5. Empiric Management of ACS With GP IIb/IIIa Platelet Receptor Blockers

6. Current Challenges in the Management of ACS  Death/MI at 30 days 8% to 16% in heparin/aspirin arms of various studies  Recurrent/refractory ischemia associated with reduced survival  Risk stratification/identification of medium/high-risk patient –Rest pain, post-MI –Recurrent ischemia –ST changes on ECG –Prior aspirin use –Serum markers  Implementing new treatment strategies using GP IIb/IIIa platelet blockers in medium- to high-risk ACS patients  Safety and cost of new agents

7. Downstream embolization DETERMINANTS OF THROMBOSIS - Local factors - Systemic factors UNSTABLE CORONARY ARTERY DISEASE ARTERY DISEASE Recanalization Lysis Remodeling DYNAMICDYNAMIC Lysis/Repair Cap disruption - Vulnerability - Triggers VULNERABLE PLAQUE Fibrous cap Inflammation and repair Core size Lipid-rich core Thrombolysis Thrombosis Fibrous tissue Atheromatous material (lipid-rich) Thrombus Plaque hemorrhage Macrophage Smooth muscle cell Théroux P, Fuster V. Circulation. 1998;97:1195-1206. Capthickness Lumen Determinants of Plaque Vulnerability

8. Late Prognosis of Inhospital Refractory Ischemia in Non-ST Segment Elevation ACS No ischemia Non-refractory recurrent ischemia Refractory recurrent ischemia* Cumulative Survival 1.00.95.90.85.80.75.70 601201802403003600 * P<0.03 vs. no ischemia. Armstrong PW et al. Circulation. 1998;98:1860-1868. Days

9. Prognostic Significance of Rest Pain in Primary UA and Postinfarction Angina 4.2 18.4 1.4 0.0 10.9 26.3 7.3 0.0 Rest Pain <48 h n=1091 No Rest Pain n=261 Cannon CP et al. Circulation. 1995;92:I-19. Death/MI at 42 Days Death/MI at 1 Year Death/MI, % of Patients UA Patients Post-MI Patients

10. Prognostic Value of ST-Segment Depression During Chest Pain in Patients With Suspected UA or NQWMI Days 1.0 0.9 0.8 0102030405060708090 Survival P<0.001 Normal ECG without changes Abnormal ST-T ECG without changes  ST  ST López de Sá E et al. J Am Coll Cardiol. 1998;31(suppl A):79A.

11. ACS: Prior Aspirin Use in PURSUIT Death/MI (30 d) Death/MI (30 d) N=10,948Risk Ratio and 95% CIPlaceboEptifibatide No Prior Aspirin36.4%12.9%13.1% Prior Aspirin63.6%17.3%14.9% EptifibatideBetterEptifibatideWorse 00.51.01.52 Alexander JH et al. J Am Coll Cardiol. 1998;31(suppl A):93A.

12. CK-MB Levels As Predictors of Mortality in PURSUIT Mortality (%) Alexander JH et al. Circulation. 1998;98(suppl):I-629. Maximal CK-MB (xULN)

13. ACS: Possible Link Between Platelets and Troponin and Benefit of GP IIb/IIIa Inhibition Atherosclerotic coronary Plaque rupture/erosion/fissure Platelet thrombus Embolization Microvascular platelet aggregation NecrosisTroponin+ GP IIb/IIIa inhibitor Courtesy of Eric J. Topol, MD.

14. Relation of Troponin Status to Thrombus Resolution With GP IIb/IIIa Inhibition in CAPTURE Hamm CW et al. Circulation. 1998;98(suppl I):I-492. % With Visible Thrombus 4.1% 2.8% 11.2% 5.9% TnT Neg TnT Pos

15. Relation of Troponin Status to Preventing Need for Premature PTCA in CAPTURE Heeschen C et al. Circulation. 1998;98(suppl):I-358. % Requiring Premature PTCA 1.4% 1.8% 6.8% 2.0% RR=61% P<0.01 TnT neg (n=625) TnT pos (n=201)

16. Troponin I (ng/mL) TnI Levels in UA/NQWMI Patients Treated With Tirofiban: PRISM-PLUS Baseline Levels Peak Levels Hahn SS et al. J Am Coll Cardiol. 1998;31(suppl A):229A. 3.1 5.2 15.5 1.6 P=NS P=0.017

17. ACS: A Change in Mind-Set When should short-acting GP IIb/IIIa platelet inhibition (tirofiban or eptifibatide) be added to aspirin and heparin Rx? + Topol EJ. J Invasive Cardiol. 1998;10(suppl D):2D-7D. Troponin,  CK-MB, ST , post-MI, rest pain, prior aspirin use, recurrent ischemia

18. Risk Stratification in ACS ST Elevation MI Spectrum of Chest Pain Syndromes Clinical Finding ECG Serum Markers Risk Assessment Noncardiac Chest Pain Stable Angina Unstable Angina Non-ST Elevation MI Rest Pain, Post-MI Low riskMedium-to-high riskHigh risk Thrombolysis, Primary PCI Aggressive antithrombotic + antiplatelet therapy Discharge Negative Positive Diagnostic Rule out MI/ACS pathway NegativeST-T wave changesST elevation + + Nonrest, Subacute Pain NegativePositive

19. GP IIb/IIIa Receptor Blockers: UA/NQWMI Trials PARAGON Lamifiban 22822 x 2Death/MI 1 & 5  g/kg/minFactorial designwithin 30 d PRISMTirofiban3232T vs hDeath/MI/refractory 0.6  g/kg/min  30 min B + I toischemia within 48 h + 0.15  g/kg/minPTT 2x control PRISM-PLUSTirofiban1915T vs hDeath/MI/refractory 0.6  g/kg/min  30 min B + I to ischemia within 7 d + 0.15  g/kg/min PTT 2x control vs 0.4  g/kg/min  30 min T + h + 0.1  g/kg/min PURSUITEptifibatide10,948AtDeath/MI 180  g/kg bolus + 2  g/kg/min physician’swithin 30 d or 1.3  g/kg/min discretion TrialAgentN Heparin Regimen The PARAGON Investigators. Circulation. 1998;97:2386-2395. The PRISM Study Investigators. N Engl J Med. 1998;338:1498-1505. The PRISM-PLUS Study Investigators. N Engl J Med. 1998;338:1488-1497. The PURSUIT Trial Investigators. N Engl J Med. 1998;339:436-443. Primary Endpoint

20. Slide #15 Notes Continued

21. GP IIb/IIIa Receptor Blockers in UA/NQWMI: Death or MI at 30 Days Odds Ratio and CI N GP IIb/IIIa Control Reduction ± SD The PARAGON Investigators. Circulation. 1998;97:2386-2395. The PRISM Study Investigators. N Engl J Med. 1998;338:1498-1505. The PRISM-PLUS Study Investigators. N Engl J Med. 1998;338:1488-1497. The PURSUIT Trial Investigators. N Engl J Med. 1998;339:436-443. PARAGON A with low-dose lamifiban 151310.6%11.7% 11%  15 152612.0%11.7% -2%  16 PRISM (tirofiban alone) 32325.8%7.1% 19%  13 PRISM-PLUS (tirofiban + heparin) 15708.7%11.9% 30%  14 PURSUIT (eptifibatide  heparin) 946114.2%15.7% 11%  5 high-dose lamifiban 0.01.00.51.52.0

22. Slide #16 Notes Continued

23. The PRISM-PLUS Study Investigators. N Engl J Med. 1998;338:1488-1497. Peterson JG et al. Circulation. 1998;98:I-360. PRISM-PLUS (n=695) PURSUIT (n=882) PURSUIT (n=882) Death or MI, 30 Days (%) Heparin Tirofiban/ no Heparin Placebo Eptifibatide/ no Heparin Interaction of Heparin and GP IIb/IIIa Platelet Inhibitors 19%  41% 

24. GP IIb/IIIa Inhibition in PRISM-PLUS: MI/Death Event Reductions at 2, 7, and 30 Days The PRISM-PLUS Study Investigators. N Engl J Med. 1998;338:1488-1497. 2 Days 7 Days RR=30% P=0.03 30 Days RR=43% P=0.006 8.3 4.9 11.9 8.7 Patients (%) RR=66% P=0.01 2.6 0.9 Heparin (n=797) Tirofiban + Heparin (n=773) 0 5 10 15

25. GP IIb/IIIa Inhibition in PRISM-PLUS: Composite Endpoint at 2, 7, and 30 Days 0 5 10 15 20 25 P=0.073 RR=22% P=0.029 2 Days7 Days30 Days The PRISM-PLUS Study Investigators. N Engl J Med. 1998;338:1488-1497. 7.8 5.7 22.3 18.5 Patients (%) Heparin (n=797) Tirofiban + Heparin (n=773) RR=32% P=0.004 17.9 12.9

26. Day Sustained Effect of GP IIb/IIIa Inhibition: PRISM-PLUS Composite Endpoint at 180 Days The PRISM-PLUS Study Investigators. N Engl J Med. 1998;338:1488-1497. 5 10 15 20 25 With Endpoint (%) Heparin Tirofiban + Heparin  = -5.0%, RR=32%, P=0.004 03060901201501807  = -3.8%, RR=22%, P=0.029  = -4.4%, RR=19%, P=0.02 30 35

27. GP IIb/IIIa Inhibition: Comparative Rates of Death or MI at 30 Days for 3 Strategies in PRISM-PLUS 20 15 5 0 10 Medical Rx PTCACABG 10.1 7.8 13.1 8.8 16.8 12.2 RR=25% (95% CI=0.46-1.23) RR=34% (95% CI=0.38-1.14) RR=30% RR=30% (95% CI=0.40-1.0) % Death/MI (30 Days) Barr et al. Circulation. 1998;98:I-504.

28. RR=31% P=0.23 RR=7% P=0.01 The PURSUIT Trial Investigators. N Engl J Med. 1998;339:436-443. % Death or MI (30 Days) Early PCI (Within 72 h After Randomization) Med Rx, Late PCI, CABG PURSUIT: Effect of GP IIb/IIIa Inhibition in Patients Undergoing Early PCI

29. PRISM-PLUS: Combined MI and Death During Initial 48 Hours in All Patients and Postprocedure in Patients Undergoing PTCA 241421287 0.12 0.08 0.04 0.00 Heparin Only RR=44% 475 Patients Undergoing PTCA Heparin Only Tirofiban + Heparin RR=66% All 1570 Patients Evaluated HoursDays Drug Infusion PTCA Probability of Death or MI The PRISM-PLUS Study Investigators. N Engl J Med. 1998;338:1488-1497. Tirofiban + Heparin 6300121824364248 0.12 0.08 0.04 0.00

30.  = -6.2% 0306090120150180Day 4 8 12 16 20 24 28 32 % With Endpoint Heparin Tirofiban + Heparin  = -6.5% RR=45% RR=27% The PRISM-PLUS Study Investigators. N Engl J Med. 1998;338:1488-1497. Barr et al. Circulation. 1998;98:I-504. Effect of GP IIb/IIIa Inhibition in Patients Undergoing PTCA: PRISM-PLUS Composite Endpoint

31. PRISM-PLUS: Selected Subgroup Benefits With GP IIb/IIIa Inhibition: Composite Endpoint (7 Days) 0.1110 Risk Ratio (95% CI) Age < 65 y 65-74 y  75 y Gender Women Men Prior heparin Yes No Prior aspirin Yes No Country US Canada Other Presentation NQWMI UAP Diabetes Yes No 0.55 The PRISM-PLUS Study Investigators. N Engl J Med. 1998;338:1488-1497.

32. PRISM-PLUS: MI/Death Outcomes in Patients With Diabetes % Patients 9.3% 1.2% P=0.004 15.5% 4.7% P=0.002 19.2% 11.2% P=0.044 Day 7Day 30Day 180 5 0 15 10 20 Théroux P et al. Circulation. 1998;98:I-359.

33. 0.79 (0.69-0.91) 1.10 (0.91-1.34) 0.78 (0.66-0.93) 0.98 (0.84-1.13) 0.90 (0.75-1.08) 0.96 (0.78-1.17) 0.81 (0.66-0.99) 0.87 (0.76-1.00) 0.96 (0.77-1.19) 0.5 1 1.5 Eptifibatide Better Placebo Better High weight Medium weight Low weight 65 or older Under 65 Women Men No diabetes Diabetes The PURSUIT Trial Investigators. N Engl J Med. 1998;339:436-443. PURSUIT: Subgroup Analysis for Death or MI at 30 Days Odds Ratio (CI)

34. Major Bleeding (TIMI) Intracranial bleeding Minor Bleeding (TIMI) Transfusions (All Blood Products) Platelets  90,000/mm 3 1.4% (11) 0.0% 10.5% 4.0% 1.9% 0.8% (6) 0.0% 8.0% 2.8% 0.8% Tirofiban + Heparin n=773 Heparinn=797 PRISM-PLUS: Hematologic Complications The PRISM-PLUS Study Investigators. N Engl J Med. 1998;338:1488-1497. AGGRASTAT ® package insert. P Value NS NS

35. GP IIb/IIIa Platelet Inhibition in Transfer Patients With UA/NQWMI: PRISM-PLUS  Are the safety and efficacy of GP IIb/IIIa inhibitors dependent on the setting in which patients are treated: community hospitals vs. tertiary care centers?  What is the safety and efficacy of GP IIb/IIIa inhibitors in patients requiring transfer? Théroux P et al. Eur Heart J. 1998;19(suppl):50. Abstract.

36. PRISM-PLUS Transfer Patients: Baseline Characteristics CommunityTransferredTertiary Hospital Subgroup Group Characteristic(n=322)(n=228) (n=512) Age (y)62  1261  1263  11 Men66%71%67% Antecedent CAD 57%54%68% ECG ischemia93%93%93% Presentation UA50%47%61% NQWMI50%53%39% Théroux P et al. Eur Heart J. 1998;19(suppl):50. Abstract.

37. PRISM-PLUS Transfer Patients: Clinical Status Prior to Transfer* CommunityTransferredTertiary Hospital Subgroup Group Endpoint(n=322)(n=228) (n=512) Composite8.4%7.4%8.0% Death0%0%0.2% MI 2.8%1.8%2.0% Death/MI2.8%1.8%2.2% Refractory ischemia 5.9%6.1%6.8% * Event rates at 48 hours after randomization (regardless of treatment allocation). Théroux P et al. Eur Heart J. 1998;19(suppl):50. Abstract.

38. PRISM-PLUS Transfer Patients: Efficacy of Tirofiban by Admitting Hospital—Death/MI 3.9* 10.8 2.7 10.3 9.1 6.4 7.1* 13.8 12.0 5.4 9.7 14.0 10.3* 17.4 14.1 16.3 8.1 15.4 7 Days 30 Days 180 Days Community Hospital % Patients * P<0.04 vs. heparin. P values for transfer subgroup not calculated as this group was defined by postrandomization events. Théroux P et al. Eur Heart J. 1998;19(suppl):50. Abstract. 7 Days 30 Days 180 Days Transfer 7 Days 30 Days 180 Days Tertiary

39. PRISM-PLUS Transfer Patients: Efficacy of Tirofiban by Admitting Hospital—Composite Endpoint 12.9* 21.6 10.8 21.4 20.4 16.5 16.2 23.9 26.4 18.1 22.2 25.4 27.1 33.5 33.9 36.7 23.4 30.8 % Patients *P<0.04 vs. heparin. P values for transfer subgroup not calculated as this group was defined by postrandomization events. P values for transfer subgroup not calculated as this group was defined by postrandomization events. Théroux P et al. Eur Heart J. 1998;19(suppl):50. Abstract. 7 Days 30 Days 180 Days Community Hospital 7 Days 30 Days 180 Days Transfer 7 Days 30 Days 180 Days Tertiary

40. T/HH T/H H T/H H Endpoint(n=155)(n=167)(n=111)(n=117)(n=248)(n=264) PRISM-PLUS Transfer Patients: Incidence of Bleeding CommunityTransferredTertiary HospitalSubgroup Group TIMI major1.9%0.6% 2.7% 0.8% 1.2% 1.1% bleeding TIMI minor10.3% 13.8% 10.8% 17.9% 14.1% 9.8% bleeding PRBC Txn 5.2% 2.4% 4.5 % 3.4% 4.4% 3.0% None of the differences achieved statistical significance. Note: The duration of study drug infusion in transfer patients was longer than in the overall community hospital group and tertiary hospital group (80.5 ± 14.3 h vs. 71.8 ± 16.7 h and 75.6 ± 17.7 h, respectively). Théroux P et al. Eur Heart J. 1998;19(suppl):50. Abstract.

41. PRISM-PLUS Transfer Patients: Conclusions  Use of GP IIb/IIIa inhibitor tirofiban improved outcomes in UA/NQWMI patients admitted to hospitals without catheterization or revascularization facilities as well as in those admitted to tertiary hospitals  Transfer of patients who were on tirofiban + heparin did not appear to alter bleeding risk and was generally safe and well tolerated Théroux P et al. Eur Heart J. 1998;19(suppl):50. Abstract.

42. Effects of GP IIb/IIIa Inhibition on Angiographic Thrombus and TIMI Flow: PRISM-PLUS Angiographic Substudy  Objective: Determine effect of tirofiban on angiographically apparent thrombus  Films prior to hour 97 analyzed by blinded core laboratory  1230 films readable and analyzed (608 in tirofiban + heparin group; 622 in heparin group) Zhao X-Q. Circulation. 1999; in press.

43. PRISM-PLUS: Intracoronary Thrombus As a Predictor of Clinical Outcomes in UA/NQWMI % Patients With Event 19% 10% 4% 12% 6% 9% 5 0 15 10 20 Odds ratio2.132.041.972.002.36 P value<0.001<0.0010.0020.0020.005 CompositeRef IschemiaMIDeathMI/Death 9% 5% 2% 5% Events at 30 Days Zhao X-Q et al. Circulation. 1998;98:I-492.

44. PRISM-PLUS: GP IIb/IIIa Receptor Inhibition and Thrombus Grade Zhao X-Q. Circulation. 1999; in press. 0 10 20 30 40 50 Cumulative % Heparin (n=622) Tirofiban + Heparin (n=608) Possible Small Moderate Overall Odds Ratio: 0.77 P=0.022 17.1% 24.1% Possible Small Moderate Large Recent Occlusion Large Recent Occlusion

45. PRISM-PLUS: TIMI Flow As a Predictor of Clinical Outcomes in UA/NQWMI Hazard ratio 1.691.491.641.39 ratio 1.691.491.641.39 P value<0.0010.040.0030.17 Patients With Event (%) 27% 17% 6% 17% 5 0 15 10 20 Composite Ref Ischemia MI MI/Death 8% 12% 8% 11% 25 30 Events at 30 Days Zhao X-Q et al. Circulation. 1998;98:I-359.

46. PRISM-PLUS: GP IIb/IIIa Receptor Inhibition and TIMI Flow Zhao X-Q. Circulation. 1999; in press. 0 5 10 15 20 25 Cumulative % Minimal Perfusion (TIMI 1) Tirofiban + Heparin (n=570) Heparin (n=580) Total Occlusion (TIMI 0) Partial Perfusion (TIMI 2) Total Occlusion (TIMI 0) Partial Perfusion (TIMI 2) Overall Odds Ratio: 0.65 P=0.002 18.1% 25.5% Minimal Perfusion (TIMI 1)

47. PRISM-PLUS: Angiographic Substudy Conclusions  TIMI flow and thrombus grade showed strong correlations with the clinical outcomes of MI, death, and refractory ischemia in ACS patients in PRISM-PLUS   48 hours of tirofiban + heparin produced significant improvements in TIMI flow and thrombus grade in UA/NQWMI  These observations suggest a mechanism by which tirofiban + heparin may have improved outcomes in PRISM-PLUS Zhao X-Q. Circulation. 1999; in press.

48. Cost-Effectiveness of GP IIb/IIIa Inhibitor Therapy in ACS  Only significant differences were counted (MI reductions in PRISM-PLUS and PURSUIT)  Assume last effect carried forward  No indirect costs were included  No discount in medication costs  72-hour infusion  Other costs were negligible or would be presented in both groups Rittenhouse BE. In: Spilker B, ed. Quality of Life and Pharmacoeconomics in Clinical Trials. 2nd ed. 1996:1093-1103. The PRISM-PLUS Investigators. N Engl J Med. 1998;338:1488-1497.

49. Tirofiban + ParameterHeparinHeparin $ Treated with GP IIb/IIIa7730 Additional medication, $/patient$1,0500812,000 Reduction in MIs18–(508,000) Increase in adverse events0–0 Net expense:$304,000 Rittenhouse BE. In: Spilker B, ed. Quality of Life and Pharmacoeconomics in Clinical Trials. 2nd ed. 1996:1093-1103. The PRISM-PLUS Investigators. N Engl J Med. 1998;338:1488-1497. An FFS Economic Model Based on 6-Month Data: PRISM-PLUS

50. An MCO Economic Model Based on 6-Month Data: PRISM-PLUS Tirofiban + ParameterHeparinHeparin $ Treated with GP IIb/IIIa7730 Additional medication, $/patient$1,0500812,000 Reduction in MIs18 – (144,000) Increase in adverse events0–0 Net expense:$668,000 Rittenhouse BE. In: Spilker B, ed. Quality of Life and Pharmacoeconomics in Clinical Trials. 2nd ed. 1996:1093-1103. The PRISM-PLUS Investigators. N Engl J Med. 1998;338:1488-1497.

51. Cost-Effectiveness of GP IIb/IIIa Regression Analysis: PRISM-PLUS Data  In the FFS model: $16,900 cost per event saved  In the MCO model: $37,100 cost per event saved Rittenhouse BE. In: Spilker B, ed. Quality of Life and Pharmacoeconomics in Clinical Trials. 2nd ed. 1996:1093-1103. The PRISM-PLUS Investigators. N Engl J Med. 1998;338:1488-1497.

52. An FFS Economic Model Based on 1-Month Data: PURSUIT Eptifibatide + ParameterHeparinHeparin $ Treated with GP IIb/IIIa47220 Additional medication, $/patient$1,35506,398,000 Reduction in MIs61 – (1,721,000) Increase in adverse events151–341,000 Net expense:$5,018,000 Rittenhouse BE. In: Spilker B, ed. Quality of Life and Pharmacoeconomics in Clinical Trials. 2nd ed. 1996:1093-1103. The PURSUIT Trial Investigators. N Engl J Med. 1998;339:436-443.

53. An MCO Economic Model Based on 1-Month Data: PURSUIT Eptifibatide + ParameterHeparinHeparin $ Treated with GP IIb/IIIa47220 Additional medication, $/patient$1,35506,398,000 Reduction in MIs61 – (479,000) Increase in adverse events136–147,000 Net expense:$6,066,000 Rittenhouse BE. In: Spilker B, ed. Quality of Life and Pharmacoeconomics in Clinical Trials. 2nd ed. 1996:1093-1103. The PURSUIT Trial Investigators. N Engl J Med. 1998;339:436-443.

54. Cost-Effectiveness of GP IIb/IIIa Regression Analysis: PURSUIT Data  In the FFS model: $82,300 cost per event saved  In the MCO model:$99,400 cost per event saved Rittenhouse BE. In: Spilker B, ed. Quality of Life and Pharmacoeconomics in Clinical Trials. 2nd ed. 1996:1093-1103. The PURSUIT Trial Investigators. N Engl J Med. 1998;339:436-443.

55. Therapeutic Options for ACS Unstable Angina/Non-ST  MI Empiric GP IIb/IIIa in ER/CCU Traditional Rx Cath Lab ± GP IIb/IIIa Cath Lab Topol EJ. J Invasive Cardiol. 1998;10:(suppl D):2D-7D.

56. Empiric Management of ACS: Conclusions  ACS: Medium- to high-risk patient = positive troponin,  CK-MB, ST , post-MI, rest pain, recurrent ischemia, prior aspirin use  GP IIb/IIIa inhibition with either eptifibatide or tirofiban significantly improves outcomes in the medium- to high-risk patient  Magnitude of benefit of tirofiban has been shown to be similar in –All treatment strategies: PCI, medical management, CABG –All patient subgroups –Community hospital, transferred patients, tertiary care setting  Data strongly support empiric use of GP IIb/IIIa inhibitors in ACS The PRISM-PLUS Investigators. N Engl J Med. 1998;33:1488-1497. Barr E et al. Circulation. 1998;98:I-504. Théroux P et al. Eur Heart J. 1998;19(suppl):50. Abstract.