Gibson CM. Ann Intern Med. 1999;130:841-847. Characteristics of the Ideal Fibrinolytic Agent Longer half-life/single-bolus administration Increased fibrin

Gibson CM. Ann Intern Med. 1999;130:841-847. Gibson CM. Ann Intern Med. 1999;130:841-847.

Characteristics of the Ideal Fibrinolytic AgentCharacteristics of the Ideal Fibrinolytic AgentCharacteristics of the Ideal Fibrinolytic AgentCharacteristics of the Ideal Fibrinolytic Agent

•Longer half-life/single-bolus administration•Increased fibrin specificity/decreased bleeding and ICH•More rapid and consistent achievement of TIMI grade 3 flow•No effect on blood pressure•No antigenicity•Lower reocclusion rates•Greater resistance to PAI-1•Compatible with other intravenous agents•Low cost

•Longer half-life/single-bolus administration•Increased fibrin specificity/decreased bleeding and ICH•More rapid and consistent achievement of TIMI grade 3 flow•No effect on blood pressure•No antigenicity•Lower reocclusion rates•Greater resistance to PAI-1•Compatible with other intravenous agents•Low cost

Fibrin SpecificityFibrin Specificity

Molecular Structures of FibrinolyticsMolecular Structures of FibrinolyticsMolecular Structures of FibrinolyticsMolecular Structures of Fibrinolytics

TNK-tPATNK-tPAt-PAt-PAr-PA / n-PAr-PA / n-PASKSK

TNK t-PA (tenecteplase) r-PA (reteplase)

t-PA (alteplase) n-PA (lanoteplase)

TenecteplaseTenecteplaseTenecteplaseTenecteplase(TNK-tPA)(TNK-tPA)(TNK-tPA)(TNK-tPA)

LanoteplaseLanoteplaseLanoteplaseLanoteplase(n-PA)(n-PA)(n-PA)(n-PA) StaphylokinaseStaphylokinaseStaphylokinaseStaphylokinase SaruplaseSaruplaseSaruplaseSaruplase

Half-life (minutes)Half-life (minutes) 2020 3737 66 99

DosingDosing Single bolusSingle bolus Single bolusSingle bolus 2 boluses2 boluses30 min apart30 min apart

Bolus + 60-Bolus + 60-min infusionmin infusion

Provides patient-

specific weight- based dosing

Provides patient-

specific weight- based dosing

YesYes YesYes ???? ????

Fibrin specificityFibrin specificity ++++++ ++ ++++++ ++

PAI-1 resistancePAI-1 resistance IncreasedIncreased ???? ???? ????

AntigenicAntigenic NoNo NoNo YesYes YesYes

PlasminogenPlasminogenactivationactivation

DirectDirect DirectDirect IndirectIndirect DirectDirect

Fibrinolytics in Development: Comparative OverviewFibrinolytics in Development: Comparative OverviewFibrinolytics in Development: Comparative OverviewFibrinolytics in Development: Comparative Overview

TNK-tPA: Molecular and Biochemical PropertiesTNK-tPA: Molecular and Biochemical PropertiesTNK-tPA: Molecular and Biochemical PropertiesTNK-tPA: Molecular and Biochemical Properties

K Domain

Ala-Ala-Ala-Ala for Lys-His-Arg at 296-299:More resistant to PAI 1, enzyme which breaks down lytic agents

K Domain

Ala-Ala-Ala-Ala for Lys-His-Arg at 296-299:More resistant to PAI 1, enzyme which breaks down lytic agents

NH2NH2 HOOCHOOC

EGFEGF

FingerFinger

Kringle 1Kringle 1Kringle 2Kringle 2

T Domain Asn for Thr at

103: Reduces clearance; single bolus

T Domain Asn for Thr at

103: Reduces clearance; single bolus

N Domain Gln for Asn at 117 : Increased fibrin specificityN Domain Gln for Asn at 117 : Increased fibrin specificity

63

19

55

22

63

16

66

22

0102030405060708090

100

t-PA TNK-tPA 30mg TNK-tPA 40mg TNK-tPA 50mg

TIMI grade 2

TIMI grade 3

63

19

55

22

63

16

66

22

0102030405060708090

100

t-PA TNK-tPA 30mg TNK-tPA 40mg TNK-tPA 50mg

TIMI grade 2

TIMI grade 3

n=312n=312 n=304n=304 n=146n=146 n=76n=76*P=0.047, TNK-tPA 30 mg vs t-PA; all others, P=NS.*P=0.047, TNK-tPA 30 mg vs t-PA; all others, P=NS.

TIMI-10B: TIMI Grade Flow at 90 MinutesTIMI-10B: TIMI Grade Flow at 90 MinutesTIMI-10B: TIMI Grade Flow at 90 MinutesTIMI-10B: TIMI Grade Flow at 90 MinutesP

erc

en

t o

f P

ati

ents

Pe

rce

nt

of

Pa

tien

ts

Cannon CP, Gibson CM, McCabe CH et al. Circulation. 1998;98:2805-2814.Cannon CP, Gibson CM, McCabe CH et al. Circulation. 1998;98:2805-2814.

0

10

20

30

40

50

60

70

TNK-tPA Dose/Weight (quintiles, mg/kg, mean)

Per

cen

t T

IMI

Gra

de

3 F

low

at

90

Min

ute

s

0

10

20

30

40

50

60

70

TNK-tPA Dose/Weight (quintiles, mg/kg, mean)

Per

cen

t T

IMI

Gra

de

3 F

low

at

90

Min

ute

s

0.20.2 0.30.3 0.40.4 0.50.5 0.60.6 0.70.7

PP=0.028=0.028PP=0.028=0.028


TIMI-10B: TIMI Grade 3 Flow at 90 Minutes by Dose/WeightTIMI-10B: TIMI Grade 3 Flow at 90 Minutes by Dose/WeightTIMI-10B: TIMI Grade 3 Flow at 90 Minutes by Dose/WeightTIMI-10B: TIMI Grade 3 Flow at 90 Minutes by Dose/Weight

No further improvement

In flow above 0.53 mg/kg

No further improvement

In flow above 0.53 mg/kg

3835

31

40

35

31

0

5

10

15

20

25

30

35

40

Culprit All 3 Arteries

3835

31

40

35

31

0

5

10

15

20

25

30

35

40

Culprit All 3 Arteries

Gibson CM, et al. Am J Cardiol. 1999;84:976-980.Gibson CM, et al. Am J Cardiol. 1999;84:976-980.

TIM

I F

ram

e C

ount

TIM

I F

ram

e C

ount

TIMI-10B: Relationship Between TIMI Frame Count & Dose / TIMI-10B: Relationship Between TIMI Frame Count & Dose / WeightWeight

TIMI-10B: Relationship Between TIMI Frame Count & Dose / TIMI-10B: Relationship Between TIMI Frame Count & Dose / WeightWeight

N=166N=166 N=174N=174 N=171N=171 N=104N=104 N=107N=107 N=127N=127

0.52 to

1.24

mg/kg

0.52 to

1.24

mg/kg

0.40 to

0.51

mg/kg

0.40 to

0.51

mg/kg

0.20 to

0.39

mg/kg

0.20 to

0.39

mg/kg

High Dose = 0.52 to 1.24 mg / Kg.

Dose of 0.53 mg / kg selected for ASSENT 2 based upon logistic regression of CTFC

High Dose = 0.52 to 1.24 mg / Kg.

Dose of 0.53 mg / kg selected for ASSENT 2 based upon logistic regression of CTFC

p = 0.007p = 0.007 p = 0.002p = 0.002

LowLow MedMed HighHigh

0.20 to

0.39

mg/kg

0.20 to

0.39

mg/kg

LowLow

0.40 to

0.51

mg/kg

0.40 to

0.51

mg/kg

MedMed

0.52 to

1.24

mg/kg

0.52 to

1.24

mg/kg

HighHigh

Pathophysiology of Improved Flow With Weight Optimized TNK Dosing: Weight Pathophysiology of Improved Flow With Weight Optimized TNK Dosing: Weight Optimizing Reduces Thrombus Burden & Improves Percent StenosisOptimizing Reduces Thrombus Burden & Improves Percent Stenosis

Pathophysiology of Improved Flow With Weight Optimized TNK Dosing: Weight Pathophysiology of Improved Flow With Weight Optimized TNK Dosing: Weight Optimizing Reduces Thrombus Burden & Improves Percent StenosisOptimizing Reduces Thrombus Burden & Improves Percent Stenosis

34.3

2925

0

5

10

15

20

25

30

35

40

Thrombus

34.3

2925

0

5

10

15

20

25

30

35

40

Thrombus

75.7

71.4

69

70

71

72

73

74

75

76

77

% Stenosis

75.7

71.4

69

70

71

72

73

74

75

76

77

% Stenosis


N=166N=166 N=174N=174 N=171N=171%

Ste

no

sis

% S

ten

osi

s

% P

atie

nts

% P

atie

nts

p = 0.06p = 0.06 p = 0.03p = 0.03


LowLow HighHigh

N=173N=173 N=173N=173

29

24

19

0

5

10

15

20

25

30

35

Post PTCA

29

24

19

0

5

10

15

20

25

30

35

Post PTCA


TIM

I F

ram

e C

ount

TIM

I F

ram

e C

ount

TIMI-10B: Weight Optimized Dosing TIMI-10B: Weight Optimized Dosing “Facilitates Adjunctive PCI”“Facilitates Adjunctive PCI”

TIMI-10B: Weight Optimized Dosing TIMI-10B: Weight Optimized Dosing “Facilitates Adjunctive PCI”“Facilitates Adjunctive PCI”

N=46N=46 N=39N=39 N=20N=20

0.52 to

1.24

mg/kg

0.52 to

1.24

mg/kg

0.40 to

0.51

mg/kg

0.40 to

0.51

mg/kg

0.20 to

0.39

mg/kg

0.20 to

0.39

mg/kg

Dose of 0.53 mg / kg selected for ASSENT 2 based upon logistic regression of Frame Count data


p = 0.05p = 0.05


TNK-tPATNK-tPATNK-tPATNK-tPA(n=8,461)(n=8,461)(n=8,461)(n=8,461)

t-PAt-PAt-PAt-PA(n=8,488)(n=8,488)(n=8,488)(n=8,488)

Relative RiskRelative RiskRelative RiskRelative Risk(95% CI)(95% CI)(95% CI)(95% CI) PP Value Value PP Value Value

Total stroke (%)Total stroke (%) 1.781.78 1.661.66 1.071.07(0.856-1.349)(0.856-1.349)

0.5550.555

IntracranialIntracranialhemorrhage (%)hemorrhage (%)

0.930.93 0.940.94 0.9910.991(0.727-1.350)(0.727-1.350)

1.0001.000

IschemiaIschemia 0.720.72 0.640.64 1.131.13(0.787-1.632)(0.787-1.632)

0.5140.514

With hemorrhagicWith hemorrhagicconversion (%)conversion (%)

0.070.07 0.090.09 0.7520.752(0.261-2.168)(0.261-2.168)

0.7900.790

Unknown type (%)Unknown type (%) 0.130.13 0.080.08 1.5761.576(0.611-4.065)(0.611-4.065)

0.3580.358

ASSENT-2 Investigators. Lancet. 1999;354:716-722.ASSENT-2 Investigators. Lancet. 1999;354:716-722.

ASSENT-2: Similar Incidence of Stroke for TNK-tPA and t-PAASSENT-2: Similar Incidence of Stroke for TNK-tPA and t-PAASSENT-2: Similar Incidence of Stroke for TNK-tPA and t-PAASSENT-2: Similar Incidence of Stroke for TNK-tPA and t-PA

Confusion in Reperfusion:Confusion in Reperfusion:The “Old Old” (>75 yrs)The “Old Old” (>75 yrs)

Confusion in Reperfusion:Confusion in Reperfusion:The “Old Old” (>75 yrs)The “Old Old” (>75 yrs)

• Highest risk for complications, but potentially have the most to gain from treatment

• Understudied in randomized trials, but now over 1/3 rd of MIs are > 75 years

• Heterogeneous group, multiple risk factors at play, potential for interactions

• Tend to present late

• Highest risk for complications, but potentially have the most to gain from treatment

• Understudied in randomized trials, but now over 1/3 rd of MIs are > 75 years

• Heterogeneous group, multiple risk factors at play, potential for interactions

• Tend to present late

CM Gibson, GW symposium, AHA 2000CM Gibson, GW symposium, AHA 2000

ICH Risk is Eight Time Higher in Elderly Females following t-PA

ICH Risk is Eight Time Higher in Elderly Females following t-PA

Gurwitz et al. 1998 Annals Int Med. 129; 597-604.

0

2

4

6

8

10

12

M<65 F<65 M 65-74 F 65-74 M>75 F>75

Ad

just

ed O

R

Unadjusted Dose Rises Rapidly in People of Low Unadjusted Dose Rises Rapidly in People of Low Body WeightBody Weight

Unadjusted Dose Rises Rapidly in People of Low Unadjusted Dose Rises Rapidly in People of Low Body WeightBody Weight

0

0.5

1

1.5

2

2.5

3

20 30 40 50 60 70 80 90 100 110

Weight (kg)

Do

se (

mg

/kg

)

tPA

Fixed dose

TNK


New Answers to the Old Old QuestionNew Answers to the Old Old QuestionNew Answers to the Old Old QuestionNew Answers to the Old Old Question

•How might weight optimized dosing of TNK favorably alter outcomes in this very high risk group of low body weight women over 75 years of age?

•How might weight optimized dosing of TNK favorably alter outcomes in this very high risk group of low body weight women over 75 years of age?

CM Gibson, 2000CM Gibson, 2000

Weight Optimizing Reduces ICH Rates : ASSENT IIWeight Optimizing Reduces ICH Rates : ASSENT II

1.72

2.62

1.77 1.78

1.44 1.41

0

0.5

1

1.5

2

2.5

3

>75 Female <67kg

TNKTNK TNKTNK TNKTNKtPAtPA tPAtPAtPAtPA

% o

f P

atie

nts

P=0.18

H Barron AHA 1999; Circulation 1999; 100: I-1H Barron AHA 1999; Circulation 1999; 100: I-1

ICH Rates Among Women > 75 Years who are < 67 Kg in ASSENT IIICH Rates Among Women > 75 Years who are < 67 Kg in ASSENT IIICH Rates Among Women > 75 Years who are < 67 Kg in ASSENT IIICH Rates Among Women > 75 Years who are < 67 Kg in ASSENT II

1.14

3.02

Pat

ien

ts (

%)

TNK-tPATNK-tPA tPAtPA

P <0.05

Weight Optimizing Reduces ICH Rates : ASSENT IIWeight Optimizing Reduces ICH Rates : ASSENT II


AgeAge

WeightWeight Diastolic Diastolic Blood Pressure Blood Pressure HypertensionHypertension TNK Treatment by TNK Treatment by high-risk females*high-risk females*

AgeAge

WeightWeight Diastolic Diastolic Blood Pressure Blood Pressure HypertensionHypertension TNK Treatment by TNK Treatment by high-risk females*high-risk females*

Odds RatioOdds Ratio

1.7881.788

0.7600.760

1.0241.024

1.5131.513

0.3000.300

Odds RatioOdds Ratio

1.7881.788

0.7600.760

1.0241.024

1.5131.513

0.3000.300

95% Confidence Ratio95% Confidence Ratio

(1.529, 2.091)(1.529, 2.091)

(0.668, 0.864)(0.668, 0.864)

(1.013, 1.036)(1.013, 1.036)

(1.096, 2.088)(1.096, 2.088)

(0.092, 0.977)(0.092, 0.977)

95% Confidence Ratio95% Confidence Ratio

(1.529, 2.091)(1.529, 2.091)

(0.668, 0.864)(0.668, 0.864)

(1.013, 1.036)(1.013, 1.036)

(1.096, 2.088)(1.096, 2.088)

(0.092, 0.977)(0.092, 0.977)

* Females >75 years and <67 kgs

Weight Optimizing Reduces ICH Rates : ASSENT II Multivariate ModelMultivariate Model

Weight Optimizing Reduces ICH Rates : ASSENT II Multivariate ModelMultivariate Model


Weight Optimizing TNK Reduces the ICH Risk Among Weight Optimizing TNK Reduces the ICH Risk Among High Risk PatientsHigh Risk Patients

Weight Optimizing TNK Reduces the ICH Risk Among Weight Optimizing TNK Reduces the ICH Risk Among High Risk PatientsHigh Risk Patients

•In women > 75 years of age and < 67 kg weight optimizing TNK reduces the risk of ICH by 70% compared with t-PA

•In women > 75 years of age and < 67 kg weight optimizing TNK reduces the risk of ICH by 70% compared with t-PA


70

81 82

6466

6870

7274

7678

8082

84

Open by 60 Min.

70

81 82

6466

6870

7274

7678

8082

84

Open by 60 Min.


% o

f P

atie

nts

% o

f P

atie

nts

N=177N=177 N=178N=178 N=174N=174



p = 0.02 vs low dosep = 0.02 vs low dose

LowLow

MedMed HighHigh

Weight Optimized Dosing of TNK Improves Rate of Opening by 60 MinutesWeight Optimized Dosing of TNK Improves Rate of Opening by 60 MinutesWeight Optimized Dosing of TNK Improves Rate of Opening by 60 MinutesWeight Optimized Dosing of TNK Improves Rate of Opening by 60 Minutes

Weight Optimized Dosing of TNK Improves Weight Optimized Dosing of TNK Improves Microvascular FunctionMicrovascular Function

Weight Optimized Dosing of TNK Improves Weight Optimized Dosing of TNK Improves Microvascular FunctionMicrovascular Function

• Improved flow in all 3 arteries (even in those without a stenosis)

• In a multivariate model correcting for % stenosis, thrombus & early opening by 60 minutes, weight optimized dose group was 5 frames faster

• Following relief of the stenosis by PCI, weight optimized dose arm was faster

• Improved flow in all 3 arteries (even in those without a stenosis)

• In a multivariate model correcting for % stenosis, thrombus & early opening by 60 minutes, weight optimized dose group was 5 frames faster

• Following relief of the stenosis by PCI, weight optimized dose arm was faster

Gibson CM, et al. Am J Cardiol. 1999; 84:976-980.Gibson CM, et al. Am J Cardiol. 1999; 84:976-980.

t-PA-accelerated regimen(weight-adjusted)

t-PA-accelerated regimen(weight-adjusted)

TNK-tPA single bolus (weight-adjusted)

TNK-tPA single bolus (weight-adjusted)

Adapted from ASSENT-2 Investigators. Lancet. 1999;354:716-722.

Patients with AMI and ST-segment elevation, Patients with AMI and ST-segment elevation, symptom onset symptom onset 6 h (n = 16,950; 6 h (n = 16,950;

1,021 hospitals)1,021 hospitals)

Patients with AMI and ST-segment elevation, Patients with AMI and ST-segment elevation, symptom onset symptom onset 6 h (n = 16,950; 6 h (n = 16,950;

1,021 hospitals)1,021 hospitals)

Objective: demonstrate “equivalence”Objective: demonstrate “equivalence”Objective: demonstrate “equivalence”Objective: demonstrate “equivalence”

Primary endpoint: all-cause 30-day mortalityPrimary endpoint: all-cause 30-day mortalityPrimary endpoint: all-cause 30-day mortalityPrimary endpoint: all-cause 30-day mortality

Aspirin (150-325 mg)Aspirin (150-325 mg)IV heparinIV heparin

>67 kg: 5000-U bolus, 1000 U/h>67 kg: 5000-U bolus, 1000 U/h<67 kg: 4000-U bolus, 800 U/h<67 kg: 4000-U bolus, 800 U/h

Aspirin (150-325 mg)Aspirin (150-325 mg)IV heparinIV heparin

>67 kg: 5000-U bolus, 1000 U/h>67 kg: 5000-U bolus, 1000 U/h<67 kg: 4000-U bolus, 800 U/h<67 kg: 4000-U bolus, 800 U/h

RandomizationRandomizationRandomizationRandomization

ASSENT-2 Trial DesignASSENT-2 Trial DesignASSENT-2 Trial DesignASSENT-2 Trial Design

Superiority: Does the 95% CI contain zero?Superiority: Does the 95% CI contain zero?

Equivalence: Does the 95% CI lie between 1% and +1%?Equivalence: Does the 95% CI lie between 1% and +1%?

1%1%1%1% 0%0%0%0% +1%+1%+1%+1%

1%1%1%1% 0%0%0%0% +1%+1%+1%+1%

To left of To left of 1%1%is clinicallyis clinicallymeaningfulmeaningful

To left of To left of 1%1%is clinicallyis clinicallymeaningfulmeaningful

Between Between 1% and +1%1% and +1%is not clinicallyis not clinically

meaningfulmeaningful

Between Between 1% and +1%1% and +1%is not clinicallyis not clinically

meaningfulmeaningful

To right of To right of 1%1%is clinicallyis clinicallymeaningfulmeaningful

To right of To right of 1%1%is clinicallyis clinicallymeaningfulmeaningful

Understanding EquivalenceUnderstanding EquivalenceUnderstanding EquivalenceUnderstanding Equivalence

CM Gibson, 2000CM Gibson, 2000

-1 0 +1

MortalityMortality(%)(%)

AbsoluteAbsoluteDifferenceDifference(95% CI)(95% CI)

OtherOtherBetterBetter BetterBetter

PP Value for Value forEquivalenceEquivalence

InTIME-26.77 6.60

0.17(1.0, 0.68)

0.047

ASSENT-26.16 6.18

0.02(0.59, 0.62) 0.006

GUSTO-III7.47 7.24

0.23(1.11, 0.66)

NS

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

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

t-PAt-PA

t-PAt-PA

t-PAt-PA

t-PAt-PA

Major Trials Comparing 30- or 35-Day Mortality Major Trials Comparing 30- or 35-Day Mortality Among Fibrinolytics Among Fibrinolytics

Major Trials Comparing 30- or 35-Day Mortality Major Trials Comparing 30- or 35-Day Mortality Among Fibrinolytics Among Fibrinolytics

12

9.2

7.4

6.37.2 7.5

9.59

6.6 6.776.15 6.17

0

2

4

6

8

10

12

ISIS-2 GUSTO-I GUSTO-III INJECT InTIME-2 ASSENT- 2

12

9.2

7.4

6.37.2 7.5

9.59

6.6 6.776.15 6.17

0

2

4

6

8

10

12

ISIS-2 GUSTO-I GUSTO-III INJECT InTIME-2 ASSENT- 2

SKSK SK t-PA SK t-PA SK r-PASK r-PAt-PA r-PAt-PA r-PA t-PA n-PA t-PA n-PAAgentsAgents

**

P=NSP=NS P=NSP=NS P=0.0003P=0.0003 P=0.006P=0.006

Mo

rta

lity

%M

ort

alit

y %

TNK -tPA

TNK -tPA PlaceboPlacebo t-PA t-PA

P=NSP=NS P=0.047P=0.0472P<0.000012P<0.00001 P=NSP=NS P=NSP=NSP=0.001P=0.001 P=NSP=NS

*Lower majorbleeds for TNK-tPA

(4.7% vs 5.9%; P=0.0002).

*Lower majorbleeds for TNK-tPA

(4.7% vs 5.9%; P=0.0002).

Equivalency:Equivalency:P=NSP=NS

Equivalency DemonstratedEquivalency

DemonstratedSuperiority

DemonstratedSuperiority

Demonstrated

Superiority:Superiority:

*Higher ICHrate for n-PA

(0.62% vs 1.13%;P=0.003).

*Higher ICHrate for n-PA

(0.62% vs 1.13%;P=0.003).CM Gibson, 2000CM Gibson, 2000

Age (years)Age (years)

<75<75

>75>75

4.6 4.6

17.417.4

4.3 4.3

19.319.3

1.063 (0.915-1.235)1.063 (0.915-1.235)

0.903 (0.754-1.081)0.903 (0.754-1.081)

0.4250.425

0.2860.286

SexSex

MaleMale

FemaleFemale

5.0 5.0

10.010.0

4.84.8

10.610.6

1.039 (0.894-1.209)1.039 (0.894-1.209)

0.943 (0.784-1.134)0.943 (0.784-1.134)

0.6270.627

0.5630.563

ASSENT-2: 30-Day Mortality By Age and SexASSENT-2: 30-Day Mortality By Age and SexASSENT-2: 30-Day Mortality By Age and SexASSENT-2: 30-Day Mortality By Age and Sex


t-PAt-PAt-PAt-PA(n=8,488)(n=8,488)(n=8,488)(n=8,488)

Relative RiskRelative RiskRelative RiskRelative Risk(95% CI)(95% CI)(95% CI)(95% CI) ValueValue ValueValuePPPP


Infarct locationInfarct location

AnteriorAnteriorOtherOther

8.08.05.05.0

8.28.24.84.8

0.975 (0.830-1.146)0.975 (0.830-1.146)1.026 (0.865-1.218)1.026 (0.865-1.218)

0.7890.7890.7830.783

Previous AMIPrevious AMI

YesYesNoNo

9.89.8

5.55.58.68.6

5.75.7

1.137 (0.897-1.441)1.137 (0.897-1.441)

0.965 (0.843-1.105)0.965 (0.843-1.105)

0.3180.318

0.6090.609

Previous CABGPrevious CABG

YesYesNoNo

9.89.86.06.0

7.77.76.16.1

1.280 (0.776-2.111)1.280 (0.776-2.111)0.987 (0.875-1.115)0.987 (0.875-1.115)

0.4060.4060.8440.844


ASSENT-2: 30-Day Mortality By Infarct Location, Previous AMI, or Previous CABG; ASSENT-2: 30-Day Mortality By Infarct Location, Previous AMI, or Previous CABG; Killip Class; and History of Hypertension or DiabetesKillip Class; and History of Hypertension or Diabetes

ASSENT-2: 30-Day Mortality By Infarct Location, Previous AMI, or Previous CABG; ASSENT-2: 30-Day Mortality By Infarct Location, Previous AMI, or Previous CABG; Killip Class; and History of Hypertension or DiabetesKillip Class; and History of Hypertension or Diabetes

TNK-tPATNK-tPA(n=8,461)(n=8,461)TNK-tPATNK-tPA(n=8,461)(n=8,461)

t-PAt-PA(n=8,488)(n=8,488)

t-PAt-PA(n=8,488)(n=8,488)

Relative RiskRelative Risk(95% CI)(95% CI)

Relative RiskRelative Risk(95% CI)(95% CI) PP Value Value PP Value Value

IIIIIIIIIIIIIVIV

4.74.713.513.529.029.051.451.4

4.84.813.413.424.524.561.161.1

0.983 (0.851-1.134)0.983 (0.851-1.134)1.011 (0.797-1.281)1.011 (0.797-1.281)1.185 (0.740-1.899)1.185 (0.740-1.899)0.842 (0.556-1.273)0.842 (0.556-1.273)

0.8180.8180.9440.9440.5160.5160.4770.477

HypertensionHypertension

YesYesNoNo

8.08.0

5.05.07.67.6

5.25.21.050 (0.888-1.241)1.050 (0.888-1.241)

0.962 (0.816-1.135)0.962 (0.816-1.135)0.5780.578

0.6570.657

DiabetesDiabetes

YesYesNoNo

8.88.8

5.65.68.78.7

5.75.71.002 (0.786-1.278)1.002 (0.786-1.278)

0.993 (0.868-1.136)0.993 (0.868-1.136)1.0001.000

0.9420.942

Killip ClassKillip Class

TNK-tPATNK-tPA(n=8,461)(n=8,461)

t-PAt-PA(n=8,488)(n=8,488)

Relative RiskRelative Risk(95% CI)(95% CI)

TNK-tPATNK-tPABetterBetter

t-PAt-PABetterBetter

PP Value Value

Total population (%) 6.16 6.18 1.00

(0.89, 1.12) 0.975

Time to therapy (h)

0-2 (%) 5.0 4.9 1.017(0.799 - 1.296) 0.897

>2-4 (%) 6.3 5.51.157

(0.970, 1.379)0.106

>4 (%) 7.0 9.2 0.766(0.617. 0.952) 0.018

0.40.4 11 1.41.4ASSENT-2 Investigators. Lancet. 1999;354:716-722.

ASSENT-2: Improved Survival forASSENT-2: Improved Survival forTNK-tPA in Late-Treated PatientsTNK-tPA in Late-Treated PatientsASSENT-2: Improved Survival forASSENT-2: Improved Survival forTNK-tPA in Late-Treated PatientsTNK-tPA in Late-Treated Patients


Pe

rce

nt

Ch

an

ge

s in

Pa

ram

ete

rs(m

edia

n)

Pe

rce

nt

Ch

an

ge

s in

Pa

ram

ete

rs(m

edia

n)

TIMI-10B: Clinical Evidence of Increased Fibrin Specificity in TIMI-10B: Clinical Evidence of Increased Fibrin Specificity in TNK-tPA TNK-tPA

TIMI-10B: Clinical Evidence of Increased Fibrin Specificity in TIMI-10B: Clinical Evidence of Increased Fibrin Specificity in TNK-tPA TNK-tPA

-50

-40

-30

-20

-10

0

0 3 6

-50

-40

-30

-20

-10

0

0 3 6

AA

AAAA

50505050

5050

3030

3030

3030

4040

40404040

-60

-50

-40

-30

-20

-10

0

0 3 6

-60

-50

-40

-30

-20

-10

0

0 3 6

AA AAAA

50505050

5050

3030 3030 3030

40404040

4040

11 11

Hours Post-DoseHours Post-DoseHours Post-DoseHours Post-Dose

FibrinogenFibrinogen PlasminogenPlasminogen

TNK-tPATNK-tPA

TNK-tPATNK-tPA

alteplase (t-PA)alteplase (t-PA) alteplase (t-PA)alteplase (t-PA)


t-PAt-PAt-PAt-PA(n=8,488)(n=8,488)(n=8,488)(n=8,488) PP Value ValuePP Value Value

Total bleeds (%)Total bleeds (%) 26.426.4 29.029.0 0.00030.0003

Major bleeds (%)Major bleeds (%) 4.74.7 5.95.9 0.00020.0002

Minor bleeds (%)Minor bleeds (%) 21.821.8 23.023.0 0.05530.0553

Units transfusedUnits transfusedAnyAny

1-2 units1-2 units>2 units>2 units

4.34.32.62.61.71.7

5.55.53.23.22.22.2

0.00020.0002----

ASSENT-2: Significantly Fewer Noncerebral Bleeding Events ASSENT-2: Significantly Fewer Noncerebral Bleeding Events With TNK-tPAWith TNK-tPA

ASSENT-2: Significantly Fewer Noncerebral Bleeding Events ASSENT-2: Significantly Fewer Noncerebral Bleeding Events With TNK-tPAWith TNK-tPA


How Does Weight Optimized Dosing Improve Patient Care?How Does Weight Optimized Dosing Improve Patient Care?How Does Weight Optimized Dosing Improve Patient Care?How Does Weight Optimized Dosing Improve Patient Care?

• Improves efficacy (earlier & better flow, less thrombus, less stenosis & better outcomes) in heavier patients

• Improves safety (lower intracranial hemorrhage) in high risk patients

• Improves efficacy (earlier & better flow, less thrombus, less stenosis & better outcomes) in heavier patients

• Improves safety (lower intracranial hemorrhage) in high risk patients


Why Not Use a Fixed 40 mg Dose in All Patients?

In light patients: These patients receive relatively more drug. Weight optimized dosing may reduce the risk of serious bleeding events and reduce the risk of intracranial hemorrhage rate in lower-weight patients.

In light patients: These patients receive relatively more drug. Weight optimized dosing may reduce the risk of serious bleeding events and reduce the risk of intracranial hemorrhage rate in lower-weight patients.

In heavy patients: These patients receive relatively less drug. Weight optimized dosing may improve rates of TIMI grade 3 flow & TIMI Frame Counts, and thereby lower mortality.

In heavy patients: These patients receive relatively less drug. Weight optimized dosing may improve rates of TIMI grade 3 flow & TIMI Frame Counts, and thereby lower mortality.


Other Acute MI Regimens Use Weight Adjusted DosingOther Acute MI Regimens Use Weight Adjusted DosingOther Acute MI Regimens Use Weight Adjusted DosingOther Acute MI Regimens Use Weight Adjusted Dosing

•Heparin•Reopro•Integrilin•Aggrastat•Low Molecular weight heparinoids•Dopamine, dobutamine•As TNK is combined with heparin &

glycoprotein 2b3a inhibitors, safety & efficacy will hopefully be improved as a result of weight optimized dosing

•Heparin•Reopro•Integrilin•Aggrastat•Low Molecular weight heparinoids•Dopamine, dobutamine•As TNK is combined with heparin &

glycoprotein 2b3a inhibitors, safety & efficacy will hopefully be improved as a result of weight optimized dosing


TNK-tPA Dosing RegimenTNK-tPA Dosing RegimenTNK-tPA Dosing RegimenTNK-tPA Dosing Regimen

Dosing categories are about 22 lb wide– Minimizes the possibility of dosing errors

< 60 kg (< 132 lbs) 6 mL61 - 70 kg (133-154 lbs) 7 mL71 - 80 kg (155-176 lbs) 8 mL81 - 90 kg (177-198 lbs) 9 mL > 90 kg (> 199 lbs) 10 mL

Dosing categories are about 22 lb wide– Minimizes the possibility of dosing errors

< 60 kg (< 132 lbs) 6 mL61 - 70 kg (133-154 lbs) 7 mL71 - 80 kg (155-176 lbs) 8 mL81 - 90 kg (177-198 lbs) 9 mL > 90 kg (> 199 lbs) 10 mL

Confusion in Reperfusion: Dose ErrorsConfusion in Reperfusion: Dose ErrorsConfusion in Reperfusion: Dose ErrorsConfusion in Reperfusion: Dose Errors

• Do dose errors cause death ?

Or

• Does death cause dose errors ?

• Do dose errors cause death ?

Or

• Does death cause dose errors ?


Dosing Errors to be StudiedDosing Errors to be StudiedDosing Errors to be StudiedDosing Errors to be Studied

•Timing of dose– No potential for error with a single bolus agent such as

TNK

•Duration of injection– Little or no real potential for error with a 5 second

administration of TNK

•Compatibility with other drugs– Little potential for error with TNK

•Timing of dose– No potential for error with a single bolus agent such as

TNK

•Duration of injection– Little or no real potential for error with a 5 second

administration of TNK

•Compatibility with other drugs– Little potential for error with TNK


Two Common Questions Asked About the 50 mg Dose of TNKTwo Common Questions Asked About the 50 mg Dose of TNKTwo Common Questions Asked About the 50 mg Dose of TNKTwo Common Questions Asked About the 50 mg Dose of TNK

•Is the 50 mg dose safe? Is there an excess risk of intracranial hemorrhage and bleeding associated with 50 mg?

•Is the 50 mg dose efficacious? Is 50 mg of TNK in heavy patients (I.e. those > 90 Kg) adequate? In other words, are very heavy patients being “under dosed”?

•Is the 50 mg dose safe? Is there an excess risk of intracranial hemorrhage and bleeding associated with 50 mg?

•Is the 50 mg dose efficacious? Is 50 mg of TNK in heavy patients (I.e. those > 90 Kg) adequate? In other words, are very heavy patients being “under dosed”?


•In TIMI 10B, 50 mg of TNK was given to patients of all weights

•In ASSENT 2, 50 mg of TNK was given only to patients weighing over 90 Kg

•In TIMI 10B, 50 mg of TNK was given to patients of all weights

•In ASSENT 2, 50 mg of TNK was given only to patients weighing over 90 Kg

Safety and Efficacy of 50 mg of TNKSafety and Efficacy of 50 mg of TNKSafety and Efficacy of 50 mg of TNKSafety and Efficacy of 50 mg of TNK

Differences Between TIMI 10B and ASSENT 2Differences Between TIMI 10B and ASSENT 2Differences Between TIMI 10B and ASSENT 2Differences Between TIMI 10B and ASSENT 2


<60 kg11%

61-70 kg17%

71-80 kg25%

81-90 kg25%

>90 kg22%

<60 kg11%

61-70 kg17%

71-80 kg25%

81-90 kg25%

>90 kg22%

• In TIMI 10B there were a small number of patients (78) who received 50 mg of TNK, the majority of whom were of lighter weights (under 90 Kg)

• Only 22.4% of pts. in TIMI 10B weighed > 90 Kg, the weight required for therapy with 50 mg of TNK in ASSENT 2 & in clinical practice

• In TIMI 10B there were a small number of patients (78) who received 50 mg of TNK, the majority of whom were of lighter weights (under 90 Kg)

• Only 22.4% of pts. in TIMI 10B weighed > 90 Kg, the weight required for therapy with 50 mg of TNK in ASSENT 2 & in clinical practice

Wide Range of Weights Among Pts. Given 50 mg TNK in TIMI 10BWide Range of Weights Among Pts. Given 50 mg TNK in TIMI 10BWide Range of Weights Among Pts. Given 50 mg TNK in TIMI 10BWide Range of Weights Among Pts. Given 50 mg TNK in TIMI 10B


Differences Between TIMI 10B and ASSENT 2 in Examining the Differences Between TIMI 10B and ASSENT 2 in Examining the Safety and Efficacy of 50 mg of TNKSafety and Efficacy of 50 mg of TNK

Differences Between TIMI 10B and ASSENT 2 in Examining the Differences Between TIMI 10B and ASSENT 2 in Examining the Safety and Efficacy of 50 mg of TNKSafety and Efficacy of 50 mg of TNK

•In TIMI 10B, only 78 patients received 50 mg of TNK•There were 3 intracranial hemorrhages•None of the patients in TIMI 10 B with an intracranial

hemorrhage weighed over 90 Kg (mean wt. only 77.2 Kg)*•These 3 patients all weighed < 90 Kg, and none of them

would have received 50mg as a weight adjusted dose in ASSENT 2 or in clinical practice

•There were 9 major hemorrhages, and only 1 patient weighed over 90 Kg*

•Thus, 89%* of all patients (8/9) who developed a major hemorrhages at the 50mg dose would not have received this dose had they been enrolled in the ASSENT 2 trial or treated in clinical practice

•This was in part the motivation for weight adjusting the dose of TNK

•In TIMI 10B, only 78 patients received 50 mg of TNK•There were 3 intracranial hemorrhages•None of the patients in TIMI 10 B with an intracranial

hemorrhage weighed over 90 Kg (mean wt. only 77.2 Kg)*•These 3 patients all weighed < 90 Kg, and none of them

would have received 50mg as a weight adjusted dose in ASSENT 2 or in clinical practice

•There were 9 major hemorrhages, and only 1 patient weighed over 90 Kg*

•Thus, 89%* of all patients (8/9) who developed a major hemorrhages at the 50mg dose would not have received this dose had they been enrolled in the ASSENT 2 trial or treated in clinical practice

•This was in part the motivation for weight adjusting the dose of TNK


ASSENT-2: Outcomes With 50 mg TNK ASSENT-2: Outcomes With 50 mg TNK vs Lower Doses of TNKvs Lower Doses of TNK

ASSENT-2: Outcomes With 50 mg TNK ASSENT-2: Outcomes With 50 mg TNK vs Lower Doses of TNKvs Lower Doses of TNK

0.57

4.7

1.07

6.4

0

1

2

3

4

5

6

7

ICH Death

%

50 mg

< 50 mg

P = 0.06

P = 0.006

• Mortality and ICH were both lower with the 50 mg dose

• The difference in outcome, however, is not significant when adjusting for multiple variables including weight

• Mortality and ICH were both lower with the 50 mg dose

• The difference in outcome, however, is not significant when adjusting for multiple variables including weight

Alexander et al, AHA 2000Alexander et al, AHA 2000

Treatment With 50 mg TNK is Associated with low ICH Rates:Treatment With 50 mg TNK is Associated with low ICH Rates:Major Trials Comparing Intracranial Hemorrhage Rates Among FibrinolyticsMajor Trials Comparing Intracranial Hemorrhage Rates Among Fibrinolytics

Treatment With 50 mg TNK is Associated with low ICH Rates:Treatment With 50 mg TNK is Associated with low ICH Rates:Major Trials Comparing Intracranial Hemorrhage Rates Among FibrinolyticsMajor Trials Comparing Intracranial Hemorrhage Rates Among Fibrinolytics

0.94

0.62

0.87

0.37

00.1

0.77

0.91

1.13

0.93

0

0.2

0.4

0.6

0.8

1

1.2

ISIS-2 INJECT GUSTO-III InTIME-II ASSENT-2

Placebo SKPlacebo SK SK r-PA SK r-PA t-PA r-PAt-PA r-PA t-PA n-PAt-PA n-PA t-PAt-PA

P =NSP =NS

2P<0.022P<0.02

P=NSP=NS

P=NSP=NS

P=0.003P=0.003

ICH

(%

)

TNK tPA TNK tPA

50 mg TNK in

ASSENT 2

0.57*

Califf RM, et al. Am Heart J. 1997;133:630-639; ISIS-2 Collaborative Group. Lancet. 1988;2:349-360; GUSTO III Investigators. N Engl J Med. 1997;337:1118-1123; INJECT. Lancet. 1995;346:329-336; Van de Werf F, et al. ACC 1999 CME Online. 1999;1-12. *Data on file, Genentech

Treatment with 50 mg TNK is Associated with low Mortality Rates: Treatment with 50 mg TNK is Associated with low Mortality Rates: Major Trials Comparing 30- or 35-Day Mortality Among FibrinolyticsMajor Trials Comparing 30- or 35-Day Mortality Among FibrinolyticsTreatment with 50 mg TNK is Associated with low Mortality Rates: Treatment with 50 mg TNK is Associated with low Mortality Rates: Major Trials Comparing 30- or 35-Day Mortality Among FibrinolyticsMajor Trials Comparing 30- or 35-Day Mortality Among Fibrinolytics

6.156.6

7.24

9.53

12

7.4

9.2

6.3

9.02

7.47

6.176.77

0

2

4

6

8

10

12

14

ISIS-2 GUSTO-I INJECT GUSTO-III InTIME-II ASSENT- 2

SKSK SK t-PASK t-PA SK r-PASK r-PA t-PA r-PAt-PA r-PA t-PA n-PA t-PA n-PA

P<0.00001P<0.00001

P=0.0003P=0.0003

Mo

rta

lity

%

TNK t-PA

TNK t-PA PlaceboPlacebo t-PA t-PA

50 mg TNK

ASSENT 2

4.78*

Califf RM, et al. Am Heart J. 1997;133:630-639; ISIS-2 Collaborative Group. Lancet. 1988;2:349-360; GUSTO III Investigators. N Engl J Med. 1997;337:1118-1123; INJECT. Lancet. 1995;346:329-336; Van de Werf F, et al. ACC 1999 CME Online. 1999;1-12. *Data on file, Genentech

Is 50 mg of TNK Administered to Patients with an Is 50 mg of TNK Administered to Patients with an Estimated Weight > 90 Kg Both Safe & Effective?Estimated Weight > 90 Kg Both Safe & Effective?Is 50 mg of TNK Administered to Patients with an Is 50 mg of TNK Administered to Patients with an Estimated Weight > 90 Kg Both Safe & Effective?Estimated Weight > 90 Kg Both Safe & Effective?

It is safe:Using the dose schedule in ASSENT 2 (I.e. 50 mg TNK for pts. with estimated

wt. > 90 Kg):

Risk of ICH in TIMI 10B: 0.0%*Risk of ICH in ASSENT 2: 0.57%*Risk of ICH in TIMI 10B & ASSENT 2 combined: 0.566%*

It is effective:Risk of mortality was 4.78% in pts. treated with 50 mg in ASSENT 2,which compares favorably with the 6.18% rate among all patients in the ASSENT 2 study*The 4.78%* mortality observed among the subgroup of pts. treated

with 50 mg of TNK is the lowest mortality rate observed among recent thrombolytic trials

It is safe:Using the dose schedule in ASSENT 2 (I.e. 50 mg TNK for pts. with estimated

wt. > 90 Kg):

Risk of ICH in TIMI 10B: 0.0%*Risk of ICH in ASSENT 2: 0.57%*Risk of ICH in TIMI 10B & ASSENT 2 combined: 0.566%*

It is effective:Risk of mortality was 4.78% in pts. treated with 50 mg in ASSENT 2,which compares favorably with the 6.18% rate among all patients in the ASSENT 2 study*The 4.78%* mortality observed among the subgroup of pts. treated

with 50 mg of TNK is the lowest mortality rate observed among recent thrombolytic trials


Therapeutic Margin of Weight Adjusted Dosing of TNKTherapeutic Margin of Weight Adjusted Dosing of TNKTherapeutic Margin of Weight Adjusted Dosing of TNKTherapeutic Margin of Weight Adjusted Dosing of TNK

• Questions have been raised about the “margin for error” with weight optimized dosing of TNK

• What if the estimated weight is off by 10 Kg (22 pounds) which would be one dose category? What if the weight estimate is off by 2 weight categories (20 Kg or 44 pounds)?

• Is this safe? Dose this pose an undue risk of ICH?

• Questions have been raised about the “margin for error” with weight optimized dosing of TNK

• What if the estimated weight is off by 10 Kg (22 pounds) which would be one dose category? What if the weight estimate is off by 2 weight categories (20 Kg or 44 pounds)?

• Is this safe? Dose this pose an undue risk of ICH?


Low Body Weight As A Risk Factor For Adverse OutcomesLow Body Weight As A Risk Factor For Adverse OutcomesLow Body Weight As A Risk Factor For Adverse OutcomesLow Body Weight As A Risk Factor For Adverse Outcomes

• Low Body weight has been identified as a risk factor for adverse outcomes following thrombolytic administration, even when the dose is administered correctly

• Low body weight is a risk factor for adverse outcomes in primary PTCA patients

• Low body weight is a risk factor for adverse outcomes even among patients who receive no reperfusion strategy

• Low Body weight has been identified as a risk factor for adverse outcomes following thrombolytic administration, even when the dose is administered correctly

• Low body weight is a risk factor for adverse outcomes in primary PTCA patients

• Low body weight is a risk factor for adverse outcomes even among patients who receive no reperfusion strategy


•Thus, low body weight is a potential confounder in the analysis of dose errors. Low body weight patients may be more likely to receive excess dosing of a drug, but may simultaneously be at risk for adverse outcomes simply on the basis of their low body weight alone

• The question becomes “Is it the low body weight of the patient or the dose error that resulted in an adverse outcome” ?

• To answer this question body weight must be accounted for in the analysis of dose errors

•Thus, low body weight is a potential confounder in the analysis of dose errors. Low body weight patients may be more likely to receive excess dosing of a drug, but may simultaneously be at risk for adverse outcomes simply on the basis of their low body weight alone

• The question becomes “Is it the low body weight of the patient or the dose error that resulted in an adverse outcome” ?

• To answer this question body weight must be accounted for in the analysis of dose errors

Low Body Weight As A Risk Factor For Adverse OutcomesLow Body Weight As A Risk Factor For Adverse OutcomesLow Body Weight As A Risk Factor For Adverse OutcomesLow Body Weight As A Risk Factor For Adverse Outcomes


Margin of Safety with TNK OverdosesMargin of Safety with TNK Overdoses Margin of Safety with TNK OverdosesMargin of Safety with TNK Overdoses

• Across all dose arms, if an overdose error of 1 to 2 dose categories (up to 20 Kg, 44 pounds) was made, the odds ratio for ICH and death were no different than in the trial as a whole in a multivariate model adjusting for patient weight

•TNK has a broad therapeutic margin of safety and errors of estimating weight by up to 20 Kg or 44 pounds are well tolerated with no increased risk of ICH or death

• Across all dose arms, if an overdose error of 1 to 2 dose categories (up to 20 Kg, 44 pounds) was made, the odds ratio for ICH and death were no different than in the trial as a whole in a multivariate model adjusting for patient weight

•TNK has a broad therapeutic margin of safety and errors of estimating weight by up to 20 Kg or 44 pounds are well tolerated with no increased risk of ICH or death


Association Between Recording of Weight on Case Report Association Between Recording of Weight on Case Report Form and MortalityForm and Mortality

Association Between Recording of Weight on Case Report Association Between Recording of Weight on Case Report Form and MortalityForm and Mortality

0

2

4

6

8

10

12

Trial as aWhole

WeightMissing

6.16%6.16%

10.1%10.1%

Mo

rta

lity

Mo

rta

lity

Recently concerns have been expressed regarding the need to weigh patients prior to administration of a thrombolytic agent.

Dosing in ASSENT 2 was based upon either estimated or actual weights

Patients with missing weights had a higher mortality

Is this a cause of a higher mortality, or is it a marker of a sicker patient or a patient who died before being weighed?

Recently concerns have been expressed regarding the need to weigh patients prior to administration of a thrombolytic agent.

Dosing in ASSENT 2 was based upon either estimated or actual weights

Patients with missing weights had a higher mortality

Is this a cause of a higher mortality, or is it a marker of a sicker patient or a patient who died before being weighed?

Among rPA Treated Patients Missing Weight is Associated with Among rPA Treated Patients Missing Weight is Associated with Higher Mortality: A Textbook Case of Statistical ConfoundingHigher Mortality: A Textbook Case of Statistical Confounding

Among rPA Treated Patients Missing Weight is Associated with Among rPA Treated Patients Missing Weight is Associated with Higher Mortality: A Textbook Case of Statistical ConfoundingHigher Mortality: A Textbook Case of Statistical Confounding

0

5

10

15

20

25

•Mortality highest if no weight recorded•No biologically plausible reason why there should be a higher mortality among patients receiving a fixed lytic dose in whom no weight was recorded• Likely explanation is statistical confounding: Missing weight is a marker of a sicker patient, or the patient died before weight obtained

Mo

rtal

ity

(%)

FDA PLA 95-1167, July 15, 1996, page 33

10.2%

16.3%

19.5%

Weight not recorded in 11% of INJECT Trial patients

Deaths N = 242 N = 48 N = 65

> 60 Kg < 60 Kg Missingweight

Weight Optimized Dosing of TNK: The AdvantagesWeight Optimized Dosing of TNK: The AdvantagesWeight Optimized Dosing of TNK: The AdvantagesWeight Optimized Dosing of TNK: The Advantages

•TNK dosing is optimized for the patient’s weight so that flow at 90 minutes after its administration is accelerated•Weight optimized dosing also improves flow after PTCA / stenting and “facilitates PCI”•Weight optimizing TNK dosing improves microvascular function and flow in all 3 arteries•While dose is optimized, the range of weights for a given dose is 22 pounds or 10 Kg, which may minimize dosing errors•TNK is a single dose agent, TNK is compatible with other medications such as heparin (other lytics may precipitate)•TNK is the only agent to demonstrate equivalency to tPA with an acceptable safety profile•Weight adjusted dosing of TNK is safe, efficacious, and has a favorable therapeutic margin of safety if errors are made•Indeed the safety profile is improved: the risk of bleeding and transfusion is reduced

•TNK dosing is optimized for the patient’s weight so that flow at 90 minutes after its administration is accelerated•Weight optimized dosing also improves flow after PTCA / stenting and “facilitates PCI”•Weight optimizing TNK dosing improves microvascular function and flow in all 3 arteries•While dose is optimized, the range of weights for a given dose is 22 pounds or 10 Kg, which may minimize dosing errors•TNK is a single dose agent, TNK is compatible with other medications such as heparin (other lytics may precipitate)•TNK is the only agent to demonstrate equivalency to tPA with an acceptable safety profile•Weight adjusted dosing of TNK is safe, efficacious, and has a favorable therapeutic margin of safety if errors are made•Indeed the safety profile is improved: the risk of bleeding and transfusion is reduced


Documents

Gibson CM. Ann Intern Med. 1999;130:841-847. Characteristics of the Ideal Fibrinolytic Agent Longer half-life/single-bolus administration Increased fibrin