Comparison of Five Major Recent Endovascular Treatment Trials Sample size 500 # sites 70 (100 planned) 316 (500 planned) 196 (833 estimated) 206 (690 planned) 16 10 22 39 4 Treatment contrasts Baseline characteristics Inclusion/ exclusion criteria Endovascular treatment with t-pa or urokinase, and/or mechanical treatment with retrievable stents or other available devices (n=233), or best medical management only, +/-intravenous t-pa (n=267). Median age: 65 years Male sex: 58% score:17 (intervention), 18 Median ASPECTS score 9 (both groups) Treatment with alteplase: 87.1% (intervention),90.6% Acute stroke, NIHSS 2, CT or MRI scan ruling out intracranial hemorrhage, intracranial arterial occlusion of the distal intracranial carotid artery Mechanical clot retrieval with the Solitaire device after receiving standard therapy with intravenous t-pa (n=35) or intravenous t-pa only (n=35) Mean age: 69 years Male sex: 49% score:17 (intervention), 13 Mean core volume 19 ml Anterior circulation acute ischemic stroke eligible using standard criteria to receive IV tpa within 4.5 h of stroke onset, 18 years (with no upper age Mechanical thrombectomy, using available devices +/- intravenous t-pa (, n=165); or best medical management +/- tpa (control group, n=150). Median age: 70 years Male sex: 48% score:16 (intervention), 17 Median ASPECTS score 9 (both groups) Treatment with alteplase: 72.7% (intervention), 78.7% Inclusion Criteria: Acute ischemic stroke, 18 years, onset-time to randomization time < 12 hours, baseline NIHSS > 5, pre-stroke independence in ADLs, confirmed Intravenous t-pa + mechanical clot retrieval with the Solitaire FR device (n=98) or treatment with intravenous t-pa only (n=98) Mean age: 66 years Male sex: 51% score:17 (both groups) Median ASPECTS score 9 (both groups) Age 18 80 years, acute ischemic stroke, prestroke MRS score 1, NIHSS 8 and < 30 at the time of randomization, initiation of IV t-pa within 4.5 hours of Mechanical thrombectomy with Solitaire FR device + best medical management (n=103) or best medical management only, which could include intravenous t-pa (n=103). Mean age: 66 years Male sex: 55% Median baseline NIHSS score: 17 (both groups). Median ASPECTS score: 7 (intervention), 8 Treatment with alteplase: 68.0% (intervention), 77.7% Age 18-85 years, with occlusion in the proximal anterior circulation that could be treated within 8 hours after symptom CSBPR Fifth Edition June 2015 Page 1 of 6
or middle (M1/M2) or anterior (A1/A2) cerebral artery, demonstrated with CTA, MRA or DSA, able to start treatment within 6 hours from onset, aged 18 years. Arterial blood pressure > 185/110 mmhg, blood glucose < 2.7 or > 22.2 mmol/l, intravenous treatment with thrombolytic therapy in a dose exceeding 0.9 mg/kg alteplase or 90 mg, intravenous treatment with thrombolytic therapy despite contraindications, cerebral infarction in the distribution of the relevant occluded artery in the previous 6 weeks. Specific exclusion criteria: Evidence of coagulation abnormalities, i.e. platelet count 50 sec or INR >3.0 (mechanical thrombectomy), History of intracerebral hemorrhage, severe head injury (contusion) in the previous 4 weeks, clinical or laboratory evidence of coagulation abnormalities, current limit), previously dependent in ADLs, no NIHSS limits, intraarterial clot retrieval treatment can commence (groin puncture) within 6 hours of stroke onset. Imaging inclusion: Arterial occlusion on CT or MR angiography of the ICA, M1, or M2, mismatch using CT or MRI with a Tmax >6 s delay perfusion volume and either CT-rCBF or DWI ischemic core volume (a) Mismatch ratio >1 2; (b) Absolute mismatch volume >10 ml; and (c) Ischemic core lesion volume <70 ml Standard contraindications to intravenous tpa, rapidly improving symptoms, prestroke mrs score of 2, inability to access the cerebral vasculature in the opinion of the neurointerventional team or contraindication to use of the Solitaire FR device, contraindication to imaging with contrast agents, participation in any investigational study in the previous 30 days, any terminal illness such symptomatic intracranial occlusion, based on single phase, multiphase or dynamic CTA, at one or more of the following locations: Carotid T/L, M1 MCA, or M1-MCA equivalent (2 or more M2- MCAs), anterior temporal artery is not considered an M2, endovascular treatment intended to be initiated within 60 minutes of baseline non-contrast CT with target CT to first recanalization of 90 minutes. Baseline non-contrast CT reveals a moderate/large core defined as extensive early ischemic changes of ASPECTS 0-5 in the territory of symptomatic intracranial occlusion, other confirmation of a moderate to large core, groin puncture not possible within 60 minutes of the end of non-contrast CT acquisition, no femoral pulses or very difficult endovascular access which would result in a CT-torecanalization time that is longer than 90 minutes, pregnancy, severe contrast allergy or absolute contraindication to iodinated contrast, onset of stroke, thrombolysis in cerebral infarction (TICI) 0-1 flow in the intracranial internal carotid artery, M1 segment of the MCA, or carotid terminus confirmed by CT or MR angiography that is accessible to the Solitaire FR Device, ability to be treated within 6 hours of onset of stroke symptoms and within 1.5 hours (90 minutes) from CTA or MRA to groin puncture, willingness to attend follow-up visits. Contraindicated to IV t-pa, pregnancy, rapid neurological improvement, known serious sensitivity to radiographic contrast agents, Nickel, Titanium metals or their alloys, current participation in another investigational drug or device treatment study, known hereditary or acquired hemorrhagic diathesis, coagulation factor deficiency, renal failure, life expectancy <90 days, clinical presentation suggests a SAH, suspicion of aortic dissection, presence of a comorbid disease or condition that would confound the neurological and functional evaluations or compromise survival or ability to complete follow-up assessments, onset, prestroke functional ability (mrs 1),baseline NIHSS score 6 points, occlusion (TICI 0-1) of the intracranial ICA (distal ICA or T occlusions), MCA- M1 segment or tandem proximal ICA/MCA-M1, on CTA, MRA or angiogram, +/- concomitant cervical carotid occlusion or stenosis Known hemorrhagic diathesis, coagulation factor deficiency, or oral anticoagulant therapy with INR > 3.0, baseline platelet count < 30.000/µL, baseline blood glucose of < 50mg/dL or >400mg/dl, severe, sustained hypertension, coma, seizures at stroke onset, serious, advanced, or terminal illness, history of life threatening allergy to contrast medium, treatment with t-pa CSBPR Fifth Edition June 2015 Page 2 of 6
Imaging treatment with oral thrombin antagonists or oral selective Factor Xa inhibitors (intraarterial thrombolysis) Baseline noncontrast CT for the ASPECTS, baseline vessel imaging that patient would not be expected to survive more than one-year. Standard multimodal CT or MR was performed before or immediately suspected intracranial dissection as a cause of stroke, clinical history, past imaging or clinical judgment suggestive of chronic intracranial occlusion, severe or fatal comorbid illness, inability to complete follow-up treatment due to co-morbid non-fatal illness. Non-contrast CT and CTA (preferably multiphase) were performed to identify current or recent history of illicit drug(s) or abuses alcohol, known history of arterial tortuosity, preexisting stent, and/or other arterial disease which would prevent the device from reaching the target vessel and/or preclude safe recovery of the device. Imaging exclusions: CT or MRI evidence of mass effect or intra-cranial tumor (except small meningioma) or cerebral vasculitis, CT showing hypodensity or MRI showing hyperintensity involving greater than 1/3 of the middle cerebral artery (MCA) territory (or in other territories, >100 cc of tissue) on presentation, baseline non-contrast CT or DWI MRI evidence of a moderate/large core defined as extensive early ischemic changes of ASPECTS < 6, CT or MRI evidence of a basilar artery (BA) occlusion or posterior cerebral artery (PCA) occlusion, CTA or MRA evidence of carotid dissection or complete cervical carotid occlusion requiring stenting at the time of the index procedure (i.e., mechanical thrombectomy). > 4.5 hours, acute stroke within the first 48 hours after percutaneous cardiac or cerebrovascular interventions and major surgery, renal insufficiency with creatinine 3 mg/dl, women known to be pregnant or lactating, cerebral vasculitis, preexisting neurological or psychiatric disease, unlikely to be available for one year follow-up. Neuroimaging criteria: Hypodensity on CT CSBPR Fifth Edition June 2015 Page 3 of 6
Treatment crossovers (CTA, MRA, or DSA) for the location of the occlusion, and follow-up CTA or MRA at 24 hours for vessel recanalization. Recanalization was classified as complete or not complete and was further evaluated with the use of the modified Arterial Occlusive Lesion score. Follow-up CT scans were conducted at 5 days and assessed for the presence of intracranial hemorrhage. Final infarct volume was assessed with the use of an automated, validated algorithm. Control to intervention group: n=1; intervention to control group n=17 after commencing intravenous tpa. Eligibility was determined using dual target vessel occlusion on CT/MR angiography and mismatch using RAPID automated software. An MRI was performed 18 30 h poststroke onset to assess reperfusion, recanalization, and ischemic core growth. The presence and degree of reperfusion was determined as the percentage difference between the coregistered 24 h and acute perfusion lesion volumes. Recanalization was determined based on 24 h MRA and classified using the Thrombolysis in Myocardial Infarction (TIMI) scale. Ischemic core growth was calculated as the absolute and relative difference in volume between CT-rCBF estimated ischemic core at baseline and 24 h DWI lesion volume. Control to intervention group: n=0; intervention to control group n=8 (4 participants with a small infarct core, an occluded proximal artery in the anterior circulation, and moderate-to-good collateral circulation. A small infarct core was defined as an ASPECTS of 6 to 10. Proximal artery occlusion in the anterior circulation was defined as occlusion of the middlecerebral-artery trunk and its immediate branches, with or without intracranial occlusion of the internal carotid artery Moderate-to good collateral circulation was defined as the filling of 50% or more of the middle-cerebralartery pial arterial circulation on CTA (preferably on multiphase CTA). Control to intervention group: n=1; intervention to control group n=14 Control to : n=0; intervention to control group n=11 or restricted diffusion amounting to an ASPECTS score of <7 on noncontrast CT, or <6 on DWI MRI, CT or MR evidence of hemorrhage, significant mass effect with midline shift, evidence of ipsilateral carotid occlusion, high grade stenosis or arterial dissection in the extracranial or petrous segment of the internal carotid artery that cannot be treated or will prevent access to the intracranial clot or excessive tortuosity of cervical vessels precluding device delivery/deployment, occlusions in multiple vascular territories, evidence of intracranial tumor. Control to : n=0; intervention to CSBPR Fifth Edition June 2015 Page 4 of 6
Primary outcome results Secondary outcome results There was a significant shift towards more favourable mrs scores among patients in the common OR=1.67, 95% CI 1.21-2.30). The odds of more favourable outcome (mrs 0-1 and mrs 0-2) at day 90 were significantly higher among patients in the OR=2.07, 95% CI 1.07-4.02 and adj OR=2.16, 95% CIU 1.39-3.38, respectively). The mean NIHSS score at day 5-7 was significantly lower among patients in the (2.9 points, 95% CI 1.5-4.3). The odds of a BI score of 19-20 were significantly higher among patients in the had no thrombus, 2 had no angiogram, 1 had wire perforation pre device deployment, 1 had ICA stent only) Median reperfusion at 24 hours was significantly higher in the intervention group (100% vs. 37%, p<0.001). A significantly greater proportion of patients in the experienced early neurological improvement (80% vs. 37%, p<0.001), There was a significant shift in mrs scores towards lower scores associated with the (p=0.006). A significantly greater proportion of patients in the were independent at day 90 (71% vs. 40%, p=0.009). The odds of improvement in mrs score by 1 point were significantly higher among patients in the OR=3.2, 95% CI 2.0-4.7). The odds of attaining a mrs score of 0-2 at 90 days were higher in the OR=1.7, 95% CI 1.3-2.2). The odds of a NIHSS score of 0-2 and Barthel Index score of 95-100 were also significantly higher in the OR=2.1, 95% CI 1.5-3.0 and 1.7, 95% CI 1.3-2.22, respectively). There was a significant shift in mrs scores towards lower scores associated with the (p=0.0002). The odds of successful perfusion (>90%) at 27 hours were significantly higher in the (82.8% vs. 40.4%, OR=7.11, 95% CI 3.03-16.7, p<0.0001). A higher percentage of patients in the intervention group were independent at day 90 (mrs 0-2) (60.2% vs. 35.5%, OR=2.75, 95% CI 1.53-4.95, p=0.0008). There was no significant reduction in the odds of death at 90 days associated with the intervention (9.2% vs. 12.4, OR=0.72, 95% CI 0.29-1.79, p=0.50). control group n=0 (treatment not performed in 5 cases) Over the range of mrs scores, the odds for improvement by 1 point at 90 days were increased significantly in the (adj OR=1.7, 95% CI 1.05-2.8) The odds of achieving mrs score of 0-2 at 90 days were increased significantly in the (adj OR=2.1, 95% CI 1.1-4.0). The odds of dramatic neurological improvement at 24 hours were increased significantly in the (adj OR=5.8, 95% CI 3.0-11.1). The median infarct volume was significantly lower in CSBPR Fifth Edition June 2015 Page 5 of 6
Safety outcomes NNT* (mrs 0-2 for independence) (adj OR=2.1, 95% CI 1.4-3.2). There was no difference in the mean number of serious adverse events between groups at 90 days. There were procedure- related complications in 26 patients (11.2%). There were no significant differences between groups in any of the safety outcomes (death, symptomatic ICH or parenchymal hematoma). The risk of death was significantly lower in the experimental group (adj RR=0.5, 95% CI 0.-0.8). The risk of large or malignant stroke was significantly lower in the RR=0.3, 95% CI 0.1-0.7). There was no significant increase in the risk of symptomatic ICH in the RR=1.2, 95% CI 0.3-4.6). There was no increased risk of serious adverse events, including symptomatic ICH, parenchymal hematoma and SAH associated with intervention. the intervention group (16.3 vs. 38.6 ml, p=0.02). At 90 days, the rates of death and symptomatic ICH were similar between groups (18.4% vs. 15.5% and 1.9% vs. 1.9%, respectively). 7.4 3.2 4.2 4.0 6.5 * Number Needed to Treat (NNT) refers to the estimated number of patients who would need to undergo an endovascular procedure in order to achieve mrs score of 0 to 2, 90 days post procedure. CSBPR Fifth Edition June 2015 Page 6 of 6