1. Relative Risk 1.31.41.51.61.71.21.11.00.90.8 Therapy A Better Therapy B Better COMPASS 95% CI no worse than 1.5 TARGET 95% CI no worse than 1.47 ASSENT-2 1.14 REPLACE 2 1.18 PROVE-IT 1.17* Criteria for Clinical Equivalence in ACS Trials Non-inferiority: upper 95% CI of the RR between 2 agents can be no worse than pre-specified range *relative risk of 1.17 at 2 years = 1.198 hazard ratio

2. INJECT: r-PA vs. Streptokinase INJECT: designed to determine the effect of reteplase on survival was at least equivalent (within 1% of fatality rate) to that of a standard streptokinase regimen. Patients (n = 6010) randomised. 35-Day Mortality: 9.02% in the reteplase 9.53% in the streptokinase group, a non-significant difference (95% CI -1.98% to 0.96%). Because the upper limit of the 90% CI (one-sided 95% CI) for this difference is 0.71%, this result shows that reteplase is at least as effective as streptokinase.. Lancet. 1995;346:329-336.

3. COBALT: double bolus vs. accelerated t-PA COBALT definition for double-bolus t-PA to be considered equivalent to an accelerated t-PA: the upper limit of the one-sided 95 percent confidence interval of the difference in 30-day mortality could not exceed an absolute difference of 0.4 percent; This difference corresponds to the lower 95 percent confidence limit of the absolute difference in 30-day mortality between an accelerated infusion of alteplase and streptokinase in the GUSTO I trial. The COBALT investigators asserted that if equivalence based on this criterion could be demonstrated, one might infer that double-bolus alteplase is superior to streptokinase. N Engl J Med 1997;337:1124-1130

4. COBALT: Results COBALT randomized 7169 patients. 30-day mortality rates: l 7.98 percent in the double-bolus t-PA l 7.53 percent in the accelerated t-PA, an unfavorable absolute difference of 0.44 percent. l Because the one-sided 95 percent confidence limit for the difference in mortality rates exceeded the prespecified limit, the authors concluded that double- bolus alteplase had not been shown to be equivalent to an accelerated infusion of alteplase. N Engl J Med 1997;337:1124-1130

5. COBALT: Results 0.40 0.4 0.4 D-B (%) Accel. (%) Absol Diff (95% CI) DB Better Accel Better 30 Day Mortality 7.98 7.53 -0.44 Absolute Event difference N Engl J Med 1997;337:1124-1130

6. TNK-tPA: Phase III study: ASSENT-2 ASSENT-2 Protocol Design ST-Segment Elevation MI < 6 h ASA Heparin (aPTT 50-75s) 1:1 (double-blind) TNK-tPA single bolus weight-adjusted Accel tPA <100 mg/90 min Primary endpoint All Cause Mortality (30 days) n=16,500 pts

7. Primary Endpoint Null and Alternative Hypotheses Primary Endpoint: 30 Day Mortality (All Causes) Null and Alternative Hypotheses H 0 : m TNK-tPA - m tPA > 1% H 1 : m TNK-tPA - m tPA  1% vs H 0 : m TNK-tPA / m tPA > 1.14 H 1 : m TNK-tPA / m tPA  1.14 vs or Absolute Difference Relative Risk

8. Null Hypotheses: Absolute vs Relative Mortality Difference If 30 Day Mortality t-PA = 10% upper 90% boundary for equivalence = 11% (10% + 1%) If 30 Day Mortality t-PA = 5% upper 90% boundary for equivalence = 5.7% (5% + 14% of 5%)

9. Sample Size Assumptions: –30-Day Mortality After rt-PA = 7.2% –Equal Mortality After TNK-tPA ïSample size of 16,500 randomized and treated patients provides 80% power to reject null hypothesis at a one- sided significance level of 5%

10. Kaplan-Meier Curve for 30 Day Mortality rt-PATNK-tPA Days to Death

11. 30-Day Mortality: Absolute Difference 1. Primary Analysis (Adjusted Rate) 2. Secondary Analysis (Unadjusted Rate) 3. Logistic Regression TNK-tPA % 6.17 6.16 6.10 rt-PA % 6.15 6.18 6.15 Absolute Difference (90% CI) 0.02 (-0.56,0.60) -0.02 (-0.62,0.59) -0.05 (-0.62,0.52) P-value for equivalence 0.006 0.003 TNK-tPA better rt-PA better 10

12. 30-Day Mortality: Relative Risk 1. Primary Analysis (Adjusted Rate) 2. Secondary Analysis (Unadjusted Rate) 3. Logistic Regression TNK-tPA % 6.17 6.16 6.10 rt-PA % 6.15 6.18 6.15 Relative Risk (90% CI) 1.00 (0.91,1.10) 1.00 (0.90,1.10) 0.99 (0.90,1.09) P-value for equivalence 0.027 0.026 0.015 TNK-tPA better rt-PA better 0.881.141

13. 1 1.147 n-PA (%) t-PA (%) RelativeRisk (95% CI) n-PA Better t-PA Better P Value for Equivalence Death 6.75 6.6 1.02 1.143 0.047 InTIME-2: n-PA and t-PA Equivalent for 30-Day Mortality InTIME-II Investigators. Eur Heart J 2000;21:2005-13.

14. 110 +1 n-PA (%) t-PA (%) Absolute Difference (95% CI) n-PA Better t-PA Better P Value for Equivalence Death 6.77 6.60.17 ( .068, 1.0) 0.047 InTIME-2: n-PA and t-PA Equivalent for 30- Day Mortality Giugliano RP, et al. Circulation. 1999;100:I-651.

15. 11 0 +1 r-PA (%) t-PA (%) Absolute Difference (95% CI) r-PA Better t-PA Better P Value for Equivalence Death 7.47 7.24   0.23  (  1.11, 0.66) P=NS GUSTO-III: r-PA and t-PA Not Equivalent for 30-Day Mortality Adapted from GUSTO-III Investigators. N Engl J Med. 1997;337:1118-1123.

16. 0 +1 Mortality (%) Absolute Difference (95% CI) T-PA BetterBetter P Value for Equivalence InTIME-2 6.776.60   0.17 (  1.0, 0.68) 0.047 ASSENT-2 6.166.18 0.02 (  0.59, 0.62) 0.006 GUSTO-III 7.477.24  0.23 (  1.11, 0.66) NS Comparison Among Equivalency Analyses for 30-Day Mortality ASSENT-2 Investigators. Lancet. 1999;354:716-722; Adapted from GUSTO-III Investigators. N Engl J Med. 1997;337:1118-1123. Adapted from Giugliano RP, et al. Circulation. 1999;100:I-651. n-PA TNK-tPA r-PA Other t-PA t-PA t-PA

17. Net Clinical Benefit Death or Non-Fatal Stroke at 30 Days (%) Death or Non-Fatal ICH (%) Death or Non-Fatal Disabling Stroke (%) Death or Non-Fatal Disabling ICH (%) TNK-tPA (n=8,462) 7.10 5.95 6.21 5.85 rt-PA (n=8,488) 7.04 5.87 6.05 5.78 Relative Risk (95% CI) 1.01 (0.91,1.13) 1.01 (0.90,1.14) 1.03 (0.91,1.15) 1.01 (0.90,1.14) P-value 0.881 0.845 0.701 0.870

18. ASSENT 2: Conclusions The Primary Objective of ASSENT-2 Has Been Achieved: Demonstration That Single Bolus TNK-tPA is Equivalent to Accelerated rt-PA in Reducing 30-Day Mortality. l Stringent Criteria for Equivalence l Mortality Rates Virtually Identical

19. Study Design A Phase (open-label) Z Phase * (double-blind) Admission UAP/NSTE-MI Unfractionatedheparin Tirofiban (48 to 108 hours) Enoxaparin Randomized Diet and placebo 4 months 1 month Simvastatin 40 mg Stabilized ** Simvastatin 80 mg Simvastatin 20 mg STE-MI Optimal treatment

20. 0.881 1.144 Enox (%) Hep (%) HazardRatio (95% CI) Enox Better Hep Better D/MI/RI 8.4 9.4 0.88 1.05 Blazing M. presented ACC 2003. Primary Endpoint at 7 days Death, MI and Refractory Ischemia

21. Primary Endpoint * * 30 day Death, MI, Urgent TVR Upper bound of 95% confidence interval = 1.52 Non-inferiority boundary RR = 1.26 1.47 1.00 Abciximabbetter Tirofibanbetter Relative Risk Tirofiban Abciximab 7.5% 6.0%