1. LBCT March 29, 08 ISAR REACT 3 A. Kastrati, F.-J. Neumann, J. Mehilli, S. Schulz, G. Richardt, R. Iijima, R.A. Byrne, P.B. Berger, A. Schömig Bivalirudin Versus Unfractionated Heparin in Biomarker Negative Patients With Stable and Unstable Angina Undergoing PCI ISAR-REACT 3 (Intracoronary Stenting and Antithrombotic Regimen- Rapid Early Action for Coronary Treatment 3) ClinicalTrials.gov Identifier NCT00262054

2. LBCT March 29, 08 ISAR REACT 3 Disclosures The trial was supported in part by a grant from Nycomed Pharma GmbH, Unterschleißheim, Germany The company did not participate in the design and conduct of the study, in the collection, analysis, and interpretation of the data, or in the preparation, review, or approval of the presentation. No other conflict of interest to disclose

3. LBCT March 29, 08 ISAR REACT 3 Participating Centers and Principal Investigators Deutsches Herzzentrum, Munich. Germany (PI: J. Pache) 1. Med. Klinik rechts der Isar, Munich. Germany (PI: J. Dirschinger) Herzzentrum Bad Krozingen, Bad Krozingen. Germany (PI: F.-J. Neumann) Herzzentrum Segeberger Kliniken, Bad Segeberg. Germany (PI: G. Richardt) Geisinger Clinic, Danville (PA). United States (PI: P.B. Berger) Med. Klinik I, Garmisch-Partenkirchen. Germany (PI: F. Dotzer) Herz- und Gefäß-Klinik, Bad Neustadt. Germany (PI: M. Schneider) Study Chairman: A. Schömig Study Principal Investigator: A. Kastrati Data Coordinating Center: J. Mehilli

4. LBCT March 29, 08 ISAR REACT 3 Background Bivalirudin has not been compared with unfractionated heparin during PCI in the modern era, or in patients who have received optimal pretreatment with clopidogrel.

5. LBCT March 29, 08 ISAR REACT 3 Prior RCTs Comparing Bivalirudin and Heparin BAS (NEJM 1995) - Control group: UFH bolus of 175 U/kg + 18-24 hr infusion - Different dose of bivalirudin than curently used as well - Balloon angioplasty only - No pretreament with clopidogrel REPLACE 2 (JAMA 2003) - Control group: UFH plus GPIIb/IIIa inhibitors - Fictional comparator of UFH alone; no pts actually received it - Clopidogrel pretreatment in <85%; 300 mg load - Provisional IIb/IIIa inhibitors in 7.2% of bivalirudin pts

6. LBCT March 29, 08 ISAR REACT 3 REPLACE 1 (AJC 2004) - Bivalirudin vs UFH; GPIIb/IIIa inhibitors in 72% in both groups - Open-label - Clopidogrel pretreatment in <60%, 300 mg ACUITY and HORIZONS – not relevant; compared bivalirudin with UFH and a GPIIb/IIIa inhibitor in high risk ACS/STEMI pts Prior RCTs Comparing Bivalirudin and Heparin

7. LBCT March 29, 08 ISAR REACT 3 Aim To compare bivalirudin alone to unfractionated heparin alone in biomarker negative pts undergoing PCI pretreated with clopidogrel 600 mg for >2 hours Hypothesis Bivalirudin is superior to UFH for biomarker negative patients undergoing PCI after optimal pretreatment with clopidogrel

8. LBCT March 29, 08 ISAR REACT 3 Inclusion Criteria Patients older than 18 years of age undergoing PCI who were biomarker negative at study entry Clopidogrel loading  2 hrs prior to PCI

9. LBCT March 29, 08 ISAR REACT 3 Exclusion Criteria Acute coronary syndromes with positive biomarkers or ST-segment elevation on ECG Cardiogenic shock Active bleeding, bleeding diathesis Impaired renal function (creatinine >3 mg/dl)

10. LBCT March 29, 08 ISAR REACT 3 Treatment Regimens Clopidogrel 600 mg at least 2 hours before PCI Aspirin >325 mg orally or intravenously Bivalirudin group Bolus of 0.75 mg/kg Infusion of 1.75 mg/kg/hr UFH group Bolus of 140 U/kg Placebo Infusion Clopidogrel 75-150 mg/day until discharge (≤3 days) 75 mg/day for at least 6 months Aspirin 80-325 mg/day indefinitely Double-blind randomization; double-dummy administration

11. LBCT March 29, 08 ISAR REACT 3 Primary (Quadruple) Endpoint at 30 Days Composite rate of: –Death –Myocardial infarction (defined as CK-MB ≥2x upper limit normal ) –Urgent target vessel revascularization –Major bleeding (according to the REPLACE-2 criteria, JAMA ′03 ) Intracranial, intraocular, or retroperitoneal bleeding, or Clinically overt bleeding resulting in a decrease in Hb>3 g/dL, or Any decrease in Hb>4 g/dL, or Transfusion of >2 units of packed red blood cells or whole blood

12. LBCT March 29, 08 ISAR REACT 3 Secondary (Triple) Endpoint at 30 Days Composite rate of: –Death –Myocardial infarction –Urgent target vessel revascularization

13. LBCT March 29, 08 ISAR REACT 3 Sample Size Calculation Assumed incidence of the 1 o quadruple endpoint: –8.0% in UFH group –5.8% in bivalirudin group (a 27.5% reduction with bivalirudin) Power = 82% Two-sided  level = 0.05 Enrollment of 4500 patients required

14. LBCT March 29, 08 ISAR REACT 3 2,289 Pts 30-day Follow-up 2,281 Pts UFHBivalirudin PCI 4,570 Patients Study Population

15. LBCT March 29, 08 ISAR REACT 3 Baseline Characteristics BivalirudinUFH Age, yrs67 Male7677 Body mass index, kg/m 2 28 Diabetes,%2728 Hypertension, %8990 Current smoker, %1415 Hypercholesterolemia, %8179 History of MI, %3230 History of CABG, %1311 Unstable angina, %18 Stable angina, %82 Serum creatinine, mg/dl11

16. LBCT March 29, 08 ISAR REACT 3 Angiographic Characteristics BivalirudinUFH Ejection fraction, %58 Multivessel disease, %80 Number of lesions/patient22 Vessel treated, % left main left anterior descending circumflex right coronary bypass graft 6 39 23 30 2 5 37 24 32 2 B2/C lesion, %64

17. LBCT March 29, 08 ISAR REACT 3 DES 84% DES 82% BMS PTCA 6% 10% 7% 11% Type of PCI Bivalirudin UFH

18. LBCT March 29, 08 ISAR REACT 3 Incidence (%) P=0.70 P=0.24 P=0.75P=0.52P=0.30 Ischemic Events Bivalirudin UFH

19. LBCT March 29, 08 ISAR REACT 3 Cumulative incidence (%) 0 2 4 6 8 10 05 15202530 Days after randomization Secondary (Triple) Endpoint Death, MI, UTVR 5.0% 5.9% RR=1.16 [95% CI, 0.91-1.49], P=0.23 Bivalirudin UFH

20. LBCT March 29, 08 ISAR REACT 3 Incidence (%) P=0.008 Bleeding Events P=0.0001P=0.15 Bivalirudin UFH

21. LBCT March 29, 08 ISAR REACT 3 Incidence (%) P=0.99 Thrombocytopenia P=0.61 50,000 to <100,000 cells/mm 3 20,000 to <50,000 cells/mm 3 Bivalirudin UFH

22. LBCT March 29, 08 ISAR REACT 3 Days after randomization Cumulative incidence (%) 0 2 4 6 8 10 05 15202530 Primary (Quadruple) Endpoint Death, MI, UTVR, Major Bleeding 8.3% 8.7% RR=0.94 [95% CI, 0.77-1.15], P=0.57 Bivalirudin UFH

23. LBCT March 29, 08 ISAR REACT 3 Age >67.6 yrs ≤67.6 yrs Sex Women Men Angina Unstable Stable Relative Risk (95% Confidence Intervals) 012 Diabetes Yes No Prespecified Subgroup Analyses Primary (Quadruple) Endpoint Bivalirudin betterUFH better Creatinine >0.9 mg/dl ≤0.9 mg/dl

24. LBCT March 29, 08 ISAR REACT 3 Incidence (%) Rates of MI and Bleeding Using Alternative Definitions TIMI Bleeding P=0.22P=0.04P=0.01 Q-wave or 3x ↑ CK-MB Bivalirudin UFH

25. LBCT March 29, 08 ISAR REACT 3 Limitations The total dose of UFH (140 U/kg bolus without ACT guidance and with no additional doses) might be higher than that used in other recent PCI trials in the USA; whether and to what degree this affected outcome cannot be determined The results ought not be generalized to pts not pretreated with clopidogrel

26. LBCT March 29, 08 ISAR REACT 3 Conclusion In biomarker negative patients with stable and unstable angina undergoing PCI pretreated with clopidogrel 600 mg for >2 hours, bivalirudin does not improve “net clinical benefit” – the quadruple endpoint – at 30 days compared to UFH, although it significantly reduces bleeding