Intracranial hemorrhage in large vessel occlusion patients receiving endovascular thrombectomy with or without intravenous alteplase: a secondary analysis of the DIRECT-MT trial

Background Alteplase before thrombectomy for patients with large vessel occlusion stroke raises concerns regarding an increased risk of intracranial hemorrhage (ICH), but the details of this relationship are not well understood. Methods This was a secondary analysis of the DIRECT-MT trial. ICH and its subtypes were independently reviewed and classified according to the Heidelberg Bleeding Classification. The effects of alteplase before thrombectomy on ICH and ICH subtypes occurrence were evaluated using logistic regression. Clinical and imaging characteristics that may modify these effects were exploratorily tested. Results Among 591 patients, any ICH occurred in 254 (43.0%), including hemorrhagic infarction type 1 in 12 (2.1%), hemorrhagic infarction type 2 in 127 (21.7%), parenchymal hematoma type 1 in 34 (5.8%), parenchymal hematoma type 2 in 50 (8.6%), and other hemorrhage types (3a-3c) in 24 (4.1%). Similar ICH frequencies were observed with combined alteplase and thrombectomy versus thrombectomy only (134/292 (45.9%) vs 120/299 (40.1%); OR 1.27, 95% CI 0.91 to 1.75, P=0.16), but patients treated with alteplase had a higher parenchymal hematoma rate (51/287 (17.8%) vs 33/297 (11.1%); OR 1.75, 95% CI 1.08 to 2.85, P=0.024). In the adjusted model, difference in parenchymal hematoma occurrence between groups remained significant (adjusted OR 1.71, 95% CI 1.00 to 2.92, P=0.049). Patients with history of diabetes (Pinteraction=0.048), hypertension (Pinteraction=0.02), antiplatelet therapy (Pinteraction=0.02), anticoagulation therapy (Pinteraction=0.04), and statin administration (Pinteraction=0.02) harbored a higher ICH rate when they received combination therapy. Conclusions Our data showed that in the DIRECT-MT trial, alteplase did not increase overall ICH for large vessel occlusion patients treated with thrombectomy, but it increased the parenchymal hematoma rate.


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The Supplements list： Table S1.Baseline Characteristics of the 591 included Patients by ICH or not.
Table S2.Baseline Characteristics of the 591 included Patients by treatment.
Table S3.Baseline Characteristics of the 591 included Patients by non-ICH versus aICH and sICH.
Table S4.Baseline Characteristics of the 591 included Patients by non-ICH versus HI, PH, and other ICH.
Table S5.Baseline characteristics of the patients of six randomized trials.BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) b.Scores on the National Institutes of Health Stroke Scale (NIHSS) range from 0 to 42, with higher scores indicating more severe neurologic deficits.c.Scores on the modified Rankin scale of functional recovery range from 0 (no symptoms) to 6 (death).A score of 2 or less indicates functional independence.
d.The cause of stroke was assessed according to the medical history, clinical features, and results on digital subtraction angiography.e. Collateral flow was graded with baseline CT angiography using a 4-point scale, with 0 representing absent collateral flow (absent filling of the occluded territory), 1 representing poor collateral flow (less than 50% filling of the occluded territory), 2 representing intermediate collateral flow (between 50% and 100% filling of the occluded territory), and 3 representing excellent collateral flow (100% filling of the occluded territory).Data was not available for 13 patients due to images missing, poor quality of the images.
f.The Alberta Stroke Program Early Computed Tomography Score (ASPECTS) is a measure of the extent of early cerebral ischemia.Scores ranges from 0 to 10, with higher scores indicating fewer early ischemic changes.Shown are values as assessed by the core laboratory.
g.The sites of intracranial artery occlusion were assessed by the core laboratory.Computed tomographic angiographic data at baseline were missing for 3 patients.BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) Scores on the modified Rankin scale of functional recovery range from 0 (no symptoms) to 6 (death).A score of 2 or less indicates functional independence.
d.The cause of stroke was assessed according to the medical history, clinical features, and results on digital subtraction angiography.e.
Collateral flow was graded with baseline CT angiography using a 4-point scale, with 0 representing absent collateral flow (absent filling of the occluded territory), 1 representing poor collateral flow (less than 50% filling of the occluded territory), 2 representing intermediate collateral flow (between 50% and 100% filling of the occluded territory), and 3 representing excellent collateral flow (100% filling of the occluded territory). f.
The Alberta Stroke Program Early Computed Tomography Score (ASPECTS) is a measure of the extent of early cerebral ischemia.Scores range from 0 to 10, with higher scores indicating fewer early ischemic changes.Shown are values as assessed by the core laboratory.
g.The sites of intracranial artery occlusion were assessed by the core laboratory.BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s)  Collateral flow was graded with baseline CT angiography using a 4-point scale, with 0 representing absent collateral flow (absent filling of the occluded territory), 1 representing poor collateral flow (less than 50% filling of the occluded territory), 2 representing intermediate collateral flow (between 50% and 100% filling of the occluded territory), and 3 representing excellent collateral flow (100% filling of the occluded territory).Data was not available for 13 patients due to images missing, poor quality of the images. f.
The Alberta Stroke Program Early Computed Tomography Score (ASPECTS) is a measure of the extent of early cerebral ischemia.Scores ranges from 0 to 10, with higher scores indicating fewer early ischemic changes.Shown are values as assessed by the core laboratory.
g.The sites of intracranial artery occlusion were assessed by the core laboratory.Computed tomographic angiographic data at baseline were missing for 3 patients.BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s)

Figure S1 .
Figure S1.Forest plot of symptomatic intracranial hemorrhage by subgroups, on as-treated population.

Figure S2 .
Figure S2.Forest plot of parenchymal hematoma by subgroups, on as-treated population.
h. Acute stenting denotes stenting in either internal carotid artery or middle cerebral artery.i.The extended Thrombolysis in Cerebral Infarction (eTICI) score (range, 0 [no reperfusion] to 3 [complete reperfusion]) is performed with digital subtraction angiography; successful reperfusion denotes an eTICI score of 2b, 2c, or 3 on the final angiogram.
h.The extended Thrombolysis in Cerebral Infarction (eTICI) score (range, 0 [no reperfusion] to 3 [complete reperfusion]) is performed with digital subtraction angiography; successful reperfusion denotes an eTICI score of 2b, 2c, or 3 on the final angiogram.
b. Scores on the National Institutes of Health Stroke Scale (NIHSS) range from 0 to 42, with higher scores indicating more severe neurologic deficits.c.Scores on the modified Rankin scale of functional recovery range from 0 (no symptoms) to 6 (death).A score of 2 or less indicates functional independence.d.The cause of stroke was assessed according to the medical history, clinical features, and results on digital subtraction angiography.e.
h. Acute stenting denotes stenting in either internal carotid artery or middle cerebral artery.i.The extended Thrombolysis in Cerebral Infarction (eTICI) score (range, 0 [no reperfusion] to 3 [complete reperfusion]) is performed with digital subtraction angiography; successful reperfusion denotes an eTICI score of 2b, 2c, or 3 on the final angiogram.

Table S1 . Baseline Characteristics of the 591 included Patients by ICH or not a .
. IQR interquartile range.ICH intracranial hemorrhage.65 patients were excluded from this study because of protocol violations or because they did not receive EVT. a

Table S2 . Baseline Characteristics of the 591 included Patients by treatment a . Variable Treatment P value EVT alone(n=299) Combination(n=292)
. Scores on the National Institutes of Health Stroke Scale (NIHSS) range from 0 to 42, with higher scores indicating more severe neurologic deficits.
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) J NeuroIntervent Surg doi: 10.1136/jnis-2022-019021 -983.bc.

Table S4 . Baseline Characteristics of the 591 included Patients by non-ICH versus HI, PH, and other ICH a .
range.EVT, endovascular treatment.Combination, combined intravenous alteplase and EVT.NA, not applicable.b.Scores on the National Institutes of Health Stroke Scale (NIHSS) range from 0 to 42, with higher scores indicating more severe neurologic deficits.c.Scores on the modified Rankin scale of functional recovery range from 0 (no symptoms) to 6 (death).A score of 2 or less indicates functional independence.d.The Alberta Stroke Program Early Computed Tomography Score (ASPECTS) is a measure of the extent of early cerebral ischemia.Scores ranges from 0 to 10, with higher scores indicating fewer early ischemic changes.Shown are values as assessed by the core laboratory.BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s)