ARNO TRIAL ( A ntithrombotic R egimens a N d O utcome)

1. ARNO TRIAL(Antithrombotic Regimens aNd Outcome) A RANDOMIZED TRIAL COMPARING BIVALIRUDIN WITH UNFRACTIONED HEPARIN IN PATIENTS UNDERGOING ELECTIVE PCI David Antoniucci, TCT 2008, Washington DC

2. Discolusure Information David Antoniucci Nothing to Disclose

3. ARNO TRIAL STUDY ORGANIZATION Steering committee:D. Antoniucci (PI), G. Parodi, A. Migliorini, R. Valenti Sponsors:Antithrombotic Regimen aNd Outcome (ARNO) trial Investigators Site:Division of Cardiology, Careggi Hospital, Florence, Italy Clinical event committee:G. Moschi, U. Signorini, B. Bellandi Data safety monitoring board:G. Cerisano, P. Buonamici. This trial is registered with Clinical Trials.gov (NCT00448461).

4. ARNO TRIAL • BACKGROUND (1) • Three large randomized trials comparing bivalirudin with unfractionated heparin plus routine use of GPI have shown that bivalirudin may decrease bleeding complications without significant increase in ischemic complications resulting in a better net clinical outcome. • These studies however did not compare directly the 2 anticoagulant drugs, but 2 different antithrombotic strategies that included in the heparin arms the routine use of GPI with the associated and expected increase in bleeding complications.

5. ARNO TRIAL • BACKGROUND (2) • As compared to heparin, bivalirudin has 2 major advantages in terms of bleeding risk, a highly predictable anticoagulant effect at a standardized dose, and the short duration of the anticoagulant effect. The latter can be cancelled by the neutralization of heparin by protamine at the end of the procedure. • It is unknown if bivalirudin is still superior to unfractionated heparin plus protamine in patients undergoing elective PCI.

6. ARNO TRIAL • The aim of this randomized study is to determine if bivalirudin is still superior to unfractionated heparin plus protamine in patients undergoing elective PCI. • All patients undergoing PCI and pretreated with aspirin (325 mg), and a 600 mg loading dose of clopidogrel at least 6 hours before PCI were considered eligible for enrolment.

7. ARNO TRIAL • EXCLUSION CRITERIA • PCI of chronic total occlusion. • Renal insufficiency (GFR < 30 ml/min or baseline creatinine value > 3 mg/dl). • Known allergy to the study medications (aspirin, clopidogrel, unfractionated heparin, bivalirudin, protamine). • Others (active bleeding, bleeding diathesis, recent bleeding, severe comorbid conditions, relevant baseline hematological deviations, age < 18 yrs, pregnancy).

8. ARNO TRIAL • TREATMENTS • Aspirin (325 mg) and clopidogrel (600 mg loading) at least 6 hours • before PCI in all patients. Abciximab on a provisional basis. • Heparin group: 100 IU per kg of body weight with or without • additional boluses to achieve an ACT of 250 to 300 seconds. Protamine 0.5 mg per 100 IU of heparin utilized. • Bivalirudin group: bolus of 0.75 mg/kg followed by infusion of • 1.75 mg/kg per hour for the duration of the procedure. • Immediate post-PCI sheath removal and routine use of closure • devices in all patients.

9. ARNO TRIAL • END POINTS • Primary: in-hospital major bleeding (REPLACE 2 definition). • Secondary: 1) 30-day composite of death, MI, TVR. 2) 30-day net clinical outcome (death/MI/TVR or major bleeding). • 3) 30-day minor bleeding. • 4) Vascuular complications. • 5) Six-month outcome.

10. ARNO TRIAL • SAMPLE SIZE • Hypothesis:bivalirudin is superior to unfractionated heprin in terms of major bleeding in elective PCI. • Assumptions: Major bleedingg in heparin group 6% • Major bleeding in the bivalirudin group 2% • Power 90% with an α-level of 0.05 • Needed number of patients 850 (425 for each group).

11. ARNO TRIAL BASELINE CHARACTERISTICS (1) Bivalirudin Heparin p (n=425) (n=425) value Age, yrs 68.7 + 10.6 69.1 + 10.6 NS Male 77.4% 75.1% NS Diabetes 21.5% 22.2% NS Hypertension 58.9% 61.2% NS Smoker 18.0% 16.9% NS Previous MI 40.7% 38.1% NS Prior CABG 9.9% 7.7% NS LVEF 48 + 12% 46 + 12% NS BMI, Kg/m2 26.5 + 3.1 26.1 + 3.4 NS Creatinine, mg/dL 0.99 + 0.62 1.02 + 0.76 NS

12. ARNO TRIAL BASELINE CHARACTERISTICS (2) Bivalirudin Heparin p (n=425) (n=425) value Stable angina 44.7% 40.2% NS Unstable angina 27.5% 26.3% NS Raised troponin I 14.6% 18.6% NS MVD 53.1% 58.5% NS

13. ARNO TRIAL PROCEDURAL CHARACTERICS Bivalirudin Heparin p (n=425) (n=425) value Femoral access 98.3% 97.6% NS No. lesion/patients 1.6 + 0.9 1.6 + 0.9 NS Stenting 84.7% 87.8% NS No. stent/patient 1.5 + 1.2 1.6 + 1.1 NS IABP 0.7% 0.5% NS Abciximab 14.6% 27.6% 0.0001 Closure device 90.9% 90.1% NS

14. ARNO TRIAL • ONE-MONTH OUTCOME - BLEEDING • Bivalirudin Heparin p • (n=425) (n=425) value • Major bleeding in-hospital 2 (0.5%) 9 (2.1%) 0.033 one-month 4 (0.9%) 12 (2.8%) 0.043 • > 3gr/dL overt source, n 2 3 • > 4gr/dL, n 0 3 • blood transfusion, n 2 6 • Minor bleeding 2.4% 2.4% NS

15. ARNO TRIAL ONE–MONTH OUTCOME Bivalirudin Heparin p (n = 425) (n = 425) value Death/MI/TVR 12 (2.8%) 27 (6.4%) 0.014 Death 1 (0.2%) 6 (1.4%) 0.057 MI 11 (2.4%) 20 (4.5%) 0.098 Q-wave 1 1 TVR 2 (0.4%) 3 (0.7%) 0.411 NCO 14 (3.3%) 33 (8.0%) 0.004 Definite stent thrombosis 2 (0.5%) 1 (0.3%) acute 1 0 subacute 1 1

16. Study 30-Day End Points Bivalirudin UFH Incidence (%) P = 0.004 P = 0.014 P = 0.043

17. ARNO TRIAL CONCLUSIONS In this randomized trial of patients undergoing elective PCI and pre-treated with aspirin and clopidogrel, bivalirudin compared to unfractionated heparin plus protamine resulted in a significant reduction of major bleeding, of the composite of death, MI, TVR, and in a better net clinical outcome.