Relative Risk 1.31.41.51.61.71.21.11.00.90.8 Therapy A Better Therapy B Better COMPASS 95% CI no...
-
Upload
philippa-ford -
Category
Documents
-
view
224 -
download
0
description
Transcript of Relative Risk 1.31.41.51.61.71.21.11.00.90.8 Therapy A Better Therapy B Better COMPASS 95% CI no...
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%