Berkhemer, 2015

MR CLEAN

Type of study: RCT

Setting: hospital

Country: The Netherlands

Source of funding: Supported by the Dutch Heart Foundation and by unrestricted grants from AngioCare Covidien/ev3, Medac/Lamepro, and Penumbra.

Inclusion criteria: Initiation of intraarterial treatment had to be possible within 6 hours after stroke onset. An occlusion of the distal intracranial carotid artery, middle cerebral artery (M1 or M2), or anterior cerebral artery (A1 or A2), established with computed tomographic (CT) angiography (CTA), magnetic resonance angiography (MRA), or digital-subtraction angiography (DSA), and a score of 2 or higher on the National Institutes of Health Stroke Scale (NIHSS; range, 0 to 42, with higher scores indicating more severe neurologic deficits). Inclusion of patients with an additional extracranial internal- carotid-artery occlusion or dissection was left to the judgment of the treating physician.

Exclusion criteria:

N total at baseline:

Intervention: 233

Control: 267

Important prognostic factors²:

Age (median)

I: 65.8

C: 65.7

Sex:

I: 57.9% M

C: 58.8% M

Groups comparable at baseline? yes

Describe intervention (treatment/procedure/test):

Intraarterial treatment consisted of arterial catheterization with a microcatheter to the level of occlusion and delivery of a thrombolytic agent, mechanical thrombectomy, or both. The method of intraarterial treatment was left to the discretion of the local interventionist.

The use of alteplase or urokinase for intraarterial thrombolysis was allowed in this trial, with a maximum dose of 90 mg of alteplase or 1,200,000 IU of urokinase. The dose was restricted to 30 mg of alteplase or 400,000 IU of urokinase if intravenous alteplase was given. Mechanical treatment could involve thrombus retraction, aspiration, wire disruption, or use of a retrievable stent.

Describe control (treatment/procedure/test):

Usual care (which could include intravenous

administration of alteplase)

Length of follow-up:

90 days

Remarks:

Intraarterial treatment was never initiated in 17 patients (7.3%) assigned to the

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: 3 (2 to 5)

C: 4 (3 to 5)

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

I: 76/233 (32.6%)

C: 51/267 (19.1%)

Death within 90 days:

52 patients were death, there was no difference between

I: 44/233 = 19%

C: 49/267 = 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: 18 (7.7%)

C: 17 (6.4%)

Actual intraarterial therapy (with or without mechanical thrombectomy) was performed in 196 of the 233 patients in the intervention group (84.1%). In 88 patients (37.8%), general anesthesia was used. A simultaneous second revascularization procedure (acute cervical carotid stenting) was performed in 30 patients (12.9%). Mechanical treatment was performed in 195 of the 233 patients (83.7%). Retrievable stents were used in 190 patients (81.5%), and other devices were used in 5 patients (2.1%) (Table S2 in the Supplementary Appendix). Additional intraarterial thrombolytic agents were given to 24 patients (10.3%).

Bracard, 2016

Thrace

Type of study: RCT

Setting: hospital

Country: USA

Source of funding: funded by the French Ministry for Health as part of its 2009 STIC programme for the support of costly innovations (grant number 2009 A00753-54)

Inclusion criteria: acute ischaemic stroke were eligible for inclusion if they were aged 18–80 years; had a US National Institutes of Health Stroke Scale (NIHSS) score of 10–25; had an occlusion of the intracranial internal carotid artery, the M1 segment of the middle cerebral artery, or the superior third of the basilar artery confirmed by CT or magnetic resonance

angiography; could be administered intra venous thrombo lysis within 4 h of symptom onset; and if thrombectomy could be initiated within 5 h of symptom onset.

Exclusion criteria: Patients who had cervical internal carotid artery occlusion and subocclusive stenosis

N total at baseline:

Intervention: 208

Control: 204

Important prognostic factors²:

For example

age ± SD:

I: 66 (54–74)

C: 68 (54–75)

Sex:

I: 57% M

C: 50% M

Groups comparable at baseline? yes

Describe intervention (treatment/procedure/test):

Intravenous thrombolysis and mechanical thrombectomy (IVTMT group)

All patients received intravenous thrombolysis as per standard care—ie, 0·9 mg/kg of alteplase (maximum 90 mg), with an initial bolus of 10% of the total dose, and then infusion of the remaining dose over 60 min, irrespective of group assignment. Initially, patients allocated to the IVTMT group were to be clinically assessed after the completion of intravenous thrombolysis but before angiography.

Describe control (treatment/procedure/test):

intravenous thrombolysis alone (IVT group).

All patients received intravenous thrombolysis as per standard care—ie, 0·9 mg/kg of alteplase (maximum 90 mg), with an initial bolus of 10% of the total dose, and then infusion of the remaining dose over 60 min, irrespective of group assignment

Length of follow-up:3 months

Loss-to-follow-up:

Intervention:

N (%) 2

Reasons (describe)

Control:

N (%) 2

Reasons (describe)

Incomplete outcome data:

Intervention: 2

N (%)

Reasons (describe)

Control:

N (%) 4

Reasons (describe)

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

Functional independence (defined as a score of 0,

1, or 2 on the modified Rankin scale) at day 90.

I: 106/200 =53%

C: 85/202 = 42%

Death within 90 days:

I: 24/202 = 12%

C: 27/206 = 13%

Occurrence of symptomatic intracranial hemorrhage (defined according to European Cooperative Acute Stroke Study III criteria as the presence of extravascular blood in the cranium that was associated with an increase in the NIHSS score of ≥4 points or death and was judged to be the predominant cause of neurologic deterioration) within 24 hours after randomization:

I: 4/185 = 2%

C: 3/192 = 2%

Broderick, 2013

IMS III

Type of study: RCT

Setting: hospital

Country: USA

Source of funding: grants from the National Institutes of Health and the National Institute of Neurological Disorders and Stroke (UC U01NS052220, MUSC U01NS054630, and U01NS077304) and by Genentech, EKOS, Concentric Medical, Cordis Neurovascular, and Boehringer Ingelheim.

Inclusion criteria:

receipt of intravenous t-PA within 3 hours after symptom onset and a moderate-to-severe neurologic deficit (defined as an NIHSS score ≥10 or, after approval of amendment 3, a score of 8 to 9 with CT angiographic evidence of an occlusion of the first segment of the middle cerebral artery [M1], internal carotid artery, or basilar artery at institutions where CT angiographic imaging at baseline was the standard of care for patients with acute stroke).

Exclusion criteria:

N total at baseline:

Intervention: 434

Control: 222

Important prognostic factors²:

age (median):

I: 69

C: 68

Sex:

I: 50% M

C: 55% M

Groups comparable at baseline? Yes, except for history of coronary artery disease

Describe intervention (treatment/procedure/test):

All participants began receiving a standard dose of intravenous t-PA (0.9 mg per kilogram), with 10% as a bolus and the remainder infused over a 1-hour period (maximum dose, 90 mg). Throughout the trial, randomization was required within 40 minutes after the initiation of the infusion.

Participants randomly assigned to the endovascular-therapy group underwent angiography as soon as possible, either at the hospital that initiated treatment with intravenous t-PA or at another participating hospital. Participants who had no angiographic evidence of a treatable occlusion received no additional treatment, and those with a treatable vascular occlusion received endovascular intervention with an approach chosen by the site neurointerventionalist.

Describe control (treatment/procedure/test):

All participants began receiving a standard dose of intravenous t-PA (0.9 mg per kilogram), with 10% as a bolus and the remainder infused over a 1-hour period (maximum dose, 90 mg). Throughout the trial, randomization was required within 40 minutes after the initiation of the infusion. The patients randomly assigned to the intravenous t-PA group received the remainder of the standard dose.

Length of follow-up: 3 months

Remarks:

An unfavorable imputation was applied for 27 participants (14 participants for whom the primary outcome was assessed outside the specified 30-day

window and 13 for whom the primary outcome was not assessed).

Loss-to-follow-up:

Not reported

Incomplete outcome data:

Not reported

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

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

I: 177/434 = 40.8%

C: 86/222 = 38.7%

absolute adjusted difference, 1.5 percentage points; 95% confidence interval [CI], −6.1 to 9.1, with adjustment for NIHSS strata)

Death within 90 days:

I: 83 (19%)

C: 48 (21.6%)

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: 27 (6.2%)

C: 13 (5.9%)

stopped early because of futility

Campbell, 2015

Extend IA

Type of study: RCT

Setting: hospital

Country: Australia

Source of funding: Supported by grants from the Australian National Health and Medical Research Council of Australia (1043242 and 1035688), Royal Australasian College of Physicians, Royal Melbourne Hospital Foundation, the National Heart Foundation of Australia, and the National Stroke Foundation of Australia; and by infrastructure funding from the state government of Victoria. The Solitaire FR device and trial infrastructure were provided under an unrestricted grant from Covidien.

Inclusion criteria: could receive intravenous alteplase within 4.5 hours after the onset of anterior circulation ischemic stroke and had occlusion of the internal carotid artery or of the first or second segment of the middle cerebral artery, as seen on CT angiography. In addition, CT perfusion imaging, which was processed with the use of fully automated software (RAPID, noncommercial research version, Stanford University), was used to identify potentially salvageable brain tissue. Brain tissue at risk for infarction (“ischemic penumbra”) was distinguished from minimally hypoperfused tissue if the time to maximum (Tmax) delay was more than 6 seconds. Irreversibly injured brain (“ischemic core”) was diagnosed if the relative cerebral blood flow was less than 30% of that in normal tissue.

Exclusion criteria: Endovascular therapy had to be initiated (groin puncture) within 6 hours after stroke onset and completed within 8 hours after onset. There were no restrictions on age or clinical severity, as assessed according to the score on the National Institutes of Health Stroke Scale (NIHSS), which ranges from 0 (normal) to 42 (death). However, patients were required to have functional independence before the stroke episode, which was defined as a score of less than 2 on the modified Rankin Scale, which ranges from 0 (normal) to 6 (death).

N total at baseline:

Intervention: 35

Control: 35

Important prognostic factors²:

For example

age ± SD:

I: 68.6±12.3

C: 70.2±11.8

Sex:

I: 49% M

C: 49% M

Groups comparable at baseline? yes

Describe intervention (treatment/procedure/test):

alteplase at a dose of 0.9 mg per kilogram as standard care plus endovascular therapy (endovasculartherapy group)

Describe control (treatment/procedure/test):

alteplase at a dose of 0.9 mg per kilogram as standard care; no further therapy (alteplase-only group)

Length of follow-up:

3 months

Loss-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 (median):

I: 1 (0 to 3)

C: 3 (1 to 5)

(generalized odds ratio, 2.0; 95% confidence interval [CI], 1.2 to 3.8; P = 0.006

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

I: 25/35 (71%)

C: 14/35 (40%)

Death within 90 days:

I: 3/35 (9%)

C: 7/35 (20%)

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%

C: 2 (6%)

The trial stopped early because of efficacy.

Ciccone, 2013

Synthesis

Type of study: RCT

Setting: hospital

Country: Italy

Source of funding: Supported by a grant from the Italian Medicines Agency (AIFA) (FARM6LN3KS). The trial received t-PA from Boehringer Ingelheim Italia, which was paid by the AIFA for use in the experimental group and by the individual participating hospitals for use in the control group. The catheters and devices used in the study were those present in the participating interventional radiologists’ apparatus and were refunded by Niguarda Ca’ Granda Hospital (Milan) with the AIFA funding.

Inclusion criteria: Patients with acute stroke and an age of 18 to 80 years, in whom intracranial hemorrhage had been ruled out, were eligible if there was a clearly defined time of stroke onset that allowed for immediate initiation of intravenous t-PA therapy (defined as within 4.5 hours after symptom onset) or for the administration of endovascular treatment as soon as possible (within 6 hours after symptom onset).

Exclusion criteria:

N total at baseline:

Intervention: 181

Control: 191

Important prognostic factors²:

For example

age ± SD:

I: 66±11

C: 67±11

Sex:

I: 59% M

C: 57% M

Groups comparable at baseline? yes

Describe intervention (treatment/procedure/test):

Patients who were assigned to this treatment group did not receive intravenous t-PA while awaiting endovascular treatment. Angiography was targeted to acquire data essential for guiding endovascular therapy. Anticoagulant therapy was recommended with an initial bolus dose of 5000 IU of intravenous heparin, followed by an infusion of 500 IU per hour until the conclusion of the angiography. Once the diagnostic information had been acquired, the interventionist could consider pharmacologic or mechanical thrombolysis or both. For pharmacologic thrombosis, a microcatheter was to be positioned close to (or within or beyond) the thrombus with the use of a microguide; the full t-PA dose infused did not exceed 0.9 mg per kilogram of body weight (maximum, 90 mg for patients with a body weight of ≥100 kg) and was to be delivered within 1 hour. If complete recanalization was achieved before the maximum dose was reached, the t-PA infusion was stopped. The option of mechanical thrombolysis was left to each interventionist’s discretion. Mechanical thrombosis could involve the use of a micro-guidewire to facilitate disintegration of the thrombus, systems to capture and extract the

thrombus, or more complex systems to crush and aspirate it.

Describe control (treatment/procedure/test):

Standard treatment that also included systemic thrombolytic treatment is indicated was to be started immediately after randomization, within 4.5 hours after symptom onset. Intravenous t-PA was administered at a dose of 0.9 mg per kilogram (maximum, 90 mg), with 10% given as an initial bolus

and the remaining 90% as a constant infusion over a period of 60 minutes.

Length of follow-up: 90 days

Loss-to-follow-up:

None

Incomplete outcome data:

Intervention:

15 did not receive the treatment (6 because of clinical improvement, 3 because of a lack of evidence of occlusion, 3 because of dissection, 1 because of an unknown bleeding diathesis, 1 because of a groin hematoma, and 1 because of the delayed availability of the interventionist). Three procedures had to be interrupted, owing to equipment breakdown (in one procedure) and intraprocedural complications (in two procedures).

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:

Not reported

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

I: (22+33+21=) 76/181 = 42%

C: (28+35+21=) 84/181 = 46%

Death within 90 days:

I: 26/181 = 14%

C: 18/181 = 9,9%

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:10/181 6%

C: 10/181 6%

Del Zoppo, 1998

ProAct I

Type of study: RCT

Setting: hospital

Country: USA

Source of funding Abbott Laboratories (Abbott Park, Ill)

Inclusion criteria: patients (1) have a new onset of focal neurological signs in the MCA distribution allowing randomization and initiation of treatment within 6 hours of the onset of symptoms; (2) have a minimum NIHSS14 score of 4, except for isolated aphasia or isolated hemianopsia; and (3) be 18 to 85 years old. Clinical exclusion criteria included an NIHSS score .30, coma, minor stroke symptoms, or a history of stroke within the previous 6 weeks; suspected lacunar stroke; seizure at stroke onset; clinical presentation suggestive of subarachnoid hemorrhage (even if the initial CT scan was normal); evidence or history of intracranial haemorrhage at any time or an intracranial neoplasm; uncompensated hypertension (blood pressure .180/100 mm Hg); presumed septic embolus or endocarditis; surgery or trauma (within 30 days); head trauma (within 90 days); active or recent hemorrhage within 14 days; known hereditary or acquired hemorrhagic diathesis; or oral anticoagulation with an international normalized ratio .1.5.

Exclusion criteria:

evidence of hemorrhage of any degree, significant mass effect with midline shift, or the presence of an intracranial tumor (except a small meningioma). Patients with early changes of ischemia on CT were included.

N total at baseline:

Intervention: 26

Control: 14

Important prognostic factors²:

For example

age ± SD:

I: 66.5 ± 11.0

C: 69.6 ± 11.1

Sex:

I: 54% M

C: 36% M

Groups comparable at baseline? yes

Describe intervention (treatment/procedure/test):

underwent diagnostic cerebral angiography of the symptomatic carotid artery territory. Angiographic inclusion criteria were complete occlusion (TIMI grade 0)15 or contrast penetration with minimal perfusion (TIMI grade 1) of either the horizontal M1 segment or the M2 division of the MCA. Patients not meeting the angiographic inclusion criteria were followed for neurological deterioration and/or serious adverse events for 24 hours or until alternative treatment was initiated, whichever came first. If an M1 or M2 occlusion was documented, the patient was allocated by the Central Randomization Center to receive either 6 mg rpro-UK or saline placebo at a 30-mL/h controlled infusion rate (tier I)

Describe control (treatment/procedure/test):

Matching placebo consisting of saline

Length of follow-up: 3 months

Loss-to-follow-up:

no

Incomplete outcome data:

no

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

Ordinal score on modified Rankin scale 0-2:

Not reported

Functional independence (defined as a score of 0,

1, or 2 on the modified Rankin scale) at day 90.

Not reported, only 0-1

Death within 90 days:

I: 7/26

C: 6/14

Absolute difference:

Occurrence of symptomatic intracranial hemorrhage (defined according to European Cooperative Acute Stroke Study III criteria as the presence of extravascular blood in the cranium that was associated with an increase in the NIHSS score of ≥4 points or death and was judged to be the predominant cause of neurologic deterioration) within 24 hours after randomization:

I:0 %

C: 0%

Furlan, 1999

Pro Act II

Type of study: RCT

Setting: hospital

Country: USA

Source of funding: funded by Abott laboratories

Inclusion criteria: new focal neurological signs in the MCA distribution allowing initiation of treatment within 6 hours of onset of symptoms; a minimum NIHSS score of 4, except for isolated aphasia or hemianopia; and age 18-85 y.

Exclusion criteria: see publication

N total at baseline:

Intervention: 121

Control: 59

Important prognostic factors²:

age ± SD:

I: 64 ± 14

C: 64 ± 14

Sex:

I: 58% M

C: 61% M

Groups comparable at baseline? yes

Describe intervention (treatment/procedure/test):

Intra-arterial recombinant pro Urokinase plus heparin

Describe control (treatment/procedure/test):

heparin

Length of follow-up: 90 days

Remarks:

Intervention: 13 did not receive pro UroK: No M1 or M2 occlusion, 3 not within 6h of onset, 2 technical difficulties and 4 other reason

Control: 5 received pro uro K: pharmacy error 2; patient/family insistence

Incomplete outcome data:

Intervention: 10

N (%)

Reasons (describe)

Control: 8

N (%)

Reasons (describe)

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

Ordinal score on modified Rankin scale:

I:. 5.5±3.8

C: 3.4±3.1

Functional independence (defined as a score of 0,

1, or 2 on the modified Rankin scale) at day 90.

I: 49/121 = 40%

C: 15/59 = 25%

Death within 90 days:

I: 25/121 = 25 %

C: 27/59 = 27%

Absolute difference:

Occurrence of symptomatic intracranial hemorrhage (defined according to European Cooperative Acute Stroke Study III criteria as the presence of extravascular blood in the cranium that was associated with an increase in the NIHSS score of ≥4 points or death and was judged to be the predominant cause of neurologic deterioration) within 24 hours after randomization:

I: 38/108 = 35%

C: 7/54 = 13%

Goyal, 2015

ESCAPE

Type of study: RCT

Setting: hospital

Country: At 22 centers in Canada (11 centers), the United States (6), South Korea (3), Ireland (1), and the United Kingdom (1)

Source of funding: Supported by Covidien through an unrestricted grant to the University of Calgary. Also supported by the University of Calgary (Hotchkiss Brain Institute, the Department of Clinical Neurosciences and Calgary Stroke Program, and the Department of Radiology), Alberta Innovates–Health Solutions, the Heart and Stroke Foundation of Canada, and Alberta Health Services.

Inclusion criteria: adults (no upper-age limit) with a disabling ischemic stroke who had been functioning independently in the community (score on the Barthel Index [range, 0 to 100, with higher scores indicating a greater ability to complete activities of daily living] ≥90) before the stroke. Enrollment could occur up to 12 hours after the onset of stroke symptoms. Noncontrast CT and CTA (preferably multiphase) were performed to identify participants with a small infarct core, an occluded proximal artery in the anterior circulation, and moderate-to-good collateral circulation. Multiphase CTA is less vulnerable to patient motion than CT perfusion, requires no additional contrast, and allows for quick determination of collateral status. The use of magnetic resonance imaging for patient selection was discouraged.

Exclusion criteria:

N total at baseline:

Intervention: 165

Control: 150

Important prognostic factors²:

Age (median):

I: 71

C: 70

Sex:

I: 48% M

C: 47% M

Groups comparable at baseline? yes

Describe intervention (treatment/procedure/test):

Before and during screening, participants were treated with intravenous alteplase when clinically appropriate as part of standard care (

rapid endovascular treatment. A cerebral angiogram was obtained. The neurointerventionist used available thrombectomy devices to achieve reperfusion. The use of retrievable stents was recommended. During thrombus retrieval, suction through a balloon guide catheter in the relevant internal carotid artery was also recommended.

Describe control (treatment/procedure/test):

Before and during screening, participants were treated with intravenous alteplase when clinically appropriate as part of standard care (

The control group received the current standard of care as described in the Canadian or local guidelines for the management of acute stroke.

Length of follow-up: 90 days

Crossover:

One participant in the control group crossed over to receive endovascular treatment.

In the intervention group, 14 participants did not receive any interventional therapy. Four participants (1.3%) were lost to follow-up; missing

data on outcomes in these participants were not imputed.

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 (median):

I: 2

C: 4

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

I: 87/164 (53%)

C: 43/147 (29%)

(rate ratio, 1.8; 95% CI, 1.4 to 2.4; P<0.001)

Death within 90 days:

I: 17/164 (10%)

C: 28/147 (19%)

(rate ratio, 0.5; 95% CI, 0.3 to 1.0; P = 0.04)

Occurrence of symptomatic intracranial hemorrhage:

I: 6 (3.6%)

C: 4 (2.7%)

(rate ratio, 1.4; 95% CI, 0.4 to

4.7; P = 0.75)

Jovin, 2015

Revascat

Type of study: RCT

Setting: hospital

Country: Spain

Source of funding: Supported by Fundació Ictus Malaltia Vascular through an unrestricted grant from Covidien, by a grant from the Spanish Ministry of Health cofinanced by Fondo Europeo de Desarrollo Regional (Instituto de Salud Carlos III, Red Temática de Investigación Cooperativa Invictus, RD 12/0014/008), and a grant from the Generalitat de Catalunya (SGR 464/2014).

Inclusion criteria:

Eligible patients were between the ages of 18 and 80 years, had an occlusion in the proximal anterior circulation that could be treated within 8 hours after symptom onset, had a prestroke functional ability of 1 or less on the modified Rankin scale (ranging from 0 [no symptoms] to 6 [death]), and had a baseline score of at least 6 points on the National Institutes of Health Stroke Scale (NIHSS), which ranges from 0 to 42, with higher values indicating more severe deficit.

Exclusion criteria: evidence of a large ischemic core, as indicated by an Alberta Stroke Program Early Computed Tomography Score (ASPECTS) of less than 7 on computed tomography (CT) without the use of contrast material or a score of less than 6 on diffusion-weighted magnetic resonance imaging

N total at baseline:

Intervention: 103

Control: 103

Important prognostic factors²:

age ± SD:

I: 65.7±11.3

C: 67.2±9.5

Sex:

I: 53% M

C: 52% M

Groups comparable at baseline? yes

Describe intervention (treatment/procedure/test):

medical therapy (including intravenous alteplase when eligible) and endovascular treatment with the Solitaire stent retriever (thrombectomy group)

Describe control (treatment/procedure/test):

medical therapy alone (control group).

Length of follow-up: 3 months

Loss-to-follow-up:

Intervention:

N (%)

Reasons (describe)

Control:

N (%)

Reasons (describe)

Incomplete outcome data:

Intervention:

N (%)

Reasons (describe)

Control:

N (%)

Reasons (describe)

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:

Not reported

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

I: 45/103 (43.7%)

C: 29/103 (28.2%)

Death within 90 days:

I: 19/103 = 18.4%

C: 116/103 = 5.5%

Occurrence of symptomatic intracranial hemorrhage:

I: 5/103 = 4.9%

C: 2/103 = 1.9%

REVASCAT

Kidwel, 2013

MR RESCUE

Type of study: RCT

Setting: hospital

Country: USA

Source of funding: Supported by a grant (P50 NS044378) from NINDS. Concentric Medical provided study catheters and devices from the initiation of the study until August 2007; thereafter, costs for all study catheters and devices were covered by study funds or third-party payers.

Inclusion criteria: patients between the ages of 18 and 85 years, with National Institutes of Health Stroke Scale (NIHSS) scores of 6 to 29 (on a scale ranging from 0 to 42, with higher scores indicating more severe neurologic deficits) who had a large-vessel, anterior-circulation ischemic stroke were randomly assigned within 8 hours after the onset of symptoms to undergo either mechanical embolectomy Patients who were treated with intravenous t-PA without successful recanalization were eligible if magnetic resonance angiography or CT angiography after the treatment showed a persistent target occlusion.

Exclusion criteria:

N total at baseline:

Intervention: 70

Control: 57

Important prognostic factors²:

age ± SD:

Penumbral

I: 66.4±13.2

C: 65.8±16.9

Nonpenumbral

I: 61.6±12.0

C: 69.4±15.9

Sex:

57% M

Groups comparable at baseline? yes

Describe intervention (treatment/procedure/test):

Patients in the embolectomy group could be treated with any combination of FDA-cleared embolectomy devices, including the Merci Retriever (since trial initiation in 2004) and the Penumbra System (since 2009). The intraarterial administration of t-PA at a dose of as much as 14 mg was allowed as rescue therapy within 6 hours after symptom onset.

Describe control (treatment/procedure/test):

The intraarterial administration of t-PA at a dose of as much as 14 mg was allowed as rescue therapy within 6 hours after symptom onset.

Length of follow-up: 90 days

Loss-to-follow-up:

Intervention: 11 (%)

Reasons (describe): excluded from per-protocol analysis (6), no target lesion on vessel imaging (5), failed perfusion imaging (1)

Control: 6 (%)

Reasons (describe): excluded from per-protocol analysis (3), no target lesion on vessel imaging (2), failed perfusion imaging (1)

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: 3.9

C: 3.9

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

I: 12/38 = 32%

C: 11/36 = 31%

Death within 90 days:

I: 12/64 = 19%

C: 13/54 = 24%

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 9%

C: 2 6%

Randomization was stratified according to whether the patient had a favourable penumbral pattern (substantial salvageable tissue and small infarct core) or a nonpenumbral pattern (large core or small or absent penumbra)

Mocco, 2016

Therapy

Type of study: RCT

Setting: hospital

Country: USA and Germany

Source of funding: Penumbra, Inc

Inclusion criteria: Eligible patients (18–85 years old) with intracranial internal carotid artery (ICA) or middle cerebral artery occlusion on CT angiography and an National Institute of Health Stroke Scale (NIHSS) score of ≥8 were treated with intravenous-alteplase based on standard eligibility criteria. Enrollment required a nonenhanced thin-section (≤2.5 mm) CT scan demonstrating ≥8 mm clot length. Investigators were trained on clot length identification methodology17 and each site submitted examples

before study initiation.

Exclusion criteria: >1 of 3 of the affected middle cerebral artery territory with established infarction, cervical ICA stenosis/occlusion requiring treatment before thrombectomy, and prestroke disability (modified Rankin Scale [mRS] score >1).

N total at baseline:

Intervention: 55

Control: 53

Important prognostic factors²:

For example

age ± SD:

I:

C:

Sex:

I: % M

C: % M

Groups comparable at baseline?

Describe intervention (treatment/procedure/test):

aspiration thrombectomy after intravenous-alteplase administration compared with intravenousalteplase

alone in patients with large vessel ischemic stroke because of ≥8 mm thrombus

Describe control (treatment/procedure/test):

intravenousalteplase

alone

Length of follow-up: 3 months

Loss-to-follow-up:

Intervention:

N (%)

Reasons (describe)

Control:

N (%)

Reasons (describe)

Incomplete outcome data:

Intervention:

N (%)

Reasons (describe)

Control:

N (%)

Reasons (describe)

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

Functional independence (defined as a score of 0,

1, or 2 on the modified Rankin scale) at day 90.

I: 19/50 = 38%

C: 14/46 = 30%

Death within 90 days:

I:6/55 = 12%

C: 12/53 = 23.9%

Absolute difference:

Occurrence of symptomatic intracranial hemorrhage (defined according to European Cooperative Acute Stroke Study III criteria as the presence of extravascular blood in the cranium that was associated with an increase in the NIHSS score of ≥4 points or death and was judged to be the predominant cause of neurologic deterioration) within 24 hours after randomization:

I: 5/55= 9.3%

C: 5 /53=9.7%

Muir, 2017

Piste

Type of study: RCT

Setting: hospital

Country: UK

Source of funding: the Stroke Association (TSA 2011/2006) from 2012 to 2015 and the National Institute of

Health Research (NIHR) Health Technology Assessment programme (HTA 14.08.47)

from 2015 to 2016, and received unrestricted grants from Codman and Covidien

(Medtronic).

Inclusion criteria: patients ≥18 years were eligible if presenting with acute supratentorial ischaemic stroke and eligible for IVT started within 4.5 hours of symptom onset. If non-invasive angiographic imaging with CT angiography (CTA) or magnetic resonance angiography showed occlusion of the intracranial ICA, M1 segment of the MCA or a single M2 MCA branch, patients were eligible for randomisation.

Exclusion criteria: contraindications to IVT, life expectancy limited to <90 days, with chronic extracranial ICA occlusion or with extensive early hypodensity on non-contrast CT brain involving more than one-third of the MCA territory

N total at baseline:

Intervention: 32

Control: 33

Important prognostic factors²:

For example

age ± SD:

I: 67±17

C: 64±16

Sex:

I: 39% M

C: 50% M

Groups comparable at baseline? Those randomised to receive MT were older, more often female, had more severe strokes, higher prevalence of some vascular risk factors (diabetes, atrial fibrillation) and a higher proportion had prestroke impairment on estimated mRS; a higher proportion had good collateral score and favourable ASPECT score.

Describe intervention (treatment/procedure/test):

Inravenous trombolysis and mechanical trombecomy

Describe control (treatment/procedure/test):

Intravenous trombolysis alone

Length of follow-up: 3 months

Loss-to-follow-up:

Intervention:

N (%)

Reasons (describe)

Control:

N (%)

Reasons (describe)

Incomplete outcome data:

Intervention:

N (%)

Reasons (describe)

Control:

N (%)

Reasons (describe)

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

Functional independence (defined as a score of 0,

1, or 2 on the modified Rankin scale) at day 90.

I: 16/32 = 51%

C: 13/33 = 40%

Death within 90 days:

I: 7/32 =22%

C: 4/33 -= 12%

Absolute difference:

Occurrence of symptomatic intracranial hemorrhage (defined according to European Cooperative Acute Stroke Study III criteria as the presence of extravascular blood in the cranium that was associated with an increase in the NIHSS score of ≥4 points or death and was judged to be the predominant cause of neurologic deterioration) within 24 hours after randomization:

I: 0%

C: 0%

Ogawa, 2007

MELT

Type of study: RCT

Setting: hospital

Country: USA

Source of funding: Grants-in-Aid from the Ministry of

Health, Labor and Welfare of Japan (H14-Shinkin-007 and

H16-Shinkin-004)

Inclusion criteria: new onset of focal neurological signs in the MCA distribution allowing randomization and initiation of fibrinolysis within 6 hours from the onset of symptoms; minimum National Institutes of Health Stroke Scale (NIHSS) score of 5, except for immediate improvement before initiation of treatment; no or only subtle early ischemic signs in the insular cortex, frontal and temporal opercula, or lenticular nuclei on initial CT allowing initiation of treatment within 2 hours of CT; and age 20 to 75

years old.

Exclusion criteria: coma; NIHSS score >22; seizure at stroke onset; premorbid disability of mRS score of >2; presumed fat embolus or endocarditis; and complication of other diagnostic angiography. Patients with high risk of hemorrhagic complication were also excluded

N total at baseline:

Intervention: 57

Control: 57

Important prognostic factors²:

age ± SD:

I: 66.9_9.3

C: 67.3

Sex:

I: 65% M

C: 65% M

Groups comparable at baseline? yes

Describe intervention (treatment/procedure/test):

Intravenous infusion of heparin (5000 IU) was administered before introducing the sheath. An infusion microcatheter with a single end hole was passed through the clot and positioned on the distal side of the thrombus. Local infusion into the clot or M1 segment was permitted if the microcatheter could not be passed through the clot. More proximal regional infusion was prohibited. Mechanical disruption of clots was permitted only with a guidewire. No other mechanical clot removal techniques were allowed. Repeat CT was required at a maximum interval of 2 hours. Only patients with no or subtle early ischemic signs on the second CT scan could be accepted for the next step. Intraarterial infusion of UK (120 000 IU over 5 minutes) was performed and repeated until the total dose reached 600 000 IU, 2 hours had passed after starting infusion, or complete recanalization was achieved. The dose of UK was determined based on previous uncontrolled studies of intraarterial infusion of UK for stroke and consensus among the investigators.

Describe control (treatment/procedure/test):

No specific treatments were indicated for the control group. Osmotic diuretics were used in patients manifesting high intracranial pressure. Intravenous infusion of fibrinolytic agents was prohibited in both UK and control groups. Any approved medical or rehabilitation treatment was allowed in all patients except for antithrombotic therapies, including heparin, warfarin, aspirin, and ticropidin, for 24 hours after fibrinolysis in the UK group.

Length of follow-up: 90 days

Loss-to-follow-up:

Intervention:

N (%)

Reasons (describe)

Control:

N (%)

Reasons (describe)

Incomplete outcome data:

Intervention:

N (%)

Reasons (describe)

Control:

N (%)

Reasons (describe)

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

Ordinal score on modified Rankin scale:

I:. 5.5±3.8

C: 3.4±3.1

Functional independence (defined as a score of 0,

1, or 2 on the modified Rankin scale) at day 90.

I: 28/57 = 49%

C: 22/57 = 39%

Death within 90 days:

I: 3/57 5%

C: 2/57 = 4%

Occurrence of symptomatic intracranial hemorrhage (defined according to European Cooperative Acute Stroke Study III criteria as the presence of extravascular blood in the cranium that was associated with an increase in the NIHSS score of ≥4 points or death and was judged to be the predominant cause of neurologic deterioration) within 24 hours after randomization:

I:1/57 = 2 %

C: 0/57 = 0%

Saver, 2015

Swift Prime

Type of study: RCT

Setting: hospital

Country: USA

Source of funding: Supported by Covidien.

Inclusion criteria:

acute ischemic stroke with moderate-to-severe neurologic deficits; had imaging-confirmed occlusion of the intracranial internal carotid artery, the first segment of the middle cerebral artery, or both; met the imaging eligibility requirements; were receiving or had received intravenous t-PA; and were able to undergo initiation of endovascular treatment within 6 hours after the time that they were last known to be well before the onset of acute stroke symptoms. Qualifying imaging had to be performed at a study hospital; imaging was repeated for patients who were transferred from outside hospitals.

Exclusion criteria:

N total at baseline:

Intervention: 98

Control: 98

Important prognostic factors²:

age ± SD:

I: 65.0±12.5

C: 66.3±11.3

Sex:

I: 55% M

C: 47% M

Groups comparable at baseline? yes

Describe intervention (treatment/procedure/test):

endovascular thrombectomy with the use of a stent retriever within 6 hours after symptom onset (intervention group).

In the intervention group, neurovascular thrombectomy was performed with the use of the Solitaire FR (Flow Restoration) or Solitaire 2 device. Concomitant stenting of the cervical internal carotid artery was not permitted, although angioplasty could be performed to permit intracranial access.

Describe control (treatment/procedure/test):

intravenous t-PA to continue with t-PA alone (control group)

Length of follow-up: 90 days

Loss-to-follow-up:

Intervention:

N (%)

Reasons (describe)

Control:

N (%)

Reasons (describe)

Incomplete outcome data:

Intervention:

N (%)

Reasons (describe)

Control:

N (%)

Reasons (describe)

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 (median):

I: 2

C: 3

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

I: 59/98 (60%)

C: 33/93 (35%)

Death within 90 days:

I: 9/98 = 9%

C: 12/97 = 12%

Occurrence of symptomatic intracranial hemorrhage within 27 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%

C: 3%

Berkhemer, 2015

MR CLEAN

The randomization procedure was Web-based, with the use of permuted blocks. We stratified randomization according to medical center, use of intravenous alteplase (yes or no), planned treatment method (mechanical or other), and stroke severity (NIHSS score of ≤14 or >14).

Unlikely

unclear, blinding was not possible

unclear, blinding was not possible

unlikely

unlikely

unlikely

unlikely

Bracard, 2016

THRACE

Randomisation was done at the coordination centre by a computer analyst who was masked to the investigation centres and to the patients. Randomisation was done with a computer-generated sequence and was stratified by centre, and sequential minimisation with a factor of 85% was used to avoid imbalance in treatment. Participants were enrolled by local investigators and assigned to the trial group according to the random number.

unlikely

unclear, blinding was not possible

unclear, blinding was not possible

unclear

unlikely

unlikely

unlikely

Broderick, 2013

IMS III

Participants were randomly assigned in a 2:1 ratio to endovascular therapy or intravenous t-PA alone with the use of an Internet-based, computerized algorithm of minimization and the biased-coin method, which accounted for two factors: clinical center and baseline NIHSS strata (scores of 8 to 19 vs. ≥20)

unlikely

unclear, blinding was not possible

unclear, blinding was not possible

unlikely

unlikely

unlikely

unlikely

Campbell, 2015

Extend IA

Patients were randomly assigned in a 1:1 ratio to receive either alteplase plus endovascular therapy (endovasculartherapy group) or no further therapy (alteplase-only group) by means of a centralized website and stratified according to the site of arterial occlusion: the internal carotid artery or the first or second segment of the middle cerebral artery.

unlikely

unclear, blinding was not possible

unclear, blinding was not possible

unlikely

unlikely

unlikely

unlikely

Ciccone, 2013

Synthesis

The study protocol provided for centralized, simple randomization online. A single randomization list was prepared with the use of a hardware system, available at www.random.org
All patients underwent randomization within 4.5 hours after

symptom onset.

Unlikely

unclear, blinding was not possible

unclear, blinding was not possible

unlikely

unlikely

unlikely

unlikely

Del Zoppo, 1998

ProActI

Allocated by central randomisation center, no further details provided

unclear

unlikely

unlikely

unlikely

unlikely

unlikely

Unlikely

Furlan, 1999

ProAct II

A blinded randomization code was assigned via telephone independent of the sponsor by Paragon Biomedical Inc, Irvine, Calif. A computer-generated master randomization schedule using block size ranging from 3 to 12 was used. The schedule was not stratified by clinical centre to preclude knowledge of the distribution of future treatment assignments at a given center.

unlikely

unlikely

unlikely

unlikely

unlikely

unlikely

unlikely

Goyal, 2015

ESCAPE

Randomization was performed with the use of a real-time, dynamic, Internet-based, randomized minimization procedure (minimal sufficient balance method) to achieve distribution balance with regard to age, sex, baseline National Institutes of Health Stroke Scale (NIHSS) score, site of arterial occlusion, baseline Alberta Stroke Program Early Computed Tomography Score, and status with respect to intravenous alteplase treatment.

unlikely

unclear, blinding was not possible

unclear, blinding was not possible

unlikely

unlikely

unlikely

unlikely

Jovin, 2015

Revascat

A real-time computerized randomization procedure that was tratified according to age, baseline NHISS score, therapeutic window, occlusion site, and participating center.

unlikely

unclear, blinding was not possible

unclear, blinding was not possible

unlikely

unlikely

unlikely

unlikely

Kidwel, 2013

MR RESCUE

Baseline multimodal imaging was automatically processed on a dedicated site computer, generating a 4-digit code that assigned patients to treatment on the basis of separate permuted-block sequences for favorable penumbral and nonpenumbral patterns.

unlikely

unclear, blinding was not possible

unclear, blinding was not possible

unlikely

unlikely

unlikely

unlikely

Mocco, 2016

Therapy

Randomization was performed through a centralized interactive voice response system, stratified according to enrolling center

unlikely

unclear, blinding was not possible

unclear, blinding was not possible

unlikely

unlikely

unlikely

unlikely

Muir, 2017

Piste

Allocation used a minimisation algorithm, including age group, stroke severity on the National Institutes of Health Stroke Scale (NIHSS) and symptom onset-to-treatment time. Randomisation was conducted using an interactive voice-response system managed by the Robertson Centre for Biostatistics, University of Glasgow.

unlikely

unclear, blinding was not possible

unclear, blinding was not possible

unlikely

unlikely

unlikely

Unlikely

Ogawa, 2007

MELT

Included patients were allocated to the Central Randomization Center through the Internet and randomized to receive either intraarterial UK infusion (UK group) or conventional treatment (control group).

unlikely

unclear, blinding was not possible

unclear, blinding was not possible

unlikely

unlikely

unlikely

unlikely

Saver, 2015

Swift Prime

Patients were randomly

assigned in a 1:1 ratio to one of two treatment

groups: intravenous t-PA plus stent retriever (intervention

group) or intravenous t-PA alone (control

group). Using a minimization algorithm,

we balanced the numbers of patients in the two

treatment groups with respect to four factors:

investigational site, baseline severity according

to the National Institutes of Health Stroke Scale

(NIHSS) score (≤17 vs. >17, on a scale of 0 to 42,

with higher scores indicating greater severity), age

(<70 years vs. ≥70 years), and occlusion location

(middle cerebral artery vs. internal carotid artery).

unlikely

unclear, blinding was not possible

unclear, blinding was not possible

unlikely

unlikely

unlikely

unlikely