Siddiqui, Adnan H.

Limited data exist on clot composition and detailed characteristics of arterial thrombi associated with large vessel occlusion in acute ischemic stroke. Advances in endovascular thrombectomy and related imaging modalities have created a unique opportunity to analyze thrombi removed from cerebral arteries. Insights into thrombus composition, etiology, physical properties and neurovascular interactions may lead to future advancements in acute ischemic stroke treatment and improved clinical outcomes. Advances in imaging techniques may enhance clot characterization and inform therapeutic decision-making prior to treatment and reveal stroke etiology to guide secondary prevention. Current imaging techniques can provide some information about thrombi, but there remains much to evaluate about relationships that may exist among thrombus composition, occlusion characteristics and treatment outcomes. Improved pathophysiological characterization of clot types, their properties and how these properties change over time, together with clinical correlates from ongoing studies, may facilitate revascularization with thrombolysis and thrombectomy. Interdisciplinary approaches covering clinical, engineering and scientific aspects of thrombus research will be key to advancing the understanding of thrombi and improving acute ischemic stroke therapy. This consensus statement integrates recent research on clots and thrombi retrieved from cerebral arteries and provides a rationale for further analyses, including current opportunities and limitations.

Abstract BACKGROUND Neuroendovascular intervention has become a key treatment option for acute ischemic stroke. The Sofia (6F) PLUS catheter was designed for neurovascular access for diagnostic or therapeutic interventions. OBJECTIVE To report the first series describing use of the Sofia PLUS intermediate/distal access reperfusion catheter in the treatment of acute ischemic stroke. METHODS In this retrospective study, 41 stroke cases were identified in which the catheter was utilized for thrombolysis/thrombectomy. Mean preprocedure National Institutes of Health Stroke Scale score was 16.5 ± 5.2 (range 4-29). Occluded vessels included the M1 segment, M2 segment, internal carotid artery terminus, cervical internal carotid artery, and basilar artery. RESULTS Successful positioning of the Sofia PLUS catheter near the occlusion site was achieved in 38 (92.7%) of 41 cases in which thrombectomy or thrombolysis was attempted using intraarterial tissue plasminogen activator, a direct aspiration first-pass technique, and/or stent retrieval. A postprocedure thrombolysis in cerebral infarction (TICI) score of 2b/3 was achieved in 37 of 41 cases. Of 15 cases where the Sofia PLUS was used for a direct aspiration first-pass technique, TICI 2b/3 was achieved in 11 (73.3%). In one case where intra-arterial tissue plasminogen activator was used as the only treatment modality, TICI 2a was achieved. No device-related or catheter-related complications were observed. The mean 7-d-postprocedure National Institutes of Health Stroke Scale score among the 39 survivors was 8.5 ± 7.3 (range 0-23). CONCLUSION Initial results with use of the Sofia (6F) PLUS for endovascular treatment of acute ischemic stroke have been encouraging. Experience with a larger series is warranted to further evaluate the safety and efficacy of this device and compare it with other reperfusion catheters.

Abstract BACKGROUND: Early and mid-term safety and efficacy of aneurysm treatment with the Pipeline Embolization Device (PED) has been well demonstrated in prior studies. OBJECTIVE: To present 5-yr follow-up for patients treated in the Pipeline for Uncoilable or Failed Aneurysms clinical trial. METHODS: In our prospective, multicenter trial, 109 complex internal carotid artery (ICA) aneurysms in 107 subjects were treated with the PED. Patients were followed per a standardized protocol at 180 d and 1, 3, and 5 yr. Aneurysm occlusion, in-stent stenosis, modified Rankin Scale scores, and complications were recorded. RESULTS: The primary endpoint of complete aneurysm occlusion at 180 d (73.6%) was previously reported. Aneurysm occlusion for those patients with angiographic follow-up progressively increased over time to 86.8% (79/91), 93.4% (71/76), and 95.2% (60/63) at 1, 3, and 5 yr, respectively. Six aneurysms (5.7%) were retreated. New serious device-related events at 1, 3, and 5 yr were noted in 1% (1/96), 3.5% (3/85), and 0% (0/81) of subjects. There were 4 (3.7%) reported deaths in our trial. Seventy-eight (96.3%) of 81 patients with 5-yr clinical follow-up had modified Rankin Scale scores ≤2. No delayed neurological deaths or hemorrhagic or ischemic cerebrovascular events were reported beyond 6 mo. No recanalization of a previously occluded aneurysm was observed. CONCLUSION: Our 5-yr findings demonstrate that PED is a safe and effective treatment for large and giant wide-necked aneurysms of the intracranial ICA, with high rates of complete occlusion and low rates of delayed adverse events.

OBJECTIVEThe authors performed a pooled analysis of 3 studies—IntrePED (International Retrospective Study of the Pipeline Embolization Device), PUFS (Pipeline for Uncoilable or Failed Aneurysms Study), and ASPIRe (Aneurysm Study of Pipeline in an Observational Registry)—in order to assess angiographic outcomes and clinical safety of the Pipeline embolization device (PED).METHODSIntrePED was a retrospective study, while PUFS and ASPIRe were prospective studies. For each patient included in these studies, the authors collected baseline demographic data, aneurysm characteristics, and procedural details. The primary outcomes for this combined analysis were clinical outcomes, including neurological morbidity and mortality and major ipsilateral intracranial hemorrhage and ischemic stroke. The secondary outcomes were angiographic occlusion rates, which were available for ASPIRe and PUFS only.RESULTSA total of 1092 patients with 1221 aneurysms were included across the 3 studies. The mean aneurysm size was 12.0 ± 7.8 mm and the mean neck size was 6.6 ± 4.8 mm. The major ipsilateral ischemic stroke rate was 3.7% (40/1091). The major ipsilateral intracranial hemorrhage rate was 2.0% (22/1091). The major neurological morbidity rate was 5.7% (62/1091). The neurological mortality rate was 3.3% (36/1091). The combined major morbidity and neurological mortality rate was 7.1% (78/1091). The complete occlusion rates were 75.0% at 180 days (111/148) and 85.5% at 1 year (94/110). The overall aneurysm retreatment rate was 3.0% (33/1091) at a mean follow-up time of 10.2 ± 10.8 months.CONCLUSIONSEndovascular treatment of intracranial aneurysms with the PED is safe and effective. Angiographic occlusion rates progressed with follow-up. Rates of stroke, hemorrhage, morbidity and mortality, and retreatment were low, especially given the fact that the aneurysms treated were generally large and wide necked.

OBJECTIVEThe long-term effectiveness of endovascular treatment of large and giant wide-neck aneurysms using traditional endovascular techniques has been disappointing, with high recanalization and re-treatment rates. Flow diversion with the Pipeline Embolization Device (PED) has been recently used as a stand-alone therapy for complex aneurysms, showing significant improvement in effectiveness while demonstrating a similar safety profile to stent-supported coil treatment. However, relatively little is known about its long-term safety and effectiveness. Here the authors report on the 3-year safety and effectiveness of flow diversion with the PED in a prospective cohort of patients with large and giant internal carotid artery aneurysms enrolled in the Pipeline for Uncoilable or Failed Aneurysms (PUFS) trial.METHODSThe PUFS trial is a prospective study of 107 patients with 109 aneurysms treated with the PED. Primary effectiveness and safety end points were demonstrated based on independently monitored 180-day clinical and angiographic data. Patients were enrolled in a long-term follow-up protocol including 1-, 3-, and 5-year clinical and imaging follow-up. In this paper, the authors report the midstudy (3-year) effectiveness and safety data.RESULTSAt 3 years posttreatment, 74 subjects with 76 aneurysms underwent catheter angiography as required per protocol. Overall, complete angiographic aneurysm occlusion was observed in 71 of these 76 aneurysms (93.4% cure rate). Five aneurysms were re-treated, using either coils or additional PEDs, for failure to occlude, and 3 of these 5 were cured by the 3-year follow-up. Angiographic cure with one or two treatments of Pipeline embolization alone was therefore achieved in 92.1%. No recanalization of a previously completely occluded aneurysm was noted on the 3-year angiograms. There were 3 (2.6%) delayed device- or aneurysm-related serious adverse events, none of which led to permanent neurological sequelae. No major or minor late-onset hemorrhagic or ischemic cerebrovascular events or neurological deaths were observed in the 6-month through 3-year posttreatment period. Among 103 surviving patients, 85 underwent functional outcome assessment in which modified Rankin Scale scores of 0–1 were demonstrated in 80 subjects.CONCLUSIONSPipeline embolization is safe and effective in the treatment of complex large and giant aneurysms of the intracranial internal carotid artery. Unlike more traditional endovascular treatments, flow diversion results in progressive vascular remodeling that leads to complete aneurysm obliteration over longer-term follow-up without delayed aneurysm recanalization and/or growth.Clinical trial registration no.: NCT00777088 (clinicaltrials.gov)

OBJECT The authors sought to determine whether flow diversion with the Pipeline Embolization Device (PED) can approximate microsurgical decompression in restoring function after cranial neuropathy following carotid artery aneurysms. METHODS This multiinstitutional retrospective study involved 45 patients treated with PED across the United States. All patients included presented between November 2009 and October 2013 with cranial neuropathy (cranial nerves [CNs] II, III, IV, and VI) due to intracranial aneurysm. Outcome analysis included clinical and procedural variables at the time of treatment as well as at the latest clinical and radiographic follow-up. RESULTS Twenty-six aneurysms (57.8%) were located in the cavernous segment, while 6 (13.3%) were in the clinoid segment, and 13 (28.9%) were in the ophthalmic segment of the internal carotid artery. The average aneurysm size was 18.6 mm (range 4–35 mm), and the average number of flow diverters placed per patient was 1.2. Thirty-eight patients had available information regarding duration of cranial neuropathy prior to treatment. Eleven patients (28.9%) were treated within 1 month of symptom onset, while 27 (71.1%) were treated after 1 month of symptoms. The overall rate of cranial neuropathy improvement for all patients was 66.7%. The CN deficits resolved in 19 patients (42.2%), improved in 11 (24.4%), were unchanged in 14 (31.1%), and worsened in 1 (2.2%). Overtime, the rate of cranial neuropathy improvement was 33.3% (15/45), 68.8% (22/32), and 81.0% (17/21) at less than 6, 6, and 12 months, respectively. At last follow-up, 60% of patients in the isolated CN II group had improvement, while in the CN III, IV, or VI group, 85.7% had improved. Moreover, 100% (11/11) of patients experienced improvement if they were treated within 1 month of symptom onset, whereas 44.4% (12/27) experienced improvement if they treated after 1 month of symptom onset; 70.4% (19/27) of those with partial deficits improved compared with 30% (3/10) of those with complete deficits. CONCLUSIONS Cranial neuropathy caused by cerebral aneurysm responds similarly when the aneurysm is treated with the PED compared with open surgery and coil embolization. Lower morbidity and higher occlusion rates obtained with the PED may suggest it as treatment of choice for some of these lesions. Time to treatment is an important consideration regardless of treatment modality.

OBJECT Neuroophthalmological morbidity is commonly associated with large and giant cavernous and supraclinoid internal carotid artery (ICA) aneurysms. The authors sought to evaluate the neuroophthalmological outcomes after treatment of these aneurysms with the Pipeline Embolization Device (PED). METHODS The Pipeline for Uncoilable or Failed Aneurysms (PUFS) trial was an international, multicenter prospective trial evaluating the safety and efficacy of the PED. All patients underwent complete neuroophthalmological examinations both before the PED procedure and at a 6-month follow-up. All examinations were performed for the purpose of this study and according to study criteria. RESULTS In total, 108 patients were treated in the PUFS trial, 98 of whom had complete neuroophthalmological follow-up. Of the patients with complete follow-up, 39 (40%) presented with a neuroophthalmological baseline deficit that was presumed to be attributable to the aneurysm, and patients with these baseline deficits had significantly larger aneurysms. In 25 of these patients (64%), the baseline deficit showed at least some improvement 6 months after PED treatment, whereas in 1 patient (2.6%), the deficits only worsened. In 5 patients (5%), new deficits had developed at the 6-month follow-up, while in another 6 patients (6%), deficits that were not originally assumed to be related to the aneurysm had improved by that time. A history of diabetes was associated with failure of the baseline deficits to improve after the treatment. The aneurysm maximum diameter was significantly larger in patients with a new deficit or a worse baseline deficit at 6 months postprocedure. CONCLUSIONS Patients treated with the PED for large and giant ICA aneurysms had excellent neuroophthalmological outcomes 6 months after the procedure, with deficits improving in most of the patients, very few deficits worsening, and few new deficits developing.

Various endovascular intraarterial approaches are available for treating patients with acute ischemic stroke who present with severe neurological deficits. Three recent randomized trials—Interventional Management of Stroke (IMS) III, Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy (MR RESCUE), and Synthesis Expansion: A Randomized Controlled Trial on Intra-Arterial Versus Intravenous Thrombolysis in Acute Ischemic Stroke (SYNTHESIS Expansion)—evaluated the efficacy of endovascular treatment of acute ischemic stroke and, after failing to demonstrate any significant clinical benefit of endovascular therapies, raised concerns and questions in the medical community regarding the future of endovascular treatment for acute ischemic stroke. In this paper, the authors review the evolution of endovascular treatment strategies for the treatment of acute stroke and provide their interpretation of findings and potential limitations of the three recently published randomized trials. The authors discuss the advantage of stent-retriever technology over earlier endovascular approaches and review the current status and future directions of endovascular acute stroke studies based on lessons learned from previous trials.

Purpose To determine the rates of neurologic adverse events following Pipeline Embolic Device (PED) placement for intracranial aneurysm treatment. Methods A retrospective review of medical records was performed at 19 centres to identify consecutive intracranial aneurysms treated with the PED following regulatory approval for marketing the device in the given country. All patients in whom at least one PED was placed and in whom follow-up was available prior to IRB or ethics panel approval were enrolled. Three anatomic/size subgroups were defined, including 1) pre-PComm, internal carotid artery aneurysms 10mm or greater (“large ICA”), 2) ICA aneurysms >10mm and/or at/distal to the PComm region (“other anterior circulation”), and 3) posterior circulation aneurysms. “Primary safety events” included stroke, haemorrhage, parent artery stenosis, permanent cranial neuropathy, and spontaneous rupture of the target aneurysm. Severe safety events were defined as any event causing significant impairment of functioning causing the inability of the subject to carry out usual activities. Statistical analysis was performed using standard summary statistics; p-values comparing subgroups were computed using Pearson's chi-square test for discrete variables and analysis of variance for continuous variables. Results To date, 580 aneurysms, including 183 large ICA, 344 other anterior circulation, and 53 posterior circulation aneurysms have been treated and followed for a mean duration of 7.8 months (SD 7.3, range 0.1 - 40.8). 437 (76%) of 580 aneurysms were saccular and 80 (14%) were fusiform; 32 (5.5%) were classified as giant (<25mm diameter). 549 (93%) were unruptured. 241 (42%) were treated with multiple PEDs. Primary safety events were noted in 62 (12%) cases. Severe neurological events occurred in 35 (6.8%) cases, and occurred more frequently in posterior circulation aneurysms (7 (13%)) than in either large ICA or other anterior circulation aneurysms (15 (8.8%) and (13 (4.5%), respectively, p=.035). Major stroke occurred in 20 (3.9%) of 515 subjects (4.1%, 3.1%, and 7.5% in large ICA, other anterior circulation, and posterior circulation aneurysms, respectively, p=.31). Ipsilateral intracranial haemorrhage occurred in 12 (2.3%) subjects (3.5%, 1.7%, and 1.9% in large ICA, other anterior circulation, and posterior circulation aneurysms, respectively, p=.47). Spontaneous aneurysm rupture occurred in 3 (0.6%) aneurysms, all of which were giant, resulting in a 9% incidence of rupture in giant aneurysms. Mortality rate was 4.3% and was significantly higher for posterior circulation aneurysms (11.3%) as compared to anterior circulation aneurysms (3.5%, p=.019). Conclusions Preliminary data indicates that in approximately 7% of aneurysms treated with PED, substantial neurologic complications occurred, with rates of both severe neurologic events and mortality occurring significantly higher in the posterior as compared to the anterior circulation. Both ipsilateral haemorrhage and spontaneous aneurysm rupture were rare, with the latter event limited to giant aneurysms. Disclosures D. Kallmes: 1; C; MicroVention, Sequent, Benvenue, eV3. 2; C; General Electric, Codman, eV3. E. Boccardi: None. A. Bonafe: None. S. Cekirge: None. D. Fiorella: 2; C; Pipeline proctor, consultant, (<10K, EV3). R. Hanel: None. P. Jabbour: None. E. Levy: None. D. Lopes: 6; C; Receives compensation for training & proctoring for Pipeline devices. P. Lylyk: None. C. McDougall: None. A. Siddiqui: None. I. Szikora: None. H. Woo: None.

Object Acute revascularization has been associated with improved stroke outcomes. The Prolyse in Acute Cerebral Thromboembolism (PROACT II) trial achieved recanalization rates of 66%. The Multi Mechanical Embolus Removal in Cerebral Ischemia (Multi MERCI) trial achieved recanalization in 70% of patients. However, these interventional tools are not always successful. The Enterprise vascular reconstruction device was recently introduced for treatment of cerebral aneurysms previously untreatable with endovascular techniques. The authors evaluated a multicenter experience using this stent as a salvage revascularization tool for acute stroke treatment. Methods Four medical centers participated in a retrospective review of endovascularly treated patients with acute stroke for cases treated with the Enterprise stent after routine interventions had been unsuccessful. Data collected included preprocedure information, intraprocedure findings, and outcomes. Results Twenty patients with acute stroke (mean age 61.6 ± 22 years) were treated with the Enterprise stent. Ten patients received intravenous recombinant tissue plasminogen activator before catheter intervention, without improvement. Intraarterial interventions attempted unsuccessfully before Enterprise deployment included the Merci retriever (12 patients), angioplasty (7 patients), glycoprotein IIb–IIIa inhibitor administration (12 patients), intraarterial nitroglycerin (1 patient), Wingspan stent deployment (3 patients), and Xpert stent deployment (1 patient). The mean preintervention National Institutes of Health Stroke Scale (NIHSS) score was 17 ± 6 (median 17). All patients presented with a Thrombolysis in Myocardial Infarction (TIMI) score of 0 or 1. Revascularization was achieved in all patients (75% with a TIMI score of 3, 25% with a TIMI score of 2). Improvement (≥ 4 points on the NIHSS) was documented in 75% of patients. Mean NIHSS improvement from intervention to discharge was 8 ± 7 points (median 9 points). Conclusions These preliminary data suggest a potential benefit to the use of the Enterprise stent when routine intervention methods fail.