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
t-PA (alteplase)
n-PA (lanoteplase)
TNK t-PA (tenecteplase)
r-PA (reteplase)
Fibrin
Specificity
SK
r-PA / n-PA
t-PA
TNK-tPA
Fibrinolytics in Development: Comparative Overview
Tenecteplase
(TNK-tPA)
Lanoteplase
(n-PA)
20
37
Single bolus
Single bolus
Provides patientspecific weightbased dosing
Yes
Fibrin specificity
PAI-1 resistance
Half-life (minutes)
Dosing
Antigenic
Plasminogen
activation
Staphylokinase
Saruplase
6
2 boluses
30 min apart
9
Bolus + 60min infusion
Yes
??
??
+++
+
+++
+
Increased
??
??
??
No
No
Yes
Yes
Direct
Direct
Indirect
Direct
TNK-tPA: Molecular and Biochemical Properties
Kringle 1
T Domain Asn for Thr at
N Domain Gln for Asn at 117 : Increased fibrin specificity
Kringle 2
103: Reduces clearance;
single bolus
EGF
K Domain
Ala-Ala-Ala-Ala
for Lys-His-Arg
at 296-299:
More resistant
to PAI 1,
enzyme which
breaks down
lytic agents
Finger
NH2
HOOC
Percent of Patients
TIMI-10B: TIMI Grade Flow at 90 Minutes
100
90
80
70
60
50
40
30
20
10
0
19
16
22
22
TIMI grade 2
TIMI grade 3
63
63
66
TNK-tPA 40mg
TNK-tPA 50mg
55
t-PA
TNK-tPA 30mg
n=312
n=304
*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.
n=146
n=76
TIMI-10B: TIMI Grade 3 Flow at 90 Minutes by Dose/Weight
Percent TIMI Grade 3 Flow
at 90 Minutes
70
60
50
40
No further improvement
In flow above 0.53 mg/kg
30
20
P=0.028
10
0
0.2
0.3
0.4
0.5
0.6
TNK-tPA Dose/Weight (quintiles, mg/kg, mean)
Cannon CP, Gibson CM, McCabe CH et al. Circulation. 1998;98:2805-2814.
0.7
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 = 0.007
40
38
35
TIMI Frame Count
35
20
35
31
31
30
25
p = 0.002
40
Low
Med
High
Low
Med
High
0.20 to
0.40 to
0.52 to
0.20 to
0.40 to
0.52 to
0.39
0.51
1.24
0.39
0.51
1.24
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
N=166
N=174
N=171
N=107
N=127
15
10
5
N=104
0
Culprit
Gibson CM, et al. Am J Cardiol. 1999;84:976-980.
All 3 Arteries
Pathophysiology of Improved Flow With Weight Optimized TNK Dosing: Weight
Optimizing Reduces Thrombus Burden & Improves Percent Stenosis
p = 0.06
% Patients
35
77
34.3
76
29
30
25
25
20
15
Low
Med
High
10
5
74
73
72
71
N=166
N=174
N=171
0
75.7
75
% Stenosis
40
p = 0.03
70
71.4
Low
High
N=173
N=173
69
Thrombus
Gibson CM, et al. Am J Cardiol. 1999;84:976-980.
% Stenosis
TIMI-10B: Weight Optimized Dosing
“Facilitates Adjunctive PCI”
35
p = 0.05
29
TIMI Frame Count
30
Dose of 0.53 mg / kg selected
for ASSENT 2 based upon
logistic regression of Frame
Count data
24
25
19
20
15
10
Low
Med
High
0.20 to
0.40 to
0.52 to
0.39
0.51
1.24
mg/kg
mg/kg
mg/kg
N=46
N=39
N=20
5
0
Post PTCA
Gibson CM, et al. Am J Cardiol. 1999;84:976-980.
ASSENT-2: Similar Incidence of Stroke for TNK-tPA and t-PA
TNK-tPA
(n=8,461)
t-PA
(n=8,488)
Relative Risk
(95% CI)
Total stroke (%)
1.78
1.66
0.555
Intracranial
hemorrhage (%)
0.93
0.94
1.07
(0.856-1.349)
0.991
(0.727-1.350)
Ischemia
0.72
0.64
1.13
(0.787-1.632)
0.514
With hemorrhagic
conversion (%)
0.07
0.09
0.752
(0.261-2.168)
0.790
Unknown type (%)
0.13
0.08
1.576
(0.611-4.065)
0.358
ASSENT-2 Investigators. Lancet. 1999;354:716-722.
P Value
1.000
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
12
Adjusted OR
10
8
6
4
2
0
M<65
F<65
M 65-74
Gurwitz et al. 1998 Annals Int Med. 129; 597-604.
F 65-74
M>75
F>75
Unadjusted Dose Rises Rapidly in People of Low
Body Weight
3
tPA
Fixed dose
TNK
Dose (mg/kg)
2.5
2
1.5
1
0.5
0
20
30
40
50
60
70
Weight (kg)
CM Gibson, GW symposium, AHA 2000
80
90
100
110
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
P=0.18
3
% of Patients
2.62
2.5
2
1.78
1.77
1.72
1.44
1.5
1.41
1
0.5
TNK
tPA
TNK
tPA
TNK
tPA
0
>75
H Barron AHA 1999; Circulation 1999; 100: I-1
Female
<67kg
Weight Optimizing Reduces ICH Rates : ASSENT II
ICH Rates Among Women > 75 Years who are < 67 Kg in ASSENT II
Patients (%)
P <0.05
3.02
1.14
TNK-tPA
H Barron AHA 1999; Circulation 1999; 100: I-1
tPA
Weight Optimizing Reduces ICH Rates : ASSENT II
Multivariate Model
Odds Ratio
95% Confidence Ratio
Age
1.788
(1.529, 2.091)
Weight
0.760
(0.668, 0.864)
Diastolic
Blood Pressure
1.024
(1.013, 1.036)
Hypertension
1.513
(1.096, 2.088)
TNK Treatment by
high-risk females*
0.300
(0.092, 0.977)
* 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
• 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
% of Patients
Dose of 0.53 mg / kg selected for
ASSENT 2 based upon logistic
regression of Frame Count data
84
82
80
78
76
74
72
70
68
66
64
p = 0.02 vs low dose
81
70
82
Med
High
N=178
N=174
Low
N=177
Open by 60 Min.
Gibson CM, et al. Am J Cardiol. 1999;84:976-980.
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
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)
Adapted from ASSENT-2 Investigators. Lancet. 1999;354:716-722.
TNK-tPA single bolus
(weight-adjusted)
Understanding Equivalence
Superiority: Does the 95% CI contain zero?
1%
0%
+1%
Equivalence: Does the 95% CI lie between 1% and +1%?
1%
To left of 1%
is clinically
meaningful
CM Gibson, 2000
0%
Between 1% and +1%
is not clinically
meaningful
+1%
To right of 1%
is clinically
meaningful
Comparison Among Equivalency Analyses for
30-Day Mortality
Mortality
(%)
InTIME-2
ASSENT-2
GUSTO-III
n-PA
t-PA
6.77
6.60
TNK-tPA
t-PA
6.16
6.18
r-PA
t-PA
7.47
7.24
Absolute
Difference
(95% CI)
Other
Better
t-PA
Better
P Value for
Equivalence
0.17
(1.0, 0.68)
0.02
(0.59, 0.62)
0.047
0.006
0.23
(1.11, 0.66)
NS
-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
Superiority:
Equivalency:
12
2P<0.00001
P=NS
12
Mortality %
10
P=0.001
P=NS
P=NS
P=0.0003
Superiority
Demonstrated
9.5
7.4
P=NS
P=0.006
7.2
9
7.5
6.6 6.77
6.3
6
P=NS
P=0.047
Equivalency
Demonstrated
9.2
8
6.15 6.17
*
4
Agents 2
P=NS
P=NS
Placebo
SK
t-PA
t-PA r-PA
GUSTO-I
GUSTO-III
SK
SK
r-PA
t-PA n-PA
t-PA
TNK tPA
0
ISIS-2
CM Gibson, 2000
INJECT
InTIME-2
ASSENT- 2
*Higher ICH
rate for n-PA
(0.62% vs 1.13%;
P=0.003).
*Lower major
bleeds for TNK-tPA
(4.7% vs 5.9%;
P=0.0002).
ASSENT-2: 30-Day Mortality By Age and Sex
TNK-tPA
(n=8,461)
t-PA
(n=8,488)
Relative Risk
(95% CI)
P Value
<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
5.0
4.8
1.039 (0.894-1.209)
0.627
10.0
10.6
0.943 (0.784-1.134)
0.563
Age (years)
Sex
Male
Female
ASSENT-2 Investigators. Lancet. 1999;354:716-722.
ASSENT-2: 30-Day Mortality By Infarct Location, Previous AMI, or Previous CABG;
Killip Class; and History of Hypertension or Diabetes
Infarct location
Anterior
Other
TNK-tPA
(n=8,461)
t-PA
(n=8,488)
Relative Risk
(95% CI)
P Value
8.0
5.0
8.2
4.8
0.975 (0.830-1.146)
1.026 (0.865-1.218)
0.789
0.783
9.8
8.6
1.137 (0.897-1.441)
0.318
5.5
5.7
0.965 (0.843-1.105)
0.609
9.8
6.0
7.7
6.1
1.280 (0.776-2.111)
0.987 (0.875-1.115)
0.406
0.844
4.7
13.5
29.0
51.4
4.8
13.4
24.5
61.1
0.983 (0.851-1.134)
1.011 (0.797-1.281)
1.185 (0.740-1.899)
0.842 (0.556-1.273)
0.818
0.944
0.516
0.477
8.0
5.0
7.6
5.2
1.050 (0.888-1.241)
0.962 (0.816-1.135)
0.578
0.657
8.8
5.6
8.7
5.7
1.002 (0.786-1.278)
0.993 (0.868-1.136)
1.000
0.942
Previous AMI
Yes
No
Previous CABG
Yes
No
Killip Class
I
II
III
IV
Hypertension
Yes
No
Diabetes
Yes
No
ASSENT-2 Investigators. Lancet. 1999;354:716-722.
ASSENT-2: Improved Survival for
TNK-tPA in Late-Treated Patients
TNK-tPA
(n=8,461)
Total
population (%)
t-PA
Relative Risk
(n=8,488)
(95% CI)
TNK-tPA
Better
t-PA
Better
P Value
6.16
6.18
1.00
(0.89, 1.12)
0.975
0-2 (%)
5.0
4.9
1.017
(0.799 - 1.296)
0.897
>2-4 (%)
6.3
5.5
>4 (%)
7.0
9.2
Time to
therapy (h)
1.157
(0.970, 1.379)
0.766
(0.617. 0.952)
ASSENT-2 Investigators. Lancet. 1999;354:716-722.
0.106
0.018
0.4
1
1.4
Percent Changes in Parameters
(median)
TIMI-10B: Clinical Evidence of Increased Fibrin Specificity in
TNK-tPA
Fibrinogen
0
40
30
30
40
50
Plasminogen
0
40
-10
50
30
TNK-tPA 50
-10
30
40
-20
-20
30
40
40
50
50
50
TNK-tPA
-30
A
30
-30
-40
-40
A
-50
A
A
alteplase (t-PA)
A
-50
alteplase (t-PA)
A
-60
0
1
3
6
0
Hours Post-Dose
Cannon CP, Gibson CM, McCabe CH et al. Circulation. 1998;98:2805-2814.
1
3
Hours Post-Dose
6
ASSENT-2: Significantly Fewer Noncerebral Bleeding Events
With TNK-tPA
TNK-tPA
(n=8,461)
t-PA
(n=8,488)
P Value
Total bleeds (%)
26.4
29.0
0.0003
Major bleeds (%)
4.7
5.9
0.0002
Minor bleeds (%)
21.8
23.0
0.0553
Units transfused
Any
1-2 units
>2 units
4.3
2.6
1.7
5.5
3.2
2.2
0.0002
-
ASSENT-2 Investigators. Lancet. 1999;354:716-722.
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
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 lowerweight patients.
CM Gibson, GW symposium, AHA 2000
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
Dosing categories are about 22 lb wide
– Minimizes the possibility of dosing errors
< 60 kg
61 - 70 kg
71 - 80 kg
81 - 90 kg
> 90 kg
(< 132 lbs)
(133-154 lbs)
(155-176 lbs)
(177-198 lbs)
(> 199 lbs)





6 mL
7 mL
8 mL
9 mL
10 mL
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
• 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
• 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
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
>90 kg
22%
<60 kg
11%
61-70 kg
17%
81-90 kg
25%
71-80 kg
25%
CM Gibson, GW symposium, AHA 2000
• 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
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
7
6
50 mg
< 50 mg
P = 0.006
6.4
5
4.7
%
4
3
2
P = 0.06
1
0
1.07
0.57
ICH
Alexander et al, AHA 2000
Death
• 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
Treatment With 50 mg TNK is Associated with low ICH Rates:
Major Trials Comparing Intracranial Hemorrhage Rates Among Fibrinolytics
P=0.003
1.2
1.13
P=NS
P=NS
1
0.87
P =NS
0.94 0.93
0.91
ICH (%)
0.77
0.8
0.62
0.57*
0.6
2P<0.02
0.37
0.4
0.1
0.2
0
0
Placebo
SK
ISIS-2
SK
r-PA
INJECT
t-PA
r-PA
GUSTO-III
t-PA
n-PA
InTIME-II
t-PA
TNK
tPA
ASSENT-2
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
Treatment with 50 mg TNK is Associated with low Mortality Rates:
Major Trials Comparing 30- or 35-Day Mortality Among Fibrinolytics
P<0.00001
14
12
12
P=0.0003
9.2
Mortality %
10
9.53 9.02
7.24 7.47
7.4
8
6.3
6.6 6.77
6.15 6.17
4.78*
6
4
2
Placebo
0
SK
ISIS-2
SK
t-PA
GUSTO-I
SK
r-PA
INJECT
t-PA
r-PA
GUSTO-III
t-PA
n-PA
InTIME-II
t-PA
TNK tPA
ASSENT- 2
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?
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:
Risk of ICH in ASSENT 2:
Risk of ICH in TIMI 10B & ASSENT 2 combined:
0.0%*
0.57%*
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
• 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
• 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 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
• 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
12
10.1%
10
Mortality
8
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
6.16%
6
Patients with missing weights had a
higher mortality
4
2
0
Trial as a
Whole
Weight
Missing
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
Higher Mortality: A Textbook Case of Statistical Confounding
Weight not recorded in 11% of INJECT Trial patients
25
Mortality (%)
19.5%
20
16.3%
15
10.2%
10
5
0
Deaths N = 242
> 60 Kg
N = 48
N = 65
< 60 Kg
Missing
weight
FDA PLA 95-1167, July 15, 1996, page 33
•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
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