Relative Risk Relative Risk 1.3 1.4 1.5 1.6 1.71.21.11.00.90.8

Therapy A BetterTherapy A Better Therapy B BetterTherapy B Better

COMPASS95% CI no worse than 1.5

TARGET95% CI no worse than 1.47

ASSENT-21.14

REPLACE 21.18

PROVE-IT1.17*

Criteria for Clinical EquivalenceCriteria for Clinical Equivalencein ACS Trialsin 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

INJECT: r-PA vs. StreptokinaseINJECT: 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.

COBALT: double bolus vs. accelerated COBALT: double bolus vs. accelerated t-PAt-PA

COBALT definition for double-bolus t-PA to be considered COBALT definition for double-bolus t-PA to be considered equivalent to an accelerated t-PA: equivalent to an accelerated t-PA:

the upper limit of the one-sided 95 percent confidence the upper limit of the one-sided 95 percent confidence interval of the difference in 30-day mortality could not interval of the difference in 30-day mortality could not exceed an absolute difference of 0.4 percent; exceed an absolute difference of 0.4 percent;

This difference corresponds to the lower 95 percent This difference corresponds to the lower 95 percent confidence limit of the absolute difference in 30-day confidence limit of the absolute difference in 30-day mortality between an accelerated infusion of alteplase and mortality between an accelerated infusion of alteplase and streptokinase in the GUSTO I trial. streptokinase in the GUSTO I trial.

The COBALT investigators asserted that if equivalence The COBALT investigators asserted that if equivalence based on this criterion could be demonstrated, one might based on this criterion could be demonstrated, one might infer that double-bolus alteplase is superior to infer that double-bolus alteplase is superior to streptokinase. streptokinase.

N Engl J Med 1997;337:1124-1130 N Engl J Med 1997;337:1124-1130

COBALT: ResultsCOBALT: Results

COBALT randomized 7169 patients.COBALT randomized 7169 patients.

30-day mortality rates: 30-day mortality rates: 7.98 percent in the double-bolus t-PA7.98 percent in the double-bolus t-PA 7.53 percent in the accelerated t-PA, an unfavorable 7.53 percent in the accelerated t-PA, an unfavorable

absolute difference of 0.44 percent. absolute difference of 0.44 percent. Because the one-sided 95 percent confidence limit for Because the one-sided 95 percent confidence limit for

the difference in mortality rates exceeded the the difference in mortality rates exceeded the prespecified limit, the authors concluded that double-prespecified limit, the authors concluded that double-bolus alteplase had not been shown to be equivalent to bolus alteplase had not been shown to be equivalent to an accelerated infusion of alteplase.an accelerated infusion of alteplase.

N Engl J Med 1997;337:1124-1130 N Engl J Med 1997;337:1124-1130

COBALT: ResultsCOBALT: Results

0.40.4 00 0.40.4

D-BD-B(%)(%)

Accel.Accel.(%)(%)

AbsolAbsolDiffDiff

(95% CI)(95% CI)DBDB

BetterBetterAccelAccelBetterBetter

30 Day30 DayMortalityMortality

7.987.98 7.537.53 -0.44-0.44

Absolute Event differenceAbsolute Event difference

N Engl J Med 1997;337:1124-1130 N Engl J Med 1997;337:1124-1130

TNK-tPA: Phase III study: ASSENT-2TNK-tPA: Phase III study: ASSENT-2

ASSENT-2 Protocol DesignASSENT-2 Protocol Design

ST-Segment Elevation MI ST-Segment Elevation MI < < 6 h6 h

ASAASA Heparin (aPTT 50-75s)Heparin (aPTT 50-75s)

1:1 (double-blind)1:1 (double-blind)TNK-tPATNK-tPA

single bolussingle bolusweight-adjustedweight-adjusted

Accel tPAAccel tPA<<100 mg/90 min100 mg/90 min

Primary endpointPrimary endpointAll Cause Mortality (30 days)All Cause Mortality (30 days) n=16,500 ptsn=16,500 pts

Primary EndpointPrimary EndpointNull and Alternative HypothesesNull and Alternative Hypotheses

Primary Endpoint: 30 Day Mortality (All Causes)Primary Endpoint: 30 Day Mortality (All Causes)

Null and Alternative HypothesesNull and Alternative Hypotheses

HH00: m: mTNK-tPA TNK-tPA - m- mtPA tPA > 1%> 1%

HH11: m: mTNK-tPA TNK-tPA - m- mtPA tPA 1% 1%

vsvs

HH00: m: mTNK-tPA TNK-tPA / m/ mtPA tPA > 1.14> 1.14

HH11: m: mTNK-tPA TNK-tPA / m/ mtPA tPA 1.14 1.14

vsvsoror

Absolute DifferenceAbsolute Difference Relative RiskRelative Risk

Null Hypotheses:Null Hypotheses:Absolute vs Relative Mortality DifferenceAbsolute vs Relative Mortality Difference

If 30 Day Mortality t-PA = 10%If 30 Day Mortality t-PA = 10%upper 90% boundary for equivalence = 11%upper 90% boundary for equivalence = 11%(10% + 1%)(10% + 1%)

If 30 Day Mortality t-PA = 5%If 30 Day Mortality t-PA = 5%upper 90% boundary for equivalence = 5.7%upper 90% boundary for equivalence = 5.7%(5% + 14% of 5%)(5% + 14% of 5%)

Sample SizeSample Size

Assumptions:Assumptions:– 30-Day Mortality After rt-PA = 7.2%30-Day Mortality After rt-PA = 7.2%– Equal Mortality After TNK-tPAEqual Mortality After TNK-tPA

Sample sizeSample size of 16,500 randomized and treated patients of 16,500 randomized and treated patients provides 80% power to reject null hypothesis at a one-provides 80% power to reject null hypothesis at a one-sided significance level of 5%sided significance level of 5%

Kaplan-Meier Curve for 30 Day MortalityKaplan-Meier Curve for 30 Day Mortality

rt-PA TNK-tPA

Days to Death

30-Day Mortality: Absolute Difference30-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

AbsoluteDifference(90% CI)

0.02(-0.56,0.60)

-0.02(-0.62,0.59)

-0.05(-0.62,0.52)

P-valuefor

equivalence

0.006

0.006

0.003

TNK-tPAbetter

rt-PAbetter

-1 10

30-Day Mortality: Relative Risk30-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

RelativeRisk

(90% CI)

1.00(0.91,1.10)

1.00(0.90,1.10)

0.99(0.90,1.09)

P-valuefor

equivalence

0.027

0.026

0.015

TNK-tPAbetter

rt-PAbetter

0.88 1.141

11 1.1471.147

n-PAn-PA(%)(%)

t-PAt-PA(%)(%)

RelativeRelativeRiskRisk

(95% CI)(95% CI)n-PAn-PABetterBetter

t-PAt-PABetterBetter

PP Value for Value forEquivalenceEquivalence

DeathDeath 6.756.75 6.66.6 1.021.021.1431.143

0.0470.047

InTIME-2: n-PA and t-PA Equivalent for InTIME-2: n-PA and t-PA Equivalent for 30-Day Mortality 30-Day Mortality

InTIME-II Investigators. Eur Heart J 2000;21:2005-13.

1 0 +1

n-PAn-PA(%)(%)

t-PAt-PA(%)(%)

AbsoluteAbsoluteDifferenceDifference(95% CI)(95% CI)

n-PAn-PABetterBetter

t-PAt-PABetterBetter

PP Value for Value forEquivalenceEquivalence

Death 6.77 6.60 .17(.068, 1.0)

0.047

InTIME-2: n-PA and t-PA Equivalent for InTIME-2: n-PA and t-PA Equivalent for 30-Day Mortality 30-Day Mortality

Giugliano RP, et al. Circulation. 1999;100:I-651.

1 0 +1

r-PAr-PA(%)(%)

t-PAt-PA(%)(%)

AbsoluteAbsoluteDifferenceDifference(95% CI)(95% CI)

r-PAr-PABetterBetter

t-PAt-PABetterBetter

PP Value for Value forEquivalenceEquivalence

Death 7.47 7.24 0.23(1.11, 0.66) P=NS

GUSTO-III: r-PA and t-PA Not GUSTO-III: r-PA and t-PA Not Equivalent for 30-Day Mortality Equivalent for 30-Day Mortality

Adapted from GUSTO-III Investigators. N Engl J Med. 1997;337:1118-1123.

-1 0 +1

MortalityMortality(%)(%)

AbsoluteAbsoluteDifferenceDifference(95% CI)(95% CI)

T-PAT-PABetterBetter BetterBetter

PP Value for Value forEquivalenceEquivalence

InTIME-2 6.77 6.600.17

(1.0, 0.68) 0.047

ASSENT-2 6.16 6.180.02

(0.59, 0.62) 0.006

GUSTO-III7.47 7.24

0.23(1.11, 0.66) NS

Comparison Among Equivalency Comparison Among Equivalency Analyses for 30-Day Mortality 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-PAn-PA

TNK-tPATNK-tPA

r-PAr-PA

OtherOther

t-PAt-PA

t-PAt-PA

t-PAt-PA

Net Clinical BenefitNet Clinical Benefit

Death or Non-FatalStroke at 30 Days (%)Death or Non-FatalICH (%)Death or Non-FatalDisabling Stroke (%)Death or Non-FatalDisabling 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

ASSENT 2: ConclusionsASSENT 2: Conclusions

The Primary Objective of ASSENT-2 Has Been Achieved: The Primary Objective of ASSENT-2 Has Been Achieved: Demonstration That Single Bolus TNK-tPA is Equivalent to Demonstration That Single Bolus TNK-tPA is Equivalent to Accelerated rt-PA in Reducing 30-Day Mortality. Accelerated rt-PA in Reducing 30-Day Mortality.

Stringent Criteria for Equivalence Stringent Criteria for Equivalence Mortality Rates Virtually IdenticalMortality Rates Virtually Identical

Study DesignStudy Design

A PhaseA Phase(open-label)(open-label) Z PhaseZ Phase**

(double-blind)(double-blind)

AdmissionAdmission

UAP/UAP/NSTE-MINSTE-MI

UnfractionatedUnfractionatedheparinheparin

TirofibanTirofiban(48 to 108 hours)(48 to 108 hours)

EnoxaparinEnoxaparin

RandomizedRandomizedDiet andDiet andplaceboplacebo

4 months4 months

1 month1 monthSimvastatin Simvastatin

40 mg40 mgStabilizedStabilized****

Simvastatin Simvastatin 80 mg80 mg

Simvastatin Simvastatin 20 mg20 mg

STE-MISTE-MIOptimal treatmentOptimal treatment

0.880.88 11 1.1441.144

EnoxEnox(%)(%)

HepHep(%)(%)

HazardHazardRatioRatio

(95% CI)(95% CI)EnoxEnoxBetterBetter

HepHepBetterBetter

D/MI/RID/MI/RI 8.48.4 9.49.4 0.880.881.051.05

Blazing M. presented ACC 2003.

PrimaryPrimary Endpoint at 7 days Endpoint at 7 days Death, MI and Refractory IschemiaDeath, MI and Refractory Ischemia

Primary Endpoint *Primary Endpoint *

* 30 day Death, MI, Urgent TVR* 30 day Death, MI, Urgent TVR

Upper bound ofUpper bound of 95% confidence 95% confidence interval = 1.52 interval = 1.52

Non-inferiorityNon-inferiority boundary boundary

RR = 1.26RR = 1.26

1.471.471.001.00

AbciximabAbciximabbetterbetter

TirofibanTirofibanbetterbetter

Relative RiskRelative Risk

TirofibanTirofiban AbciximabAbciximab

7.5% 7.5% 6.0%6.0%