1. Translating Advances in NSTEMI and STEMI into Real World Institutional Practice Harold L. Dauerman, MD Director, Cardiovascular Catheterization Laboratories Professor of Medicine University of Vermont Fletcher Allen Health Care Harold L. Dauerman, MD Director, Cardiovascular Catheterization Laboratories Professor of Medicine University of Vermont Fletcher Allen Health Care The Science and Medicine of ACS

2. University of Vermont Post-PCI Bleeding and Vascular Complication Rates NNE Rate: 2.0% in 2006 Any Transfusion, RPH or Repair = Bleeding Complication Introduction of Bivalirudin to Cath Lab Bivalirudin to Cath Lab Introduction of Bivalirudin to Cath Lab Bivalirudin to Cath Lab Introduction of Upstream Bivalirudin

3. Incorporation of Bivalirudin in Cath Lab for NSTEMI in 2003—A Cautious Beginning Bivalirudin GP IIb/IIIa Inhibitor UFH alone Bivalirudin GP IIb/IIIa Inhibitor UFH alone

4. P < 0.001 for temporal trend Arterial injury and/or arterial injury related bleeding N= 36,631 Patients Undergoing PCI, NNE Registry Arterial injury and/or arterial injury related bleeding N= 36,631 Patients Undergoing PCI, NNE Registry Signs of Hope Since 2004 Dauerman, Applegate and Cohen, JACC 2007

5. How We Introduced Upstream and Downstream Bivalirudin: The UVMC Time Line ► 2003: Put bivalirudin on the cath lab shelf as an option for NSTEMI ► 2007: Educational programs for fellows, floor staff and attendings ► We did not remove GPI option ► We did NOT involve community hospitals in this decision. They can do whatever they want as long as they transfer and don’t overdose patients. ► 2008: A standardized STEMI bivalirudin approach ► For upstream AMI utilization, bivalirudin ordered from pharmacy ► In collaboration with ED (EDICT for ACS Strategy) ► 2003: Put bivalirudin on the cath lab shelf as an option for NSTEMI ► 2007: Educational programs for fellows, floor staff and attendings ► We did not remove GPI option ► We did NOT involve community hospitals in this decision. They can do whatever they want as long as they transfer and don’t overdose patients. ► 2008: A standardized STEMI bivalirudin approach ► For upstream AMI utilization, bivalirudin ordered from pharmacy ► In collaboration with ED (EDICT for ACS Strategy)

6. NSTEMI Transfers, Upstream Strategies, and Results of Clinical Trials Non ST-Elevation Myocardial Infarction

7. What We Really Do With Transfers? September 24, 2007 email from me To:Sullivan, Claudia A. Cc:Ades, Philip A. Subject: Transfer of John XXXXX, DOB 11/08/25 81M with NSTEMI/old LBBB, Tn 3.0 Pain free, but with NSVT. ASA/clopidogrel 300 po/enoxaparin. From Adirondack Medical Center. Class I transfer. Change to bivalirudin on arrival. DNR—reverse POLST (wants a cath, but no CABG). Echo today, cath tomorrow (or today if unstable). Thanks, Harry To:Sullivan, Claudia A. Cc:Ades, Philip A. Subject: Transfer of John XXXXX, DOB 11/08/25 81M with NSTEMI/old LBBB, Tn 3.0 Pain free, but with NSVT. ASA/clopidogrel 300 po/enoxaparin. From Adirondack Medical Center. Class I transfer. Change to bivalirudin on arrival. DNR—reverse POLST (wants a cath, but no CABG). Echo today, cath tomorrow (or today if unstable). Thanks, Harry

8. Protocol Major/Minor Bleed by SWITCH and Randomized Therapy *P=NS for all 3-way comparisons versus bivalirudin alone; † P<.05 vs prior treatment with UFH or enoxaparin; ‡ naïve=no prior AT therapy in preceding 48 hours. Protocol major/minor bleed Naïve→ Bivalirudin ‡ (n=2,345) LMWH→ Bivalirudin (n=258) UFH→ Bivalirudin (n=287) LMWH→UFH + GP IIb/IIIa (n=313) Naïve→ UFH + GP IIb/IIIa ‡ (n=2,325) UFH→UFH + GP IIb/IIIa (n=349) * † Gibson CM et al. Am J Cardiol. 2007;99:1687-1690.

9. 4.13.6 2.9 2.3 1.4 1.5 1.5 6.94.3 3.9 3.0 2.6 1.86.8 *UA at any time, within preceding 48 hours or before. † ACS defined as UA within preceding 48 hours or MI within prior 7 days. CrCl= creatinine clearance. (n=1,330) (n=2,553) REPLACE-2 One-Year Cumulative Mortality in Prespecified High-Risk Subgroups Cumulative mortality at 1 year 0 2 4 6 8 DiabetesUA* UA* or ACS † ACS † (n=2,489) (n=1,606) (n=2,046) Lincoff AM et al. JAMA. 2004;292:696-703. Stone GW. J Invasive Cardiol. 2004;16(suppl G):12-17. Heparin + GP IIb/IIIa Bivalirudin with “provisional” GP IIb/IIIa Percentage (%) (n=1,010) CrCl ≤60 Age >75 Age >65 (n=795)

10. Transfer to Cardiology Floor ► Enoxaparin held—wait 8 hours from community hospital last dose. ► Then, start upstream bivalirudin ► Patient pain free—1 st case next A.M ► DES, no eptifibatide, closure device, 150 mg clopidogrel ► Ambulate at 6 hours ► D/C following 0900 A.M. ► Enoxaparin held—wait 8 hours from community hospital last dose. ► Then, start upstream bivalirudin ► Patient pain free—1 st case next A.M ► DES, no eptifibatide, closure device, 150 mg clopidogrel ► Ambulate at 6 hours ► D/C following 0900 A.M.

11. The University of Vermont Experience—GPI Trigger Strategy Impact of REPLACE 2 and ACUITY Trials: 91% Bivalirudin Use ► Elective PCI—24% ► Urgent PCI—30% ► Emergent PCI—30% ► Pre-Load Clopidgrel in 60% and Switching in 45% of Patients ► Note: Increasing utilization of bivalirudin but with maintained trigger-induced adjunctive use of GP IIb/IIIa antagonist ► Elective PCI—24% ► Urgent PCI—30% ► Emergent PCI—30% ► Pre-Load Clopidgrel in 60% and Switching in 45% of Patients ► Note: Increasing utilization of bivalirudin but with maintained trigger-induced adjunctive use of GP IIb/IIIa antagonist Ahmed B and Dauerman HL, Submitted ESC 2008 REPLACE 2 ACUITY

12. Not Thienopyridine Exposed If Patient is not Clopidogrel Exposed, Do We Use Bivalirudin? Definitions? If Patient is not Clopidogrel Exposed, Do We Use Bivalirudin? Definitions? RR [95%CI] 0.81 (0.68-0.96) RR [95%CI] 0.96 (0.77-1.20) RR [95%CI] 0.50 (0.37-0.67) RR [95%CI] 1.07 (0.83-1.39) RR [95%CI] 1.37 (1.00-1.88) RR [95%CI] 0.61 (0.39-0.97) Stone GW, McLaurin BT. NEJM. 2006 Nov 23;355(21):2203-16 Thienopyridine Exposed

13. Risk ratio (RR) ±95% CI for the triple ischemic endpoint (death, MI, unplanned revascularization) Risk ratio (RR) ±95% CI for the triple ischemic endpoint (death, MI, unplanned revascularization) Bivalirudin alone better Heparin + GPIIb/IIIa better Peri-PCI Clopidogrel N=1044, RR 1.26 [95% CI 0.82,1.92] Peri-PCI Clopidogrel N=1044, RR 1.26 [95% CI 0.82,1.92] Post-PCI Clopidgrel (> 30 minutes After PCI) N=519 RR 1.48 [95% CI 0.89, 2.47] Post-PCI Clopidgrel (> 30 minutes After PCI) N=519 RR 1.48 [95% CI 0.89, 2.47] Pre-PCI clopidogrel N=3429, RR 0.92 [95% CI 0.74,1.15] Pre-PCI clopidogrel N=3429, RR 0.92 [95% CI 0.74,1.15] No Clopidogrel N=88 RR 2.62 [95% CI 0.89, 7.72] No Clopidogrel N=88 RR 2.62 [95% CI 0.89, 7.72] p interaction = 0.35 0 0 1 1 2 2 3 3 4 4 5 5 6 6 7 7 8 8 Timing of Clopidogrel Administration and 30-Day Risk of Ischemic Outcomes S. Steinhubl TCT 2007

14. 1.07 (0.66-1.73) 1.09 (0.46-2.58) 0.56 (0.17-1.93) 3.07 (0.32-29.49) ACUITY PCI: Impact of Clopidogrel PCI troponin+ patients 1-year Mortality Hazard Ratio ±95% CI HR (95% CI) Bivalirudin Alone Better UFH/Enox + IIb/IIIa Better H.White ESC 2007 Clopidogrel at any time prior to hospitalization, randomization or end of angiography (n=1,891) Clopidogrel after end of angio- graphy to 30’ post PCI (n=649) Clopidogrel after 30’ post PCI (n=307) No clopidogrel (n=51) 0.1110

15. Does Periprocedural Infarct Increase With Upstream and Downstream Bivalirudin? No! Outcome2005 1 st 6 months N=3732007 1 st 6 Months N=361 P value Any Transfusion (%) 2.01.0NS Death (%) 3.01.00.08 Urgent revascularization (%) 2.01.0NS MI, 50% CK-MB Rise (%) MI, 50% CK-MB Rise (%)4.01.00.02 Mechanical Complication (%) 8.06.0NS Clopidogrel preload in approx 60% of PCI patients CK-MB on all patients the day after PCI (University of Vermont data)

16. STEMI Switching, Clopidogrel and Stent Thrombosis ST-Elevation Myocardial Infarction

17. Dauerman and French, Coronary Artery Disease, 2006 The Standard of Care for STEMI PCI in 2005: National Registry of Myocardial Infarction-5

18. Implementation of HORIZONS AMI PCI Pharmacologic Aspects of Management ► Unfractionated heparin ● 60 U/kg IV*; subsequent boluses titrated by nomogram to ACT 200-250 secs; terminated at procedure end unless prolonged antithrombin needed ► Bivalirudin at the REPLACE-2 Dosing (NOT ACUITY) ● Bolus 0.75 mg/kg IV**, infusion 1.75 mg/kg/h, not titrated to ACT; terminated at procedure end unless prolonged antithrombin needed (0.25 mg/kg/hr infusion) ► Glycoprotein IIb/IIIa inhibitors ● Routine use in UFH arm; recommended only for giant thrombus or refractory no reflow in bivalirudin arm ● Abciximab or double bolus eptifibatide as per investigator discretion – dosing per FDA label, renal adjusted; continued for 12  (abciximab) or 12-18  (eptifibatide) ► Unfractionated heparin ● 60 U/kg IV*; subsequent boluses titrated by nomogram to ACT 200-250 secs; terminated at procedure end unless prolonged antithrombin needed ► Bivalirudin at the REPLACE-2 Dosing (NOT ACUITY) ● Bolus 0.75 mg/kg IV**, infusion 1.75 mg/kg/h, not titrated to ACT; terminated at procedure end unless prolonged antithrombin needed (0.25 mg/kg/hr infusion) ► Glycoprotein IIb/IIIa inhibitors ● Routine use in UFH arm; recommended only for giant thrombus or refractory no reflow in bivalirudin arm ● Abciximab or double bolus eptifibatide as per investigator discretion – dosing per FDA label, renal adjusted; continued for 12  (abciximab) or 12-18  (eptifibatide) * If pre randomization UFH administered, ACT is checked first ** If pre randomization UFH administered, started 30’ after last bolus

19. Primary PCI for STEMI: Community Hospital Algorithm ASA, Clopidogrel and UFH and then Switch to Bivalirudin at UVM Time from ED Presentation at NWMC to Open Artery at FAHC: 88 Minutes Time from ED Presentation at NWMC to Open Artery at FAHC: 88 Minutes 27 miles, on interstate highway

20. UFH + GP IIb/IIIa (N=1802)Bivalirudin(N=1800) UFH pre randomization UFH pre randomization65.6%65.6% Antithrombin in CCL Antithrombin in CCL ► UFH 98.9%4.1% ► Bivalirudin 0.4%96.9% ► Peak ACT 264 [228, 320] 357 [300, 402] GP IIb/IIIa in CCL GP IIb/IIIa in CCL94.5%*7.2%* ► Bail-out per protocol** -4.4% ► Abciximab 49.9%4.0% ► Eptifibatide 44.4%3.1% ► Tirofiban 0.2%0.1% Do I Have to Load Bivalirudin in the ED or Can I Start in the Cath Lab? The HORIZONS AMI Switching Perspective *97.7% and 7.5% during PCI. ** For giant thrombus or refractory no reflow after PCI. CCL = cardiac catheterization laboratory G Stone TCT 2007

21. Bivalirudin Improves Mortality in STEMI Bivalirudin Improves Mortality in STEMI Death (%) Time in Days 3.1% 2.1% HR [95%CI] = 0.66 [0.44, 1.00] P=0.048 HR [95%CI] = 0.66 [0.44, 1.00] P=0.048 Heparin + GPIIb/IIIa inhibitor (n=1802) Bivalirudin monotherapy (n=1800) G Stone TCT 2007

22. The UVM STEMI Order Sheet One Pathway for Primary PCI and ED Collaboration TESTS AND MEDICATIONS EKG: EKG for diagnosis performed within 10 minutes of ED arrival. No further EKG required. LABORATORY: 7. CBC,lytes, BUN, CR, PT, PTT, Lipids, LFT’s, CK, CK-MB and TnI sent immediately on arrival: STAT 8. Other labs: MEDICATIONS: Weight: __kg Estimated / Actual (Circle one) Check patient not allergic to aspirin 9. Aspirin Non- Enteric Coated 325 mg PO Daily 10. Clopidogrel 600 mg PO x one 11. Bivalirudin bolus 0.75 mg/kg IV, then infusion 1.75 mg/kg/hr (STAT from Pharmacy) 12. Saline Lock with routine flushes every 8 hours OPTIONAL: 13. Nitroglycerin infusion: 400 mcg/ml infusion at _______ mcg/kg/min IV Titrate to chest pain, keep systolic BP >90. 14. Lopressor 5 mg IVP x 1 if HR > 80 and SBP > 140 TESTS AND MEDICATIONS EKG: EKG for diagnosis performed within 10 minutes of ED arrival. No further EKG required. LABORATORY: 7. CBC,lytes, BUN, CR, PT, PTT, Lipids, LFT’s, CK, CK-MB and TnI sent immediately on arrival: STAT 8. Other labs: MEDICATIONS: Weight: __kg Estimated / Actual (Circle one) Check patient not allergic to aspirin 9. Aspirin Non- Enteric Coated 325 mg PO Daily 10. Clopidogrel 600 mg PO x one 11. Bivalirudin bolus 0.75 mg/kg IV, then infusion 1.75 mg/kg/hr (STAT from Pharmacy) 12. Saline Lock with routine flushes every 8 hours OPTIONAL: 13. Nitroglycerin infusion: 400 mcg/ml infusion at _______ mcg/kg/min IV Titrate to chest pain, keep systolic BP >90. 14. Lopressor 5 mg IVP x 1 if HR > 80 and SBP > 140

23. The Bivalirudin Strategy for STEMI PCI ASA, clopidogrel 600 po x 1, bivalirudin and stent

24. What About The Stent Thrombosis Risk? What About The Stent Thrombosis Risk? *Protocol definition of stent thrombosis, CEC adjudicated UFH + GP IIb/IIIa (N=1553)Bivalirudin(N=1571)PValue ARC definite or probable* 1.9%2.5%0.33 Definite Definite1.4%2.2%0.11 Probable Probable0.5%0.3%0.26 Acute (≤24 hrs) Acute (≤24 hrs)0.3%1.3%0.0009 Subacute (>24 hrs – 30d) Subacute (>24 hrs – 30d)1.7%1.2%0.30 G Stone TCT 2007

25. Sianos, G. et al. J Am Coll Cardiol 2007;50:573-583 Risk Stratification For STEMI Stent Thrombosis The Importance of Thrombus Burden Large thrombus burden (LTB), defined as thrombus burden > 2 vessel diameters: Approx 25% of STEMI

26. Sianos, G. et al. J Am Coll Cardiol 2007;50:573-583 Drug Eluting Stent Thrombosis and Large Thrombus Burden: Modifying Strategy In Highest Risk Patients Drug Eluting Stent Thrombosis and Large Thrombus Burden: Modifying Strategy In Highest Risk Patients ► Large Thrombus ► Burden> 5 fold ► Increased Risk of 30 Day Stent Thrombosis ► Large Thrombus ► Burden> 5 fold ► Increased Risk of 30 Day Stent Thrombosis Thrombectomy Prolonged Bivalirudin GPI Thrombectomy Prolonged Bivalirudin GPI LTB vs. STB, p<0.001 Total Population STB LTB 2.7% 3.2% 5.8% 8.2% 1.1% 1.4% 2.1% 3.2% 0.5% 0.7% 1.3% 0 1 3 6 9 12 15 18 21 24 15 12 9 6 3 0 15 12 9 6 3 0 Months of follow-up Cumulative IRA-ST Rate (%)

27. ACUITYHeparin + IIb/IIIa + IIb/IIIa(N=222) Bivalirudin + IIb/IIIa (N=241) Bivalirudin alone (N=249) P value 3-way Any thrombotic complication post PCI 8.6%3.7%5.6%0.09 Final TIMI flow 3 90.5%93.7%90.7%0.37 Final blush grade 3 81.5%79.0%79.5%0.78 ACUITY and Large Thrombus Data The Rationale for Selective Adjunctive GPI * New or ↑ thrombus, abrupt closure, no reflow, or distal embolization G. Stone AHA 2006

28. The Data on GPI and Bivalirudin for Large Thrombus Patients is Favorable (ACUITY) p=0.37p=0.58 p=0.22p=0.61 p=0.67p=0.03 G. Stone et al. Lancet 2007; 369: 907–19

29. Projecting What Happens if You Use GPI in 25% of Your Bivalirudin STEMI Patients Assumes Bival + GPI bleeding rate of 6.8% P < 0.001 Still P < 0.001 HORIZONS 7% UVM Implemented HORIZONS—25% UVM Implemented HORIZONS—25%

30. Incorporation of HORIZONS AMI and Large Thrombus Data—STEMI Algorithm ► ED STEMI—25% of Patients ► ASA/clopidogrel 600 mg po load and bivalirudin ► Bolus and infusion of eptifibatide after wiring vessel shows Large Thrombus Burden ► Angiojet and Bare Metal Stent ► 150 mg clopidogrel and 18 hours of eptifibatide ► No ambulation until eptifibatide off (18 hours) ► D/C on Day 3 post MI ► ED STEMI—25% of Patients ► ASA/clopidogrel 600 mg po load and bivalirudin ► Bolus and infusion of eptifibatide after wiring vessel shows Large Thrombus Burden ► Angiojet and Bare Metal Stent ► 150 mg clopidogrel and 18 hours of eptifibatide ► No ambulation until eptifibatide off (18 hours) ► D/C on Day 3 post MI

31. STEMI: Within 24 Hours CP UFH (60 U/Kg) Beta Blockers only if HTN UFH or Bivalirudin: UFH or Bivalirudin: GPI Optional: Avoid if High Bleed Risk B Blockers ONLY if HTN PCI Capability or < 60 minute Transfer Time No PCI Capability and > 60 minute Transfer Time Primary PCI with Stenting: GPI/Thrombectomy if Large Thrombus or as Bailout; Otherwise, Bivalirudin Alone 90 minutes To Open Artery Lytic LyticContraindicated Emergent Transfer TNK and UFH Transfer from Community ER To PCI Site If no CP and less than 50% ST Elevations, PCI at 12-24 Hours with Stent If Reperfusion Fails, Emergent PCI with stent ASA/ClopidogrelStatin Groin Closure Cardiac Rehab Lopressor 12.5 bid Transfer Rescue PCI: Class I Indication The NSTEMI Paradigm of 4-48 Hours ASA 325 po Clopidogrel 600 po Clopidogrel 300 po Continue bivalirudin for 2 hours after PCI

32. Conclusions Key Implementation Points ► Bivalirudin can be safely instituted across the spectrum of PCI patients, including those with NSTE-ACS and STEMI. ► Clopidogrel 600 mg po load may be done in ED or immediately after PCI. ► Community referring hospitals may use antithrombotic therapy of choice—then switch to bivalirudin on arrival to PCI institution. ► STEMI requires an algorithm for care and bivalirudin is the baseline strategy. But, bivalirudin may be instituted in the ED or the cath lab, depending upon local issues. ► Enhanced management of large thrombus burden should be considered especially during the most “vulnerable” 2 hours after PCI.

33. Questions for the Panel ► Does a consistent, unified upstream strategy for anticoagulation across the STEMI and NSTE-ACS risk spectrum make sense? When does it? When doesn’t it? ► Given that bleeding appears to be a driver of MACE events, including mortality, in ACS and STEMI, and since switching to bivalirudin appears to decrease bleeding, should this switching strategy be promulgated in patients undergoing PCI? ► What are the best ways, from an institutional/process-of-care perspective, to establish a consistent antithrombotic strategy for this patient population? ► Other issues? We’ll answer your questions!