1. A Prospective, Randomized Comparison of Bivalirudin vs. Heparin Plus Glycoprotein IIb/IIIa Inhibitors During Primary Angioplasty in Acute Myocardial Infarction – One Year Results – Roxana Mehran MD for the HORIZONS-AMI Investigators, TCT 2008 HORIZONS AMI Trial

2. Background ● Numerous studies have demonstrated a strong association between hemorrhagic complications and subsequent mortality in pts with ACS and after PCI ● In the HORIZONS-AMI trial, among high risk pts with STEMI undergoing primary PCI, randomization to bivalirudin monotherapy compared to UFH + GPI resulted in reduced rates of bleeding, thrombocytopenia, and blood transfusions; non significantly different rates of reinfarction, stent thrombosis and TVR; and improved survival at 30 days ● Whether these benefits are maintained at 1-year is unknown Mehran R, TCT 2008

3. Emergent angiography, followed by triage to primary PCI, CABG or medical therapy HORIZONS AMI Aspirin, thienopyridine R 1:1 R 1:3 Paclitaxel-eluting TAXUS stentBare metal EXPRESS stent Clinical FU at 30 days, 6 months, 1 year, and then yearly through 5 years Clinical FU at 30 days, 6 months, 1 year, and then yearly through 5 years UFH + GP IIb/IIIa inhibitor (abciximab or eptifibatide) Bivalirudin monotherapy (± provisional GP IIb/IIIa) 3,602 pts with STEMI with symptom onset ≤12 hours 3006 pts eligible for stent randomization Stone GW. NEJM 2008;358:2218-30.

4. HORIZONS AMI Aspirin, thienopyridine R 1:1 UFH + GP IIb/IIIa inhibitor (abciximab or eptifibatide) Bivalirudin monotherapy (± provisional GP IIb/IIIa) 3,602 pts with STEMI with symptom onset ≤12 hours Pharmacology Arm Primary and Secondary Endpoints 1-Year Intention to Treat Population Outcomes in the 4 randomized groups Mehran R, TCT 2008

5. Inclusion Criteria ● STEMI >20 mins and <12 hours in duration –ST-segment elevation of  1 mm in  2 contiguous leads; or –Presumably new left bundle branch block; or –True posterior MI with ST depression of  1 mm in  2 contiguous anterior leads –Patients with cardiogenic shock, left main disease, etc., were not excluded ● Age ≥18 years ● Written, informed consent Stone GW. NEJM 2008;358:2218-30.

6. Principal Exclusion Criteria ● Contraindication to any of the study medications ● Prior administration of thrombolytic therapy, bivalirudin, GP IIb/IIIa inhibitors, LMWH or fondaparinux for the present admission (prior UFH allowed) ● Current use of coumadin ● History of bleeding diathesis or known coagulopathy (including HIT), or will refuse blood transfusions ● History of intracerebral mass, aneurysm, AVM, or hemorrhagic stroke; stroke or TIA within 6 months or any permanent neurologic deficit; GI or GU bleed within 2 months, or major surgery within 6 weeks; recent or known platelet count <100,000 cells/mm 3 or hgb <10 g/dL ● Planned elective surgical procedure that would necessitate interruption of thienopyridines during the first 6 months post enrollment Stone GW. NEJM 2008;358:2218-30.

7. Study Medications (i) ● 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 –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  (abcx) or 12-18  (eptif) * If pre randomization UFH administered, ACT is checked first ** If pre randomization UFH administered, started 30’ after last bolus Stone GW. NEJM 2008;358:2218-30.

8. Study Medications (ii) ● Aspirin –324 mg chewed non enteric coated or 500 mg IV in the ER, followed by 300-325 mg/day in-hospital and 75-81 mg/day as out patient indefinitely ● Thienopyridines –Clopidogrel 300 mg or 600 mg loading dose (per investigator discretion) in the ER followed by 75 mg PO QD for at least 6 months (1 year or longer recommended) – Ticlopidine load + daily dose permissible if clopidogrel is unavailable or patient is allergic ● Other –Beta blockers: IV pre procedure followed by PO QD in the absence of contraindications; ACE inhibitors for HTN, CHF or LVEF 100 mg/dl Stone GW. NEJM 2008;358:2218-30.

9. 2 Primary Endpoints (at 30 Days) 2) Major Bleeding (non-CABG) Intracranial bleeding Intraocular bleeding Retroperitoneal bleeding Access site bleed requiring intervention/surgery Hematoma ≥5 cm Hgb  ≥3 g/dL with an overt source Hgb  ≥4 g/dL w/o overt source Reoperation for bleeding Blood product transfusion and 1) Net Adverse Clinical Events Stone GW. NEJM 2008;358:2218-30.

10. 2 Primary Endpoints (at 30 Days) = or All-cause death Reinfarction Ischemic TVR Stroke Major adverse cardiovascular events (major secondary endpoint) 2) Major Bleeding (non-CABG) 1) Net Adverse Clinical Events Stone GW. NEJM 2008;358:2218-30.

11. * Biomarkers WNL and no DS >50% by core lab determination → 30 day FU only Withdrew Withdrew Lost to FU Lost to FU 26462253 3602 pts with STEMI Not true MI* Not true MI* 2829Randomized 1-Year FU Eligible 30 Day FU 1-Year FU UFH + GP IIb/IIIa N=1802 N=1791 (99.4%) N=1774 N=1702 (95.9%) Bivalirudin N=1800 N=1787 (99.3%) N=1771 N=1696 (95.8%) HORIZONS AMI R 1:1 Mehran R, TCT 2008

12. Baseline Characteristics (i) UFH + GP IIb/IIIa (N=1802) Bivalirudin (N=1800) Age (years)60.7 [52.9, 70.1]59.8 [51.9, 69.5] Male76.1%77.1% Diabetes17.3%15.6% Hypertension55.2%51.8% Hyperlipidemia42.7%43.4% Current smoking45.0%47.2% Prior MI11.4%10.4% Prior PCI11.0%10.5% Prior CABG2.6%3.3% *P=0.04 * Stone GW et al. NEJM 2008;358:2218-30

13. Baseline Characteristics (ii) UFH + GP IIb/IIIa (N=1802) Bivalirudin (N=1800) Weight (kg)80 [71, 90] Chest pain – ER, hrs2.1 [1.3, 3.9]2.2 [1.3, 4.0] Killip class 2-48.5% Anterior MI43.9%41.2% LVEF50 [41, 59]50 [45, 60] Femoral a. access93.6%93.9% Venous access8.4%9.3% Closure device27.7%28.3% Aspiration catheter11.1%11.9% Stone GW et al. NEJM 2008;358:2218-30

14. Study Drugs UFH + GP IIb/IIIa (N=1802) Bivalirudin (N=1800) UFH pre randomization65.6% Antithrombin in CCL - UFH98.9%2.6% - Bivalirudin0.2%96.9% - Peak ACT264 [228, 320]357 [300, 402] GP IIb/IIIa in CCL94.5%*7.2%* - Bail-out per protocol**—4.4% - Abciximab49.9%4.0% - Eptifibatide44.4%3.1% - Tirofiban0.2%0.1% *97.7% and 7.5% during PCI. ** For giant thrombus or refractory no reflow after PCI. CCL = cardiac catheterization laboratory Stone GW. NEJM 2008;358:2218-30.

15. Primary Management Strategy* UFH + GP IIb/IIIa Inhibitor N=1802 Bivalirudin Monotherapy N=1800 Primary PCIDeferred PCICABGMedical Rx *Primary ITT analysis includes all pts regardless of treatment 0% 2.1% 5.4% 92.5% 0.1% 1.3% 5.3% 93.4% Stone GW. NEJM 2008;358:2218-30.

16. Diff = Diff = 0.0% [-1.6, 1.5] RR = 0.99 RR = 0.99 [0.76, 1.30] P sup = 0.95 Primary Endpoints at 30 Days Diff = Diff = -3.3% [-5.0, -1.6] RR = RR = 0.60 [0.46, 0.77] P NI ≤ 0.0001 P sup ≤ 0.0001 Diff = Diff = -2.9% [-4.9, -0.8] RR = RR = 0.76 [0.63, 0.92] P NI ≤ 0.0001 P sup = 0.005 1  endpoint Major 2  endpoint Stone GW et al. NEJM 2008;358:2218-30

17. Aspirin and Thienopyridine Use Antiplatelet agent use (%) Regular* aspirin use (%) Regular* thieno. use (%) *Taken >50% of days since last visit All P=NS Mehran R, TCT 2008

18. *MACE or major bleeding (non CABG) Number at risk Bivalirudin alone Heparin+GPIIb/IIIa 18001559151414831343 18021499145914271281 Time in Months 18.3% 15.7% Diff [95%CI] = -2.6% [-5.1, -0.1] HR [95%CI] = 0.84 [0.71, 0.98] P=0.03 1-Year Net Adverse Clinical Events* NACE (%) Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) Mehran R, TCT 2008

19. Number at risk Bivalirudin alone Heparin+GPIIb/IIIa 18001621160115861448 18021544153215151368 Major Bleeding (%) Time in Months 9.2% 5.8% Diff [95%CI] = -3.4% [-5.2, -1.7] 2 HR [95%CI] = 0.61 [0.48, 0.78] P<0.0001 1-Year Major Bleeding (non-CABG) Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) Mehran R, TCT 2008

20. 1-Year Bleeding Endpoints* UFH + GP IIb/IIIa (N=1802) Bivalirudin (N=1800) P Value Protocol Major, non CABG**9.2%5.8%<0.0001 Protocol Major, All11.8%7.7%<0.0001 Protocol Minor16.5%9.1%<0.0001 Blood transfusion4.0%2.7%0.02 TIMI Major5.5%3.6%0.005 TIMI Minor4.8%3.0%0.008 TIMI Major or Minor10.2%6.5%<0.0001 GUSTO LT*** or Severe0.7%0.8%0.70 GUSTO Moderate5.4%3.7%0.01 GUSTO LT or Sev or Mod6.0%4.4%0.02 *Kaplan-Meier estimates; all CEC adjudicated, except protocol minor; **Primary endpoint; ***Life threatening Mehran R, TCT 2008

21. Number at risk Bivalirudin alone Heparin+GPIIb/IIIa 18001627157915441394 18021619157315401380 MACE (%) Time in Months 11.9% 11.9% Diff [95%CI] = 0.0% [-2.1, 2.2] HR [95%CI] = 1.00 [0.83, 1.21] P=0.98 *MACE = All cause death, reinfarction, ischemic TVR or stroke 1-Year Major Adverse CV Events* Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) Mehran R, TCT 2008

22. Number at risk Bivalirudin alone Heparin+GPIIb/IIIa 18001705168416691520 18021678166316461486 Mortality (%) Time in Months 4.8% 3.4% Diff [95%CI] = -1.5% [-2.8,-0.1] HR [95%CI] = 0.69 [0.50, 0.97] P=0.029 3.1% 2.1% Δ = 1.0% P=0.049 Δ = 1.4% 1-Year All-Cause Mortality Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) Mehran R, TCT 2008

23. 1-Year Mortality: Cardiac and Non Cardiac Number at risk Bivalirudin alone Heparin+GPIIb/IIIa 18001705168416691520 18021678166316461486 Cardiac Non Cardiac Mortality (%) Time in Months 3.8% 2.1% 1.3% 1.1% HR [95%CI] = 0.57 [0.38, 0.84] P=0.005 2.9% Δ = 1.1% P=0.03 Δ = 1.7% Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) Mehran R, TCT 2008

24. Number at risk Bivalirudin alone Heparin+GPIIb/IIIa 18001670163816171469 18021648161715931431 Death or MI (%) Time in Months 8.5% 6.6% HR [95%CI] = 0.77 [0.61, 0.98] P=0.04 4.5% 3.8% Δ = 0.7% P=0.30 Δ = 1.9% 1-Year Death or Reinfarction Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) Mehran R, TCT 2008

25. 1-Year MACE Components* UFH + GPI (N=1802) Bivalirudin (N=1800) HR [95%CI] P Value Death4.8%3.4%0.69 [0.50,0.97]0.029 - Cardiac3.8%2.1%0.57 [0.38,0.84]0.005 - Non cardiac1.1%1.3%1.14 [0.62,2.11]0.67 Reinfarction4.4%3.6%0.81 [0.58,1.14]0.22 - Q-wave2.1%2.2%1.06 [0.67,1.67]0.81 - Non Q-wave2.7%1.4%0.53 [0.32,0.86]0.01 Death or reinfarction8.5%6.6%0.77 [0.61,0.98]0.04 Ischemic TVR5.9%7.2%1.23 [0.94,1.60]0.12 - Ischemic TLR4.5%6.0%1.34 [1.00,1.80]0.051 - Ischemic remote TVR2.0%2.3%1.13 [0.71,1.79]0.60 Stroke1.2%1.1%1.00 [0.54,1.85]0.99 *All Kaplan-Meier estimates, CEC adjudicated Mehran R, TCT 2008

26. Adverse Events Between 30 Days and 1-Year UFH + GPI (N=1802) Bivalirudin (N=1800) P Value Death1.8%1.4%0.31 - Cardiac0.9%0.4%0.046 - Non cardiac0.9%1.0%0.75 Reinfarction2.8%1.7%0.04 Death or reinfarction4.4%3.0%0.02 Ischemic TVR4.3%4.7%0.57 Stroke0.5%0.4%0.77 MACE7.3%6.8%0.52 Major bleeding (non CABG)0.7%0.8%0.71 NACE7.8%7.3%0.52 *Kaplan-Meier estimates, landmark analysis, CEC adjudicated Mehran R, TCT 2008

27. Number at risk Bivalirudin alone Heparin+GPIIb/IIIa 16111525150414861356 15911495147514571315 Stent Thrombosis (%) Time in Months 3.5% 3.2% HR [95%CI] = 1.11 [0.76, 1.63] P=0.59 2.7% 2.2% Δ = 0.5% P=0.31 Δ = 0.3% 1-Year Stent Thrombosis (ARC Definite/Probable) Bivalirudin alone (n=1611) Heparin + GPIIb/IIIa (n=1591) Mehran R, TCT 2008

28. 1-Year Stent Thrombosis* (N=3,202) UFH + GPI (N=1591) Bivalirudin (N=1611) P Value ARC definite or probable, ≤24 hrs0.3%1.5%0.0002 - definite, ≤24 hours0.2%1.4%<0.0001 - probable, ≤24 hours0.1% 1.0 ARC definite or probable, >1 - ≤30d1.9%1.3%0.14 - definite, >1 day - ≤30 days1.3%1.1%0.60 - probable, >1 day - ≤30 days0.6%0.2%0.049 ARC definite or probable, >30d – 1y1.1%0.9%0.53 - definite, >30 days – 1-year1.0%0.9%0.65 - probable, >30 days – 1-year0.1% 0.55 ARC definite or probable, ≤1-year3.2%3.5%0.59 - definite, ≤1-year2.4%3.2%0.15 - probable, ≤1-year0.8%0.3%0.06 *All Kaplan-Meier estimates except ≤24 hours; all CEC adjudicated Mehran R, TCT 2008

29. R 3:1 HORIZONS AMI R 1:1 R 3:1 TAXUS N=1111 UFH + GP IIb/IIIa N=1802 Bivalirudin N=1800 3,602 pts with STEMI Stent rand. eligible Stent rand. eligible N=1479N=1527 EXPRESS N=368 TAXUS N=1146 EXPRESS N=381 Stratified by 1 st rand. Stone G, TCT 2008

30. Interaction Between Drug and Stent Randomization 30 Day Pharmacology Endpoints (N=3006) Kaplan-Meier estimates UFH + GPI (N=1479) Bivalirudin (N=1527) HR [95%CI]P int NACE, all*11.3%8.7%0.76 [0.60,0.95]— - TAXUS subgroup11.5%9.1%0.78 [0.60,1.01] 0.95 - EXPRESS subgroup10.6%7.4%0.69 [0.42,1.11] Major bleeding, all**8.4%5.1%0.59 [0.44,0.78]— - TAXUS subgroup8.9%5.4%0.59 [0.43,0.81] 1.0 - EXPRESS subgroup7.1%4.2%0.58 [0.31,1.09] MACE, all***4.7%4.9%1.05 [0.75,1.45]— - TAXUS subgroup4.6%5.1%1.11 [0.76,1.62] 0.89 - EXPRESS subgroup4.9%4.2%0.86 [0.44,1.69] *MACE or major bleeding; **Protocol defined (non CABG); ***Death, reinfarction, stroke or ischemic TVR Mehran R, TCT 2008

31. Interaction Between Drug and Stent Randomization 1-Year Stent Endpoints (N=3006) Kaplan-Meier estimates TAXUS (N=2257) EXPRESS (N=749) HR [95%CI]P int Ischemic TLR, all4.5%7.5%0.59 [0.43,0.83]— - UFH + GPI subgroup3.3%7.9%0.42 [0.25,0.68] 0.17 - Bivalirudin subgroup5.6%7.1%0.78 [0.50,1.24] Safety MACE, all*8.1%8.0%1.02 [0.76,1.36]— - UFH + GPI subgroup8.2%8.8%0.92 [0.66,1.27] 0.89 - Bivalirudin subgroup8.0%7.2%1.17 [0.83,1.64] Binary restenosis, all**10.0%22.9%0.44 [0.33,0.57]— - UFH + GPI subgroup10.9%19.2%0.57 [0.38,0.84] 0.18 - Bivalirudin subgroup9.2%26.7%0.34 [0.24,0.49] *Death, reinfarction, stroke or stent thrombosis **1081 lesions in the TAXUS group, 332 in the EXPRESS group Mehran R, TCT 2008

32. 4.0% 3.0% P int =0.75 4.6% 2.6% Mortality (%) Time in Months 1-Year Mortality (All-Cause) Heparin + GPI / TAXUS (n=1111) Heparin + GPI / EXPRESS (n=368) Bivalirudin / TAXUS (n=1146) Bivalirudin / EXPRESS (n=381) Mehran R, TCT 2008

33. Limitations ● Open label design –Potential bias was mitigated by high protocol procedure compliance and use of blinded clinical event adjudication committees and core laboratories ● Underpowered for low frequency safety endpoints and subgroup interactions –All such observations should be considered hypothesis- generating Mehran R, TCT 2008

34. Conclusions ● In this large scale, prospective, randomized trial of pts with STEMI undergoing a primary PCI management strategy, bivalirudin monotherapy compared to UFH plus the routine use of GP IIb/IIIa inhibitors resulted in: –A significant 16% reduction in the 1-year rate of composite net adverse clinical events –A significant 39% reduction in the 1-year rate of major bleeding Mehran R, TCT 2008

35. Conclusions ● In this large scale, prospective, randomized trial of pts with STEMI undergoing a primary PCI management strategy, bivalirudin monotherapy compared to UFH plus the routine use of GP IIb/IIIa inhibitors resulted in: –Significant 31% and 43% reductions in the 1-year rates of all-cause and cardiac mortality (absolute 1.4% and 1.7% reductions), with non significantly different rates of reinfarction, stent thrombosis, stroke and TVR at 1-year Mehran R, TCT 2008

36. Clinical Implications ● HORIZONS has demonstrated that the prevention of hemorrhagic complications after primary PCI in STEMI results in improved early and late survival –Optimal drug selection and technique to minimize bleeding are essential to enhance outcomes for pts undergoing interventional therapies Mehran R, TCT 2008