectomy0.6%0.7%1.0% Cutting Balloon3.2%4.0%2.8% Distal Protection1.7%2.4%1.1% Brachytherapy0.0%0.1%0.3% All comparisons p= NS † 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 PCI96.3%97.1%7.9% - Eptifibatide63.9%67.0%3.7% - Tirofiban16.2%16.0%0.4% - Abciximab16.2%14.0%3.7%

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

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

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

30 day events (%) Diabetic ACS Patients Undergoing PCI: Myocardial Infarction Classification* 6.3% 5.6% Heparin † + IIb/IIIa vs. Bivalirudin Alone *CEC-adjudicated † 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, all9.2%5.3% Major, non-CABG8.5%4.6% Minor, non-CABG24%14.1%<0.001 TIMI Scale - Any8.7%4.3%< Major3.1%0.7%< Minor8.4%4.0%<0.001 *P value for bivalirudin alone vs. heparin + IIb/IIIa inhibitor † Heparin=unfractionated or enoxaparin

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

Diabetic ACS Patients Undergoing PCI: Median Time Intervals Time (hours) (interquartile range) Heparin † + GP IIb/IIIa Bivalirudin + GP IIb/IIIa Bivalirudin alone Overall Admission to angiography [ ] [ ] [ ] [ ] Randomization to angiography 4.80 [ ] 4.13 [ ] 4.68 [ ] 4.50 [ ] Randomization to first PCI 5.67 [ ] 4.63 [ ] 5.55 [ ] 5.28 [ ] Duration of 1 st PCI (min) 26.0 [ ] 27.0 [ ] 26.5 [ ] 26.0 [ ] Antithrombin study drug to PCI 4.92 [ ] 3.70 [ ] 4.40 [ ] 4.33 [ ] All comparisons p= NS † Heparin = unfractionated or enoxaparin