HORIZONS AMI Trial

1. HORIZONS AMI Trial 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

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

4. HORIZONS AMI 3,602 pts with STEMI with symptom onset ≤12 hours Aspirin, thienopyridine R 1:1 UFH + GP IIb/IIIa inhibitor (abciximab or eptifibatide) Bivalirudin monotherapy (± provisional GP IIb/IIIa) 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/mm3 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 <40%; Statin if LDL >100 mg/dl Stone GW. NEJM 2008;358:2218-30.

9. 2 Primary Endpoints (at 30 Days) 1) Net Adverse Clinical Events and 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 Stone GW. NEJM 2008;358:2218-30.

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

11. Randomized 30 Day FU 1-Year FU Eligible 1-Year FU HORIZONS AMI 3602 pts with STEMI R 1:1 UFH + GP IIb/IIIa N=1802 Bivalirudin N=1800 N=1791 (99.4%) N=1787 (99.3%) • • • Not true MI* • • • 28 29 N=1774 N=1771 26 46 • • • Withdrew • • • • • • Lost to FU • • • 22 53 N=1702 (95.9%) N=1696 (95.8%) * Biomarkers WNL and no DS >50% by core lab determination → 30 day FU only Mehran R, TCT 2008

12. Baseline Characteristics (i) * *P=0.04 Stone GW et al. NEJM 2008;358:2218-30

13. Baseline Characteristics (ii) Stone GW et al. NEJM 2008;358:2218-30

14. Study Drugs *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 PCI Deferred PCI CABG Medical Rx 2.1% 1.3% 0% 5.4% 5.3% 0.1% 92.5% 93.4% *Primary ITT analysis includes all pts regardless of treatment Stone GW. NEJM 2008;358:2218-30.

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

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

18. Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) 1-Year Net Adverse Clinical Events* 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 NACE (%) Time in Months Number at risk Bivalirudin alone 1800 1559 1514 1483 1343 Heparin+GPIIb/IIIa 1802 1499 1459 1427 1281 • *MACE or major bleeding (non CABG) Mehran R, TCT 2008

19. Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) 1-Year Major Bleeding (non-CABG) 9.2% 5.8% Major Bleeding (%) Diff [95%CI] = -3.4% [-5.2, -1.7]2 HR [95%CI] = 0.61 [0.48, 0.78] P<0.0001 Time in Months Number at risk 1800 1621 1601 1586 1448 Bivalirudin alone 1802 1544 1532 1515 1368 Heparin+GPIIb/IIIa Mehran R, TCT 2008

20. 1-Year Bleeding Endpoints* *Kaplan-Meier estimates; all CEC adjudicated, except protocol minor; **Primary endpoint; ***Life threatening Mehran R, TCT 2008

21. Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) 1-Year Major Adverse CV Events* 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 (%) Time in Months Number at risk Bivalirudin alone 1800 1627 1579 1544 1394 Heparin+GPIIb/IIIa 1802 1619 1573 1540 1380 • *MACE = All cause death, reinfarction, ischemic TVR or stroke Mehran R, TCT 2008

22. Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) 1-Year All-Cause Mortality 4.8% Δ = 1.4% 3.4% 3.1% Mortality (%) Diff [95%CI] = -1.5% [-2.8,-0.1] HR [95%CI] = 0.69 [0.50, 0.97] P=0.029 2.1% Δ = 1.0% P=0.049 Time in Months Number at risk 1800 1705 1684 1669 1520 Bivalirudin alone 1802 1678 1663 1646 1486 Heparin+GPIIb/IIIa Mehran R, TCT 2008

23. Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) 1-Year Mortality: Cardiac and Non Cardiac HR [95%CI] = 0.57 [0.38, 0.84] P=0.005 3.8% Δ = 1.7% 2.9% Cardiac Mortality (%) 2.1% Δ = 1.1% P=0.03 Non Cardiac 1.3% 1.1% Time in Months Number at risk Bivalirudin alone 1800 1705 1684 1669 1520 Heparin+GPIIb/IIIa 1802 1678 1663 1646 1486 Mehran R, TCT 2008

24. Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) 1-Year Death or Reinfarction 8.5% Δ = 1.9% 6.6% 4.5% Death or MI (%) HR [95%CI] = 0.77 [0.61, 0.98] P=0.04 3.8% Δ = 0.7% P=0.30 Time in Months Number at risk Bivalirudin alone 1800 1670 1638 1617 1469 Heparin+GPIIb/IIIa 1802 1648 1617 1593 1431 Mehran R, TCT 2008

25. 1-Year MACE Components* *All Kaplan-Meier estimates, CEC adjudicated Mehran R, TCT 2008

26. Adverse Events Between 30 Days and 1-Year *Kaplan-Meier estimates, landmark analysis, CEC adjudicated Mehran R, TCT 2008

27. Bivalirudin alone (n=1611) Heparin + GPIIb/IIIa (n=1591) 1-Year Stent Thrombosis (ARC Definite/Probable) Δ = 0.3% 3.5% 3.2% 2.7% Stent Thrombosis (%) HR [95%CI] = 1.11 [0.76, 1.63] P=0.59 2.2% Δ = 0.5% P=0.31 Time in Months Number at risk Bivalirudin alone 1611 1525 1504 1486 1356 Heparin+GPIIb/IIIa 1591 1495 1475 1457 1315 Mehran R, TCT 2008

28. 1-Year Stent Thrombosis* (N=3,202) *All Kaplan-Meier estimates except ≤24 hours; all CEC adjudicated Mehran R, TCT 2008

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

30. Interaction Between Drug and Stent Randomization 30 Day Pharmacology Endpoints (N=3006) • *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) • *Death, reinfarction, stroke or stent thrombosis • **1081 lesions in the TAXUS group, 332 in the EXPRESS group Mehran R, TCT 2008

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