1. ISAR-REACT 4: Discussion Deepak L. Bhatt MD, MPH, FACC, FAHA Chief of Cardiology, VA Boston Healthcare System Director, Integrated Interventional Cardiovascular Program at Brigham and Women’s Hospital and the VA Boston Healthcare System Associate Professor of Medicine, Harvard Medical School Senior Investigator, TIMI Study Group

2. Disclosure for Dr. Bhatt Research grants from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Sanofi Aventis, The Medicines Company. This presentation discusses off-label and/or investigational uses of various drugs and devices.

3. Background Majority of patients with NSTEMI undergo PCI, as the evidence supports ISAR-REACT 2 showed that abciximab plus heparin was superior to heparin alone in PCI of NSTEMI patients ACUITY showed that in NSTE-ACS, bivalirudin was non- inferior to GPIIb/IIIa inhibitors plus heparin versus heparin alone, with significantly less major bleeding Bavry et al. AJM 2006. Kastrati et al. JAMA 2006. Stone et al. NEJM 2006.

4. Primary Endpoint Death, Large MI, UTVR, Major Bleeding Days since Randomization 0 5 10 15 20 051015202530 Cumulative Incidence (%) Relative risk, 0.99 (95% CI, 0.74–1.32) P=0.94 Bivalirudin Abciximab 10.9% 11.0% Kastrati et al. NEJM 2011. Curves virtually superimposable

5. Secondary Efficacy Endpoint Death, Any MI, UTVR Bivalirudin Abciximab Relative risk, 0.96 (95% CI, 0.74–1.25) P=0.76 0 5 10 15 20 051015202530 Cumulative Incidence (%) Days since Randomization Abciximab Bivalirudin Death, % 1.41.6 Any MI, %12.011.4 uTVR, %0.81.3 12.8% 13.4% Kastrati et al. NEJM 2011. Even with increased power of a more sensitive MI definition curves appear identical

6. Secondary Safety Endpoint Major Bleeding 0 5 10 15 20 051015202530 Cumulative Incidence (%) Days since Randomization Relative risk, 1.82 (95% CI, 1.10–3.07) P=0.02 Bivalirudin Abciximab 4.6% 2.6% Kastrati et al. NEJM 2011. Large relative and absolute risk reduction

7. ISAR-REACT 4: Strengths Rigorous double-blind, double-dummy design (ACUITY was open-label, which - in theory - could affect ascertainment of non-fatal endpoints) Comparison was against abciximab (which some still consider the gold standard GPIIb/IIIa inhibitor) Strict definition of bleeding (intracranial, intraocular, or retroperitoneal; Hb decrease >4g/dL plus either overt bleeding or need for transfusion of 2 or more units) – difficult to argue with the importance of that

8. ISAR-REACT 4: Caveats Patients pretreated with ASA + clopidogrel 600 mg –Results may not apply to ASA/clop untreated Prasugrel or ticagrelor not used –Difficult to see how this would change the results Bleeding advantage would have been attenuated if more radial cases were performed –But still numerically lower pericardial, GI, and GU bleeds, and no apparent loss of efficacy

9. Conclusions In patients pretreated w/ ASA and clopidogrel 600 mg, –Bivalirudin results in less major bleeding than heparin + abciximab; also lower rate of severe thrombocytopenia –Similar efficacy –Shorter duration infusion –Likely lower cost Coupled with HORIZONS-AMI, data from ISAR-REACT 4 support use of bivalirudin during PCI across the full spectrum of ACS