Intravenous tenecteplase compared

with alteplase for acute ischemic

stroke in Canada (AcT)
Emily Johnson, PharmD
PGY-1 Pharmacy Resident
Acute Ischemic Stroke Background
2019 AHA/ASA Guidelines for the Early Management of Patients with
Acute Ischemic Stroke

2
 Acute Ischemic Stroke

Definition

•An acute focal injury due to lack of oxygen to the central nervous system
resulting in neurological deficits

Epidemiology

•Approximately 700,000 people have an acute ischemic stroke each year in

the US

Goals of Therapy

•Limit extent of neurologic injury and long-term disability, decrease mortality,

and prevent future strokes

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Powers WJ. N Engl J Med. 2020;383(3):252-60.
Zhu A, et al. Res Pract Thromb Haemost. 2022;6(6):e12795.
 Pathophysiology

Atherosclerosis of large and small arteries limits blood flow

Emboli that originate from the heart can result in obstruction within
a cerebral artery

Powers WJ. N Engl J Med. 2020;383(3):252-60.

 Risk Factors

Cigarette smoking
Hypertension
Diabetes
Dyslipidemia
Atrial fibrillation
Age
Race (African American)
Female gender
5

Powers WJ. N Engl J Med. 2020;383(3):252-60.

 Symptoms

Dysphasia Facial droop Unilateral weakness

Vision changes Headache

Powers WJ. N Engl J Med. 2020;383(3):252-60.

 Initial Acute Ischemic Stroke Assessment

▪ Timing of symptom onset

▪ National Institutes of Health Stroke Scale (NIHSS) is used to evaluate stroke
severity
▪ Noncontrast CT (NCCT) is effective to exclude intracerebral hemorrhage and guide
potential treatment
▪ Vital signs
▪ Blood pressure and oxygen saturation
▪ Labs
▪ Blood glucose
▪ INR (if applicable)
7
Powers WJ, et al. Stroke. 2019;50(12):e344-e418.
Zhu A, et al. Res Pract Thromb Haemost. 2022;6(6):e12795.
 Initial Acute Ischemic Stroke Management

▪ Hypoglycemia treatment
▪ Acute blood pressure management
▪ Revascularization treatment
▪ Consider fibrinolytic agent for patients who meet criteria
⎻ Alteplase is currently recommended in the guidelines
▪ Endovascular thrombectomy

8
Powers WJ, et al. Stroke. 2019;50(12):e344-e418.
Zhu A, et al. Res Pract Thromb Haemost. 2022;6(6):e12795.
 Alteplase vs. Tenecteplase

Alteplase MOA: binds to fibrin in a clot and converts plasminogen to

plasmin, resulting in fibrinolysis
Dosing: 0.09 mg/kg bolus, followed by a 60-minute infusion of
0.81 mg/kg (max: 90 mg)
Tenecteplase MOA: binds to fibrin and converts plasminogen to plasmin

Dosing: 0.25 mg/kg IV once (max: 25 mg)

Differences Tenecteplase has a longer half-life, is more fibrin specific, results

in less systemic depletion of circulating fibrinogen, and is more
resistant to plasminogen activator inhibitor than alteplase

Powers WJ, et al. Stroke. 2019;50(12):e344-e418.

Previous Clinical Trials

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 Tissue Plasminogen Activator for Acute Ischemic Stroke

NINDS Study

Objective To determine if administration of alteplase in acute ischemic stroke

reduces mortality or improves clinical outcomes at three months
Study Design Double blind, randomized, placebo-controlled
Methods Patients (N=624) were randomized to receive placebo or IV alteplase
Results • Patients in the alteplase group were 30 percent more likely to have
minimal disability at three months based on assessment scales
• Mortality at three months was 17% in the alteplase group and 21%
in the placebo group (P=0.30)

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N Engl J Med. 1995;333(24):1581-7.

 Thrombolysis with Alteplase 3 to 4.5 Hours after Acute Ischemic
Stroke

ECASS III Study

Objective To determine if alteplase is efficacious when administered between 3

and 4.5 hours after onset of stroke symptoms
Study Design Double-blind, randomized, placebo-controlled, phase 3 trial
Methods Patients (N=821) were randomized to receive placebo or IV alteplase
Results A greater proportion of patients had a favorable outcome with alteplase
administered between 3 and 4.5 hours after onset of symptoms than
with placebo (52.4% vs. 45.2%; odds ratio, 1.34; 95% confidence
interval [CI], 1.02 to 1.76; P=0.04)

12

Hacke W, et al. N Engl J Med. 2008;359(13):1317-29.

 Article Summary and Critique
Intravenous tenecteplase compared with alteplase for acute ischemic stroke in
Canada (AcT)

Objective: To evaluate tenecteplase compared with alteplase among patients

with acute ischemic stroke

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Menon BK, et al. Lancet. 2022;400(10347):161-169.

 Journal and Authors
▪ Lancet
▪ Impact factor: 202.731
▪ Provides high quality medical information
▪ Author
▪ Lead author is Bijoy K Menon
⎻ Professor of Neurology at the University of Calgary in Canada
⎻ Has hundreds of peer-reviewed publications in the field of neurosciences
▪ Study was funded by Canadian Institutes of Health Research

Menon BK, et al. Lancet. 2022;400(10347):161-169. 14

University of Calgary. Bijoy Menon. Accessed October 2, 2022.
Journal Citation Reports. Lancet. Accessed October 1, 2022.
 Study Design/Methods

Multicenter, open-label, parallel-group, registry-linked, randomized, controlled, non-inferiority trial

1600 patients were randomized in a 1:1 ratio to receive IV tenecteplase 0.25 mg/kg (max: 25
mg) or alteplase 0.09 mg/kg bolus + 0.81 mg/kg (max: 90 mg) infused over 60 minutes

Patients received standard care and follow-up imaging

The median follow-up was 97 days after randomization

Modified Rankin Scale (mRS) scores were determined via phone interviews by trained research
coordinators

15

Menon BK, et al. Lancet. 2022;400(10347):161-169.

 Study Design/Methods Critique

Multicenter Increases generalizability and external validity

Open-label Increases risk of bias
Randomized Ensures equal distribution of baseline characteristics, which
maintains internal validity
Noninferiority Design • Appropriate design to determine alternative fibrinolytic
agent
• Placebo unethical

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 Key Inclusion/Exclusion Criteria
Inclusion Criteria
•>18 years of age
•Diagnosis of ischemic stroke resulting in
disabling neurological deficit
•Presentation within 4.5 hours of symptom
onset
Menon BK, et al. Lancet. 2022;400(10347):161-169.
Exclusion Criteria
•Any active hemorrhage/condition that may
increase the risk of major hemorrhage after
alteplase administration
•History of intracranial hemorrhage
•Serious head or spinal trauma in the
previous three months
•Major surgery in the previous 14 days
•Symptoms indicative of subarachnoid
hemorrhage
•BP >185/>110
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Key Inclusion/Exclusion Criteria Critique

Inclusion/exclusion criteria seem appropriate

Identical to the other trials that established efficacy of

alteplase, such as the NINDS trial

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 Study Subjects

▪ Average age: 74 years old

▪ 52% male
▪ Median baseline NIHSS score: 10
▪ Stroke symptom onset to IV
thrombolysis initiation (minutes):
▪ Tenecteplase group: 128 minutes
▪ Alteplase group: 131 minutes

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Menon BK, et al. Lancet. 2022;400(10347):161-169.

Study Subjects Critique

The average age of 74 years is representative of patients who suffer from

ischemic stroke as the risk of ischemic stroke increases with age

52% of the subjects were male, indicating equal representation of gender

• Improves external validity

Slight imbalance in stroke severity at presentation in the two groups

• NIHSS score <8 in 40.5% in the tenecteplase group and 38.4% in the
alteplase group
• Potentially reduces internal validity

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 Primary Endpoint

Proportion of patients who had a score of 0

or 1 on the modified Rankin Scale (mRS) at
90 days

21

Menon BK, et al. Lancet. 2022;400(10347):161-169.

 Modified Rankin Scale (mRS)
Score Description
0 No symptoms at all
1 Symptoms are present but no significant disability
2 Slight disability, unable to carry out all previous
activities
3 Moderate disability, requires some assistance but
can walk independently
4 Moderately severe disability, unable to walk without
assistance
5 Severe disability, bedridden and consistently
requires care
6 Dead 22

Saver JL, et al. Stroke. 2021;52(9):3054-62.

Primary Endpoint Critique

The modified Rankin Scale (mRS) is the most widely used primary
outcome measure in stroke trials

The mRS is a valid tool for evaluating functional outcomes in

patients after stroke occurrence

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 Secondary Outcomes

mRS score 0-1 at 90-120

days

mRS score 0-2 at 90-120

days

Return to baseline function

Endovascular
thrombectomy use
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Menon BK, et al. Lancet. 2022;400(10347):161-169.

 Statistical Analysis

The noninferiority margin was defined a priori as 5%

• This margin is a fraction of the lower bound of the 95% CI in a meta-analysis of

randomized controlled trials (alteplase vs. placebo)
The study was adequately powered at 90% to evaluate non-inferiority of
tenecteplase to alteplase
• This is appropriate as the standard accepted minimum power is 80%

A generalized linear mixed-effects regression was used to perform the primary

endpoint analysis

25
Emberson J, et al. Lancet. 2014;384(9958):1929-35.
Menon BK, et al. Lancet. 2022;400(10347):161-169.
 Primary Outcome Results

Primary Outcome Tenecteplase group (n=806) Alteplase group (n=771)

mRS score 0-1 at 90-120 296/802 (36.9%) 266/765 (34.8%)

days (n=1567)

▪ Unadjusted risk difference 2.1% [95% CI -2.6 to 6.9]

▪ The lower bound 95% CI of the difference in primary outcome rate (-2.6%)
was greater than -5%
▪ Tenecteplase was not superior to alteplase in secondary analyses (p=0.19)

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Menon BK, et al. Lancet. 2022;400(10347):161-169.

Safety Outcomes

Symptomatic
intracerebral
hemorrhage

Orolingual angioedema

Extracranial bleeding
requiring blood
transfusion

90-day all-cause
mortality

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 Safety
Tenecteplase group Alteplase group
(n=800) (n=763)
Death within 90 days 15.3% 15.4%
of randomization

24 h symptomatic 3.4% 3.2%

intracerebral
hemorrhage
Extracranial bleeding 0.8% 0.8%
requiring blood
transfusions
Orolingual angio- 1.1% 1.2%
oedema
Other serious adverse 10.0% 9.1%
events
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Menon BK, et al. Lancet. 2022;400(10347):161-169.

 Summary of Strengths

▪ The trial was monitored by an independent data and safety monitoring committee
which reduces bias
▪ Both intention-to-treat and per-protocol analyses were used in the study
▪ Results were the same for both which maintains the internal validity of the
study
▪ Blinded endpoint adjudication process improves internal validity

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Menon BK, et al. Lancet. 2022;400(10347):161-169.

 Summary of Limitations

▪ Assessment of functional outcomes using the mRS may result in variability in the
results due to differences in clinical judgement, reducing internal validity
▪ Assessments of primary and secondary outcomes were performed via phone
interviews
▪ May reduce internal validity as assessment via telephone is likely less thorough
than in person assessment
▪ Safety outcomes were restricted to within 24 hours of thrombolysis, which may
limit definitive conclusions about safety
▪ Subjects and trial personnel were aware of treatment assignments
▪ Reducing internal validity

30

Menon BK, et al. Lancet. 2022;400(10347):161-169.

Conclusion/Impact on Practice

Based on these trial results, tenecteplase can be recommended as an alternative to

alteplase for the management of acute ischemic stroke

Benefits of tenecteplase

•Ease of administration
•Lower risk of dosing errors without infusion
•Faster treatment

Disadvantages of tenecteplase

•Unable to stop infusion if clinical status of patient changes

Clinical practice guidelines are expected to modify current recommendations

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 References
▪ Journal Citation Reports. Lancet. Accessed October 1, 2022. https://jcr.clarivate.com/jcr-jp/journal-
profile?journal=LANCET&year=2021&fromPage=%2Fjcr%2Fbrowse-journals.
▪ Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;333(24):1581-7.
▪ University of Calgary. Bijoy Menon. Accessed October 2, 2022. https://cumming.ucalgary.ca/departments/dcns/about/faculty/menon.
▪ Menon BK, Buck BH, Singh N, et al. Intravenous tenecteplase compared with alteplase for acute ischemic stroke in Canada (AcT): a pragmatic,
multicenter, open-label, registry-linked, randomised, controlled, non-inferiority trial. Lancet. 2022;400(10347):161-69.
▪ Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the
2018 guidelines for the early management of acute ischemic stroke: a guideline for healthcare professionals from the American heart
association/American stroke association. Stroke. 2019;50(12):e344-e418. doi: 10.1161/STR.0000000000000211.
▪ Powers WJ. Acute ischemic stroke. N Engl J Med. 2020;383(3):252-60. doi: 10.1056/NEJMcp1917030.
▪ Saver JL, Chaisinanunkul N, Campbell BC. Standardized nomenclature for modified Rankin scale global disability outcomes: consensus
recommendations from stroke therapy academic industry roundtable XI. Stroke. 2021;52(9):3054-62. doi: 10.1161/strokeaha.121.034480.
▪ Emberson J, Lees KR, Lyden P, et al. Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with
alteplase for acute ischemic stroke: a meta-analysis of individual patient data from randomized trials. Lancet. 2014;384(9958):1929-35. doi:
10.1016/S0140-6736(14)60584-5.
▪ Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med.
2008;359(13):1317-29. doi: 10.1056/NEJMoa0804656.
▪ Zhu A, Rajendram P, Tseng E, et al. Alteplase or tenecteplase for thrombolysis in ischemic stroke: an illustrated review. Res Pract Thromb 32
Haemost. 2022;6(6):e12795. doi: 10.1002/rth2.12795.
Intravenous tenecteplase compared
with alteplase for acute ischemic
stroke in Canada (AcT)
Emily Johnson, PharmD
PGY-1 Pharmacy Resident
Questions?

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