1. Switch Switch Safety and Efficacy of Crossover (Switch) from UFH/Enox to Bivalirudin: Results from ACUITY Dr. Harvey White Green Lane Cardiovascular Service Auckland City Hospital, Auckland, NZ Dr. Harvey White Green Lane Cardiovascular Service Auckland City Hospital, Auckland, NZ

2. Disclosure  Research Grants :  AlexionFournier Laboratories Sanofi Aventis Johnson & JohnsonEli Lilly Proctor & Gamble  Merck Sharpe & Dohme Schering Plough Roche  The Medicines Company Glaxo Smith Kline Pfizer  Neuren Pharmaceuticals NIH  Consultant:  Sanofi Aventis The Medicines Company  Research Grants :  AlexionFournier Laboratories Sanofi Aventis Johnson & JohnsonEli Lilly Proctor & Gamble  Merck Sharpe & Dohme Schering Plough Roche  The Medicines Company Glaxo Smith Kline Pfizer  Neuren Pharmaceuticals NIH  Consultant:  Sanofi Aventis The Medicines Company

3. Background  ACS patients  87% of patients receive either UFH or Enox within 24 hours after admission 1  72% of patients in Synergy and 50 % of patients in OASIS- 5 received prior antithrombin 2,3  Published studies and perceptions  Patients in Synergy who crossed over between UFH and Enox had an increase in bleeding complications 2  This activity occurred at various times through the study period: at times in response to clinical or clinician perception  Consistent therapy is better 4  ACS patients  87% of patients receive either UFH or Enox within 24 hours after admission 1  72% of patients in Synergy and 50 % of patients in OASIS- 5 received prior antithrombin 2,3  Published studies and perceptions  Patients in Synergy who crossed over between UFH and Enox had an increase in bleeding complications 2  This activity occurred at various times through the study period: at times in response to clinical or clinician perception  Consistent therapy is better 4 1 CRUSADE( 1Q-2006 results); 2 Synergy results; JAMA 2004; 3 OASIS -5; Yusuf et al,NEJM 2006; 4 Cohen et al, JACC 2006;

4. Scope of Analysis  This analysis will address the question of the safety and efficacy of switching from indirect thrombin inhibition (UFH or Enox) to direct thrombin inhibition (bivalirudin)  A protocol-driven activity of the ACUITY study at the time of randomization  This analysis will address the question of the safety and efficacy of switching from indirect thrombin inhibition (UFH or Enox) to direct thrombin inhibition (bivalirudin)  A protocol-driven activity of the ACUITY study at the time of randomization

5. ACUITY: Primary results  Heparin* + IIb/IIIa vs. Bivalirudin + IIb/IIIa vs. Bivalirudin Alone P NI <0.001 P Sup = 0.015 P NI = 0.011 P Sup = 0.32 P NI <0.001 P Sup <0.001 *Heparin=unfractionated or enoxaparin

6. UF HeparinEnoxaparinBivalirudin U/Kgmg/Kgmg/kg Bolus601.0 sc bid0.1 iv Infusion/h12 1 0.25 iv PCI ACT 200-250s 0.30 iv bolus 2 0.75 iv bolus 3 0.50 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 50-75 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 GPIIb/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

7. Prior treatment  ACUITY Protocol requirements  Patients on an antithrombin (either UFH or Enox) prior to randomization:  Continued the same treatment if randomized into Heparin(s) + GP IIb/IIIa arm  Switched to bivalirudin if randomized to one of the bivalirudin arms  Following results of Synergy UFH was allowed in the trial  Sites prospectively determined the preferred anti- thrombin strategy of either UFH or Enox  Switch between UFH and Enox was not permitted  ACUITY Protocol requirements  Patients on an antithrombin (either UFH or Enox) prior to randomization:  Continued the same treatment if randomized into Heparin(s) + GP IIb/IIIa arm  Switched to bivalirudin if randomized to one of the bivalirudin arms  Following results of Synergy UFH was allowed in the trial  Sites prospectively determined the preferred anti- thrombin strategy of either UFH or Enox  Switch between UFH and Enox was not permitted

8. Current Analysis  Hypothesis  Bivalirudin improves bleeding outcomes while preserving ischemic protection for ACS patients even if the patients are switched from either UFH or enoxaparin to bivalirudin (monotherapy) at the time of presentation.  Is it better to switch to bivalirudin or remain on consistent therapy?  Hypothesis  Bivalirudin improves bleeding outcomes while preserving ischemic protection for ACS patients even if the patients are switched from either UFH or enoxaparin to bivalirudin (monotherapy) at the time of presentation.  Is it better to switch to bivalirudin or remain on consistent therapy?

9. Current Analysis  Methods  Patients on prior antithrombin  Consistent: No switching from pre-randomization anti-thrombin to randomized therapy:  Enox →Enox or UFH → UFH  Switch: Single switch to bivalirudin determined by randomization code  from Enox → bivalirudin or UFH →bivalirudin  Event rates at 30-days  Net Clinical Outcome  Ischemic Composite  Major Bleeding  Methods  Patients on prior antithrombin  Consistent: No switching from pre-randomization anti-thrombin to randomized therapy:  Enox →Enox or UFH → UFH  Switch: Single switch to bivalirudin determined by randomization code  from Enox → bivalirudin or UFH →bivalirudin  Event rates at 30-days  Net Clinical Outcome  Ischemic Composite  Major Bleeding

10. ACUITY Primary Endpoints at 30 days  Net Clinical Endpoint  Composite ischemic and non-CABG major bleeding endpoints  Ischemic Endpoint  Death, MI, or unplanned revascularization  Non-CABG Major Bleeding Endpoint  Intracranial, intraocular, or retroperitoneal bleeding  Access site bleed requiring intervention/surgery  Hematoma ≥5 cm  Hgb  ≥3g/dL with an overt source or  ≥4g/dL w/o overt source  Blood transfusion  Net Clinical Endpoint  Composite ischemic and non-CABG major bleeding endpoints  Ischemic Endpoint  Death, MI, or unplanned revascularization  Non-CABG Major Bleeding Endpoint  Intracranial, intraocular, or retroperitoneal bleeding  Access site bleed requiring intervention/surgery  Hematoma ≥5 cm  Hgb  ≥3g/dL with an overt source or  ≥4g/dL w/o overt source  Blood transfusion

11. Consort Diagram ACUITY ACUITY N = 13819 Arm A Arm A Heparins + IIb/IIIa N = 4603 Arm C Arm C Bivalirudin N = 4612 Arm B Bivalirudin + GP IIb/IIIa N = 4604

12. Consort Diagram ACUITY ACUITY N = 13819 Arm A Arm A Heparins + IIb/IIIa N = 4603 Arm C Arm C Bivalirudin N = 4612

13. Consort Diagram ACUITY ACUITY 13819 Arm A: CONSISTENT Arm A: CONSISTENT Heparins + IIb/IIIa N = 2223 Arm C: SWITCH Arm C: SWITCH Bivalirudin N = 2237 Pts on Prior AT N = 6606 ╪ ╪ excludes Arm B and pts. with multiple crossovers, missing data

14. Consort Diagram ACUITY ACUITY 13819 CONSISTENT CONSISTENT UFH/Enox N = 2223 SWITCH SWITCH Bivalirudin* N = 2237 UFH→UFH N = 1294 Enox→Enox N = 929 UFH→Biv N = 1313 Enox→Biv N = 857 Pts on Prior AT N = 6606 ╪ * Includes 67 pts. who had UFH and Enox ╪ excludes Arm B and pts. with multiple crossovers, missing data

15. Baseline Characteristics Consistent UFH/Enox vs. Switch to Biv * creatinine clearance <60 mL/min *Elevated cardiac markers and/or ST changes Consistent UFH/Enox N = 2223 Switch Bivalirudin N = 2237 P-value Age (median [range], yrs)63 [23, 91]62 [20, 92]0.02 Male (%)71.670.0NS Weight (median [IQR], kg)83 [73, 96]84 [73, 96]NS Diabetes(%)27.625.00.05 Hypertension (%)64.563.8NS Hyperlipidemia (%)54.654.0NS Current smoker (%)29.530.7NS Prior MI (%)31.030.4NS Prior PCI (%)36.8 NS Prior CABG (%)18.418.1NS Thienopyridine exposure63.866.1NS Renal insufficiency* (%)19.617.4NS High Risk* (%)77.674.60.02 Troponin + (%)65.463.6NS

16. Comparing Consistent therapy on UFH/Enox vs. Switch Bivalirudin Alone Comparing Consistent therapy on UFH/Enox vs. Switch Bivalirudin Alone Consistent vs. Switch P=0.002 0.77 [0.63 – 0.91] P=0.601 0.95 [0.76 – 1.17] P<0.001 0.47 [0.35 – 0.64]

17. 0.83 (0.67-1.02) OR (95% CI) Odds ratio±95% CI Switch to Bivalirudin alone better Consistent UFH/Enox better Major Bleeding Ischemia Net Clinical Outcome 1.10 (0.86-1.41) 0.47 (0.34-0.65) P-value 0.073 0.464 <0.001 * Comparing consistent Hep/Enox vs Switch Bivalirudin Consistent vs. Switch All Patients - Adjusted

18. Consistent vs. Switch High Risk - Unadjusted Comparing Consistent UFH/Enox vs Switch Bivalirudin Consistent UFH/Enox N = 1654 Switch Bivalirudin N = 1623 RR Net Clinical Outcome 13.1%10.6% 0.81 [0.67-0.98] Ischemia8.0%7.8% 0.97 [0.76-1.22] Major Bleeding6.6%3.5% 0.52 [0.38-0.72]

19. 0.86 (0.68-1.07) OR (95% CI) Odds ratio±95% CI Switch to Bivalirudin alone better Consistent UFH/Enox better Major Bleeding Ischemia Net Clinical Outcome 1.11 (0.85-1.46) 0.51 (0.36-0.72) P-value 0.177 0.445 <0.001 Consistent vs. Switch High Risk - Adjusted Comparing Consistent UFH/Enox vs Switch Bivalirudin

20. Consistent vs. Switch Patients undergoing PCI - Unadjusted Comparing Consistent UFH/Enox vs Switch Bivalirudin Consistent UFH/Enox N = 1293 Switch Bivalirudin N = 1390 RR Net Clinical Outcome 13.3%11.8% 0.89 [0.73 -1.08] Ischemia8.1%9.0% 1.06 [0.81 -1.40] Major Bleeding6.9%3.5% 0.50 [0.36-0.71]

21. Comparing Consistent therapy on Enox vs. Switch from Enox to Bivalirudin Alone Comparing Consistent therapy on Enox vs. Switch from Enox to Bivalirudin Alone Consistent vs. Switch P=0.145 0.81 [0.61 – 1.07] P=0.626 0.92 [0.65 – 1.30] P=0.013 0.54 [0.34 – 0.88]

22. 0.89 (0.64 – 1.23) OR (95% CI) Odds ratio±95% CI Switch to Bivalirudin alone better Consistent Enox better Major Bleeding Ischemia Net Clinical Outcome 1.07 (0.72-1.59) 0.55 (0.32-0.95) P-value 0.472 0.732 0.032 * Comparing consistent Enox +GPI vs Switch Bivalirudin Consistent vs. Switch Adjusted Comparing Consistent Enox vs Switch Enox to Bivalirudin

23. Comparing Consistent therapy on UFH vs. Switch from UFH to Bivalirudin Alone Comparing Consistent therapy on UFH vs. Switch from UFH to Bivalirudin Alone Consistent vs. Switch P=0.012 0.75[0.60 – 0.94] P=0.857 0.98[0.74 – 1.28] P<0.001 0.44[0.30 – 0.65]

24. 0.78 (0.59-1.03) OR (95% CI) Odds ratio±95% CI Switch to Bivalirudin alone better Consistent UFH better Major Bleeding Ischemia Net Clinical Outcome 1.18 (0.86-1.63) 0.40 (0.26-0.61) P-value 0.081 0.312 <0.001 * Comparing consistent Hep+GPI vs Switch Bivalirudin Consistent vs. Switch Adjusted Comparing Consistent UFH vs Switch from UFH to Bivalirudin

25. P=0.145 0.81 [0.61 – 1.07] P=0.626 0.92 [0.65 – 1.30] P=0.013 0.54 [0.34 – 0.88] P=0.012 0.75 [0.60 – 0.94] P=0.857 0.98 [0.74 – 1.28] P<0.001 0.44 [0.30 – 0.65] UFH vs. bivalirudinEnox vs. bivalirudin Consistent vs. Switch Comparing Consistent therapy on UFH/Enox vs. Switch from heparins to Bivalirudin Alone Comparing Consistent therapy on UFH/Enox vs. Switch from heparins to Bivalirudin Alone

26. 0.89 (0.64-1.23) OR (95% CI) Odds ratio±95% CI Switch to Bivalirudin alone better Consistent Enox better Major Bleeding Ischemia Net Clinical Outcome 1.07 (0.72-1.59) 0.55 (0.32-0.95) P-value 0.472 0.732 0.032 0.78 (0.59-1.03) OR (95% CI) Odds ratio±95% CI Switch to Bivalirudin alone better Consistent UFH better Major Bleeding Ischemia Net Clinical Outcome 1.18 (0.86-1.63) 0.40 (0.26-0.61) P-value 0.081 0.312 <0.001 Consistent vs. Switch Adjusted Comparing Consistent UFH/Enox vs Switch to Bivalirudin Consistent Enox vs. bivalirudin Consistent UFH vs. bivalirudin

27. Limitations  Post-hoc subgroup analysis  Pre-randomization use of anti-thrombin was not stratified  Timing and dose of last UFH and Enox was not collected in the CRF  Post-hoc subgroup analysis  Pre-randomization use of anti-thrombin was not stratified  Timing and dose of last UFH and Enox was not collected in the CRF

28. Conclusions  Switching to bivalirudin is safe  Switching from any heparin (either enoxaparin or UFH) to bivalirudin monotherapy is not associated with an increased risk for ischemic events.  Furthermore  Switch to bivalirudin provides patients the 50% bleeding advantage of bivalirudin compared with consistent therapy on UFH or enoxaparin.  Switching to bivalirudin is safe  Switching from any heparin (either enoxaparin or UFH) to bivalirudin monotherapy is not associated with an increased risk for ischemic events.  Furthermore  Switch to bivalirudin provides patients the 50% bleeding advantage of bivalirudin compared with consistent therapy on UFH or enoxaparin.