Drug Evaluation

Safety and efficacy of

tenecteplase in acute myocardial
infarction
1. Introduction Daniel R Guerra, Juhana Karha & C Michael Gibson†
Department of Medicine, Brigham Women’s Hospital, Harvard Medical School, 75 Francis Street,
2. Pharmacology
Boston, MA 02115, USA
3. Clinical development and trials
4. Clinical trials of tenecteplase The use of intravenous thrombolytic agents has revolutionised the treatment
combination therapy of acute myocardial infarction. However, the improved mortality achieved
5. Safety profile with these drugs is tempered by the risk of serious bleeding complications,
especially intracranial haemorrhage (ICH). Tenecteplase (TNKase™, Genetech
7. Conclusion
Inc.) is an engineered variant of alteplase (Activase®, Genentech Inc.)
8. Expert opinion designed to have increased fibrin specificity, greater efficacy and a longer
half-life. The longer half-life of tenecteplase compared to alteplase allows
for convenient single bolus administration of the drug. In addition, tenect-
eplase dosing is based on actual or estimated patient weight, which enhances
both the safety and efficacy outcomes. Large clinical trials have demon-
strated equivalence in mortality and ICH between tenecteplase and alteplase.
Compared to alteplase, tenecteplase use leads to lower rates of bleeding
complications and a decreased risk of ICH among low weight, elderly women.

Keywords: acute myocardial infarction, tenecteplase

Expert Opin. Pharmacother. (2003) 4(5):791-798

1. Introduction

Acute ST-elevation myocardial infarction (STEMI) is a life-threatening condition

that affects ∼ 7.3 million people annually worldwide [101]. Plaque rupture within the
culprit epicardial coronary artery initiates the pathophysiological cascade of events in
STEMI, leading to thrombus formation and occlusion of the artery. The manage-
ment of acute STEMI is predicated on the open artery hypothesis, which calls for
early, complete and sustained restoration of antegrade blood flow in the inf-
arct-related epicardial artery (IRA). Early achievement of coronary artery patency is
critically important in improving mortality, limiting infarct size and reducing the
amount of left ventricular dysfunction [1,2]. Currently, the two main strategies to
achieve epicardial recanalisation and reperfuse the affected myocardium are thrombo-
lytic administration and primary angioplasty. A number of clinical trials have com-
pared the two methods to guide clinical decision making. A meta-analysis on ten
prospective, randomised trials (including GUSTO IIb [3], PAMI [4] and Zwolle [5]
trials) that icluded a total of 2606 patients demonstrated that primary angioplasty
was associated with an improved 30-day mortality compared to thrombolytic therapy
For reprint orders, please using streptokinase or alteplase (Activase®, Genentech Inc.) [6]. However, the use of
contact: primary angioplasty is not available at all hospitals. Indeed, the American College of
reprints@[Link]
Cardiology/American Heart Association (ACC/AHA) guidelines recommend the use
of primary angioplasty for the treatment of acute myocardial infarction (AMI) only
when specific criteria are met (i.e., balloon inflation within 90 min of admission; per-
formed by an individual who performs > 75 angioplasty procedures/year; in centres
which perform > 200 procedures/year and have cardiac surgical capability) [7]. In
Ashley Publications contrast to angioplasty, thrombolytic therapy can be administered by emergency
[Link]
room physicians with little or no dependence on operator experience and does not
require the cardiac catheterisation laboratory. Because of these factors, thrombolytic

2003 © Ashley Publications Ltd ISSN 1465-6566 791

Tenecteplase

Table 1. Pharmacokinetic characteristics of tenecteplase and alteplase in patients with myocardial infarction.

Tenecteplase Alteplase
(n = 103) (n = 56)
Terminal plasma half-life (min) 115 144
Initial plasma half-life (min) 22 –
Plasma clearance (ml/min) 105 453
Initial volume of distribution (l) 4.7 7.2
Mode of excretion Hepatic Hepatic

administration is the more common strategy of treating 2.2 Pharmacodynamics

patients with STEMI, worldwide. These modifications have important clinical implications. The
The main limitations with the use of thrombolytic therapy increased fibrin specificity theoretically enhances the enzymatic
are reocclusion leading to recurrent infarction and bleeding activity at the clot and reduces systemic fibrinolysis. Further-
complications, most importantly ICH [8]. Patients who are at a more, the increased resistance to PAI-1, an enzyme secreted by
higher risk of bleeding complications following thrombolytic platelets that inhibits thrombolytics, may enhance the efficacy
therapy include those of increased age, low body weight or of tenecteplase [14]. Observations in animal models have dem-
female gender [9]. The GUSTO I trial established that a 90-min onstrated the improved efficacy of tenecteplase. Benedict et al.
(so-called front-loaded) infusion of alteplase produced early and [15] showed that tenecteplase given as a bolus of 1.5 mg/kg was
sustained IRA patency and conferred a survival benefit com- as effective as a 9 mg/kg front-loaded infusion of alteplase in
pared to streptokinase [10].The development of novel thrombo- recanalisation of arterial thrombus [15]. The mean time to
lytic agents has been driven by the goal of improving upon the reperfusion was also shorter with tenecteplase compared to
efficacy and safety of alteplase. Tenecteplase (TNKase™, alteplase (11 versus 23 min, respectively; p < 0.02). Using an
Genentech Inc.) is an engineered variant of alteplase with sev- arterial-venous shunt model, Keyt et al. [12] showed that a
eral important features. Compared to alteplase, tenecteplase has 0.18 mg/kg bolus dose of tenecteplase induced 50% lysis of
increased fibrin specificity, a longer half-life and increased resist- whole blood clots three times as rapidly as the same dose of
ance to plasminogen activator inhibitor-1 (PAI-1). These prop- alteplase given as an accelerated 90 min infusion (35 versus
erties allow for weight-based bolus dosing of tenecteplase, 120 min, respectively). The reduction of systemic fibrinolysis
which avoids wide fluctuations in the drug plasma concentra- with tenecteplase compared to alteplase is supported by find-
tion and enhances both the safety and efficacy of the drug. This ings in humans that systemic fibrinogen and plasminogen lev-
article will review the data that supports the use of tenecteplase els are reduced by only 3 and 13%, respectively, at the 50 mg
as a first-line agent for the treatment of STEMI. dose [16]. In contrast, alteplase leads to a 50 – 60% decrease in
both fibrinogen and plasminogen levels [17,18].
2. Pharmacology
2.3 Pharmacokinetics
2.1 Overview The initial volume of distribution of tenecteplase approxi-
All thrombolytics induce the dissolution of blood clots by con- mates plasma volume and the major route of clearance is via
verting plasminogen to plasmin, which then digests fibrin into hepatic metabolism. Observations in an animal model dem-
soluble degradation products [11]. Tenecteplase is a 527 amino onstrated a reduction in the clearance of tenecteplase by a fac-
acid glycoprotein synthesised by amino acid substitutions at tor of 8.4 compared to alteplase, as assessed by the area under
three sites in alteplase: Asn for Thr at position 103 (T103N), curve (AUC) of plasma concentration versus time [12]. A
Glu for Asn at position 117 (N117Q) and the replacement of TIMI 10B substudy compared the pharmacokinetics of
amino acids Lys 296, His 297, Arg 298 and Arg 299 with Ala 30, 40 and 50 mg boluses of tenecteplase with those of the
(tetra-Ala substitution: KHRR296-299AAAA). The T103N accelerated 90-min infusion regimen of ≤ 100 mg of alteplase
and N117Q substitutions result in the relocation of a glyco- (Table 1) [19]. Tenecteplase clearance exhibits a biphasic distri-
sylation site in the kringle domain of the protein. This varia- bution with a mean plasma clearance of 105 ml/min com-
tion decreases the plasma clearance of tenecteplase fourfold pared to 453 ml/min for alteplase. The initial and terminal
when compared to alteplase [12]. The decreased clearance per- half-lives for bolus administration of tenecteplase were 22 and
mits single-bolus administration of tenecteplase over 5 s. The 115 min, respectively, compared to a terminal half-life of
tetra-Ala substitution in the protease domain of alteplase 144 min for accelerated 90 min alteplase infusion. Older age
confers two properties: a 14-fold increase in fibrin specificity and lower body weight were both associated with reduced
and an 80-fold increase in resistance to PAI-1 [13]. clearance of tenecteplase [19].

792 Expert Opin. Pharmacother. (2003) 4(5)

 Guerra, Karha & Gibson

3. Clinical development and trials However, treatment with tenecteplase 30 mg resulted in signifi-
cantly less TIMI grade 3 flow compared to alteplase (54.3%, n
3.1 TIMI 10A = 302; p = 0.035). Serious bleeding was defined as fatal or life-
The TIMI 10A trial was a Phase I dose-ranging study designed threatening, requiring or prolonging hospitalisation, resulting
to investigate the pharmacokinetics, safety and efficacy of ten- in significant disability or requiring medical or surgical inter-
ecteplase in acute STEMI patients [16]. Patients (n = 113) were vention to prevent impairment of body function. The inci-
treated with one of eight doses of tenecteplase (5 – 50 mg) as a dence of serious bleeding was 8.5% in the alteplase group, and
single bolus over 5 – 10 s. Tenecteplase was not administered 1.9, 5.2 and 11.5% in the tenecteplase 30, 40 and 50 mg
on a weight-tiered basis in this study. Between 57 and 64% of groups, respectively. The high rate of serious bleeding in this
patients in the 30, 40 and 50 mg dose groups had TIMI grade trial may be explained by the use of angiography, which intro-
3 flow 90 min following tenecteplase administration. There duces the need for vessel instrumentation and is associated with
were no cases of ICH. Seven (6%) patients developed major higher heparin dosing during adjunctive or rescue percutaneous
haemorrhage, with the events distributed among all doses coronary intervention (PCI) [14]. Similar to ICH, the incidence
(1, 2, 1, 2, 1 patients at 15, 20, 30, 40 and 50 mg, respec- of major haemorrhage was related to body weight. Eight of the
tively). These results demonstrated that bolus administration nine patients (89%) who experienced major haemorrhage
of tenecteplase was feasible and associated with acceptable among the tenecteplase 50 mg dose group weighed < 90 kg.
safety and efficacy profiles. Tenecteplase doses of 30 and
50 mg were identified for further testing. 3.3 Weight-corrected dosing
The observations that low body weight may be associated
3.2 TIMI 10B with increased risk of bleeding led to an objective evaluation
The TIMI 10B trial, a randomised, Phase II, dose-finding of the association between body weight and safety and efficacy
trial, compared the safety and efficacy of tenecteplase to outcomes. The goal of this analysis was to identify the lowest
alteplase in 886 acute STEMI patients [20]. The trial set out to weight-based dose that yielded maximal efficacy and safety.
identify an appropriate dose of tenecteplase for testing in a Using a weight-corrected dose of tenecteplase ([mg] divided
large mortality trial. Patients were randomised to receive ten- by patient’s weight [kg]), the investigators determined that a
ecteplase (30 or 50 mg bolus) or alteplase (front-loaded dos- dose of 0.53 mg/kg was the inflection point between contin-
ing of 15 mg bolus with 50 mg infusion over 60 min, ued reperfusion benefit with increasing dose and the plateau
followed by a 35 mg infusion over the next 60 min). Similar of no further benefit with further dose increases [20,22-24]. The
to TIMI 10A, patients were not treated with tenecteplase on a efficacy end points used in this analysis were angiographic
weight-tiered basis. The primary efficacy end point of this outcomes at 60 min: TIMI grade 3 flow, corrected TIMI
angiographic study was the rate of TIMI grade 3 flow 90 min frame count (CTFC), thrombus burden and residual stenosis.
following tenecteplase administration. Furthermore, 2-year clinical outcomes also were improved
Early in the study, the tenecteplase 50 mg dose was reduced with the weight-corrected dosing [25].
to 40 mg because of an unacceptably high rate of ICH in the
50 mg dose group (3 of 78; 3.8%). Further review of the data 3.4 ASSENT-1
revealed that higher doses of intravenous unfractionated The Assessment of the Safety and Efficacy of a New Throm-
heparin (UFH) (e.g., 80 U/kg bolus and 18 U/kg/h infusion) bolytic (ASSENT-1) trial [26] was a large Phase II safety study
were associated with higher incidence of ICH. This prompted conducted to further evaluate the risk of major bleeding
a reduction in heparin dosing to 5000 U bolus and a events and ICH with tenecteplase. A total of 3235 acute
1000 U/h infusion in patients weighing > 67 kg (4000 U STEMI patients were randomised to receive tenecteplase
bolus followed by an 800 U/h infusion if ≤ 67 kg) with a target 30, 40 or 50 mg. The tenecteplase dosing was not weight-
activated partial thromboplastin time (aPTT) of 55 – 80 s. tiered as the trial was concurrent with the TIMI 10B trial.
Furthermore, the treatment protocol was amended to specify The 50 mg dose was discontinued and replaced by the 40 mg
that no additional UFH be administered before diagnostic dose when the increased risk of ICH with the 50 mg dose was
angiography if the patient was already receiving intravenous observed in the TIMI 10B trial. A total of 1705, 1457, and
heparin. This protocol was used in subsequent tenecteplase 73 patients received tenecteplase 30, 40 and 50 mg, respec-
trials (ASSENT-1 and ASSENT-2) and was associated with a tively. The reduced-dose intravenous heparin protocol initi-
reduced incidence of ICH among tenecteplase-treated patients ated during the TIMI 10B trial was also used in the ASSENT-
(0.73 versus 1.82%, p = 0.046) [21]. It was notable that the 1 trial. At 30 days, the incidence of ICH and total stroke was
three people who developed ICH on the tenecteplase 50 mg 0.77 and 1.5%, respectively. Sixteen ICH events occurred in
dose had a relatively low mean body weight of 77.2 kg. the 30 mg treatment group and nine in the 40 mg treatment
Patients (n = 311) in the alteplase group had a 62.7% inci- group. No ICH events occurred in the 73 patients who
dence of TIMI grade 3 flow 90 min following alteplase admin- received tenecteplase 50 mg. Severe bleeding occurred in
istration. This was similar to the tenecteplase 40 and 50 mg 2.8% of patients and 30-day mortality was 6.4%. It is notable
dose groups (62.8 and 65.8%; n = 148 and 76, respectively). that there were no ICH events among the patients in the

Expert Opin. Pharmacother. (2003) 4(5) 793

Tenecteplase

Table 2. Weight-optimised dosing ranges for tenecteplase.

Patient weight (kg) Tenecteplase (mg) Volume of tenecteplase to be

administered (ml)*
< 60 30 6
≥ 60 to < 70 35 7
≥ 70 to < 80 40 8
≥ 80 to < 90 45 9
≥ 90 50 10
*From one vial of tenecteplase reconstituted with 10 mg sterile water for injection [102].

highest dose group (50 mg). This reduction in severe bleeding actual body weight. The dosing categories are 10 kg (22 lb)
events is most likely because of the use of the lower UFH dos- wide (Table 2). The wide tenecteplase dosing range and the
ing adopted as a result of the TIMI 10B experience and requirement of a single bolus of tenecteplase should minimise
underscores the importance of weight-based UFH dosing in the likelihood of dosing error that has been purported to
the setting of thrombolytic administration for acute STEMI. occur with thrombolytic therapy [29]. An analysis of the
ASSENT-2 trial subgroup of patients who received tenect-
3.5 ASSENT-2 eplase 50 mg on a weight-based dosing demonstrated that
The ASSENT-2 trial [27] was a Phase III, placebo-controlled, they did not have increased risk of ICH or death compared
double-blind trial designed to demonstrate equivalence in to patients whose weight-based tenecteplase dose was
30-day mortality between tenecteplase and alteplase. A total of < 50 mg [30]. In fact, 30-day mortality among the patients in
16,949 acute STEMI patients were randomised to receive the 50 mg group tended to be lower than in all patients
weight-tiered tenecteplase or alteplase. Based on observations (4.8 versus 6.4%, respectively), suggesting that the weight-
from TIMI 10B and ASSENT-1 trials, the tenecteplase dose of optimised dosing maintains efficacy in high-weight patients.
0.53 mg/kg was selected as the target for the weight-tiered dos- Likewise, the key safety outcome of ICH tended to be less
ing schedule (Table 2). The primary end point was total mor- common in the high-weight group compared to all patients
tality at 30 days. Secondary end points included stroke-free (0.6 versus 1.1%, respectively).
survival, major adverse cardiac events and stroke. There was no
difference in the 30-day mortality between the two treatment 4. Clinical trials of tenecteplase combination
arms (6.18 versus 6.15%, for tenecteplase and alteplase, therapy
respectively; p = 0.006 for equivalence). Likewise, the rates of
ICH (0.93 versus 0.94%, for tenecteplase and alteplase, 4.1 ASSENT-3
respectively; p = NS) and total stroke (1.78 versus 1.66%, for The ASSENT-3 trial [31] explored the efficacy and safety of
tenecteplase and alteplase, respectively; p = NS) were similar in combination therapy with the platelet glycoprotein IIb/IIIa
the two treatment arms. The rates of ICH were also similar to inhibitor abciximab plus reduced-dose tenecteplase in acute
those observed in the GUSTO-III trial, which compared the STEMI. A total of 6095 patients were randomised to one of
thrombolytic reteplase to alteplase (0.91 and 0.87%, for three regimens: full-dose tenecteplase plus UFH, full dose ten-
reteplase and alteplase, respectively) [28]. In ASSENT-2, ecteplase plus the low-molecular weight heparin (LMWH),
patients treated with tenecteplase did have a lower incidence of enoxaparin, or half-dose tenecteplase plus abciximab (with
bleeding episodes (26.1 versus 28.4%, p < 0.001), including weight-adjusted low-dose UFH). The UFH dosing schedule
major bleeding (4.7 versus 5.9%, p < 0.001), and they used in conjunction with full-dose tenecteplase in ASSENT-3
required fewer blood transfusions (4.3 versus 5.5%, p < 0.001) was more conservative than previous trials (60 U/kg bolus with
than patients treated with alteplase. Overall, these ASSENT-2 a maximum bolus of 4000 U, a 12 U/kg/h infusion with a
trial results demonstrated that weight-optimised dosing of ten- maximum rate of 1000 U/h; target: aPTT 50 – 70). The pri-
ecteplase has similar efficacy to alteplase with the clinical mary efficacy end point was the composite of 30-day mortal-
advantage of fewer bleeding events. ity, in-hospital reinfarction and in-hospital refractory
ischaemia. The primary safety end point was the above
3.6 Tenecteplase dosing regimen for acute myocardial primary efficacy end point plus the incidence of in-hospital
infarction ICH or major bleeding. The incidence of the primary efficacy
Based on the TIMI 10 and ASSENT-1 and 2 trials, the FDA end point was similar between the tenecteplase plus abciximab
approved tenecteplase for use in acute STEMI. The dosing combination therapy group and the tenecteplase plus LMWH
regimen is tiered according to the patient’s estimated or group (11.1 versus 11.4%, respectively; p = NS). However,

794 Expert Opin. Pharmacother. (2003) 4(5)

 Guerra, Karha & Gibson

both the enoxaparin and abciximab treatment arms had signif- efficacy end point among patients < 75 years of age in the ten-
icantly lower rates of the 30-day primary efficacy end point ecteplase plus enoxaparin group compared to the tenecteplase
when compared to tenecteplase plus UFH. The 30-day pri- plus UFH group (11.2 versus 15.2%, respectively; p = 0.033).
mary efficacy end points were 11.4 versus 15.4% (p = 0.0009) However, the tenecteplase plus enoxaparin group had higher
for the enoxaparin and UFH groups, respectively, and rates of ICH (2.2 versus 1.0%, p = 0.047) and total stroke
11.1 versus 15.4% (p < 0.0001) for the abciximab and UFH (2.9 versus 1.3%, p = 0.026) when compared to the tenect-
groups, respectively. Major bleeding was more common in the eplase plus UFH group. It is notable that in both the ASSENT-
tenecteplase plus abciximab combination therapy group com- 3 and ENTIRE-TIMI 23 trials, the combination of tenect-
pared to tenecteplase monotherapy group (4.3 versus 2.2%, eplase plus enoxaparin was generally associated with improved
p < 0.001). In a subgroup analysis, the patients > 75 years of safety and efficacy outcomes compared to tenecteplase plus
age and those with diabetes who received combination therapy UFH. It is unclear why these results were not reproduced in the
had more adverse events than those treated with UFH. This prehospital setting in the ASSENT-3 PLUS trial. Possible expla-
suggests that treatment with half-dose tenecteplase plus abcixi- nations include the older age and higher risk of the population
mab confers no benefit and may produce harm among these studied in ASSENT-3 PLUS as well as the additional dose of
patient populations. It is notable that the mortality rate of enoxaparin that was inadvertently administered in nearly
5.4% for the full-dose tenecteplase plus enoxaparin group is one-third of patients. The combination of enoxaparin and ten-
the lowest seen in a major thrombolytic trial. ecteplase will be further investigated in the EXTRACT trial.

4.2 ENTIRE-TIMI 23 5. Safety profile

The ENTIRE-TIMI 23 trial [32] evaluated the use of enoxa-
parin as part of the treatment for acute STEMI. A total of 5.1 High-risk patient groups
483 patients were randomised to receive full-dose tenecteplase Although the benefits of fibrinolytic therapy for acute STEMI
or a combination of abciximab plus half-dose tenecteplase. In are well-established, the risk of ICH remains a major limita-
addition, patients were randomised to receive UFH or enoxa- tion. Approximately two-thirds of patients who suffer this
parin in various doses. The rates of TIMI grade 3 flow 60 min complication die, and two-thirds of the survivors experience
following tenecteplase administration were similar across treat- important disability [36]. Known risk factors for major bleed-
ment arms (47 – 58%). There was no difference in 30-day ing include older age, female sex and low body weight [9,28,37].
death or reinfarction between the tenecteplase monotherapy In fact, women aged > 75 years have an eight-fold greater risk
group and the combination therapy group. However, bleeding for ICH compared with men aged < 65 years [38]. In the
complications were more common among the patients treated INJECT trial, which compared streptokinase and reteplase,
with the combination of abciximab plus half-dose tenecteplase. the incidence of bleeding complications was almost two times
Similar to what was observed in ASSENT-3, adjunctive enoxa- greater among low-weight patients (< 65 kg) compared to
parin was superior to UFH both in the setting of successful high-weight (> 80 kg) patients [37]. It is notable that analyses
thrombolysis and with rescue PCI. Enoxaparin treatment was of tenecteplase clinical trials suggest that the use of weight-
associated with a lower 30-day combined end point of death or optimised dosing may improve safety outcomes in elderly
reinfarction (4.9 versus 11.3%, p = 0.01) compared with female patients of low body weight.
UFH. This difference was due, predominantly, to a lower rein- Using data from ASSENT-2, Van de Werf et al. [39] com-
farction rate (1.8 versus 8.2%, p = 0.002). pared ICH rates among elderly, low-weight women (< 67 kg,
> 75 years) with all other women in the study. These high-risk
4.3 ASSENT-3 PLUS women tended to have lower rates of ICH if they were treated
The improved outcomes among patients treated early during with weight-optimised tenecteplase compared to alteplase
the course of acute STEMI have led to the consideration and (1.1 versus 3.0%, respectively; p < 0.05 in multivariate
evaluation of prehospital administration of fibrinolytic therapy. model). Patients in this subgroup were also less likely to suffer
This strategy has been demonstrated to reduce time-to-treat- a major bleeding event (8.3 versus 15.2%, for tenecteplase and
ment and improve mortality, especially in regions where the alteplase, respectively). The improved outcomes observed with
time-to-hospital arrival is prolonged [33,34]. The ease of admin- tenecteplase in this subgroup may reflect the benefits of
istration of both tenecteplase and enoxaparin makes this combi- weight-optimised dosing and/or improved fibrin specificity.
nation an especially attractive regimen for prehospital treatment Given the controversy regarding the use of fibrinolytic therapy
of acute STEMI. The ASSENT-3 PLUS trial [35] enrolled among high-risk subgroups such as the elderly [40,41], the lower
1639 acute STEMI patients who received prehospital adminis- rates of complications seen with tenecteplase among low-
tration of tenecteplase to randomised treatment with either weight, elderly women are especially encouraging.
UFH or enoxaparin. There was no difference between the treat-
ment arms in the composite end point of 30-day mortality, in- 5.2 Highbody weight patients
hospital myocardial infarction and in-hospital refractory ischae- The other important group of patients in the weight-opti-
mia. Subgroup analysis revealed a lower rate of the primary mised dosing schedule is the subset with high body weight

Expert Opin. Pharmacother. (2003) 4(5) 795

Tenecteplase

Table 3. Comparison of intracranial haemorrhage and mortality of thrombolytic agents in major clinical trials.

Drug Clinical trial ICH (%) Mortality (%) Reference

Tenecteplase ASSENT-2 0.93 6.17 [27]

Alteplase ASSENT-2 0.94 6.15 [27]

GUSTO-I 0.72 6.3 [10]

Streptokinase GUSTO-I 0.54 7.4 [10]

INJECT 0.37 9.53 [37]

Reteplase GUSTO-III 0.91 7.47 [28]

INJECT 0.77 9.02 [37]

Lanoteplase InTIME-2 1.13 6.77 [42]

ICH: Intracranial haemorrhage.

(> 90 kg). The concern in this population is that not enough Therefore, the possible association of weight-based tenecteplase
drug (i.e., less than the target dose of 0.53 mg/kg) is adminis- treatment with medication dosing error has been carefully eval-
tered. As mentioned previously, the patients in ASSENT-2 uated. Analysis of pooled data from > 4000 patients in the
who weighed > 90 kg, and therefore received tenecteplase TIMI 10B and ASSENT-1 trials revealed that dosing errors
50 mg (n = 1924), had a lower mortality compared to all the were less common with tenecteplase than with alteplase [43].
patients in the trial (4.8 versus 6.4%, respectively) [30]. This This analysis also revealed that errors in estimating patient
observation suggests that the efficacy of weight-optimised ten- weight were uncommon. These observations suggest that dos-
ecteplase was maintained in the high-weight patients. Like- ing of tenecteplase based on estimated patient weight rarely
wise, with regard to safety, the incidence of ICH among the leads to dosing error. Furthermore, post hoc analysis of data
high-weight patients was 0.57 compared to 1.08% for all the from ASSENT-2 indicated that incorrect dosing of tenecteplase
patients in the trial. Thus, weight-optimised dosing of tenect- of up to two dosing intervals (that is, up to a 20 kg weight
eplase in high-weight patients is safe and efficacious. error) is not associated with an excess risk of death or ICH [44].
These data in total indicate that weight-optimised dosing of
5.3 Safety outcomes with other thrombolytic agents tenecteplase provides a broad therapeutic margin of safety.
A comparison with other large trials indicates that weight-opti- The higher mortality rate among patients treated with ten-
mised dosing with tenecteplase is associated with low-to-mod- ecteplase who were not weighed raises concern about the safety
erate incidence of ICH and mortality (Table 3) [10,27,28,37,42]. of the weight-tiered dosing of tenecteplase. It is notable that in
the INJECT trial, which evaluated the two fixed dose fibrino-
6. Medication error and weight-optimised lytics reteplase and streptokinase, patients who were not
dosing weighed also had a higher mortality compared to patients who
were weighed [14]. This data illustrates the clear association
Medication errors are an important problem in delivering opti- between failure to weigh a patient and an increased risk of
mal medical care, including emergency cardiac care. Compli- death. The direction of causality in this association is not clear.
cated medication dosing regimens may increase the risk of That is, does the failure to record weight lead to worse out-
medication error. Thrombolytic agents such as alteplase and comes, perhaps by medication dosing errors, or are patients
reteplase require attention to the timing of medication adminis- who die early in their hospital course less likely to have their
tration (for instance, the duration of alteplase infusion and the weight recorded? Given that this association is seen with fixed
timing of the second dose of reteplase). On the other hand, ten- dose fibrinolytics, as well as tenecteplase, it would seem more
ecteplase is administered as a single bolus over 5 s, thus reduc- likely that the latter is the case. Indeed, in a separate ASSENT-2
ing these sources of medication error. Furthermore, whereas substudy, Angeja et al. [45] demonstrated that weight-optimised
reteplase and alteplase may precipitate in solution with the con- tenecteplase dosing based on a patient’s estimated weight was as
current administration of intravenous heparin, tenecteplase is safe and efficacious as alteplase across all weight categories.
compatible with this commonly used drug.
Another possible source of medication error arises when 7. Conclusion
treatment is based on patient weight. The challenge of accu-
rately determining patient weight is common to many emer- The use of thrombolytic agents in the management of acute
gency cardiac medications (including heparin, abciximab, STEMI is widely accepted. Tenecteplase is an engineered vari-
dobutamine and many others). The fact that excessive doses of ant of alteplase that has a longer half-life, greater fibrin specifi-
alteplase are associated with significantly higher rates of ICH city and greater resistance to PAI-1. In clinical trials comparing
[38] highlights the importance of accurate fibrinolytic dosing. tenecteplase and alteplase, the two agents had similar efficacy

796 Expert Opin. Pharmacother. (2003) 4(5)

 Guerra, Karha & Gibson

and similar risk of ICH. However, tenecteplase was associated 8. Expert opinion
with a lower incidence of bleeding complications. In addition,
the data suggest that tenecteplase may have an improved safety Numerous clinical trials have demonstrated the efficacy and
profile among high-risk populations such as elderly women safety of tenecteplase in the treatment of AMI. Biochemical
with low body weight. Careful analysis of weight-optimised modifications of tenecteplase allow for convenient single
dosing indicates that dosing errors with tenecteplase are rare bolus administration of the drug and a dosing schedule based
and do not lead to an increased risk of ICH or death. The on actual or estimated patient weight optimises safety and
recent studies suggesting that combination therapy with tenect- efficacy outcomes. The excellent clinical efficacy, safety profile
eplase and enoxaparin may be a highly efficacious regimen are and ease of use of tenecteplase make this drug a first-line
very encouraging and warrant further investigation. agent for the treatment of AMI.

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Affliation
Coronary Arteries (GUSTO III) Daniel R Guerra MD1, Juhana Karha MD1 &
infarction. Participants in the National
Investigators. N. Engl. J. Med. (1997) C Michael Gibson MS, MD†2
Registry of Myocardial Infarction 2. †Author for correspondence
337:1118-1123. Ann. Intern. Med. (1998) 129:597-604. 1Department of Medicine, Brigham and Women’s
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and efficacy of 50 mg of TNK-tPA in agents: a comparison of TNK-tPA and 2TIMI Data Coordinating Center and
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combination with enoxaparin, abciximab, in patients with myocardial infarction who E-mail: mgibson@[Link]
or unfractionated heparin: the ASSENT-3 are older than 75 years. Circulation (2000)
101:2239-2246.

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