1120211

research-article2022
AOPXXX10.1177/10600280221120211Annals of PharmacotherapyWalton et al

Research Report
Annals of Pharmacotherapy

Major Bleeding Postadministration of

2023, Vol. 57(5) 535­–543
© The Author(s) 2022
Article reuse guidelines:
Tenecteplase Versus Alteplase in Acute sagepub.com/journals-permissions
DOI: 10.1177/10600280221120211
https://doi.org/10.1177/10600280221120211

Ischemic Stroke journals.sagepub.com/home/aop

Mary N. Walton, PharmD, BCCCP1,2 ,

Leslie A. Hamilton, PharmD, FCCP, FCCM, FNCS, BCPS, BCCCP1,2 ,
Sonia Salyer, PharmD2, Brian F. Wiseman, MD3, Ann M. Forster, FNP-BC3,
and A. Shaun Rowe, PharmD, MS, BCCCP, FNCS, FCCP1,2

Abstract
Background: Tenecteplase is a genetically engineered fibrinolytic with growing interest in the treatment of acute
ischemic stroke. Compared to alteplase, tenecteplase is effective for neurologic improvement following ischemic
stroke in patients with large vessel occlusions who are eligible for thrombectomy and for mild ischemic strokes with
National Institutes of Health Stroke Scale of 0 to 5. Objective: The purpose of this study is to determine if safety
outcomes are different in patients receiving tenecteplase and alteplase for acute ischemic stroke. Methods: This
retrospective cohort reviewed all patients who received alteplase or tenecteplase from January 2019 to December
2020. Patients admitted before April 28, 2020, received alteplase intravenous bolus over 1 minute followed by an
infusion over 1 hour, for a total of 0.9 mg/kg. Patients admitted after this date received tenecteplase 0.25 mg/kg as an
intravenous bolus over 5 to 10 seconds. Any patient transferring from an outside facility was excluded. The primary
outcome was major bleeding. Results: There was no significant difference in major bleeding between alteplase and
tenecteplase (40 [18%] vs 21 [18.1%], P = 0.985). There was no significant difference in all-cause inpatient mortality
for alteplase versus tenecteplase (10 [5%] vs 5 [4%], P = 0.934) or in adverse events between the groups (22 [9%] vs
14 [12%], P = 0.541) for alteplase and tenecteplase, respectively. Conclusions and Relevance: Tenecteplase had
similar rates of major bleeding versus alteplase and may be a reasonable alternative in the treatment of acute ischemic
stroke.

Keywords
stroke, ischemic stroke, tenecteplase, alteplase, thrombolytic

Introduction approximately $7000, and each 100 mg vial of TPA is approx-

Historically, alteplase (TPA) has been the drug of choice for
the treatment of acute ischemic stroke (AIS); however, data
are emerging supporting the use tenecteplase (TNK) as an
alternative fibrinolytic. TNK is a genetically engineered fibri-
nolytic with greater specificity for fibrin-bound clots com-
pared to TPA. In addition to its higher fibrin affinity, it also has
greater resistance to plasminogen activator inhibitor-1 (PAI-
1).1 Whereas TPA is rapidly inactivated by PAI-1, TNK has 80
times the resistance to this inactivation, making it more potent.
TNK is easier to administer; the half-life of TNK is longer at
20 to 40 minutes initially and then 90 to 130 minutes termi-
nally allowing for intravenous (IV) bolus compared to TPA at
5 minutes, which requires a bolus and infusion.1 In addition,
TNK is less expensive. Based on average wholesale pricing in
the United States as of June 2022, each 50 mg vial of TNK is
imately $10 000.2,3 With growing support from primary litera-
ture, the American Heart Association/American Stroke
Association (AHA/ASA) guidelines updated their recommen-
dation in 2019 to include TNK as a reasonable alternative to
1
Department of Pharmacy, University of Tennessee Medical Center,
Knoxville, TN, USA
2
Department of Clinical Pharmacy and Translational Science, University
of Tennessee Health Science Center College of Pharmacy, Knoxville,
TN, USA
3
Brain and Spine Institute, University of Tennessee Medical Center,
Knoxville, TN, USA
Corresponding Author:
Mary N. Walton, Department of Pharmacy, University of Tennessee
Medical Center, 1924 Alcoa Hwy, Knoxville, TN 37920, USA.
Email: marywalton18@gmail.com
536
Table 1. Primary Outcome Definitions.
2005 International Society on Thrombosis and Haemostasis (ISTH)15:
• Fatal bleeding and/or
• Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or
pericardial, or intramuscular with compartment syndrome, and/or
• Bleeding causing 2 g/dL or greater fall in hemoglobin or leading to a transfusion or 2 units or greater of whole blood or red cells
Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) definition16:
• Intracranial hemorrhage
• Bleeding that causes hemodynamic compromise and requires intervention
TPA in AIS in patients who are eligible to undergo mechani-
cal thrombectomy.4
The use of TNK outside of these populations remains an
area of uncertainty. Previous studies have shown that TNK is
as effective as TPA for neurologic improvement. A 2017 trial
by Logallo and colleagues5 (NOR-TEST) found no signifi-
cant differences in safety or efficacy. The 2018 EXTEND-IA
TNK trial found higher rates of recanalization with TNK
0.25 mg/kg versus TPA 0.9 mg/kg (22% vs 10%, P = 0.002,
respectively) and had a lower 90-day modified Rankin Scale
(mRS) (2 vs 3, P = 0.04).6 In these trials, TNK has displayed
similar efficacy to TPA for stroke in the literature.6-8
TNK, when administered at 0.25 mg/kg, may have fewer
bleeding complications versus TPA. In 2020, the
EXTEND-IA TNK part 2 trial reviewed TNK 0.4 mg/kg
versus 0.25 mg/kg.9 In this study, there was a trend toward
lower bleeding with 0.25 mg/kg dosing.9 However, no stud-
ies yet to date have reviewed safety outcomes as the pri-
mary endpoint when comparing the 2 medications in
all-comer ischemic stroke patients (ie, those with and with-
out a large vessel occlusion). The purpose of this study is to
compare safety outcomes of TNK compared to TPA for the
treatment of AIS in a real-world cohort regardless of pres-
ence of large vessel occlusion or degree of neurological
impairment as defined by baseline National Institutes of
Health Stroke Scale (NIHSS) scores.
Methods
Study Design
This study was a single-center, retrospective cohort evaluat-
ing adults admitted to an advanced comprehensive stroke
center. It was approved by the Institutional Review Board at
the institution. Data were collected via retrospective chart
review. All patients receiving TPA or TNK for AIS from
January 1, 2019, to December 31, 2020, were reviewed.
Study data were collected and managed using Research
Electronic Data Capture (REDCap) tools hosted at the
university.10
Study site. The institution where this research was per-
formed is an academic medical center and comprehensive
Annals of Pharmacotherapy 57(5)
stroke center caring for over 1000 stroke patients annually.
The medical center switched from TPA to TNK for AIS on
April 28, 2020. While TPA remains on formulary for cath-
eter clearance, myocardical infarction, and pulmonary
embolism, TNK is the thrombolytic of choice for ischemic
stroke. The same standard inclusion and exclusion criteria
for TPA are used for TNK. Thrombolysis is not routinely
used outside of the 4.5-hour window at our institution. All
inclusion and exclusion criteria for the use of thrombolytics
before and after implementation of TNK followed the 2015,
2018, and 2019 AHA/ASA Acute Ischemic Stroke Guide-
lines respective of their time of publication.11-13 Of note,
this institution does not utilize magnetic resonance imag-
ing–guided thrombolysis for stroke with unknown time of
onset as studied in the WAKE-UP trial,14 and a pharmacist
prepares the thrombolytic at the patient’s bedside.
Patient selection. Patients admitted before April 28, 2020,
received TPA 0.9 mg/kg (maximum dose of 90 mg) as a
10% IV bolus over 1 minute followed by the remaining
dose as an IV infusion over 1 hour. Patients admitted after
this date received TNK 0.25 mg/kg (maximum dose of 25
mg) IV bolus over 5 to 10 seconds. All patients 18 years and
older were included. Any patient transferring from an out-
side facility or receiving pharmacologic thrombolytic out-
side of AHA/ASA Acute Ischemic Stroke Guidelines
criteria was excluded.
Outcomes. The primary objective of this study was to deter-
mine if major bleeding, as defined by the 2005 International
Society on Thrombosis and Haemostasis (ISTH)15 or Global
Utilization of Streptokinase and Tissue Plasminogen Acti-
vator for Occluded Coronary Arteries (GUSTO) defini-
tion,16 is significantly different in patients receiving TNK
versus TPA for AIS until discharge. The definitions are out-
lined in Table 1.
The secondary objectives included 90-day mRS, post-
thrombectomy reperfusion of the ischemic territory based on
Thrombolysis in Cerebral Infarction (TICI) score, and mortal-
ity until discharge.17 Successful recanalization was defined as
a TICI score of 2b to 3. Computed tomography imaging of
intracranial hemorrhages (ICHs) was reviewed by an unblinded
neurologist and determined to be either symptomatic or
Walton et al
asymptomatic based on European Cooperative Acute Stroke
Study (ECASS) 3 criteria.18 The mRS scores were assessed by
providers or occupational therapists during the patient’s stay
and reported in the electronic medical record. Patients without
reported mRS scores were assessed by investigators through
documentation in the electronic medical record. Investigators
conducting data collection received training and certification
from the Neurological Emergencies Treatment Trials Network.
Statistical analysis. All statistical analysis was conducted with
IBM SPSS Statistic for Windows v.27.0.1.0 (IBM Corp.,
Armonk, NY, USA). Continuous variables were evaluated
for normality using the Shapiro-Wilk test and Kolmogorov-
Smirnov test and through visual inspection of histograms. All
continuous variables were found to have a nonnormal distri-
bution. Thus, all continuous variables were presented as
median and interquartile range, and between-group compari-
sons were conducted with a Mann-Whitney U test. Categori-
cal variables were presented as count and proportion of
group. Between-group comparisons were conducted with a
chi-square or Fisher’s exact test as appropriate.
An a priori power analysis was conducted based on pre-
vious literature. With an alpha of 0.05, 115 TNK and 172
TPA patients would need to be included in the study to meet
80% power to observe a 14% absolute difference in the
occurrence of major bleeding.
Results
A total of 367 patients were screened; 338 patients were
included in the analysis. As outlined in Figure 1, 29 patients
were excluded. Of the 338 patients analyzed, 222 (66%)
received TPA and 116 (34%) received TNK. The median
dose of TPA was 76.9 mg (IQR = 63.2, 90) and of TNK was
22 mg (IQR = 18.5, 25). The median time from symptom
onset to initiation of pharmacologic thrombolysis was 121
(IQR = 95, 183) minutes for TPA and 125 (IQR = 97, 173)
minutes for TNK (P = 0.498), and the time from arrival to
initiation of thrombolysis was 35 (IQR = 26, 53) minutes
for TPA and 37 (IQR = 28, 50) for TNK (P = 0.155).
General Characteristics
Baseline characteristics are outlined in Table 2. Characteris-
tics between the groups were similar. Significantly, more
patients in TPA had a large vessel occlusion (85 [38%] vs
25 [22%], P = 0.002). Patients had a longer hospital
length of stay for TPA versus TNK (4.5 [3,7] vs 4 [3,7],
P = 0.046).
Primary Outcome
There was no difference in major bleeding between groups
(40 [18%] vs 21 [18.1%], P = 0.985). In addition, there was
537
no difference in rates of ICH for TPA compared to TNK (35
[16%] vs 20 [17%], P = 0.727) as well as symptomatic ICH
(6 [2.7%] vs 2 [1.7%], P = 0.720). The primary outcome
results are outlined in Table 3.
Secondary Outcomes
There was no difference in all-cause inpatient mortality
between groups (10 [5%] TPA vs 5 [4%] TNK, P = 0.934).
Of the 59 TPA patients and 21 TNK patients with mechanical
thrombectomy and reported mTICI (modified Thrombolysis
in Cerebral Infarction) scale scores, 52 (88.1%) in TPA had
successful recanalization with a post-thrombectomy mTICI of
2b to 3 compared to 17 (81%) in TNK (P = 0.467). Functional
outcomes when assessed by mRS at 90 to 180 days in 92 TPA
and 40 TNK patients were not different for TPA versus TNK
(3 [1, 5] vs 2 [0, 5], P = 0.361); see Figure 2.
There was no difference in overall adverse events
between TPA and TNK (22 [10%] vs 14 [12%], P = 0.541),
including angioedema for TPA versus TNK (1 [0.5%] vs 3
[2.6%], P = 0.119). Other adverse events included infusion
reactions, progression of stroke, seizure, and neurologic
decline. All secondary outcomes are in Table 4.
Discussion
Our study found no significant difference in major bleeding
when comparing TPA and TNK for the treatment of AIS.
While the rates of ICH were comprehensively studied in
randomized controlled trials for ischemic stroke, we hoped
to address a gap in the literature by reviewing the incidence
of over major bleeding in all-comer strokes. Bleeding out-
comes for TNK were studied extensively in cardiology lit-
erature. The ASSENT-2 trial randomized patients with
myocardial infarction to TPA or TNK. The authors found
significantly less rates of noncerebral bleeding in the TNK
group, defined as bleeding requiring blood transfusion or
leading to hemodynamic compromise (5.94% [n = 8488]
TPA vs 4.66% [n = 8461] TNK, P = 0.0002).19 A 2016
meta-analysis of 3 trials and more than 17 000 patients
found a reduction in major bleeding with TNK compared to
TPA (RR = 0.79, 95% CI, 0.69-0.90, P = 0.0002). The tri-
als included patients with acute pulmonary embolism or
acute coronary syndrome; major bleeding was defined
using the 2005 ISTH or GUSTO definition, which our study
also used.20 Interestingly, our study found similar rates of
bleeding for TPA and TNK at 18% each for overall major
bleeding. In addition, our rates of intracranial bleeding were
similar to previous literature with 16% for TPA and 17% for
TNK and symptomatic ICH at 2.7% versus 1.7%, respec-
tively.5,6 Notably, the dosing for myocardial infarction is
higher than stroke; 35 mg for a 70 kg patient in myocardial
infarction versus roughly 17 mg for ischemic stroke, as well
as for TPA (15 mg bolus with 50 mg infusion over 30
538
Figure 1. Inclusion and exclusion criteria for patient selection.
Abbreviations: AIS, acute ischemic stroke; OSH, outside hospital.
minutes, then 35 mg over 1 hour for patients over 67 kg,
maximum total dose of 100 mg, for myocardial infarction
vs 0.9 mg/kg for stroke, maximum dose of 90 mg).2,3
When safety outcomes were studied in AIS, a recent meta-
analysis comparing rates of ICH for TNK versus TPA found
no significant difference but noted a trend toward less ICH
with TNK (OR = 0.81, 95% CI, 0.56-1.17, P = 0.26). This
analysis included both 0.25 mg/kg and 0.4 mg/kg dosing
Annals of Pharmacotherapy 57(5)
strategies from 5 randomized controlled trials of over 1500
patients.21 Of note, our study utilized only the lower dosing of
0.25 mg/kg. In a 2020 systematic review with meta-analysis
which included 8 trials and over 2000 patients, this also held
true for similar rates of ICH with TNK versus TPA (absolute
risk difference = 0.11, 95% CI, –0.06 to 0.01) as well as
symptomatic ICH (absoulte risk difference = 0.00, 95% CI,
–0.01 to 0.02).22 TNK dosing ranged from 0.1 mg/kg to
Walton et al 539

Table 2. Baseline Characteristics.

TPA TNK
Variable (n = 222) (n = 116) P value
Age, years—median (IQR) 66.9 (55.00, 85.00) 66 (50.2, 81.8) 0.585
Female—n (%) 95 (42.8) 58 (50) 0.206
Race/ethnicity—n (%) 0.490
White 207 (93.2) 98 (84.5) 0.010
African American 10 (4.5) 10 (8.6) 0.128
Asian 1 (0.5) 1 (0.9) 1.00
Hispanic 1 (0.5) 0 (0) 1.00
Other 3 (1.4) 7 (6.0) 0.036
Weight, kg—median (IQR) 87.00 (64.70, 109.30) 87.70 (66.30, 109.10) 0.796
Height, inches—median (IQR) 67.5 (63.4, 71.6) 66.7 (62.6, 70.8) 0.094
Comorbidities—n (%)
Previous myocardial infarction 33 (14.9) 9 (7.8) 0.060
Congestive heart failure 32 (14.4) 13 (11.2) 0.410
Peripheral vascular disease 13 (5.9) 2 (1.7) 0.080
Cerebrovascular disease (excluding hemiplegia) 109 (49.1) 47 (40.5) 0.133
Dementia 23 (10.4) 10 (8.6) 0.609
Chronic pulmonary disease 34 (15.3) 19 (16.4) 0.798
Connective tissue 6 (2.7) 1 (0.9) 0.429
Ulcer disease 34 (15.3) 2 (1.7) <0.001
DM without complications 42 (19.9) 26 (22.4) 0.447
DM with end organ damage 28 (12.6) 12 (10.3) 0.540
Hemiplegia 131 (59) 75 (64.7) 0.312
Moderate or severe renal diseasea 44 (19.8) 23 (19.8) 0.999
COVID-19 0 (0) 4 (3.5) 0.013
Smoker 80 (36) 41 (35.3) 1.000
Hypertension 167 (75.2) 92 (79.3) 0.420
Atrial fibrillation 45 (20.3) 24 (20.7) 0.151
Presence of LVO—n (%) 85 (38.3) 25 (21.6) 0.002
Cause of stroke—n (%) 0.680
Cardioembolic 61 (27.5) 26 (22.4)
Large artery atherosclerotic disease 34 (15.3) 19 (16.4)
Small vessel occlusion 26 (11.7) 10 (8.6)
Other 22 (9.9) 13 (11.2)
Undetermined 79 (35.6) 48 (41.4)
Time from stroke onset to first hospital arrival— 85 (57, 129) 79.5 (55, 116) 0.529
median (IQR), minutes
Time from stroke onset to initiation of intravenous 121 (95, 183) 125 (97.5, 172.5) 0.498
thrombolysis—median (IQR), minutes
Time from arrival to initiation of intravenous 35 (26, 53) 37 (28.5, 50) 0.155
thrombolysis—median (IQR), minutes
Received mechanical thrombectomy—n (%) 66 (29.7) 26 (22.4) 0.151
Charlson comorbidity index—median (IQR) 4 (2, 5) 3 (2, 4) 0.053
APACHE II score—median (IQR) 12 (9, 18) 13 (9, 17) 0.654
NIHSS score (n = 220, n = 114)—median (IQR) 7 (3, 14) 8 (4, 13) 0.912
Premorbid mRS (n = 125, n = 48)—median (IQR) 0 (0, 1) 0 (0, 1) 0.399

Abbreviations: APACHE, acute physiologic assessment and chronic health evaluation; COVID-19, coronavirus disease 2019; DM, diabetes mellitus;
IQR, interquartile range; LVO, large vessel occlusion; mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale; TNK,
tenecteplase; TPA, alteplase.
a
Defined as severe: dialysis, status post kidney transplant, uremia, and moderate: creatinine >3 mg/dL (0.27 mmol/L).

0.4 mg/kg. Our study also found no difference in major bleed- correlate with safety and efficacy data of previous literature.
ing for TPA compared to TNK (18% TPA vs 18% TNK, P = The EXTEND-IA TNK part 2 trial reviewed TNK dosing of
0.985).5,6 Our findings with a dosing strategy of 0.25 mg/kg 0.4 mg/kg versus 0.25 mg/kg.9 There were 150 patients in
540
Table 3. Primary Outcome.
Variable—n (%)
Bleeding
2005 International Society on Thrombosis and Haemostasis (ISTH) bleeding definition
Any fatal bleeding
Symptomatic bleeding in a critical area or organa
Bleeding causing 2 g/dL or greater fall in hemoglobin
Bleeding leading to a transfusion of 2 units or greater of whole blood or red cells
Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) bleeding definition
Intracranial hemorrhage
Symptomatic intracranial hemorrhage
Bleeding that causes hemodynamic compromise and requires intervention
Abbreviations: TNK, tenecteplase; TPA, alteplase.
a
Critical area or organ defined as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or intramuscular with compartment
syndrome.
Figure 2. Distribution of 90-day follow-up modified Rankin
scores for tenecteplase (TNK) (n = 40) and alteplase (TPA)
(n = 92).
each group with a mean age of 70 and median NIHSS score of
17. Doses of 0.25 mg/kg had similar reperfusion rates prior to
thrombectomy (19% vs 19%, P = 0.89) versus 0.4 mg/kg.9
There was no significant difference in all-cause deaths (17%
vs 15%; unadjusted risk difference, 2.7%) or symptomatic
ICH (5% vs 1%; unadjusted risk difference, 3.3%). Rates of
adverse events were similar in our groups; however, the rate
of angioedema was surprisingly low in the TPA group (0.5%)
when compared to TNK (2.3%), though not statistically sig-
nificant. We believe this was possibly due to a heightened
awareness of monitoring for adverse events after switching
primary thrombolytic to TNK, leading to increased reporting.
Our trial further cements the findings of recent random-
ized controlled trials for TNK in ischemic stroke. In the
2018 EXTEND-IA TNK trial, TNK was compared to TPA
for patients receiving mechanical thrombectomy within 4.5
hours of symptom onset. In all, 202 patients were enrolled
with a median baseline NIHSS of 17, time from stroke onset
to IV thrombolysis of 130 minutes, and mean age of 70. The
Annals of Pharmacotherapy 57(5)
TPA (n = 222) TNK (n = 116) P value
40 (18.0) 21 (18.1) 0.985
3 (1.4) 2 (1.7) 1.000
5 (2.3) 1 (0.9) 0.669
6 (2.7) 2 (1.7) 0.720
0 0
35 (15.8) 20 (17.2) 0.727
6 (2.7) 2 (1.7) 0.720
2 (0.9) 2 (1.7) 0.609
investigators found higher rates of reperfusion, as defined
by modified restoration of blood flow to greater than 50%
of involved territory or absence of retrievable thrombus,
with TNK (10% TPA vs 22% TNK, 95% CI, 2-21, P =
0.002) as well as significantly better functional outcomes as
defined by mRS at 90 days (median mRS of 3 TPA [IQR =
1, 5] vs 2 TNK [IQR = 0, 3], P = 0.04]; however, func-
tional outcomes were not different when looking at the pro-
portion of patients who were left with minimal or no deficit
or to the proportion of patients with early clinical improve-
ment of their stroke deficit or incidence of recovery to inde-
pendent function. Notably, the median baseline NIHSS
scores of our groups were classified as low to moderate
compared to a median of 17 seen in EXTEND-IA TNK.
They also found no significant difference in rates of cere-
bral hemorrhage (1% TPA vs 1% TNK). Symptomatic ICH
occurred in one patient each in the TPA and TNK groups.9,23
The 2017 NOR-TEST trial randomized 1100 patients to
either 0.4 mg/kg TNK or standard dose TPA24; patients were
administered thrombolysis within 4.5 hours of symptom
onset or within awakening with symptoms. Patients were a
mean age of 77 years old, and the median NIHSS score was
4 points at baseline. The authors found no significant differ-
ences in safety or efficacy, utilizing a mRS of 0 to 1 at 3
months as an excellent functional outcome.24 However, the
majority of patients experienced minor strokes based on
baseline NIHSS scores. Conversely, in the 2022 NOR-TEST
2 part A trial, the authors found worse safety and functional
outcomes for TNK at 0.4 mg/kg compared to TPA at 0.9 mg/
kg in patients with moderate or severe stroke.25 The rate of
favorable functional outcomes, defined as mRS of 0 to 1 at 3
months, was lower in the TNK compared to TPA (31 [32%]
vs 52 [51%], P = 0.0064). There was also more cases of
symptomatic ICH with TNK versus TPA (6 [6%] vs 1 [1%],
P = 0.061), for which the trial was terminated early. However,
this trial had several limitations—most notably, the use of 0.4
Walton et al 541

Table 4. Secondary Outcomes.

Variable TPA (n = 222) TNK (n = 116) P value

mRS at 90-180 days—median (IQR) 3 (1, 5) 2 (0, 5) 0.361
All-cause inpatient mortality—n (%) 10 (4.5) 5 (4.3) 0.934
Successful recanalizationa (n = 59, 21)—n (%) 52 (88.1) 17 (81.0) 0.467
Length of stay—median (IQR)
Hospital 4.5 (3, 7) 4 (3, 7) 0.047
ICU 3 (2, 3) 3 (2, 3) 0.140
Discharge disposition—n (%) 0.470
Home 115 (51.8) 53 (45.7)
SNF 37 (16.7) 17 (14.7)
Rehab 19 (8.6) 8 (6.9)
Deceased 12 (5.4) 6 (5.2)
Hospice 7 (3.2) 4 (3.5)
Left AMA 4 (1.8) 6 (5.2)
Home Health 22 (9.9) 19 (16.4)
Other 6 (2.7) 3 (2.6)
IA TPA given—n (%) 1 (1.5) 0 (0) 1.00
Adverse events—n (%) 22 (9.9) 14 (12.1) 0.541
Angioedema 1 (0.5) 3 (2.6) 0.119
Infusion reaction 0 0
Progression of stroke 11 (5) 6 (5.2) 0.931
Seizures 0 0
Neurologic decline 14 (6.3) 7 (6) 0.922
Other 2 (0.9) 0 (0) 0.548

Abbreviations: AMA, against medical advice; IA, intra-arterial; ICU, intensive care unit; IQR, interquartile range; mRS, modified Rankin Scale; SNF,
skilled nursing facility; TICI, Thrombolysis in Cerebral Infarction; TNK, tenecteplase; TPA, alteplase.
a
Successful recanalization defined as TICI 2b, 2c, or 3 post-thrombectomy.

mg/kg dosing which was shown to be inferior in previous
studies.21 Part B of this trial is ongoing utilizing 0.25 mg/kg
dosing. The patients assigned to TNK were older (median =
75 [IQR = 65, 83] vs 72 [58, 78] years old), had a mRS score
of 1 or greater before treatment (40 [40%] vs 28 [26.9%]),
and had more final diagnosis of ischemic stroke (17 [17%] vs
10 [9.6%]) compared to TPA.25
Major bleeding has not yet been studied as the primary
outcome of interest to these authors’ knowledge for TNK
use in ischemic stroke. A follow-up study to the EXTEND-IA
TNK trial further concluded that there was no advantage for
0.4 mg/kg dosing over 0.25 mg/kg dosing. There were no
significant differences in any of the functional outcomes
between the 0.4 mg/kg and 0.25 mg/kg groups as well as
symptomatic ICH (7 [4.7%] vs 2 [1.3%]; unadjusted risk
difference, 3.3% [95% CI, −0.5% to 7.2%]).9 Future pro-
spective trials should be conducted reviewing TNK at 0.25
mg/kg with a maximum of 25 mg for stroke for any patient
qualifying for TPA administration.
Study Limitations
One of the strengths of this article was the large consecutive
cohort of patients who received TNK for the treatment of
AIS at a comprehensive stroke center. The retrospective
nature of this study is a major limitation, which we sought
to overcome through this consecutive enrollment over a
substantial period of time. A large unforeseen limitation of
the study was the beginning of the coronavirus disease 2019
(COVID-19) pandemic in the United States around the time
of TNK’s implementation as the primary thrombolytic at
this institution in March 2020; patients hesitated to seek
health care during this time due to fear of the spread of
COVID-19. We believe that is the reason why we saw no
difference in time from symptom onset to initiation of phar-
macologic thrombolysis as well as time from arrival to ini-
tiation of thrombolysis for TNK, although we hypothesized
TNK would shorten the time as it is faster and easier to
administer. In normal circumstances, we believe the aver-
age time to pharmacologic thrombolysis will be shorter for
TNK compared to TPA, and this should be reviewed in
future literature. When evaluating hospital length of stay,
there was a statistical difference between groups, but the
median length of stay is numerically the same. We believe
this was due to outliers in the TPA group, so this difference
may not be clinically significant. Despite these limitations,
our study was able to review a significant number of patients
receiving either TPA or TNK. The 2 groups were similar in
acuity; both groups had Charlson comorbidity index scores
of moderate severities. We believe this study adds to the
542
growing literature supporting TNK in AIS and may be gen-
eralizable to the US population based on our real-world
experience.
Conclusion and Relevance
This trial adds to the growing literature supporting TNK’s
safety in ischemic stroke; additionally, it adds practical
experience from its implementation in a comprehensive
stroke center in the United States. TNK appears to be as
safe as TPA in treatment of AIS regardless of presence of
large vessel occlusion or requirements for mechanical
thrombectomy. Furthermore, TNK’s lower cost and easier
administration increase its applicability in practice. Based
on the results of this study, TNK may be considered as the
primary thrombolytic over TPA for AIS.
Authors’ Note
This work was presented in abstract form at the American Society
of Health System Pharmacists Annual Meeting, the Southeastern
Residency Conference, and the Society of Critical Care Medicine
Congress.
Acknowledgments
Each author has significantly contributed to this work per the
International Committee of Medical Journal Editors criteria and
has approved the manuscript in current form.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect
to the research, authorship, and/or publication of this article.
Funding
The authors received no financial support for the research, author-
ship, and/or publication of this article.
ORCID iDs
Mary N. Walton https://orcid.org/0000-0003-3299-4559
Leslie A. Hamilton https://orcid.org/0000-0002-7570-7380
A. Shaun Rowe https://orcid.org/0000-0002-2533-9233
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