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Characteristics 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

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Characteristics of the Ideal Fibrinolytic Agent

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Characteristics of the ideal fibrinolytic agent l.jpg

Characteristics 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

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


Molecular structures of fibrinolytics l.jpg

SK

r-PA / n-PA

t-PA

TNK-tPA

Molecular Structures of Fibrinolytics

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

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

Fibrin Specificity


Fibrinolytics in development comparative overview l.jpg

Fibrinolytics in Development: Comparative Overview

Tenecteplase

Lanoteplase

Staphylokinase

Saruplase

(TNK-tPA)

(n-PA)

Half-life (minutes)

20

37

6

9

2 boluses

Bolus + 60-

Dosing

Single bolus

Single bolus

30 min apart

min infusion

Provides patient- specific weight- based dosing

Yes

Yes

??

??

Fibrin specificity

+++

+

+++

+

PAI-1 resistance

Increased

??

??

??

Antigenic

No

No

Yes

Yes

Plasminogen

Direct

Direct

Indirect

Direct

activation


Tnk tpa molecular and biochemical properties l.jpg

TNK-tPA: Molecular and Biochemical Properties

N Domain Gln for Asn at 117 : Increased fibrin specificity

Kringle 1

Kringle 2

T Domain Asn for Thr at 103: Reduces clearance; single bolus

K Domain

Ala-Ala-Ala-Ala for Lys-His-Arg at 296-299:

More resistant to PAI 1, enzyme which breaks down lytic agents

EGF

Finger

NH2

HOOC


Timi 10b timi grade flow at 90 minutes l.jpg

TIMI-10B: TIMI Grade Flow at 90 Minutes

Percent of Patients

n=312

n=304

n=146

n=76

*P=0.047, TNK-tPA 30 mg vs t-PA; all others, P=NS.

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


Timi 10b timi grade 3 flow at 90 minutes by dose weight l.jpg

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

No further improvement

In flow above 0.53 mg/kg

P=0.028

0.2

0.3

0.4

0.5

0.6

0.7

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


Timi 10b relationship between timi frame count dose weight l.jpg

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

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 = 0.002

p = 0.007

Low

Med

High

High

Low

Med

0.20 to

0.39

mg/kg

0.40 to

0.51

mg/kg

0.52 to

1.24

mg/kg

0.20 to

0.39

mg/kg

0.40 to

0.51

mg/kg

0.52 to

1.24

mg/kg

TIMI Frame Count

N=166

N=104

N=107

N=127

N=174

N=171

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


Slide8 l.jpg

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

p = 0.06

p = 0.03

% Patients

% Stenosis

Low

Med

High

High

Low

N=173

N=166

N=173

N=174

N=171

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


Timi 10b weight optimized dosing facilitates adjunctive pci l.jpg

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

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

p = 0.05

TIMI Frame Count

Low

Med

High

0.20 to

0.39

mg/kg

0.40 to

0.51

mg/kg

0.52 to

1.24

mg/kg

N=46

N=20

N=39

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


Assent 2 similar incidence of stroke for tnk tpa and t pa l.jpg

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

TNK-tPA

t-PA

Relative Risk

P Value

(n=8,461)

(n=8,488)

(95% CI)

Total stroke (%)

1.78

1.66

1.07

0.555

(0.856-1.349)

Intracranial

0.93

0.94

0.991

1.000

hemorrhage (%)

(0.727-1.350)

Ischemia

0.72

0.64

1.13

0.514

(0.787-1.632)

With hemorrhagic

0.07

0.09

0.752

0.790

conversion (%)

(0.261-2.168)

Unknown type (%)

0.13

0.08

1.576

0.358

(0.611-4.065)

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


Confusion in reperfusion the old old 75 yrs l.jpg

Confusion in Reperfusion: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

CM Gibson, GW symposium, AHA 2000


Ich risk is eight time higher in elderly females following t pa l.jpg

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

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


Unadjusted dose rises rapidly in people of low body weight l.jpg

Unadjusted Dose Rises Rapidly in People of Low Body Weight

CM Gibson, GW symposium, AHA 2000


New answers to the old old question l.jpg

New 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?

CM Gibson, 2000


Weight optimizing reduces ich rates assent ii l.jpg

Weight Optimizing Reduces ICH Rates : ASSENT II

P=0.18

% of Patients

TNK

TNK

tPA

tPA

tPA

TNK

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


Ich rates among women 75 years who are 67 kg in assent ii l.jpg

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

Weight Optimizing Reduces ICH Rates : ASSENT II

P <0.05

tPA

TNK-tPA

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


Slide17 l.jpg

Weight Optimizing Reduces ICH Rates : ASSENT II Multivariate Model

Odds Ratio

1.788

0.760

1.024

1.513

0.300

95% Confidence Ratio

(1.529, 2.091)

(0.668, 0.864)

(1.013, 1.036)

(1.096, 2.088)

(0.092, 0.977)

Age

Weight

Diastolic

Blood Pressure

Hypertension

TNK Treatment by

high-risk females*

* Females >75 years and <67 kgs

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


Weight optimizing tnk reduces the ich risk among high risk patients l.jpg

Weight Optimizing TNK Reduces the ICH Risk Among High 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

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


Weight optimized dosing of tnk improves rate of opening by 60 minutes l.jpg

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

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

p = 0.02 vs low dose

% of Patients

Med

High

Low

N=177

N=174

N=178

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


Weight optimized dosing of tnk improves microvascular function l.jpg

Weight Optimized Dosing of TNK Improves Microvascular 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

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


Assent 2 trial design l.jpg

ASSENT-2 Trial Design

Patients with AMI and ST-segment elevation, symptom onset 6 h (n = 16,950; 1,021 hospitals)

Objective: demonstrate “equivalence”

Primary endpoint: all-cause 30-day mortality

Aspirin (150-325 mg)

IV heparin

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

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

Randomization

t-PA-accelerated regimen

(weight-adjusted)

TNK-tPA single bolus (weight-adjusted)

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


Understanding equivalence l.jpg

Understanding Equivalence

Superiority: Does the 95% CI contain zero?

1%

0%

+1%

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

1%

+1%

0%

To left of 1%

is clinically

meaningful

To right of 1%

is clinically

meaningful

Between 1% and +1%

is not clinically

meaningful

CM Gibson, 2000


Comparison among equivalency analyses for 30 day mortality l.jpg

Comparison Among Equivalency Analyses for 30-Day Mortality

Absolute

Other

Mortality

t-PA

Difference

P Value for

(%)

(95% CI)

Better

Better

Equivalence

n-PA

t-PA

0.17

InTIME-2

0.047

6.77

6.60

(1.0, 0.68)

TNK-tPA

t-PA

0.02

0.006

ASSENT-2

(0.59, 0.62)

6.16

6.18

r-PA

t-PA

0.23

GUSTO-III

NS

(1.11, 0.66)

7.47

7.24

+1

0

-1

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.


Major trials comparing 30 or 35 day mortality among fibrinolytics l.jpg

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

Superiority:

2P<0.00001

P=0.001

P=NS

P=NS

P=NS

P=NS

P=NS

P=NS

P=NS

P=0.0003

P=0.047

P=0.006

Equivalency:

SuperiorityDemonstrated

Equivalency Demonstrated

Mortality %

*

TNK -tPA

Agents

Placebo

SK

t-PA r-PA

SK r-PA

t-PA n-PA

t-PA

SK t-PA

*Higher ICHrate for n-PA(0.62% vs 1.13%;P=0.003).

*Lower majorbleeds for TNK-tPA(4.7% vs 5.9%;P=0.0002).

CM Gibson, 2000


Assent 2 30 day mortality by age and sex l.jpg

Value

P

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

TNK-tPA

t-PA

Relative Risk

(n=8,461)

(n=8,488)

(95% CI)

Age (years)

<75

4.6

4.3

1.063 (0.915-1.235)

0.425

>75

17.4

19.3

0.903 (0.754-1.081)

0.286

Sex

Male

5.0

4.8

1.039 (0.894-1.209)

0.627

Female

10.0

10.6

0.943 (0.784-1.134)

0.563

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


Slide26 l.jpg

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

TNK-tPA(n=8,461)

t-PA

(n=8,488)

Relative Risk

(95% CI)

P Value

Infarct location

8.0

Anterior

8.2

0.975 (0.830-1.146)

0.789

5.0

Other

4.8

1.026 (0.865-1.218)

0.783

Previous AMI

9.8

Yes

8.6

1.137 (0.897-1.441)

0.318

5.5

No

5.7

0.965 (0.843-1.105)

0.609

Previous CABG

9.8

Yes

7.7

1.280 (0.776-2.111)

0.406

6.0

No

6.1

0.987 (0.875-1.115)

0.844

Killip Class

I

4.7

4.8

0.983 (0.851-1.134)

0.818

II

13.5

13.4

1.011 (0.797-1.281)

0.944

III

29.0

24.5

1.185 (0.740-1.899)

0.516

IV

51.4

61.1

0.842 (0.556-1.273)

0.477

Hypertension

Yes

8.0

7.6

1.050 (0.888-1.241)

0.578

No

5.0

5.2

0.962 (0.816-1.135)

0.657

Diabetes

Yes

8.8

8.7

1.002 (0.786-1.278)

1.000

No

5.6

5.7

0.993 (0.868-1.136)

0.942

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


Assent 2 improved survival for tnk tpa in late treated patients l.jpg

1.00

(0.89, 1.12)

1.017

(0.799 - 1.296)

1.157

(0.970, 1.379)

0.766

(0.617. 0.952)

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

TNK-tPA

t-PA

Relative Risk

TNK-tPA

t-PA

P Value

(n=8,461)

(n=8,488)

(95% CI)

Better

Better

Total population (%)

6.16

6.18

0.975

Time to therapy (h)

0-2 (%)

5.0

4.9

0.897

>2-4 (%)

6.3

5.5

0.106

>4 (%)

7.0

9.2

0.018

0.4

1

1.4

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


Timi 10b clinical evidence of increased fibrin specificity in tnk tpa l.jpg

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

Fibrinogen

Plasminogen

30

40

40

40

30

30

30

30

30

50

40

50

40

40

TNK-tPA

50

50

50

50

Percent Changes in Parameters

(median)

TNK-tPA

A

A

A

A

A

alteplase (t-PA)

A

alteplase (t-PA)

1

1

Hours Post-Dose

Hours Post-Dose

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


Assent 2 significantly fewer noncerebral bleeding events with tnk tpa l.jpg

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

TNK-tPA

t-PA

P Value

(n=8,461)

(n=8,488)

26.4

29.0

0.0003

Total bleeds (%)

4.7

5.9

0.0002

Major bleeds (%)

21.8

23.0

0.0553

Minor bleeds (%)

Units transfused

4.3

5.5

0.0002

Any

-

1-2 units

2.6

3.2

-

>2 units

1.7

2.2

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


How does weight optimized dosing improve patient care l.jpg

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

CM Gibson, GW symposium, AHA 2000


Slide31 l.jpg

Why Not Use a Fixed 40 mg Dose in All 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 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.

CM Gibson, GW symposium, AHA 2000


Other acute mi regimens use weight adjusted dosing l.jpg

Other 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

CM Gibson, GW symposium, AHA 2000


Tnk tpa dosing regimen l.jpg

TNK-tPA Dosing Regimen

Dosing categories are about 22 lb wide

  • Minimizes the possibility of dosing errors

    < 60 kg (< 132 lbs)  6 mL

    61 - 70 kg (133-154 lbs) 7 mL

    71 - 80 kg(155-176 lbs) 8 mL

    81 - 90 kg(177-198 lbs) 9 mL

    > 90 kg(> 199 lbs)10 mL


Confusion in reperfusion dose errors l.jpg

Confusion in Reperfusion: Dose Errors

  • Do dose errors cause death ?

    Or

  • Does death cause dose errors ?

CM Gibson, GW symposium, AHA 2000


Dosing errors to be studied l.jpg

Dosing 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

CM Gibson, GW symposium, AHA 2000


Two common questions asked about the 50 mg dose of tnk l.jpg

Two 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”?

CM Gibson, GW symposium, AHA 2000


Slide37 l.jpg

Safety and Efficacy of 50 mg of TNK

Differences Between TIMI 10B and ASSENT 2

  • 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

CM Gibson, GW symposium, AHA 2000


Wide range of weights among pts given 50 mg tnk in timi 10b l.jpg

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

  • 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

CM Gibson, GW symposium, AHA 2000


Differences between timi 10b and assent 2 in examining the safety and efficacy of 50 mg of tnk l.jpg

Differences Between TIMI 10B and ASSENT 2 in Examining the Safety 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

CM Gibson, GW symposium, AHA 2000


Assent 2 outcomes with 50 mg tnk vs lower doses of tnk l.jpg

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

  • 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 2000


Slide41 l.jpg

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

P=0.003

P =NS

P=NS

P=NS

0.57*

ICH (%)

2P<0.02

TNK tPA

t-PA

SK r-PA

t-PA r-PA

Placebo SK

t-PA n-PA

50 mg TNK in ASSENT 2

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


Slide42 l.jpg

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

P<0.00001

P=0.0003

Mortality %

4.78*

TNK t-PA

Placebo

SK t-PA

SK r-PA

t-PA r-PA

t-PA n-PA

SK

t-PA

50 mg TNK

ASSENT 2

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 estimated weight 90 kg both safe effective l.jpg

Is 50 mg of TNK Administered to Patients with an 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

CM Gibson, GW symposium, AHA 2000


Therapeutic margin of weight adjusted dosing of tnk l.jpg

Therapeutic 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?

CM Gibson, GW symposium, AHA 2000


Low body weight as a risk factor for adverse outcomes l.jpg

Low 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

CM Gibson, GW symposium, AHA 2000


Low body weight as a risk factor for adverse outcomes46 l.jpg

Low Body Weight As A Risk Factor For Adverse Outcomes

  • 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

CM Gibson, GW symposium, AHA 2000


Margin of safety with tnk overdoses l.jpg

Margin 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

CM Gibson, GW symposium, AHA 2000


Association between recording of weight on case report form and mortality l.jpg

Association Between Recording of Weight on Case Report Form and Mortality

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?

10.1%

6.16%

Mortality


Slide49 l.jpg

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

Weight not recorded in 11% of INJECT Trial patients

  • 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

19.5%

16.3%

Mortality (%)

10.2%

N = 242

N = 48

N = 65

Deaths

> 60 Kg

< 60 Kg

Missing

weight

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


Weight optimized dosing of tnk the advantages l.jpg

Weight 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

CM Gibson, GW symposium, AHA 2000


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