Study reference

Study characteristics

Patient characteristics ²

Intervention (I)

Comparison / control (C) ³

Follow-up

Outcome measures and effect size ⁴

Comments

Campbell, 2018

Type of study: RCT

Setting: hospital

Country: Australia

Source of funding: the National Health and Medical Research Council of Australia (1043242, 1035688, 1113352, 1111972), the Royal Australasian College of Physicians, the Royal Melbourne Hospital Foundation, the National Heart Foundation of Australia, and the Stroke Foundation of Australia, by infrastructure funding from the state government of Victoria, and by an unrestricted grant from Medtronic.

Inclusion criteria: Patients were eligible if they could undergo intravenous thrombolysis within 4.5 hours after the onset of ischemic stroke and had cerebral vascular occlusion on CT angiography of the internal carotid artery, the first segment of the middle cerebral artery, the second segment of the middle cerebral artery, or the basilar artery and if treatment to retrieve the intraarterial clot could commence (arterial puncture) within 6 hours after stroke onset. No upper age limit; no restriction on clinical severity assessed NIHSS score

Exclusion criteria: severe preexisting disability, defined as a modified Rankin scale score of more than 3

N total at baseline:

Intervention: 101

Control: 101

Important prognostic factors²:

Age (mean ± SD)

I: 70.4±15.1

C: 71.9±13.7

Sex:

I: 57% M

C: 51% M

Groups comparable at baseline? yes

Describe intervention (treatment/procedure/test):

intravenous tenecteplase (at a dose of 0.25 mg per kilogram of body weight; maximum dose, 25 mg)

Describe control (treatment/procedure/test):

alteplase (at a dose of 0.9 mg per kilogram; maximum dose, 90 mg).

Length of follow-up: 90 days

Lost to follow-up:

Not reported

Incomplete outcome data:

Not reported

Outcome measures and effect size (include 95%CI and p-value if available):

Ordinal score on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]) at day 90:

I: 2

C: 3

Functional independence (defined as a score on the modified Rankin scale of 0 to 2) at day 90.

I: 65/101 = 64%

C: 52/101 = 51%

Death within 90 days:

52 patients were death, there was no difference between

I: 10/101 10%

C: 18/101 18%

Occurrence of symptomatic intracranial hemorrhage within 36 hours, defined as an increase of at least 4 points in the NIHSS score that was associated with brain haemorrhage on imaging within 36 hours after symptom onset:

I: 1/101= 1%)

C: 1/101 = 1%)

Huang, 2015

Type of study: RCT

Setting: hospital

Country: Scotland

Source of funding: This study was funded by a grant (TSA 2010/04) from The Stroke Association.

Inclusion criteria: clinically diagnosed supratentorial acute ischaemic stroke with measurable defi cit on the National Institutes of Health stroke scale (NIHSS),10 were within 4·5 h of symptom onset, were aged 18 years or older, were living independently pre-stroke, and were considered eligible for intravenous thrombolysis according to clinical guidelines.

Exclusion criteria: refl ected the current evidence regarding contraindications

N total at baseline:

Intervention: 47

Control: 49

Important prognostic factors²:

Age (SD)

I: 71 (13)

C: 71 (12)

Sex:

I: 64% M

C: 63% M

Groups comparable at baseline? yes

Describe intervention (treatment/procedure/test):

Tenecteplase (0·25 mg per kg, to a maximum 25 mg as a single bolus)

Describe control (treatment/procedure/test):

Alteplase (0·9 mg per kg to a maximum 90 mg, with 10% of dose as initial bolus, followed by 90% in a 1 h infusion) or

Length of follow-up: 3 months

Remarks:

Eight patients ultimately had a diagnosis other

than stroke and were excluded from the protocol-defined

analysis.

Incomplete outcome data:

Not reported

Outcome measures and effect size (include 95%CI and p-value if available):

Ordinal score on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]) at day 90:

I:

C:

Functional independence (defined as a score on the modified Rankin scale of 0 to 2) at day 90.

I: 17/47 = 36%

C: 19/49 =39%

Death within 90 days:

52 patients were death, there was no difference between

I: 8/47 = 17%

C: 6/49 = 12%

Occurrence of symptomatic intracranial hemorrhage within 36 hours, defined as an increase of at least 4 points in the NIHSS score that was associated with brain haemorrhage on imaging within 36 hours after symptom onset:

I: 3/52 (6%)

C: 4/51 (8%)

.

Logallo, 2017

Type of study: RCT

Setting: hospital

Country: Norway

Source of funding: This study was funded by a grant from the Research Council of Norway.

Inclusion criteria:

eligible if they had clinically suspected acute ischaemic stroke with measurable deficits on the National Institutes of Health Stroke Scale (NIHSS), were admitted within 4·5 h of symptom onset or within 4·5 h of awakening with symptoms, were aged 18 years or older, were living independently pre-stroke, and were judged eligible for intravenous thrombolysis according to Norwegian clinical guidelines, which are similar to European guidelines. 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 and patients with minor neurological deficits at presentation, previous history of stroke, and concomitant diabetes mellitus was allowed.

Exclusion criteria:

See current evidence for contraindications

N total at baseline:

Intervention: 549

Control: 551

Important prognostic factors²:

Age (median)

I: 70.8 ± 14.4

C: 71.2 ± 13.2

Sex:

I:58 % M

C: 62% M

Groups comparable at baseline? yes

Describe intervention (treatment/procedure/test):

Tenecteplase

tenecteplase (0·4 mg/kg to a maximum of 40 mg as a single bolus intravenously)

Describe control (treatment/procedure/test):

Alteplase

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)

Length of follow-up: 3 months

Lost to follow-up:

7 excluded (withdrawal of informed consent or reconsidered eligibility)

Incomplete outcome data:

Remarks

Outcome measures and effect size (include 95%CI and p-value if available):

Ordinal score on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]) at day 90:

I:

C:

Functional independence (defined as a score on the modified Rankin scale of 0 to 2) at day 90.

I: (202+152+67=421)/549 = 77%

C: (173+172+87=432)/551 = 78%

(Excellent functional outcome (defined as a score on the modified Rankin scale of 0 to 1) at day 90.

I: 354/549 = 64%

C: 345/551 = 63%)

Death within 90 days:

52 patients were death, there was no difference between

I: 29/549.= 5%

C: 26/551 = 5%

Occurrence of symptomatic intracranial hemorrhage within 36 hours, defined as an increase of at least 4 points in the NIHSS score that was associated with brain haemorrhage on imaging within 36 hours after symptom onset:

I: 15/549 = 3%)

C: 13/551 = 2%)

Median National Institutes of Health Stroke Scale score at baseline was 4 points (IQR 2-8).

Haley, 2010

Type of study: RCT

Setting: hospital

Country: USA

Source of funding: grants from National Institute of Neurological Disordes and Stroke NIH

Inclusion criteria:

age 18 or over with serious neurological deficits believed to be on the basis of acute focal cerebral ischemia, and who were otherwise suitable for treatment with intravenous rt-PA within 3 hours of stroke onset using contemporary guidelines.

Exclusion criteria:

Reasons for exclusion were reported

N total at baseline:

Intervention: TNK in three doses 31 +31 + 19 = 81

Control: rt-PA = 31

Important prognostic factors²:

Age (median)

I: 68

C: 72

Sex:

I: (12+16+13)/81 51% M

C: 51 % M

Groups comparable at baseline? Patients randomized to rt-PA were older and had more severe stroke deficits at baseline than patients in the tenecteplase groups

Describe intervention (treatment/procedure/test):

TNK in three doses

the dose-selection component of Phase IIB compared three tenecteplase doses: 0.1

mg/kg, 0.25 mg/kg, and 0.4 mg/kg.

Describe control (treatment/procedure/test):

Rt PA

Length of follow-up:

3 months

Incomplete follow-up:

Four patients were either lost to follow up or voluntarily withdrew from the trial. Their 3 month Rankin categories were imputed using the last observation carried forward or the last recorded NIH Stroke Scale score using a pre-specified algorithm

Outcome measures and effect size (include 95%CI and p-value if available):

Ordinal score on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]) at day 90:

I:

C:

Functional independence (defined as a score on the modified Rankin scale of 0 to 2) at day 90.

I: (14+15+7=36)/(31+31+19=81)=44%

C: 13/31 = 42 %

Death within 90 days:

52 patients were death, there was no difference between

I: (2+7+3)/(31+31+19) 15%

C: (8/31) 26%

Occurrence of symptomatic intracranial hemorrhage within 36 hours, defined as an increase of at least 4 points in the NIHSS score that was associated with brain haemorrhage on imaging within 36 hours after symptom onset:

I: ((0+2+3)/(31+31+19)=6%)

C: (1/31) 3%)

Three doses of tenecteplase compared

The trial was prematurely terminated for slow enrollment after only 112 patients had been randomized at 8 clinical centers between 2006 and 2008. The 0.4 mg/kg dose was discarded as inferior after only 73 patients were randomized, but the selection procedure was still unable to distinguish between 0.1 mg/kg and 0.25 mg/kg as a propitious dose at the time the trial was stopped

Parsons, 2012

Type of study: RCT

Setting: hospital

Country: Australia

Source of funding: Supported by a grant from the Australian National Health and Medical Research Council. Dr. Parsons reports receiving advisory-board fees from Bayer Australia; Dr. Campbell, consultancy fees from Lundbeck, speaker payments from Boehringer Ingelheim Australia, and grant support from Cardiovascular Lipid Australia; Dr. Bladin, advisory-board fees from Bayer Australia; Dr. Donnan, consultancy fees from Boehringer Ingelheim Australia and Bayer Australia; Dr. Davis, consultancy fees from Orsan Technologies and Ever Pharma; and Dr. Levi, consultancy fees from Boehringer Ingelheim Australia. No other potential conflict of interest relevant to this article was reported.

Inclusion criteria: first-ever hemispheric ischemic stroke who were 18 years of age or older, had a score greater than 4 on the National Institutes of Health Stroke Scale (NIHSS; a 42-point scale that quantifies neurologic deficits in 11 categories, with higher scores indicating more severe deficits), and a premorbid score of 2 or less on the modified Rankin scale (which ranges from 0 to 6, with 0 indicating no symptoms and 6 indicating death) (Table 1).

Exclusion criteria:

Standard contra-indications to alteplase

N total at baseline:

Intervention: 50 (25 each dose)

Control: 25

Important prognostic factors²:

Age (median)

I 0.1: 72±6.9

I 0.25: 68±9.4

C: 70±8.4

Sex:

I: 52% M

C: 48% M

Groups comparable at baseline? the alteplase group included fewer persons who smoked (P = 0.01); this group also included fewer persons with diabetes (P = 0.01)

Describe intervention (treatment/procedure/test):

Tenecteplase (0.1 mg per kilogram, administered as a single bolus, with a maximum dose of 10 mg; or 0.25 mg per kilogram, administered as a single bolus, with a maximum dose of 25 mg).

Describe control (treatment/procedure/test):

Standard dose of alteplase (0.9 mg per kilogram, the first 10% administered as an initial bolus and the remainder over a 1-hour period, with a maximum dose of 90 mg)

Length of follow-up:

Remarks:

Incomplete outcome data:

Outcome measures and effect size (include 95%CI and p-value if available):

Ordinal score on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]) at day 90:

I:

C:

Functional independence (defined as a score on the modified Rankin scale of 0 to 2) at day 90.

I: 36/50 = 72%

C: 11/25 = 44%

Death within 90 days:

52 patients were death, there was no difference between

I: 4/50 = 8%

C: 3/25 = 12%

Occurrence of symptomatic intracranial hemorrhage within 36 hours, defined as an increase of at least 4 points in the NIHSS score that was associated with brain haemorrhage on imaging within 36 hours after symptom onset:

I: 2/50 = 4%

C: 3/25 = 12%

mean (±SD) NIHSS score for all patients in the trial was relatively high at 14.4±2.6

Study reference

(first author, publication year)

Describe method of randomisation¹

Bias due to inadequate concealment of allocation?²

(unlikely/likely/unclear)

Bias due to inadequate blinding of participants to treatment allocation?³

(unlikely/likely/unclear)

Bias due to inadequate blinding of care providers to treatment allocation?³

(unlikely/likely/unclear)

Bias due to inadequate blinding of outcome assessors to treatment allocation?³

(unlikely/likely/unclear)

Bias due to selective outcome reporting on basis of the results?⁴

(unlikely/likely/unclear)

Bias due to loss to follow-up?⁵

(unlikely/likely/unclear)

Bias due to violation of

intention to treat analysis?⁶

(unlikely/likely/unclear)

Campbell, 2018

Randomization was performed with the use of a centralized Web server, with stratification according to the site of the involved vessel (internal carotid artery, basilar artery, first segment of the middle cerebral artery, or second segment of the middle cerebral artery).

unlikely

unlikely

unlikely

unlikely

unlikely

unlikely

unlikely

Haley, 2010

Patients were randomized using a web-based randomization procedure, within sites to quadruplets – one of the three tenecteplase doses, or rt-PA – but only the triplet tenecteplase arms were involved in the selection procedure. (The rt-PA patients provided concurrent randomized controls for later comparisons of 3 month outcome with the selected tenecteplase dose.)

unlikely

unlikely

unlikely

unlikely

unlikely

unlikely

unlikely

Huang, 2015

A mixed minimisation and randomisation approach. Within each block of eight patients, two were allocated at random (one to alteplase, one to tenecteplase) and six were allocated using minimisation with respect to age (≤80 years and ≥81 years) and NIHSS score (1–9, 10–15, and 16–42).

When the minimisation algorithm did not favour allocation to either group, the allocation was random.

The order with which patients were allocated by randomisation or minimisation (and the random allocation to be used, if required) was defined by a prespecified sequence generated using the method of randomised permuted blocks. The allocation to treatment groups was obtained by telephone to an interactive voice response system (IVRS) developed at the Robertson Centre for Biostatistics, University of Glasgow. The computer program (and random seed) used to generate the minimisation and randomisation sequence was written by a statistician who was not involved with the final analysis, and was stored in a secure network location with access restricted to staff responsible for the development and maintenance of the study IVRS. Clinicians responsible for routine clinical care were aware of treatment assignment because drug administration schedules differ (alteplase requires to be administered as an infusion over 1 h).

unlikely

unlikely

Unclear, not blinded

unlikely

unlikely

unlikely

unlikely

Logallo, 2017

Patients meeting inclusion criteria were randomly assigned (1:1) to receive either tenecteplase or 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 (block size of four) stratified for site of inclusion but not for baseline characteristics. A biostatistician (JA) created the randomisation sequence using computer-generated random numbers. Envelopes were used to simplify and speed up logistics. To minimise predictability of content in future envelopes and ensure proper randomisation, centres were not informed about block size and envelopes were numbered from 1 to 150. Patients were not informed of treatment allocation.

unlikely

unlikely

Unclear, not blinded

unlikely

unlikely

unlikely

unlikely

Parsons, 2012

central block randomization

was performed by the Centre for

Clinical Epidemiology and Biostatistics, University

of Newcastle, in blocks of 15 to allow the data and

safety monitoring board to review blinded safety

data after the recruitment of every 15 patients.

Randomization was performed by means of a central

telephone service.

unlikely

unlikely

Unclear, not blinded

unlikely

unlikely

unlikely

unlikely

Auteur en jaartal

Redenen van exclusie

Bivard, 2017

Gaat over target mismatch criteria, sluit niet aan op de PICO

Campbell, 2018

Alleen studie design

Huang, 2015

Uitkomsten fibrinolytic activity en protrombinetijd, dat komt niet overeen met PICO

Huang, 2015

Dit is hetzelfde artikel als Huang, 2016

Huang, 2016

Analyse van patiëntdata van 3 RCTs, inmiddels zijn er 5 RCTs beschikbaar

Rother, 2013

Breed beschrijvend artikel, sluit niet aan op PICO

Thelengana, 2018

Systematische review van 4 RCTs, inmiddels zijn er 5 RCTs beschikbaar

Tsivgoulis, 2014

Opzet van dit artikel is veel breder dan de PICO, ook allerlei andere strategieën worden vergeleken

Wardlaw

Artikel niet vindbaar, wellicht alleen een abstract