Clin. Cardiol.

24,577-584 (2001)

Review

Issues in the Assessment of the Safety and Efficacy of Tenecteplase (TNK-tPA)

[Link]
GIBSON, M.S.. M.D., A N D S U S A N J. MARBLE,
M.S., R.N.

Harvard Clinical Research Institute,Boston, Massachusetts, USA

Summary: While thrombolytic agents have demonstrated Introduction

improved mortality over the use of placebo, this has come at
the expense of bleeding complications such as intracranial More than 1 million persons in the United States and 7 mil-
hemorrhage (ICH). Tenecteplase(TNK-tPA)is a novel throm- lion patients worldwide sustain an acute myocardial infarction
bolytic agent engineered to improve upon the ease of use and (AMI) each year.I While the use of thrombolytic therapy has
safety ofalteplase (t-PA).Given its longer half-life, TNK-tPA led to improved survival over treatment with placebo, bleeding
can be administered as a single bolus. The dosing of TNK-tPA complications, such as intracranial hemorrhage (ICH), may
has been weight optimized to enhance both safety and efficacy offset some of this benefit.’ Patients who are at higher risk for
outcomes. Weight-optimized TNK-tPA dosing requires body bleeding complications following thrombolytic therapy in-
weight estimation, which may introduce the potential for med- clude those of increased age, low body weight, female gender,
ication error. However, data from TNK-tPA clinical trials sug- or African ancestry.3
gest that body weight estimates can err by up to 20 kg (44 Ib) Pnor to the development of tenecteplase (TNK-tPA), and
without an increased risk of ICH or death. Furthermore, the re- with the exception of the weight-based infusion of alteplase
sults ofTNK-tPA clinical trials showed that even at the highest (t-PA) for patients of low body weight, thrombolytic agents
weight-optimizeddosage of50 mg, ICH rates were among the were administered using one dosage for all patients. However,
lowest reported in clinical trials of thrombolytics for acute while simple, this fixed dosing of thrombolytic agents can lead
myocardial infarction. In elderly female patients of low body to wide variations in serum or plasma drug concentration?
weight, the use of weight-optimized TNK-tPA lowered the Considering the association between the thrombolytic dose
risk of ICH compared with the use of t-PA, expanding the po- and bleeding complications, it seems intuitive that patient out-
tential use of thrombolytics to this high-risk patient popu- comes would be optimized with weight-based dosing.
lation. Tenecteplase has demonstrated clinical equivalence to Tenecteplase, recently approved by the Food and Drug
t-PA, but with a wider therapeutic margin of safety. Administration, is a novel thrombolytic agent that was engi-
neered to improve upon the characteristics of t-PA. Results of
the clinical trials of TNK-tPA for AM1 resulted in the retine-
Key words: tenecteplase, weight-optimized dosing, acute ment of the TNK-tPA dosing regimen. In fact, weight-opti-
myocardial infarction, r-PA. t-PA, streptokinase mized dosing of TNK-tPA improved both safety and efficacy
outcomes. Review of the TNK-tPA clinical trials and compar-
isons of this agent to other thrombolytics suggest that TNK-
tPA is efficacious and exhibits a wide therapeutic margin of
safety, particularly with regard to high-risk groups such as
low-body-weight women and the elderly.

The Pharmacology of Tenecteplase

Address for reprints:
C. Michael Gibson, M.S.. M.D. Many attempts have been made to improve upon t-PA. In
Harvard Clinical Research Institute both the case of r-PA and n-PA, large sections or domains oft-
900 Commonwealth Avenue PA were completely removed from the molecular structure.
Boston, MA 022 15, USA More than a thousand mutants of t-PA were tested to arrive at
e-mail: mgibson@[Link] the molecular structure of TNK-tPA. Rather than eliminating
Received: May 4, 2001 large domains of t-PA, TNK-tPA was made by substituting
Accepted: May 8. 2001 three single amino acids at the T, N, and K domains (Fig. 1).s-8
578 Clin. Cardiol. Vol. 24, September 2001

FIG.1 Distinctive structural elementsof tenecteplase(TNK-PA) provides improved fibrin specificity,reduced clearance, and greater resistance
to inactivationof PAI- 1. EGF = epidermalgrowth factor. Source:Product data on file. Genentech, Inc., South San Francisco,Calif., USA.

Tenecteplase was altered at the T domain to achieve clearance

- Fibrinogen

from the body four times more slowly than t-PA. This permits
convenient,single-bolusadministration of TNK-PA over 5 s.
In patients with AMI, TNK-PA exhibits a biphasic disposition
from the plasma when administeredas a single bolus? In clin-
ical studies, TNK-tPA was cleared from the plasma with an
initial half-life of 20 to 24 min, a much longer half-life than
that reported for t-PA (i.e., less than 5 min).I0 The terminal
m
c
0
phase half-life of TNK-tPA was 90 to 130 min. In 99 of 104
F -501
patients mated with TNK-PA, mean plasma clearanceranged
from 99 to 119 ml/min. Liver metabolism is the major clear- n
E 0 1 3
Hours post dose
6
i

ance mechanism of TNK-PA.

At the N domain, an amino acid substitution was made to in- I

crease the fibrin specificityof TNK-tPA by a factor of 14over

t-PA. Theoretically, this permits enzymatic activity preferen-
tially at the clot rather than the periphery by minimizing the
induction of a systemic fibrinolytic state. In fact, levels of fib-
rinogen, fibrin degradation products, and other coagulation fac-
tors are fairly stable following TNK-tPA administration (Fig. :. -40.1 \
2).” At the K domain on the TNK-tPA molecule, an amino
acid substitution was made to enhance its resistance against
plasminogen activator inhibitor-1 (PAI-1).Plasminogen acti-
m 0 1 3 6
vator inhibitor-1 is an enzyme secreted by platelets that inter- n
ii Hours post dose
acts with thrombolyticsto inhibittheir activity. Tenecteplaseis
80 times more resistant to inactivation by PAI- 1 than t-PA. FIG.2 The benefits of fibrin specificity:There was a 5 to 10%drop
in fibrinogen and an 18 to 15% fall in plasminogen after administra-
tion of 30 mg, 40 mg, and 50 mg doses of tenecteplase (TNK-tPA)
compared with a 40 and 50% drop, respectively, for t-PA in TIMI
The ClinicalDevelopmentof Tenecteplase [Link] from Ref. No. 1 1 with permission.

TIMI 10A: A Dose-Ranging Study

The Thrombolysis in Myocardial Infarction (TIMI) 10A eight doses of TNK-tPA ranging from a single 5 to 50 mg bo-
trial was a small dose-ranging study that enrolled and treated lus dose of TNK-PA over 5 to 10 s. Tenecteplase was not ad-
1 13 patients with acute ST-segment elevation presenting ministered on a weight-tiered basis in this study. The majori-
within 12 h of symptom onset, who had no contraindications ty of patients ( 5 7 4 % ) experienced TIMI grade 3 flow at 90
to thrombolysis. The goal of this small dose-escalation study min when treated with the 30 to 50 mg doses. Seven patients
was to identify TNK-tPA doses for testing in a second moder- (6%)developed a major hemorrhage, but no patients experi-
ate-size angiographictrial.12 Patients were treated with one of enced [Link] events were distributed across the
 C.M. Gibson and S.J. Marble: Safety and efficacy of TNK-tPA 579

doses: one patient at 15 mg; two patients at 20 mg; one patient Weight-CorrectedDosing Improves outcomes
at 30 mg; two patients at 40 mg; and one patient at 50 mg.
Thus, TNK-tPA doses of 30 and 50 mg were identified for These valuable observations led to a formal, objective anal-
further testing. ysis of the impact of body weight on both safety and efficacy
outcomes, and a “weight-corrected”dose was calculated us-
TIMI 1OB: A Dose-Finding Study ing the TNK-tPA dose divided by the patient’s weight (i.e.,
TNK-tPA dose [milligram] per unit of body weight @do-
The goal of TIMI 10B, a Phase II dose-findingstudy, was to gram])!. I 4 This analysis showed that higher doses per ki-
compare 30 and 50 mg doses of TNK-PA with front-loaded logram of body weight improved TIMI grade 3 flow until a
t-PA. This was a larger study that included 886 patients with plateau was reached between 0.5 and 0.6 mgikg TNK-tPA
acute ST-segment elevation myocardial infarction presenting (Fig. 3).” The weight-corrected analysis assisted in the de-
within 12h of onset of ischemic [Link] were ran- termination of the most appropriate TNK-tPA dosage per
domized to a single bolus of 30 or 50 mg of TNK-PA or the kilogram of body weight to maximize efficacy outcomes and
accelerated regimen of t-PA.’ I Similar to TIMI IOA, patients minimize bleeding complications. Adjusting the dose of
were not treated with TNK-tPA on a weight-tieredbasis. TNK-tPA to approximately0.53 mgkg resulted in correcting
In all, 78 patients were treated with the 50 mg dosage. TIMI frame counts more quickly in both the culprit artery and
Three patients who were treated with TNK-tPA 50 mg plus in uninvolved arteries, achieving earlier vessel patency (by 60
heparin ( 10,OOOU) experienced ICH; therefore, the 50 mg bo- min), reducing thrombus burden, and reducing the severity of
lus was eliminated and was replaced with a 40 mg bolus. In residual stenoses compared with other dosedweight.I 4 Even
fact, these results also prompted a protocol amendment that after the stenosis is relieved by PCI,this weight-adjusted dose
instituted the use of reduced and weight-adjustedheparin dos- of TNK-tPA “facilitated PCI,” in that it resulted in faster flow
es. It also specified that no additional heparin was to be given at the completion of the intervention and improved 2-year
before diagnostic angiography if the patient was already re- outcomes in TIMI lOB.15
ceiving intravenous heparin. This protocol amendment was
initiated during the TIMI 1OB study and was utilized in subse- ASSENT-1: A Safety Study
quent TNK-PA trials, including Assessment of the Safety and
Efficacy of a New Thrombolytic (ASSENT)-1 and ASSENT- The ASSENT- 1 trial was the largest safety study ever done
2. Following the heparin protocol amendment, ICH rates as- on a [Link] enrolled a total of 3,235 patients presenting
sociated with TNK-PA treatment were reduced significantly within 12h of symptom onset; 1,705 received a 30 mg dose of
from 1.82to 0.73% (p = 0.046).13Notably, the results of this TNK-PA, 1,457received a 40 mg dose, and 73 received a 50
study suggested a relationshipbetween body weight, efficacy, mg dose.I6 The TIMI 1OB and ASSENT- 1trial were conduct-
and safety outcomes.” For example, with regard to the three ed simultaneously;therefore, TNK-PA was not administered
patients who experienced ICH on the 50 mg dose of TNK- on a weight-tiered basis in ASSENT- 1. However, following
P A , all weighed < 90 kg (mean weight 77.2 kg). the observation of bleeding complications associated with the
At the completion of this angiographicdose-finding trial, a 50 mg dose in the TIMI 1OB study, the 50 mg dose of TNK-
comparison of TNK-tPA and t-PA demonstrated that the 40 PA was discontinued and replaced by a 40 mg dose. The dif-
mg dose resulted in similar rates of TIMI grade 3 flow at 90 ference between TIMI 1OB and ASSENT- 1 was that heparin
min (62.8 vs. 62.7%, respectively).The 30 mg dose produced was dosed according to the heparin protocol amendment.
a significantly lower rate (54.3%; p = 0.035), and the 50 mg
dose produced a similar rate (65.8%). Rates of ICH for TNK-
tPA were 1 .O% for the 30 mg dose, 1.9% for the 40 mg dose,
and 3.8% for the 50 mg dose. The ICH rate for t-PA was
1.9%.Serious bleeding rates for TNK-PA were 1.9% for the
30 mg dose, 5.2% for the 40 mg dose, and 11.5% for the 50
mg dose. The serious bleeding rate for t-PA was 8.5%. These
bleeding rates are higher than those generally observed in
large-scale safety trials and in clinical practice. This most
likely is due to the fact that bleeding rates are generally high- Em 10 p=0.028
0
er in angiographictrials. Two reasons have been suggestedfor a8 0.2 0.3 0.4 0.5 0.6 0.7 0.8
this fact. The first is the need for vessel instrumentation. The TNK-tPA dose/weight (quintiles,mg/kg, mean)
second reason is that higher heparin dosing is used in these tri-
als because many patients undergo adjunctive or rescue per- FIG.3 Weight-corrected dosing analysis in TlMI 10B demonstrat-
cutaneous coronary intervention (PCI).Similar to ICH, the ed that reperfusion benefit plateaus between 0.5 and 0.6 mgkg
tenecteplase (TNK-tPA).Figure shows TIMI flow grade at 90min
incidence of major hemorrhage was related to body weight. among TNK-PA-treated patients with dose expressed in TNK-tPA
Nine patients who received the 50 mg dose experienced ma- (mg) per patient body weight (kg). Data shown are quintiles of
jor hemorrhage, but the vast majority of these patients (eight weight-corrected dose of TNK-PA. P for trend was 0.028 across
of the nine patients, or 89%) weighed < 90 kg. [Link] from Ref. No. 1 1 with permission.
580 Clin. Cardiol. Vol. 24, September 2001

The incidence of all strokes at 30 days was IS%,and the in- t-PA (Table I).1xImproved safety was noted in both major and
cidence of ICH was 0.77%. Of the 25 patients who experi- minor noncerebral bleeding events. These differences may
enced ICH, 16 were treated with 30 mg of TNK-tPA, and 9 have reflected weight-optimized dosing or the greater fibrin
were treated with 40 mg. The incidence of ICH was lower in specificityof TNK-tPA, or both. The lower rates of transfusion
patients treated within 6 h of symptom onset (0.56%for 30 mg associated with TNK-tPA therapy may translate into greater
TNK-tPA and 0.58% for 40 mg TNK-tPA). Severe bleeding cost effectiveness. This high cost is not due to the cost of blood
complications were reported in 2.8% of patients, and 30-day products per se, but rather to all the ancillary costs associated
mortality was 6.4%. with transfusion, including longer stays in the intensive care
It is interesting to note that there were no strokes reported unit, the costs of imaging studies to determine the site of bleed-
among the 73 patients treated with the 50 mg dose prior to the ing, the cost of therapeutic modalities such as endoscopy, and
protocol amendment that eliminated this dose from the study. so forth. In the ASSENT-2 trial, rates of ICH were similar be-
The main difference between this study and the TIMI 10B tri- tween the treatment groups (i.e., 0.93% for TNK-tPA and
al, in which three patients treated with the 50 mg dose experi- 0.94% for t-PA). The rates also were similar to those observed
enced ICH, was that none of the patients in ASSENT- 1 re- in the Global Utilization of Streptokinase and Tissue Plasmin-
ceived high-dose heparin (10,OOO U), which was given con- ogen Activator for Occluded Coronary Arteries (GUSTO)-I11
comitantly to the three patients who experienced ICH in TIMI study, which compared r-PA with t-PA (i.e., 0.91 % for r-PA
1 OB. As noted earlier, the elimination of high-dose heparin and 0.87% for t-PA).19 Overall, the ASSENT-2 study con-
resulted in a sharp reduction in ICH rates associated with fumed that weight-optimized dosing of TNK-tPA could be
TNK-tPA.13 These findings further substantiate the need to utilized effectively and more safely to treat patients with AMI.
use weight-optimized heparin dosages when treating patients
with thrombolytic agents. Tenecteplase Dosing Regimen for Acute Myocardial
Infarction
ASSENT-2: An Equivalence Trial
The TNK-tPA dosing regimen that has received approval
The practical weight-based analyses conducted on data from the Food and Drug Administration includes dosing cate-
from TIMI IOB refined the dosing regimen for TNK-tPA and gories that are about 10kg (22 lb) wide and permits dosing ac-
permitted the selection of an optimal dosage for study in the cording to the patient's actual or estimated weight (Table II).?"
Phase 111 ASSENT-2 trial. Dosing was determined using The wide TNK-tPA dosing range and the requirement of a sin-
weight-based calculations and a logistic regression analysis gle bolus of TNK-tPA should minimize the likelihood of dos-
of the TIMI frame count data from TIMI 10B and safety data ing error that has been purported to occur with thrombolytic
from ASSENT- 1. A TNK-tPA dosage of 0.53 m a g was se- therapy.21It is important to note that the three patients who
lected as the most appropriate for the ASSENT-2 trial!. l 6 were treated with 50 mg of TNK-tPA and experienced ICH in
ASSENT-2 was a Phase 111trial that randomized 16,949pa- TIMI IOB would not have received this dose ofthe agent in ei-
tients with AM1 and ST-segmentelevation presenting within 6 ther clinical practice or in the ASSENT-2 trial. An analysis of
h to a weight-optimized TNK-tPA regimen or t-PA.I7. IxThe all patients in ASSENT-2, who were treated with the 50 mg
study was designed to demonstrate equivalence between the TNK-tPA dosage on a weight-optimized basis, demonstrated
drugs. In an equivalency trial, the goal is to say with 95% sta- that there was no increased risk of 30-day mortality or ICH
tistical confidence that the mortality rates of the two drugs lie compared with patients who received less than the 50 mg
within 1% of each other. Not only were t-PA and TNK-tPA dosage.22In fact, the rates of ICH and death were lower among
found to be statistically equivalent, but the covariate-adjusted, these patients. Thirty-day mortality in this patient population
30-day mortality rates were almost identical between TNK-
tPA- and t-PA-treated patients (6.18 and 6.15%, respectively).
There were significantlyfewer noncerebral bleeding events
and less need for blood transfusion with TNK-tPA than with TABLE
I1 Weight-optimized dosing ranges for tenecteplase(TNK-tPA)
TNK-PA Volume of TNK-tPA to
Patient weight (kg) (mn) be administered (d)"
TABLEI ASSENT-2: Tenecteplase induced fewer noncerebral <60 30 6
bleeding events than t-PA 2 60 to < 70 35 7
2 70 to < 80 40 8
TNK-tPA t-PA
2 80 to < 90 45 9
Event (n = 8,461) (n = 8,488) p Value
290 50 ~~
10
Total bleeds (%) 26.43 28.95 0.0003
From one vial of TNK-tPA reconstituted with 10 mg sterile water
Major bleeds (%) 4.66 5.94 0.0002
for injection, USP.
Minor bleeds (%) 21.76 22.99 0.0553
TNKase(tm)(tenecteplase)prescribing [Link]. Inc.,
Any transfusion (%) 4.25 5.49 0.0002
South San Francisco, Calif. Available at http:[Link]/prod-
Reprinted from Ref. No. 18 with permission. ucts/tnkas/[Link]. Accessed August 2000.
 C.M. Gibson and S.J. Marble: Safety and efficacy of TNK-tPA 58 1

was actually slightly lower than that observed in all patients tality in this patient population was actually slightly lower
(4.8 vs. 6.2%), suggesting that this weight-optimized dosage than that observed in all patients (4.88 vs. 6.28%). These
maintained efficacy in high-weightpatients. Concerning safe- findings indicate that weight-optimized dosing of TNK-tPA
ty outcomes, the risk of ICH in these patients was 0.6% com- maintained efficacy in high-weight patients. Likewise, with
pared with 0.9%for all TNK-tPA-treated patients.23 respect to safety outcomes, the risk of ICH in these patients
was 0.57% compared with 0.93% for all TNK-tPA-treated
patients. The therapeutic action appears to plateau, and there
Analyses of High-RiskPatients: A Favorable Safety Profile
is no incremental benefit to adding more drug for patients
with Tenecteplase
weighing above 90 kg. Thus, weight-optimized dosing of
TNK-tPA in high-weight patients can produce safe and effT
Elderly female patients are at particular risk for ICH com- cacious outcomes.22.29
plications associated with thrombolytic therapy, yet such pa-
tients represent a substantialproportion of persons presenting
with 24-26 Women aged >75 years have an 8-fold SafetyOutcomes with Other ThrombolyticAgents
greater risk for ICH compared with men aged <65 years.25
Concerns about the risk of ICH have limited the use of such Several large clinical trials have examined the impact of
thrombolyticsin this population despite the potential for sub- variousthrombolytic agents on safety and efficacy. A compar-
stantial survival benefits with treatment.2Of interest is the fact ison of these trials indicates that weight-optimizeddosing with
that analysesof TNK-tPA clinical trials suggest that the use of TNK-tPA is associated with a low to moderate incidence of
weight-optimized dosing may improve safety outcomes in el- ICH and mortality (Fig. 4).18-19*3@33Another important ob-
derly female patients of low body weight. servation is that patients who received a 50 mg dosage of
Using data from ASSENT-2, Barron et [Link] ICH TNK-tPA calculated on a body weight basis were at no greater
rates among elderly, low-weight women (i.e., < 67 kg and risk for ICH or mortality than patients who received other
aged >75 years) with all other women in the study (Table weight-optimizeddoses of TNK-tPA given in the ASSENT-2
III).27 Among low-weight, elderly women, the ICH risk was study, or patients treated with most other thrombolytic agents
1.1% for TNK-tPA-treatedpatients, compared with 3.0%for assessed in large clinical trials (Fig. 4). In fact, the risk of ICH
t-PA-treated patients. When multivariate analyses were per- and mortality observedin patients treated with 50 mg of TNK-
formed, controlling for other confounding factors, this lower tPA as a weight-optimized dose was actually lower than the
rate of ICH for TNK-tPA reached statisticalsignificancewith- risks observed with TNK-tPA overall and with other throm-
in thls subgroup (p < 0.05).18 This analysis demonstrated that bolytic agents. Aside from TNK-tPA and the infusion portion
TNK-tPA was safer for low-weight,elderly women than t-PA, of t-PA administration,all thrombolytics are administered as
an outcome that may reflect weight-optimized dosing and/or one dosage for patients of all body weights. Clinical trials of
improved fibrin specificity. r-PA, streptokinase, and t-PA demonstrate that patients with
At the other end of the spectrum are patients whose body low body weights who receive the non-weight-based throm-
weight exceeds 90 kg. Patients of greater weight may theo- bolytic dosage are at greater risk for bleeding complications
retically not receive enough drug. As a result, questions have compared with higher-weight patients.19g 31 In a subgroup
been raised about drug efficacy in these heavier patients.28In analysis of GUSTO-III data, the incidence of bleeding epi-
ASSENT-2, a total of 1,924 patients weighed more than 90 sodes in low-body-weight women was consistently higher in
kg and thus were treated with the 50 mg dosage of TNK-tPA patients treated with r-PA than with t-PA.34In the International
(approximately 1 1 % of patients).I8It is interesting that mor- Joint Efficacy Comparison of Fibrinolytics Trial (INJECT),
which compared streptokinase (1.5 MU intravenouslyover 60
min) and r-PA (2 boluses of 10 MU given 30 min apart), the
frequency of bleeding complicationsand the need for transfu-
TABLE III ASSENT-2: Low-weight,elderly women are at less risk sion were greater among patients with low body weight (Table
for intracranial hemorrhage (ICH) when treated with tenecteplase IV).31In fact, the incidence of bleeding complicationswas al-
(TNK-PA)rather than with t-PA" most twice as great in the low-weight patients (i.e., 165 kg)
Rates of intracranialhemorrhage (%) than the higher-weightpatients (i.e., 2 80 kg). The importance
Group TNK-tPA, % t-PA, % of a weight-based dosing strategy for heparin was demon-
strated in the GUSTO-I trial, where an analysis of the relation-
Low-weight, elderly women ship between the degree of anticoagulation (activated partial
(< 67 kg and > 75 years)" I . 1 (3/264) 3.0(8/265) thromboplastin time [m]) and 30-day clinical outcomes in
All other women 1.5(25/1,677) 1.6 (27/1,715) nearly 30,000 patients was performed.24Low body weight,
All women 1.4(28/1,941) 1.8(35/1,908) older age, female gender, and nonsmoking status were associ-
" When multivariate analyses were performed, controlling for con- ated with significantly higher m s . Furthermore, the degree
founding factors,this lower rate of ICH for TNK-PA reached statis- of mortality risk increased with higher and lower aPTTs.
tical significance within this subgroup (p <0.05). Similar relationships were observed between aPTTs and the
Adapted from Ref. No. 27 with permission. risk of stroke and bleeding events.
582 Clin. Cardiol. Vol. 24, September 2001

p=0.003
1.2 1 113

1.0

0.8
h

g 0.6
I
0
0.4

0.2

0.0
ISIS-2 INJECT GUSTO-Ill InTIME-2 ASSENT-2 50 mq TNK-tPA
(A) in ASSENT-2

14 1 p<[Link]

" ISIS-2 GUSTO-II INJECT GUSTO-Ill InTIME-2 ASSENT-2 50 mg TNKtPA

(B) in ASSENT-2
FIG.4 Comparison of intracranial hemorrhage (ICH) (A) and mortality (B)among major clinical trials of thrombolytics revealed that
tenecteplase (TNK-tPA)was associated with low to moderate ICH and mortality rates. SK = streptokinase.

ConcernsAbout Medication Error with error. Furthermore, error can be introduced by complicated
Weight-Optimized Dosing drug administration regimens that require bolus dosing plus
infusion or multiple bolus doses.2' The latter is the case for
A recent report from the Institute of Medicine established thrombolytic agents such as t-PA and r-PA. The timing of
that medication errors are a serious and costly problem in the drug administration also is critical. The duration of the t-PA
US healthcare industry.35Multiple factors contribute to med- infusion may be either too long or too short. The timing of the
ication error. For emergency cardiac care, drugs must be se- second bolus of r-PA at 30 min may occur too early or too late,
lected and dosing regimens must be administered under ex- or may be missed entirely. The bolus of r-PA may be given
treme time pressures, potentially increasing the likelihood of more or less rapidly than over 2 min. As a single-bolus agent
to be administered over 5 s, TNK-tPA reduces these sources
of medication error. Finally, TNK-tPA is compatible with a
broad range of other medications, while r-PA and t-PA may
TABLEIV The INJECT study: Patients with lower body weight precipitate with the administration of heparin, a drug com-
were more likely to experience bleeding complications and require monly used in treating AMI.
transfusion than patients of higher body weight Drugs that require weight-based dosing and body weight
~ ~~~

r-PA Streptokinase estimations also may introduce medication error. Nonetheless,

weight-based dosing is essential for drugs that possess a nar-
All bleeds row therapeutic window, such as thrombolytics and other
565 kg (%) 20.4 21.3 emergency cardiac medications. Indeed, many drugs used in
65 to 80 kg (a) 15.8 15.3 emergency cardiac care require weight-based dosing, includ-
> 80 kg (%) 12.4 13.2 ing heparin and the low-molecular-weight heparinoids, abcix-
Bleeds requiring transfusion imab, amiodarone, dobutamine, dopamine, eptifibatide, nitro-
265 kg (%) 1.1 1.6
prusside, and procainamide, among others. The American
65to80kg (%) I .o 1.o
> 80 kg (%) 0.1 0.7
College of Cardiology/American Heart Association guide-
lines have recently been revised to reflect the importance of
Reprinted from Ref. No. 3 1 with permission. weight-based heparin dosing.3638
 C.M. Gibson and S.J. Marble: Safety and efficacy of TNK-tPA 583

Odds of death or ICH with errors in to 20 kg (44 Ib). The attributes of TNK-tPA, including bio-
weight-optimized dosing of TNK chemical improvements, the potential for a decreased risk of
c 1 .o 10.0 medication error, and refined safety and efficacy outcomes
Overdose 1-2 subsequent to weight-optimized dosing make this agent a pre-
intervals:
ferred thrombolytic for the treatment of AMI, particularly in
ICH
high-risk patients such as low-weight elderly women. Further
Death
study of this agent will likely expand its clinical use into the
prehospital setting.
Underdose:
ICH
Death References
I
Decreased Increased
odds odds I . American Heart Association: Coronay Heart Disease andAiiginu
fecroris. Accessed October 2000 at [Link]
FIG.S Overdosing or underdosing tenecteplase (TNK-tPA) for one 2. Fibrinolytic Therapy Trialists’ (FIT) CollaborativeGroup: Indica-
or two dosing intervals-that is, by up to a 20 kg or 44 Ib weight er- tions for fibrinolytic therapy in suspected acute myocardial infarc-
ror-was not associated with intracranial hemorrhage (ICH) or tion: Collaborativeoverview of early mortality and major morbidi-
death in ASSENT-2. This was determined using a multivariate mod- ty results from all randomised trials of more than loo0 patients.
el accounting for body weight. Source: Ref. No. 29. Lancet 1994;343:31 1-322
3. Berkowitz SD, Granger CB, Pieper KS, Lee KL, Gore JM,
Simoons M, Armstrong PW, Topol El, Califf RM: Incidence and
predictors of bleeding after contemporary thrombolytic therapy for
In the case of TNK-tPA, the results of clinical studies indi- myocardial infarction: The Global Utilization of Streptokinaseand
Tissue Plasminogen Activator for Occluded coronary arteries
cate that most errors in TNK-tPA dosing do not increase the (GUSTO) I Investigators. Circulation 1997;95:2508-25I6
risk of either ICH or mortality. In ASSENT-2, overdosage oc- 4. Gibson CM, Cannon CP, Murphy SA, Adgey JA, Schweiger MI,
curred in 2.7% of patients (n = 2 18; median weight error 8 kg) Sequeira RF, Grollier G, Fox NL, Berioli S, Weaver WD. Van de
and underdosage in 4.0% of patients (n = 326; median weight Werf F, Braunwald E : Weight-adjusted dosing of TNK-tPA-tissue
error 1 kg); underdosing or overdosing of one to two dosing in- plasminogen activator and its relation to angiographic outcomes in
the Thrombolysis in Myocardial Infarction 1OB trial. Am J Cczrdiol
tervals-that is, up to a 20 kg or 44 Ib weight error-was not 1999;84:976-980
associated with ICH or death in a multivariate model account- 5. Product data on file. Genentech, Inc. South San Francisco,Calif.
ing for body weight (Fig. S).29In short, weight-optimized dos- 6. Keyt BA, Paoni NF, Refino CJ,Berleau L, Nguyen H. Chow A. Lai
ing of TNK-tPA provides a broad therapeutic margin of safety. J, PeRa L, Pater C, Ogez J, Etcheverry T,Botstein D, Bennett WF:
A faster-acting and more potent form of tissue plasminogen activa-
Finally, concerns have been raised about the higher mortal-
tor. Pmc Natl Acad Sci USA 1994;91(9):367&3674
ity rate among patients treated with TNK-tPA who were not 7. Sobel BE: The language of lysis: A proposal to standardize the
weighed. However, data from the INJECT study show that nomenclature. JAm Coll Cardiol1999;341226-1 227
there also is a higher rate of mortality among patients who re- 8. Ross AM: New plasminogen activators: A clinical review. Clin
ceived fixed doses of either streptokinase or r-PA who were Cardiol 1999;22:165-171
9. Modi NB, Fox NL, Clow FW, Tanswell P, Cannon CF! Van de Wed
not weighed. Failure to weigh a patient and higher mortality F, Braunwald E: Pharmacokinetics and pharmacodynamics of
are clearly associated. The question relates to causality: Does tenecteplase: Results from a phase I1 study in patients with acute
failure to weigh the patient lead to mortality or does a patient’s myocardial infarction.J Clin fharmacol20o0;40508-5 15
failure to survive AM1 lead to failure to weigh a patient? Given 10. TNKase’” (tenecteplase) full prescribing information. In Physi-
that the same observation is seen among fixed-dose lytic cians’ Desk Reference, 55 edition, 1316-1318. Montvale, NJ:
Medical Economics, 2001
agents, the second possibility appears more likely, namely, that I I . Cannon CP, Gibson CM, McCabe CH, Adgey J. Schweiger MJ,
patients who die early during their hospital course are more Sequeira RF, Grollier G, Giugliano FP, Frey M, Mueller HS.
likely not to have a weight recorded. Thus, the relationship is Steingart RM. Weaver WD. Van de Werf F, Braunwald E: TNK-tis-
confounded by both survival bias and selection bias. sue plasminogen activator compared with front-loadedalteplme in
acute myocardial infarction: Results of the TIM1 IOB trial.
Circulation 1998;98:2805-2814
12. Cannon CP, McCabe CH, Gibson M, Ghali M, Sequeira RF,
Conclusions McKendall GR, Breed J. Modi NB, Fox NL, Tracy RP, Love TW,
Braunwald E, TIMI 10A Investigators:TNK-tPA-tissue plasmino-
Thrombolytic agents are widely used in the management of gen activator in acute myocardial infarction: Results of the
Thrombolysis in Myocardial Infarction (TIMI) 10A dose-ranging
AMI. Recent improvements such as the development of trial. Circulation 1997;95:351-356
TNK-tPA and the implementation of weight-optimized dos- 13. Giugliano Rp,Cannon CP, McCabe CH, Van de Werf F, Braunwald
ing have resulted in greater safety and efficacy outcomes. E Lower dose heparin with thrombolysis is associated with lower
Weight-tiered dosing can prompt concerns about medication rates of intracranial hemorrhage: Results from TIM1 10B and AS-
error stemming from the need to estimate patient body weight. SENT 1 (abstr). Circulation 1997:96;1-535
14. Gibson CM, Murphy SA, Rizzo MJ, Ryan KA, Marble SJ,
It is important to note that analyses of data from clinical trials McCabe CH, Cannon CP, Van de Werf F, Braunwald E: Relation-
of TNK-tPA suggest that there is no excess risk of death or ship between TIMI frame count and clinical outcomes after throm-
ICH with dose errors when estimating a patient’s weight of up bolytic [Link] I999:99:1945-1 950
584 Clin. Cardiol. Vol. 24, September 200 1

15. Gibson CM, Murphy SA, Marble SJ, Barron HV, Cannon CP: 28. Lundergan CF, Reiner JS, McCarthy WF, Coyne KS, Califf RM.
Relation of epicardial blood flow and myocardial perfusion to long Ross AM: Clinical predictorsof early infarct-related artery patency
term outcomes 2 years followingthrombolysis in acute MI: A TIM1 following thrombolytic therapy: Importanceof body weight, smok-
lob substudy (abstr). Circulation2000,102:11-435 ing history, infarct-related artery and choice of thrombolytic regi-
16. Van de Werf FJ, Cannon CP, Luyten A, Houbracken K, McCabe men: The GUSTO-I experience. J Am Coll Curdiol 1998;32:
CH, Berioli S, Bluhmki E, Sarelin H, Wang-Clow F, Fox NL, 641-647
Braunwald E Safety assessment of a single bolus administrationof 29. Gibson CM: Weight-AdjustedDosing of Fibrinolytic Agents: The
TNK-tPA-tissueplasminogen activator in acute myocardial infarc- Goodand the Bad. Presented at the George Washington University
tion: The ASSENT- 1 trial. Am Heart J 1999;137:78679 I satellite symposium at the American Heart Association annual sci-
17. Van de Werf FJ: The ideal fibrinolytic: Can drug design improve entific program, November I I , 2000, New Orleans, La. (2000a)
clinical results? Eur Heart J 1999;20:1452-1458 30. ISIS-2 CollaborativeGroup. Randomised trial of intravenous strep-
18. Assessment of the Safety and Efficacy of a New Thrombolytic tokinase, oral aspirin, both, or neither among 17, I87 cases of sus-
(ASSENT-2) Investigators: Single-bolus tenecteplase compared pected acute myocardial infarction: ISIS-2. Luncet I988;2:349-360
with front-loadedalteplasein acute myocardial infarction: The AS- 31. INJECT Investigators: Randomised, double-blind comparison of
SENT-2 double-blind randomised trial. Lancet I999;354:7 16-722 reteplase double-bolus administration with streptokinase in acute
19. Global Use of Strategies to Open Occluded Coronary Arteries myocardial infarction (INJECT): Trial to investigate equivalence.
(GUSTO Ill) Investigators: A comparison of reteplase with al- Luncet 1995:346:329-336
teplase for acute myocardial infarction. N Engl J Med 1997;337: 32. Antman EM, Wilcox RG, Giugliano RP, McCabe CH, Foxley A,
1 118-1 I23 Pangerl A, Chew PH, Skene AM, Neuhaus KL, Braunwald E, and
20. TNKase'" (tenecteplase)prescribing [Link], Inc., TIME 11 Investigators: Long-term comparison of lanoteplase and
South San Francisco, Calif. Available at http:[Link]/prod- alteplase in ST elevation myocardial infarction: 6 month followup
uctdtnkase/[Link] August 2000. inTIMEIItrial (abstr). Circulation 1999;100:1498
21. Cannon C P Thrombolysis medication errors: Benefits of bolus 33. Klootwijk P, Langer A, Meij S, Green C, Veldkamp RF, Ross AM,
thrombolytic [Link] J Curdiol 2000,85: I7C-22C Armstrong PW, Simoons ML: Non-invasive prediction of reperfu-
22. Alexander J, Li X, Chin R: Safety and efficacy of 50 milligrams of sion and coronary artery patency by continuous ST segment moni-
TNK-tPA in patients with acute myocardial infarction: Results toring in the GUSTO-I trial. Eur Hear/ J 1996;17:689498
from ASSENT-2 (abstr).Circulation2000; I02:11-258 34. Gore JM. Goldberg RJ: Optimal dosing of fibrinolyticagents: One
23. Gibson CM: The Impact of Fibrinolytic Dose on Outcome. Pre- size does not fit all (a CME white paper). Califon. New Jersey:
sented at the 16th International Symposium on Thrombolysis and Gardiner-CaldwellSynerMed, 2000
InterventionalTherapy in Acute Myocardial Infarction;November 35. Institute of Medicine: To Err is Human. Building a Safer Health
1 I , 2000, New Orleans, La. (2000b) System. Washington DC:National Academy Press, 2000. Accessed
24. Gore JM, Granger CB, Simoons ML, Sloan MA, Weaver WD, at [Link] June 5,2000
White HD. Barbash GI, Van de Werf F, Aylward PE, Topol El, 36. Brown G, Dodek P: An evaluation of empiric versus nomogram-
Calif RM: Stroke after thrombolysis: Mortality and functionalout- based dosing of heparin in an intensive care unit. Crit Care Med
comes in the GUSTO-I hial. Circulation 1995;92:281 1-28 18 1997;25:1534.1538
25. Gurwitz JH, Gore JM, Goldberg RJ, Barron HV, Breen T, Rundle 37. Hassan WM, Flaker GC,Feutz C, Petroski F, Smith D: Improved
AC, Sloan MA, French W, Rogers WJ: Risk for inuacranial hemor- anticoagulation with a weight-adjusted heparin nomogram in pa-
rhage after tissue plasminogen activator treatment for acute my- tients with acute coronary syndromes: A randomized hial. J Thmmb
ocardial [Link] lntem Med 1998;129597-604 T h ~ ~ m b ~I995;2:245-249
ly~i~
26. Mosca L, Manson JE, Sutherland SE, Langer RD, ManolioT, Bar- 38. Ryan TJ, Antman EM, Brooks NH, Calif RM. Hillis LD, Hiratzka
rettconnor E: Cardiovasculardisease in women: A statement for LF, Rapaport E, Riegel B, Russell RO, Smith EE 111, Weaver WD:
healthcare professionals from the American Heart Association. 1999update: ACUAHA guidelines for the management of patients
Circulation 1997;96:2468-2482 with acute myocardial infarction: Executive summary and recom-
27. Barron HV, Fox NL, Berioloi S, Danays T, Li X, Wang-Clow F, mendations: A report of the American College of Cardiology/
Van de Wed F A comparison of intracranial hemorrhage rates in American Heart Association task force on practice guidelines
patients treated with rt-PA and t-PA-TNK-tPA: Impact of gender, (Committee on Management of Acute Myocardial Infarction).
age and low body weight (abstr). Circulation 1999;1OO:I-1 Circulation 1999;100:10I 61030