Relative Risk Therapy A Better Therapy B Better COMPASS 95% CI no worse than 1.5 TARGET 95% CI no worse than 1.47 ASSENT REPLACE 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 = hazard ratio
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:
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:
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:
COBALT: Results D-B (%) Accel. (%) Absol Diff (95% CI) DB Better Accel Better 30 Day Mortality Absolute Event difference N Engl J Med 1997;337:
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
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
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%)
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%
Kaplan-Meier Curve for 30 Day Mortality rt-PATNK-tPA Days to Death
30-Day Mortality: Absolute Difference 1. Primary Analysis (Adjusted Rate) 2. Secondary Analysis (Unadjusted Rate) 3. Logistic Regression TNK-tPA % rt-PA % Absolute Difference (90% CI) 0.02 (-0.56,0.60) (-0.62,0.59) (-0.62,0.52) P-value for equivalence TNK-tPA better rt-PA better 10
30-Day Mortality: Relative Risk 1. Primary Analysis (Adjusted Rate) 2. Secondary Analysis (Unadjusted Rate) 3. Logistic Regression TNK-tPA % rt-PA % 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 TNK-tPA better rt-PA better
n-PA (%) t-PA (%) RelativeRisk (95% CI) n-PA Better t-PA Better P Value for Equivalence Death InTIME-2: n-PA and t-PA Equivalent for 30-Day Mortality InTIME-II Investigators. Eur Heart J 2000;21:
110 +1 n-PA (%) t-PA (%) Absolute Difference (95% CI) n-PA Better t-PA Better P Value for Equivalence Death ( .068, 1.0) InTIME-2: n-PA and t-PA Equivalent for 30- Day Mortality Giugliano RP, et al. Circulation. 1999;100:I-651.
1 r-PA (%) t-PA (%) Absolute Difference (95% CI) r-PA Better t-PA Better P Value for Equivalence Death 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:
0 +1 Mortality (%) Absolute Difference (95% CI) T-PA BetterBetter P Value for Equivalence InTIME 0.17 ( 1.0, 0.68) ASSENT ( 0.59, 0.62) GUSTO-III 0.23 ( 1.11, 0.66) NS Comparison Among Equivalency Analyses for 30-Day Mortality ASSENT-2 Investigators. Lancet. 1999;354: ; Adapted from GUSTO-III Investigators. N Engl J Med. 1997;337: Adapted from Giugliano RP, et al. Circulation. 1999;100:I-651. n-PA TNK-tPA r-PA Other t-PA t-PA t-PA
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) rt-PA (n=8,488) 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
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
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
Enox (%) Hep (%) HazardRatio (95% CI) Enox Better Hep Better D/MI/RI Blazing M. presented ACC Primary Endpoint at 7 days Death, MI and Refractory Ischemia
Primary Endpoint * * 30 day Death, MI, Urgent TVR Upper bound of 95% confidence interval = 1.52 Non-inferiority boundary RR = Abciximabbetter Tirofibanbetter Relative Risk Tirofiban Abciximab 7.5% 6.0%