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Do T irofiban A nd R eoPro G ive Similar E fficacy Outcomes T rial

Do T irofiban A nd R eoPro G ive Similar E fficacy Outcomes T rial. N Engl J Med 2001;344:1888-94. GP IIb/IIIa Inhibition in PCI. Consistent reduction in adverse events Optimal outcome when combined with stents No comparative data between agents. 0.0. 0.5. 1.0. 2.0. Background.

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Do T irofiban A nd R eoPro G ive Similar E fficacy Outcomes T rial

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  1. Do Tirofiban And ReoPro Give Similar Efficacy Outcomes Trial N Engl J Med 2001;344:1888-94

  2. GP IIb/IIIa Inhibition in PCI • Consistent reduction in adverse events • Optimal outcome when combined with stents • No comparative data between agents

  3. 0.0 0.5 1.0 2.0 Background 30-Day Death, MI, Urgent Revascularization % Odds Ratio Trial N Agent IIb/IIIa Control (95% CI) EPIC 2099 Abciximab 8.3 12.8 EPILOG 2792 Abciximab 5.3 11.7 EPISTENT 1603 Abciximab 5.3 10.8(stent arms only) IMPACT-II 4010 Eptifibatide 9.5 11.4 ESPRIT 2064 Eptifibatide 6.8 10.4 RESTORE 2141 Tirofiban 8.0 10.5 Presented at AHA Scientific Sessions Nov. 15, 2000

  4. Tirofiban non-peptide 495 dalton MW recovery of platelet function: hours specific for IIb/IIIa receptor Abciximab monoclonal antibody 47,615 dalton MW recovery of platelet function: days binds to IIb/IIIa, MAC-1, v3 Characteristics of Tirofiban and Abciximab Presented at AHA Scientific Sessions Nov. 15, 2000

  5. PrimaryHypothesis Tirofiban will have comparable efficacy to abciximab in reducing the incidence of adverse cardiac ischemic events during the first 30 days after intracoronary stent placement. N Engl J Med 2001;344:1888-94

  6. Statistical Considerations Sample size provides 88% power to declare tirofiban non-inferior to abciximab, based on the relative efficacy of abciximab to placebo in EPISTENT* * the upper bound of the 1-sided 95% C.I. for the odds ratio (tirofiban relative to abciximab) must be below 1.47. N Engl J Med 2001;344:1888-94

  7. PrimaryEndpoint 30 day composite of: • death • myocardial infarction • CK-MB > 3x ULN in two samples • new Q waves • urgent TVR • PCI or CABG N Engl J Med 2001;344:1888-94

  8. Study Design Inclusion Criteria • stable CAD or ACS, scheduled to undergo PCI in native vessel and/or graft with planned stent • primary or rescue PCI for ST elevation MI • increased risk of bleeding • allergy, intolerance, or recent exposure to study medications • creatinine > 2.5 mg/dl • cardiogenic shock Exclusion Criteria Am Heart J 2000;140:722-6

  9. Study Design Bolus + 18-24 hr infusion Tirofiban or Pbo 30 Days 6 Mos 1 Yr Abciximab or Pbo Bolus + 12 hr infusion PCI ASA Clopidogrel* Heparin Primary Endpoint Long term follow up * Investigator’s discretion Am Heart J 2000;140:722-6

  10. Concomitant Medications Clopidogrel* • 300 mg 2-6 hours pre-PCI (or immediately pre-PCI in patients with unknown anatomy) • 75 mg daily for 29 days Heparin • 70 U/kg IV bolus • ACT target of 250 seconds Aspirin *Investigator’s discretion Am Heart J 2000;140:722-6

  11. Study Drug Administration • Study drug boluses administered at start of procedure • Study drug infusions started immediately after completion of study drug boluses Am Heart J 2000;140:722-6

  12. Enrollment • December 30, 1999 - August 25, 2000 • 149 sites; 18 countries • 4809 patients received study drug N Engl J Med 2001;344:1888-94

  13. Participating Sites Presented at AHA Scientific Sessions Nov. 15, 2000

  14. Baseline Demographics Tirofiban Abciximab n = 2398 n = 2411 US (n) 1950 1960 Ex-US (n) 448 451 age (yr) 62.1 62.6 gender (M/F, %) 74/26 73/27 diabetes (%) 23 23 hypertension (%) 64 65 smoking (%) 65 64 prior MI (%) 40 39 prior PCI (%) 29 30 prior CABG (%) 17 17 N Engl J Med 2001;344:1888-94

  15. Indication for Procedure ACS (%) 63 63 Stable Angina (%) 22 21 Positive Stress Test (%) 11 12 Other (%) 4 5 Tirofiban Abciximab n = 2398 n = 2411 Presented at AHA Scientific Sessions Nov. 15, 2000

  16. Procedural Characteristics Tirofiban Abciximab n = 2398 n = 2411 Patients with stent placed (%) 95 95 Stents/Patient 1.3 1.3 Patients with thrombus present(%) 10 9 Vein grafts (%) 6 5 Restenotic vessel(%) 5 5 Maximum ACT (median) 281 283 Presented at AHA Scientific Sessions Nov. 15, 2000

  17. Medications Tirofiban Abciximab n = 2398 n = 2411 ASA pre-procedure (%) 99 99 Mean Heparin dose (U) 6355 6461 Clopidogrel any pre-procedure (%) 93.4 92.2 300 mg load pre-procedure(%) 87.2 85.6 Study drug infusion duration (hrs) 18.2 12.0 Presented at AHA Scientific Sessions Nov. 15, 2000

  18. Primary Endpoint 30 day Death, MI, Urgent TVR Non-inferiority boundary RR = 1.26 Upper bound of 95% confidence interval = 1.51 p=0.038 RR = 1.26 1.47 10.0% 7.6% 9.0% Abciximab better 8.0% 6.0% 7.0% 6.0% 30 day Death, MI, Urgent TVR (%) 1.00 5.0% 4.0% Tirofiban better 3.0% 2.0% 1.0% 0.0% Tirofiban Abciximab N Engl J Med 2001;344:1888-94

  19. 10 8 6 4 2 0 Primary EndpointD/MI/Urgent TVR 7.6% 6.0% % Patients Tirofiban Abciximab 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 Time (Days) N Engl J Med 2001;344:1888-94

  20. Primary Endpoint Analysis p = 0.038 p = 0.66 p = 0.04 p = 0.04 p = 0.49 7.6 7.2 6.9 6.0 5.7 5.4 Event Rate % Tirofiban Abciximab 0.8 0.7 0.5 0.4 Composite Death MI Death/MI Urgent TVR N Engl J Med 2001;344:1888-94

  21. Primary Endpoint Analysis Tirofiban Abciximab RR CI % % 7.6 6.0 1.26 1.05,1.51 7.2 5.7 1.26 1.01,1,58 6.9 5.4 1.27 1.01,1.60 0.5 0.4 1.21 0.52, 2.81 0.8 0.7 1.26 0.65, 2.44 Primary composite endpoint Death/MI MI Death Urgent TVR 1 Tirofiban better Abciximab better N Engl J Med 2001;344:1888-94

  22. Time to MIMIs within the first 72 hrs 10 8 6 % Patients 4 Tirofiban Abciximab 2 0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 Time (Hours) Presented at AHA Scientific Sessions Nov. 15, 2000

  23. Tirofiban Abciximab RR CI % % 6.3 5.4 1.16 0.72, 1.90 7.9 6.2 1.29 1.01, 1.64 6.6 4.6 1.45 1.05, 2.01 8.8 7.8 1.13 0.82, 1.50 7.2 6.5 1.10 0.86, 1.43 8.7 4.7 1.86 1.19, 2.89 Subgroup Analysis Diabetes No Diabetes Age < 65 Age > 65 Male Female 1 Tirofiban better Abciximab better N Engl J Med 2001;344:1888-94

  24. Subgroup Analysis Tirofiban Abciximab RR CI % % • Pre-procedure Clopidogrel • Yes • No • ACS • non-ACS • U.S. • Ex-U.S. 7.2 5.8 1.24 1.00, 1.58 12.5 8.3 1.50 0.73, 2.68 9.3 6.3 1.49 1.15, 1.94 4.5 5.6 0.82 0.54, 1.24 7.7 6.7 1.14 0.91, 1.45 6.9 2.9 2.42 1.27, 4.64 1 Tirofiban better Abciximab better N Engl J Med 2001;344:1888-94

  25. Substudy of U.S. vs International Primary Endpoint Results 9 Tirofiban 7.7 Abciximab 8 • The separation between Tirofiban and Abciximab in the U.S. was 18 events in 3910 patients treated • The separation outside the US was 18 events in the 899 patients treated 6.9 6.7 7 6 5 % of Patients with Event 4 2.9 3 2 1 0 U.S. International Death / MI / Urgent TVR at 30 Days N Engl J Med 2001;344:1888-94

  26. Safety Analysis Tirofiban Abciximab P % % • TIMI Major Bleeding • IC hemorrhage • TIMI Minor Bleeding • Thrombocytopenia (< 100,000) • RBC Transfusion • Platelet Transfusion 0.9 0.7 0.04 0.04 2.8 4.3 <0.001 0.5 2.4 <0.001 1.2 1.5 0.4 0.5 N Engl J Med 2001;344:1888-94

  27. 30-Day Conclusions • Abciximab was superior to tirofiban in reducing the incidence of the primary endpoint of the trial: The composite endpoint of death / MI / urgent target vessel revascularization at 30 days after intracoronary stent placement. • There were no differences in rates of TIMI major bleeding, but significant differences in minor bleeding and thrombocytopenia were observed favoring tirofiban. N Engl J Med 2001;344:1888-94

  28. 6-Month Composite Events(Death/MI/TVR) 0.20 P=0.591 HR 1.04 95% CI: 0.90,1.21 Tirofiban, N=2398 Abciximab, N=2411 14.8% 0.15 14.3% Composite Event Rate 0.10 0.05 0.00 0 30 120 150 60 90 180 Days

  29. 6-Month Analysis p = 0.591 p = 0.89 p = 0.07 p = 0.11 p = 0.50 HR 1.21 95% CI: 0.98,1.50 HR 0.93 95% CI: 0.77,1.14 HR 1.04 95% CI: 0.90,1.21 HR 1.04 95% CI: 0.60,1.80 HR 1.18 95% CI: 0.96,1.44 16.0 14.8 14.3 14.0 12.0 10.0 8.6 8.7 8.1 Event Rate % 8.0 7.4 8.0 6.6 6.0 4.0 1.1 1.0 2.0 0.0 Composite Death MI Death/MI TVR Tirofiban (N=2398) Abciximab (N=2411)

  30. 6-Month Composite Endpoint Analysis Tirofiban Abciximab RR CI % % 14.8 14.3 1.04 0.90,1.21 8.7 7.4 1.18 0.96,1.44 8.0 6.6 1.21 0.98,1.50 1.1 1.0 1.04 0.60, 1.80 8.1 8.6 0.93 0.77, 1.14 Primary composite endpoint Death/MI MI Death TVR 1 Tirofiban better Abciximab better

  31. 6-Month Subgroup Analysis Tirofiban Abciximab RR CI % % 15.7 16.9 0.93 0.69, 1.24 14.6 13.5 1.08 0.91, 1.29 10.2 13.0 0.77 0.59, 1.02 17.6 15.1 1.19 1.00, 1.42 15.6 15.7 1.00 0.85, 1.17 11.6 8.4 1.39 0.91, 2.11 Diabetes No Diabetes non-ACS ACS U.S. Ex-U.S. Pre-procedure Clopidogrel: 14.4 14.1 1.03 0.88,1.20 Yes 21.1 17.2 1.21 0.74,1.99 No 1 Tirofiban better Abciximab better

  32. Substudy of U.S. vs International Composite Endpoint Results P=0.97 • U.S.: • Tirofiban N=1950 • Abciximab N=1960 • Ex-US: • Tirofiban N=448 • Abciximab N=451 P=0.12 % of Patients with Event Death / MI / TVR at 6-Months

  33. 6-Month Analysis: Non-ACS Patients p = 0.07 p = 0.81 p = 0.55 p = 0.62 p = 0.05 HR 0.88 95% CI: 0.59,1.32 HR 0.70 95% CI: 0.49,1.00 HR 0.77 95% CI: 0.59,1.02 HR 1.15 95% CI: 0.35,3.79 HR 0.91 95% CI: 0.62,1.33 13.0 14.0 12.0 10.2 10.0 8.0 Event Rate % 8.0 6.2 5.8 5.7 5.7 6.0 5.1 4.0 2.0 0.7 0.6 0.0 Composite Death MI Death/MI TVR Tirofiban (N=884) Abciximab (N=899)

  34. 6-Month Analysis: ACS Patients p = 0.06 p = 0.99 p = 0.01 p = 0.03 p = 0.56 HR 1.37 95% CI: 1.07,1.76 HR 1.07 95% CI: 0.85,1.36 HR 1.19 95% CI: 1.00,1.42 HR 1.01 95% CI: 0.54,1.87 HR 1.30 95% CI: 1.03,1.65 20.0 17.6 18.0 15.1 16.0 14.0 12.0 10.4 Event Rate % 9.6 9.5 9.0 10.0 8.1 7.1 8.0 6.0 4.0 1.3 1.3 2.0 0.0 Composite Death MI Death/MI TVR Tirofiban (N=1514) Abciximab (N=1512)

  35. 6-Month Analysis: US Patients p = 0.97 p = 0.76 p = 0.39 p = 0.44 p = 0.37 HR 1.11 95% CI: 0.88,1.39 HR 0.91 95% CI: 0.74,1.12 HR 1.00 95% CI: 0.85,1.17 HR 1.10 95% CI: 0.61,1.98 HR 1.09 95% CI: 0.88,1.35 15.7 15.6 16.0 14.0 12.0 9.4 10.0 8.9 8.6 Event Rate % 8.2 8.1 7.3 8.0 6.0 4.0 1.2 2.0 1.1 0.0 Composite Death MI Death/MI TVR Tirofiban (N=1950) Abciximab (N=1960)

  36. 6-Month Analysis: Ex-US Patients p = 0.69 p = 0.01 p = 0.02 p = 0.67 p = 0.12 HR 2.15 95% CI: 1.19,3.90 HR 1.13 95% CI: 0.65,1.98 HR 1.39 95% CI: 0.91,2.11 HR 0.73 95% CI: 0.16,3.28 HR 1.96 95% CI: 1.11,3.47 12.0 11.6 10.0 8.4 7.8 7.6 8.0 Event Rate % 5.8 5.1 6.0 4.0 3.6 4.0 2.0 0.9 0.7 0.0 Composite Death MI Death/MI TVR Tirofiban (N=448) Abciximab (N=451)

  37. 6-Month Analysis: Non-Diabetics p = 0.47 p = 0.10 p = 0.11 p = 0.82 p = 0.36 HR 1.22 95% CI: 0.96,1.55 HR 0.97 95% CI: 0.77,1.23 HR 1.08 95% CI: 0.91,1.29 HR 1.30 95% CI: 0.64,2.60 HR 1.21 95% CI: 0.96,1.52 16.0 14.6 13.5 14.0 12.0 10.0 8.8 Event Rate % 8.3 7.9 7.7 7.3 8.0 6.8 6.0 4.0 2.0 1.0 0.8 0.0 Composite Death MI Death/MI TVR Tirofiban (N=1838) Abciximab (N=1854)

  38. 6-Month Analysis: Diabetics p = 0.47 p = 0.50 p = 0.70 p = 0.37 p = 0.61 HR 1.17 95% CI: 0.74,1.86 HR 0.84 95% CI: 0.59,1.22 HR 0.93 95% CI: 0.69,1.24 HR 0.72 95% CI: 0.29,1.78 HR 1.09 95% CI: 0.72,1.65 18.0 16.9 15.7 16.0 14.0 11.1 12.0 9.5 Event Rate % 10.0 8.2 7.5 7.0 8.0 5.9 6.0 4.0 2.0 1.4 2.0 0.0 Composite Death MI Death/MI TVR Tirofiban (N=560) Abciximab (N=557)

  39. Composite Endpoint(Death/MI/TVR) P=0.038 P=0.591 HR 1.04 95% CI: 0.90,1.21 HR 1.26 90% CI: 1.05,1.51 14.8% 15% 14.3% Tirofiban (N=2398) 10% 7.6% Abciximab 6.0% (N=2411) 5% 0% 30-Day 6-Months

  40. Death P=0.66 P=0.893 2% HR 1.21 95% CI: 0.52,2.81 HR 1.04 95% CI: 0.60,1.80 Tirofiban (N=2398) 1.1% 1.0% Abciximab (N=2411) 0.5% 0.4% 0% 30-Day 6-Months

  41. Death/MI P=0.04 P= 0.11 15% HR 1.26 95% CI: 1.01,1.58 HR 1.18 95% CI: 0.96,1.44 Tirofiban (N=2398) 10% 8.7% 7.4% 7.2% Abciximab 5.7% (N=2411) 5% 0% 30-Day 6-Months

  42. Target Vessel Revascularization P=0.49 P=0.50 15% HR 1.26 95% CI: 0.65,2.44 HR 0.93 95% CI: 0.77,1.14 Tirofiban (N=2398) 10% 8.6% 8.1% Abciximab (N=2411) 5% Urgent TVR 0.8% 0.7% 0% 30-Day 6-Months

  43. Diabetics: Composite Endpoint (Death/MI/TVR) 16.9 P= 0.61 15.7 15% HR 0.93 95% CI: 0.69,1.24 P= 0.54 HR 1.16 95% CI: 0.72,1.90 Tirofiban (N=560) 10% Abciximab 6.3 (N=557) 5.4 5% 0% 30-Day 6-Months

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