1. Safety and Effectiveness of Bivalirudin in NSTE ACS by duration of the upstream infusion in the ACUITY trial: Implications for ED and upstream management Charles Pollack, MA, MD, FACEP, FAAEM Professor and Chair, Emergency Medicine Pennsylvania Hospital, University of Pennsylvania

2. 2 Presenter Disclosure ►Consultant to:  The Medicines Company  Schering-Plough  sanofi-aventis  BMS ►Speakers Bureau:  Schering-Plough  sanofi-aventis ►Direct Research Support:  GSK

3. 3 Objective, Methods, and Patient Population ►Objective:  To determine whether the results of ACUITY inform ED and upstream decisions on choice and timing of antithrombotic therapy in contemporary management of NSTE ACS, in which the typical approach involves medical management for > 20 hours prior to intervention (CRUSADE) ►Methods:  Comparison of 30-day event rates for ischemia and bleeding in patients undergoing angiography within 24 hours from randomization, versus > 24 hours. ►Patient Population  13,650 patients in ACUITY with duration data – 11,178 (81.9%) to angiography or intervention within 24 hours  Longer-duration patients were more likely to have poorer renal function, thienopyridine administered prior to angiography, and elevated biomarkers.  Shorter-duration patients were more likely to have prior PCI.

4. 4 Primary Results by Treatment ►Overall ACUITY Results UFH/Enox + GP IIb/IIIa Bivalirudin + GP IIb/IIIa Bivalirudin alone EndpointRate P ValueRateP Value Ischemic events 7.3%7.7%0.007 NI7.8%0.011 NI Major bleeding 5.7%5.3%<0.001 NI3.0%<0.001 Sup Net clinical outcome 11.7%11.8%<0.001 NI10.1%0.015 Sup NI = non-inferiority; Sup = superiority Gregg Stone, ACC 2006 Presentation

5. 5 Primary Endpoint Measures by Duration of Preangio/Intervention Randomized AT* Time to angio/intervention < 24 hrsTime to angio/intervention > 24 hrs 1.10 (0.93-1.29) p = 0.26 0.60 (0.48-0.76) p < 0.001 0.92 (0.81-1.06) p = 0.25 0.98 (0.72-1.33) p = 0.89 0.37 (0.24-0.57) p < 0.001 0.69 (0.54-0.88) p = 0.003 * Results persist after adjusting for differences in baseline characteristics

6. 6 Primary Endpoint Measures by Duration of Preangio/Intervention Randomized AT: High-Risk Cohort*‡ Time to angio/intervention < 24 hrsTime to angio/intervention > 24 hrs 1.08 (0.90-1.30) p = 0.41 0.63 (0.48-0.81) p = 0.0004 0.94 (0.81-1.10) p = 0.45 1.04 (0.75-1.43) p = 0.83 0.42 (0.27-0.66) p = 0.0002 0.76 (0.59-0.98) p = 0.04 * Results persist after adjusting for differences in baseline characteristics ‡ “High-Risk” defined by positive biomarkers or dynamic ST-T changes of ischemia

7. 7 0.90 (0.75-1.09) OR (95% CI) Odds ratio ±95% CI Odds ratio ±95% CI Bivalirudin alone better Heparin + IIb/IIIa better Bleeding Ischemia Net Clinical Outcome 1.14 (0.92-1.41) 0.59 (0.45-0.76) ≤24h prior to cath/intervention P-value 0.2760 0.2281 <.0001 0.66 (0.49-0.89) OR (95% CI) Odds ratio ±95% CI Odds ratio ±95% CI Bivalirudin alone better Heparin + IIb/IIIa better Bleeding Ischemia Net Clinical Outcome 0.98 (0.67-1.43) 0.34 (0.21-0.55) >24h prior to cath/intervention P-value 0.0069 0.9223 <.0001 ACUITY patients, by duration of treatment* * Results persist after adjusting for differences in baseline characteristics

8. 8 0.95 (0.79-1.14) RR (95% CI) Risk ratio ±95% CI Risk ratio ±95% CI Bivalirudin alone better Heparin + IIb/IIIa better Bleeding Ischemia Net Clinical Outcome 1.13 (0.89-1.43) 0.61 (0.46-0.82) ≤24h prior to cath/intervention P-value 0.5904 0.3097 0.0009 0.73 (0.53-1.01) RR (95% CI) Risk ratio ±95% CI Risk ratio ±95% CI Bivalirudin alone better Heparin + IIb/IIIa better Bleeding Ischemia Net Clinical Outcome 0.99 (0.66-1.48) 0.41 (0.26-0.67) >24h prior to cath/intervention P-value 0.0545 0.9405 0.0004 ACUITY High-Risk‡ patients, by duration of treatment* * Results persist after adjusting for differences in baseline characteristics ‡ “High-Risk” defined by positive biomarkers or dynamic ST-T changes of ischemia

9. 9 Discussion ►NSTE ACS patients who receive extended ( > 24 hours) medical management prior to cath, have poorer ischemic outcomes  These ACUITY data are consistent with previous trial (ISAR- COOL) and registry (CRUSADE) data.  There are multiple reasons, both clinical and logistic, why the median time to cath in CRUSADE is 21 hours ►NSTE ACS patients who receive extended ( > 24 hours) medical management prior to cath, have poorer bleeding outcomes  Consistent with CRUSADE data  In ACUITY, significantly improved with bivalirudin monotherapy ►Both findings are consistent in the high-risk cohort  Particularly relevant to ED and upstream decision making  Numbers of prolonged therapy patients are relatively small, and economic impact not yet clear

10. 10 Conclusions ►Medical therapy for NSTE ACS for more than 24 hours prior to angiography and intervention is associated with increased ischemia and bleeding compared to more rapid interventional management in NSTE ACS. ►Compared with Heparin/Enoxaparin with platelet GP IIb/IIIa inhibitor, bivalirudin monotherapy significantly reduces major bleeding while providing similar ischemic protection, regardless of time to angiography ►Compared with Heparin/Enoxaparin with platelet IIb/IIIa inhibitor, bivalirudin monotherapy improves net clinical outcome, regardless of time to angiography