Journal club nortest trial

JOURNAL CLUB
Dr Prashant Shringi
Senior Resident
Neurology

NOR-TEST TRIAL
• Published on 2 August 2017 in Lancet Neurology

Introduction
• Intravenous thrombolysis is of proven benefit for
treatment of patients with ischaemic stroke within 4·5 h of
symptom onset, and alteplase is currently the only
agent approved for this purpose.

Alteplase has several shortcomings, such as low
recanalisation rate, risk of intracranial haemorrhage and
short half-life requiring continuous infusion.

Tenecteplase
• Mechanism of action:
• Half Life-90-130 min
• Promotes thrombolysis by converting plasminogen to
plasmin which degrades fibrin and fibrinogen.
• Genetically engineered variant of alteplase with multiple
point mutations of tPA molecule.

Advantage of Tenecteplase over
Aleteplase
• Longer plasma half –life
• Enhanced fibrin specificity
• Increased resistance to inactivation by plasminogen
activator inhibitor 1(PAI-1) compared to alteplase
• Less bleeding complications.

• In vitro and in animal models, tenecteplase has shown
a better thrombolytic profile and potency compared with
alteplase.
• In myocardial infarction, tenecteplase 0·5 mg/kg is the
thrombolytic agent of choice after a large, phase 3,
randomised controlled trial .

• Lower rates of non-cerebral bleeding complications in the
tenecteplase group than in the alteplase group

• In a phase 2b trial in highly selected patients with acute
ischaemic stroke and major intracranial occlusion,
• Patients receiving tenecteplase achieved better clinical
outcome and higher rates of reperfusion than those
receiving alteplase.

Previous Studies
• Phase 2B trial
• Result:Tenecteplase was asociated with significant
better outcome than alteplase in storke patients who
were selected on basis of CT perfusion imaging

• RESULTS OF ATTEST TRIAL:
• Between jan. 2012 and sept. 2013 157 eligible patient for
IV thrombolysis included .
• Neruological and radiological outcomes did not differ
between the tenecteplase and alteplase group

AIMS
• Investigate the safety and efficacy of tenecteplase
versus alteplase in patients eligible for intravenous
thrombolysis according to Norwegian guidelines

• Including patients further referred to endovascular
treatment, and patients with stroke symptoms on
awakening (wake-up stroke) whose MRI scans showed
mismatch between diffusion-weighted imaging (DWI) and
fluid-attenuated inversion recovery (FLAIR) imaging.

Methods
• Study design and participants:
• The Norwegian Tenecteplase Stroke Trial (NOR-TEST)
was a multicentre, prospective, randomised, open-label,
blinded endpoint, phase 3 study done in 13 stroke units
in Norway.

Eligibility
• Clinically suspected acute ischaemic stroke with
measurable deficits on the NIHSS Scale, were admitted
within 4·5 h of symptom onset or within 4·5 h of
awakening with symptoms, were aged 18 years or older

INCLUSION CRITERIA
• Patients who had symptoms on awakening or unknown
onset were included in the study and treated off-label if
mismatch between DW-MRI and FLAIR-MRI was
detected.
• Patients eligible for intravenous thrombolysis as bridging
therapy before endovascular treatment were included
in the study

• Inclusion of patients older than 80 years
• Patients with minor neurological deficits at
presentation,
• Previous history of stroke
• Concomitant diabetes mellitus was allowed

EXCLUSION CRITERIA
• Exclusion criteria reflected the current evidence regarding
contraindications.

METHODS
• Patients were enrolled between Sept 1, 2012, and Sept
30, 2016, and patients follow-up was completed on Dec
31, 2016.
• Written informed consent was obtained from the patient,
or from a close relative if the patient not able to sign

Randomisation and masking
• Patients meeting inclusion criteria were randomly
assigned (1:1) to receive either tenecteplase (0·4 mg/kg
to a maximum of 40 mg as a single bolus intravenously)
• Alteplase (0·9 mg/kg to a maximum of 90 mg, with 10% of
the dose as initial bolus, followed by 90% in a 1 h
intravenous infusion), via block randomisation

• Patients were not informed of treatment allocation.
• Residents and nurses in the emergency room were
aware of treatment allocation, whereas physicians and
nurses in the stroke unit were kept masked to treatment
allocation.

Demographic,clinicalstroke characterstic

Demographic,clinicalstroke charecterstic

Procedures
• Neurological deficits were measured with the NIHSS,
which was assessed at baseline, at 2 h, at 24–48 h, and
at 7 days after treatment (or at discharge if earlier).

• Functional outcomes were measured with the modified
Rankin Scale (mRS)
• mRS was assessed at 7 days (or at discharge if earlier),
and at approximately 3 months via telephone or as an
outpatient consultation

• Brain CT, CT angiography, and brain MRI were done on
admission before eligibility for thrombolytic treatment and
study inclusion
• Follow-up imaging consisted preferably of brain MRI, or
brain CT, at 24–48 h after treatment

Outcomes
• Primary study endpoint was excellent (0–1 points)
functional outcome at 3 months measured with mRS

• secondary outcomes were -
• Any intracranial haemorrhage occurring within 24–48 h
• Symptomatic intracranial haemorrhage occurring within
24–48 h
• Major neurological improvement at 24 hr measured with
NIHSS
• Ordinal shift analysis of mRS at 3 months
• Death within 3 months after inclusion

• Major neurological improvement was defined as either
NIHSS score of 0 at 24 h or a reduction in NIHSS score
of at least 4 points at 24 h compared with baseline.

Statistical analysis
• Two Arms-
• Intention –to-treat analysis
• Per-protocol analysis

Statistical analysis
• Main analysis of the outcomes was an intention-to- treat
analysis (including all randomly assigned
participants) without stratification
• Missing data for mRS were replaced by mRS score at 7
days or discharge and NIHSS score at 2 h, respectively
(last-observation-carried- forward imputation method)

• The per-protocol analysis excluded –
 patients found to stroke (stroke mimics)
patients with NIHSS score of 0 at admission,
patients with premorbid mRS score 2
patients with missing outcome data
 patients included in the NOR-SASS trial who were
randomised to ultrasound and microbubble contrast

Results
• Between Sept 1, 2012, and Sept 30, 2016, 1107 patients
were enrolled.
• Seven patients were excluded because informed
consent was withdrawn after inclusion or because
eligibility for thrombolytic treatment was reconsidered
before randomisation.
• Of the remaining 1100 patients, 549 were randomly
assigned to receive tenecteplase and 551 to receive
alteplase

• Descriptive methods were used to characterise the
sample
• Primary and secondary outcomes were tested with χ²,
Fisher’s exact test, or ordered logistic regression (mRS
shift analysis)

Intention-to-treat analysis:
354 (64%) of 549 patients in the tenecteplase group
and 345 (63%) of 551 patients in the alteplase group
achieved the primary outcome of mRS score 0–1 points at
3 months (odds ratio [OR] 1·08, 95% CI 0·84–
1·38;p=0·52)

• During the first 24–48 h after thrombolytic treatment,
any intracranial haemorrhage occurred in 47 (9%)
patients in the tenecteplase group and 50 (9%) patients
in the alteplase group (OR 0·94, 95% CI 0·60–1·45;
p=0·82)

• Symptomatic intracranial haemorrhage in 15 (3%) and
13 (2%) patients, respectively (OR 1·16, 95% CI
0·51–2·68; p=0·70)

• No difference in major neurological improvement at 24 h
or ordinal shift analysis at 3 months .
• By 3 months, 29 (5%) of 549 patients had died in the
tenecteplase group compared with 26 (5%) of 551 in
the alteplase group (OR 1·12, 95% CI 0·63–2·02;
p=0·68)

• Per-protocol analysis:
• 327 patients were excluded from the per-protocol
analysis because of one or several protocol violations
• Per-protocol analysis of the primary outcome
included 773 patients, of whom 382 were assigned
to tenecteplase and 391 to alteplase

• Excellent functional outcome was achieved by 244
(64%) patients in the tenecteplase group and 250 (64%)
patients in the alteplase group (OR 0·99, 95% CI 0·74–
1·33; p=0·98)
• No differences in any of the secondary outcomes
between the two treatment groups in the per-protocol
analysis

Discussion
• In this study, patients with acute ischaemic stroke treated
with tenecteplase showed similar rates of excellent
clinical outcome and intracranial haemorrhage to
patients treated with alteplase.

• NOR-TEST is the first randomised controlled phase 3
trial to investigate the safety and efficacy of
tenecteplase in acute ischaemic stroke

• A large number of patients were recruited within the
planned inclusion period, and the results of the study
are likely to be generalisable to a substantial
proportion of patients treated in a modern stroke unit

• Previous phase 2 studies showed that tenecteplase was
superior to alteplase in patients with major intracranial
occlusion and a salvageable penumbra

Not enough evidence to conclude that treatment with
tenecteplase 0·4 mg/kg exposes patients to higher risk of
bleeding complications than does alteplase
Study aimed to exploit fully the therapeutic potential of
tenecteplase

• On these premises, chose to use the previously
discarded tenecteplase dose of 0·4 kg/mg
• Results clearly suggest that this tenecteplase dose
might not be harmful compared with alteplase

• Low number of patients with severe stroke might also
account for the low rates of overall intracranial
haemorrhage and symptomatic intracranial haemorrhage
seen in both treatment groups
• which were lower than in previous phase 2 trials of
tenecteplase and earlier phase 3 trials comparing the
effect of alteplase versus placebo

Limitations
• 1. Assessment of NIHSS at baseline was done by the
emergency room physician before randomisation, and
later assessments by nurses or physicians at the stroke
unit instructed to not access the patient’s case report
form however, unmasking of the clinical assessment
cannot be ruled out.

• 2. Open-label design of the study might therefore have led
to potential bias in measurement of clinical outcomes,
especially in the acute phase

• 3.About 10% of the included patients had a premorbid
mRS score of 2 or more points and could therefore not
have achieved 0 or 1 point at 3-month mRS assessment
as required by the primary outcome

CONCLUSIONS
• In conclusion, tenecteplase was not superior, but
not inferior to alteplase for treatment of acute ischemic
stroke
• Similar safety profile as alteplase
• In future promising molecule for intrvenous thrombolysis
,but further phase 3 trials needed.

Journal club nortest trial

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