Translating Advances in NSTEMI and STEMI into Real World Institutional Practice

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 The Science and Medicine of ACS

2. Potential conflicts of interest Speaker’s name: Harold L. Dauerman, MD I have the following potential conflicts of interest to report: Consulting: The Medicines Company, Abbott Vascular  Employment in industry  Stockholder of a healthcare company  Owner of a healthcare company  Other(s)  I do not have any potential conflict of interest

3. University of Vermont Post-PCI Bleeding and Vascular Complication Rates Introduction of Bivalirudin to Cath Lab Introduction of Upstream Bivalirudin 4 3.5 3 NNE Rate: 2.0% in 2006 2.5 Bleeding Complication, % 2 1.5 1 0.5 0 2001 2002 2003 2004 2005 2006 2007 Any Transfusion, RPH or Repair = Bleeding Complication

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

5. Signs of Hope Since 2004 4 P < 0.001 for temporal trend 3.37 3.5 3.2 3 2.51 2.5 2.11 1.96 Major Vascular Complications, %* 2 1.5 1 0.5 0 2002 2003 2004 2005 2006 Arterial injury and/or arterial injury related bleeding N= 36,631 Patients Undergoing PCI, NNE Registry Dauerman, Applegate and Cohen, JACC 2007

6. 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)

7. NSTEMI Transfers, Upstream Strategies, andResults of Clinical Trials Non ST-Elevation Myocardial Infarction

8. 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

9. 34.8% 33.8% 35% 28.6% 30% 25% 20% 16.7% 15.6% 15.3% 15% 10% 5% 0% Protocol Major/Minor Bleed by SWITCH and Randomized Therapy † Protocol major/minor bleed * Naïve→ UFH + GP IIb/IIIa‡ (n=2,325) UFH→Bivalirudin (n=287) LMWH→Bivalirudin (n=258) UFH→UFH + GP IIb/IIIa (n=349) LMWH→UFH + GP IIb/IIIa (n=313) Naïve→Bivalirudin‡ (n=2,345) *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. Gibson CM et al. Am J Cardiol. 2007;99:1687-1690.

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

11. 12.7% 11.8% 10.3% 7.5% 5.7% 3.5% Net clinical Ischemic Major bleeding outcomes composite If Patient is not Clopidogrel Exposed, Do We Use Bivalirudin? Definitions? UFH/Enoxaparin + IIb/IIIa (N=811) UFH/Enoxaparin + IIb/IIIa (N=1722) Bivalirudin Alone (N=804) Bivalirudin Alone (N=1789) 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) 13.8% 11.1% 8.4% 8.1% 7.2% 3.6% Net clinical Ischemic Major bleeding outcomes composite Not Thienopyridine Exposed Thienopyridine Exposed Stone GW, McLaurin BT. NEJM. 2006 Nov 23;355(21):2203-16

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

13. Does Periprocedural Infarct Increase With Upstream and Downstream Bivalirudin? No! • Submitted, TCT 2008 Clopidogrel preload in approx 60% of PCI patients CK-MB on all patients the day after PCI (University of Vermont data)

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

15. Primary PCI for STEMI N= 7,629 Bivalirudin PCI No Bivalirudin PCI N=320 (4%) N= 7,309 Bivalirudin and GPIIbIIIa PCI Bivalirudin Alone N=177 (55%) N=143 (45%) Clopidogrel Prior Clopidogrel to PCI Clopidogrel Prior to PCI Not Prior to PCI N=6878 (94%) Clopidogrel N=1466 (21%) N=171 (97%) N=37 (21%) N= 140 (79%) N=137 (96%) Prior to PCI GP IIbIIIa Inhibitor use Clopidogrel N=31 (23%) N=6,873 (94%) Prior to PCI N=41 (24%) Abciximab N=64 (36%) Eptifibatide N=93 (52%) Prior to PCI Not Prior to PCI Tirofiban N=1 (1%) N=2,489 (36%) N= 4,384 (64%) Unkown N=19 (11%) Abciximab N=2,283 (33%) Abciximab N=8 (22%) Abciximab N=56 (40%) Eptifibatide N=3,551 (52%) Eptifibatide N=27 (73%) Eptifibatide N=66 (47%) Tirofiban N=154 (2%) Tirofiban N=1 (3%) Tirofiban N=0 (0%) Unknown N= 885 (13%) Unknown N=1 (2%) Unknown N=18 (13%) Abciximab N=622 (25%) Abciximab N=1661 (38%) Eptifibatide N=1621 (65%) Eptifibatide N=1930 (44%) Tirofiban N=99 (4%) Tirofiban N=55 (1%) Unknown N=147 (6%) Unknown N=738 (17%) The Standard of Care for STEMI PCI in 2005: National Registry of Myocardial Infarction-5 Dauerman and French, Coronary Artery Disease, 2006

16. Implementation of HORIZONS AMI PCIPharmacologic 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) * If pre randomization UFH administered, ACT is checked first ** If pre randomization UFH administered, started 30’ after last bolus

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

18. 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

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

20. The UVM STEMI Order SheetOne 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

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

22. What About The Stent Thrombosis Risk? G Stone TCT 2007 *Protocol definition of stent thrombosis, CEC adjudicated

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

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

25. ACUITY and Large Thrombus DataThe Rationale for Selective Adjunctive GPI * New or ↑ thrombus, abrupt closure, no reflow, or distal embolization G. Stone AHA 2006

26. Bival + 9 8.3 8.3 UFH + GPI 8 7 6 4.9 5.2 5 Major Bleeding, % 4 3 2 1 0 Projecting What Happens if You Use GPI in 25% of Your Bivalirudin STEMI Patients P < 0.001 Still P < 0.001 UVM Implemented HORIZONS—25% HORIZONS 7% Assumes Bival + GPI bleeding rate of 6.8%

27. 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

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

29. ConclusionsKey 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.

30. 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!