Richard Dowling

A multicenter, randomized, controlled study to investigate EXtending the time for Thrombolysis in Emergency Neurological Deficits with Intra-Arterial therapy (EXTEND-IA)

Background and Hypothesis Thrombolysis with tissue plasminogen activator is proven to reduce disability when given within 4.5 h of ischemic stroke onset. However, tissue plasminogen activator only succeeds in recanalizing large vessel arterial occlusion in a minority of patients. We hypothesized that anterior circulation ischemic stroke patients, selected with ‘dual target’ vessel occlusion and evidence of salvageable brain using computed tomography or magnetic resonance imaging ‘mismatch’ within 4.5 h of onset, would have improved reperfusion and early neurological improvement when treated with intra-arterial clot retrieval after intravenous tissue plasminogen activator compared with intravenous tissue plasminogen activator alone. Study Design EXTEND-IA is an investigator-initiated, phase II, multicenter prospective, randomized, open-label, blinded-endpoint study. Ischemic stroke patients receiving standard 0.9 mg/kg intravenous tissue plasminogen activator within 4.5 h of stroke onset who have good prestroke functional status (modified Rankin Scale <2, no upper age limit) will undergo multimodal computed tomography or magnetic resonance imaging. Patients who also meet dual target imaging criteria: vessel occlusion (internal carotid or middle cerebral artery) and mismatch (perfusion lesion: ischemic core mismatch ratio >1.2, absolute mismatch >10 ml, ischemic core volume <70 ml) will be randomized to either clot retrieval with the Solitaire FR device after full dose intravenous tissue plasminogen activator, or tissue plasminogen activator alone. Study Outcomes The coprimary outcome measure will be reperfusion at 24 h and favorable clinical response (reduction in National Institutes of Health Stroke Scale by ≥8 points or reaching 0–1) at day 3. Secondary outcomes include modified Rankin Scale at day 90, death, and symptomatic intracranial hemorrhage.

Does Treatment of Ruptured Intracranial Aneurysms Within 24 Hours Improve Clinical Outcome

Background and Purpose— The purpose of this study was to analyze whether treating ruptured intracranial aneurysms within 24 hours of subarachnoid hemorrhage improves clinical outcome. Methods— An 11-year database of consecutive ruptured intracranial aneurysms treated with endovascular coiling or craniotomy and clipping was analyzed. Outcome was measured by the modified Rankin Scale at 6 months. Our policy is to treat all cases within 24 hours of subarachnoid hemorrhage. Treatment delays are due to nonclinical logistical factors. Results— Two hundred thirty cases were coiled or clipped within 24 hours of subarachnoid hemorrhage and 229 at >24 hours. No difference in age, gender, smoking, family history of subarachnoid hemorrhage, aneurysm size, or aneurysm location was found between the groups. Poor World Federation of Neurological Surgeons clinical grade patients were overrepresented in the ultra-early group. Increasing age and higher World Federation of Neurological Surgeons clinical grade were predictors of poor outcome. Eight point zero percent of cases treated within 24 hours of subarachnoid hemorrhage (ultra-early) were dependent or dead at 6 months compared with 14.4% of those treated at >24 hours (delayed), a 44.0% relative risk reduction and a 6.4% absolute risk reduction (&khgr;2, P=0.044). A total of 3.5% of cases coiled within 24 hours were dependent or dead at 6 months compared with 12.5% of cases coiled at 1 to 3 days, an 82% relative risk reduction and a 10.2% absolute risk reduction (&khgr;2, P=0.040). These groups did not differ in age, World Federation of Neurological Surgeons clinical grade, aneurysm size, or aneurysm location. Conclusions— Treatment of ruptured aneurysms within 24 hours is associated with improved clinical outcomes compared with treatment at >24 hours. The benefit is more pronounced for coiling than clipping.

Radioembolization in Combination with Systemic Chemotherapy as First-line Therapy for Liver Metastases from Colorectal Cancer

PURPOSE To report clinical experience with radioembolization (RE) plus systemic chemotherapy as a first-line treatment for liver metastases from colorectal cancer (CRC). MATERIALS AND METHODS Clinical outcomes were evaluated retrospectively among 19 patients with unresectable liver metastases from CRC who had a good performance status and a low burden of extrahepatic disease (EHD) and were eligible for RE. Most (74%) had disease confined to the liver. Concurrent treatment with 5-fluorourail/leucovorin (n = 7) or 5-fluorourail/leucovorin/oxaliplatin (FOLFOX; n = 12) was started 3-4 days before single treatment with RE. RESULTS Overall response rate according to the Response Evaluation Criteria in Solid Tumors was 84% (two complete responses and 14 partial responses). Median progression-free survival (PFS) time was 10.4 months and median overall survival (OS) time was 29.4 months. For patients with disease confined to the liver, PFS improved (10.7 mo vs 3.6 mo; P = .09), with significant prolongation of OS (median, 37.8 mo vs 13.4 mo; P = .03) compared with those who had EHD. Nine patients, including three long-term (> 3 y) survivors, remained alive after a median follow-up of 18.6 months. Serious treatment-related toxicities included febrile neutropenia with concurrent FOLFOX treatment, a perforated duodenal ulcer, and one death from hepatic toxicity. CONCLUSIONS The present findings confirm the effectiveness of RE plus systemic chemotherapy for metastatic CRC. Patients with liver-confined disease derived the greatest benefit, with median survival times beyond 36 months. Larger datasets from ongoing phase III trials are needed to further define the safety and efficacy of RE in the first-line setting.

Clopidogrel Hyper-Response and Bleeding Risk in Neurointerventional Procedures

Patients may respond to antiplatelet medication in 2 ways: resistance leading to higher incidence of ischemic events and hyper-response resulting in bleeds. Here, 47 patients treated with clopidogrel were tested for P2Y12 receptor-mediated platelet inhibition. Clopidogrel hyper-response was more common in patients with major (n=10) than in those with minor bleeds. Of 7 patients defined as hyper-responders, 43% had major bleeding complications. Thus, hyper-response to clopidogrel is associated with increased risk of major hemorrhage. (See the related article by Comin and Kallmes.) BACKGROUND AND PURPOSE: Antiplatelet therapy is associated with decreased ischemic events after neurointerventional procedures. Antiplatelet resistance negates the protective effects of antiplatelet medication, leading to a higher incidence of ischemic events. A possible link between antiplatelet hyper-response and increased hemorrhagic complications has been inadequately investigated. We aimed to examine the correlation between antiplatelet hyper-response and the risk of hemorrhagic complications. MATERIALS AND METHODS: Patients who were treated with antiplatelet medications and underwent neurointerventional procedures were prospectively recruited. We collected the following data: demographics, vascular risk factors, antiplatelet and anticoagulation treatment, antiplatelet responsiveness, coagulation profile, and hemorrhagic complications. P2Y12 receptor–mediated platelet inhibition was tested by using the VerifyNow assay device. The primary end points were postprocedural major and minor hemorrhagic complications. Receiver operator characteristic analysis was used to evaluate the percentage of platelet inhibition as a diagnostic tool for bleeding events. The association between hemorrhage and percentage of platelet inhibition was investigated by using logistic regression modeling. RESULTS: Forty-seven patients were enrolled. The mean age was 56 ± 12 years, and 28% were men. Ten patients (21.3%) developed hemorrhagic complications. Clopidogrel response was higher in patients with a major bleeding complication compared with those with minor or no bleeding (median, 94% versus 24% platelet inhibition; P = .0084). Of the 7 patients (14.9%) defined as hyper-responders with ≥72% platelet inhibition, 42.8% had a major bleeding complication. CONCLUSIONS: Hyper-response to clopidogrel is associated with increased risk of hemorrhagic complications. Larger studies are urgently needed to validate a clinically useful threshold to define clopidogrel hyper-response and to examine the clinical effects of antiplatelet dosage adjustment.

Machine learning for outcome prediction of acute ischemic stroke post intra-arterial therapy.

Introduction Stroke is a major cause of death and disability. Accurately predicting stroke outcome from a set of predictive variables may identify high-risk patients and guide treatment approaches, leading to decreased morbidity. Logistic regression models allow for the identification and validation of predictive variables. However, advanced machine learning algorithms offer an alternative, in particular, for large-scale multi-institutional data, with the advantage of easily incorporating newly available data to improve prediction performance. Our aim was to design and compare different machine learning methods, capable of predicting the outcome of endovascular intervention in acute anterior circulation ischaemic stroke. Method We conducted a retrospective study of a prospectively collected database of acute ischaemic stroke treated by endovascular intervention. Using SPSS®, MATLAB®, and Rapidminer®, classical statistics as well as artificial neural network and support vector algorithms were applied to design a supervised machine capable of classifying these predictors into potential good and poor outcomes. These algorithms were trained, validated and tested using randomly divided data. Results We included 107 consecutive acute anterior circulation ischaemic stroke patients treated by endovascular technique. Sixty-six were male and the mean age of 65.3. All the available demographic, procedural and clinical factors were included into the models. The final confusion matrix of the neural network, demonstrated an overall congruency of ∼80% between the target and output classes, with favourable receiving operative characteristics. However, after optimisation, the support vector machine had a relatively better performance, with a root mean squared error of 2.064 (SD: ±0.408). Discussion We showed promising accuracy of outcome prediction, using supervised machine learning algorithms, with potential for incorporation of larger multicenter datasets, likely further improving prediction. Finally, we propose that a robust machine learning system can potentially optimise the selection process for endovascular versus medical treatment in the management of acute stroke.

Thrombus composition in acute ischemic stroke: A histopathological study of thrombus extracted by endovascular retrieval

BACKGROUND AND PURPOSE The composition of occlusive thrombus in acute ischemic stroke may affect treatment success. Neuroimaging characteristics may correlate with thrombus composition. In this study we aimed to investigate the relationship between the hyperdense artery sign (HAS) on imaging and thrombus composition. MATERIALS AND METHODS Acute ischemic stroke patients who underwent endovascular thrombus retrieval from 2010-2012 were prospectively recruited. One blinded pathologist prepared the histology sections of retrieved thrombi whereby staining with haematoxylin and eosin and CD34 immunostain were performed. Histology sections were categorised into 4 phases of thrombus formation: red blood cell (RBC) dominant, RBC proportion equal to fibrin, fibrin dominant and organised fibrin. Computed tomography (CT) brain scans were assessed for HAS. Fishers exact test was performed to identify an association between HAS and thrombus composition. RESULTS Forty patients were included. The mean age was 65.6±12.9 years and 67.5% were male. Atrial fibrillation was detected in 19 (47.5%) patients, diabetes mellitus in 6 (15.0%), hypercholesterolaemia in 11 (27.5%), hypertension in 20 (50.0%) and previous stroke or transient ischemic attack in 8 (20.0%) patients. Of the retrieved thrombi, 11 (27.5%) were RBC dominant, 11 (27.5%) RBC proportion was equal to fibrin, 7 (17.5%) fibrin dominant and 11 (27.5%) organised fibrin pathology. HAS was present in 29 (72.5%) patients and was significantly associated with thrombus early phase pathology (P<0.05). CONCLUSION HAS was significantly associated with early phase thrombus composition. This may enable the prediction of thrombus composition and allow for targeted selection of therapeutic modality.

Is general anaesthesia preferable to conscious sedation in the treatment of acute ischaemic stroke with intra-arterial mechanical thrombectomy? A review of the literature

IntroductionIntra-arterial mechanical thrombectomy (IAMT) is an endovascular technique that allows for the acute retrieval of intravascular thrombi and is increasingly being used for the treatment of acute ischaemic stroke (AIS). There are currently two anaesthetic options during IAMT: general anaesthesia (GA) and conscious sedation (CS). The decision to use GA versus CS is the source of controversy, as it requires careful balance between patient pain, movement and airway protection whilst minimising time delay and haemodynamic fluctuations. This review examines and summarises the evidence for the use of GA versus CS in the treatment of AIS by IAMT.MethodsStudies were identified using systematic bibliographic searches. The five applicable studies were analysed with reference to overall outcomes and the key parameters that govern the decision to use GA or CS. The key parameters included the impact of GA and CS on pain, complication rates, time delays, airway protection and haemodynamic stability.ResultsSeveral retrospective analyses have shown that the use of GA is associated with adverse outcomes.ConclusionIntra-arterial mechanical thrombectomy under general anaesthesia is associated with poor outcomes in observational studies. It is reasonable to offer conscious sedation as the preferred option where adverse patient factors such as agitation are lacking.

Current Status of Pipeline Embolization Device in the Treatment of Intracranial Aneurysms: A Review

OBJECTIVE Pipeline embolization device (PED) implantation is a novel endovascular treatment option for the treatment of intracranial aneurysms. It is emerging as a useful alternative to coiling and to open surgery, and its use is increasing worldwide. We performed a literature review to examine its efficacy, technical challenges, and safety. METHODS PubMed database was used to identify all articles relating to PED. RESULTS The review outlines the indications for PED, its technical aspects, complications, and clinical outcomes. CONCLUSIONS PED offers an alternative to endovascular coiling for aneurysms with complex morphology. The indication for its use has evolved from the limited scope of treatment of giant aneurysms with wide necks to the inclusion of smaller aneurysms. The procedural safety profile of PED is comparable with or possibly superior to balloon-remodeling or stent-assisted coil embolization in specific circumstances. However, questions remain regarding the incidence of post-procedural subarachnoid hemorrhage. Ongoing monitoring and meticulous documentation of PED postimplantation safety is strongly recommended.

Antiplatelet Resistance and Thromboembolic Complications in Neurointerventional Procedures

Antiplatelet resistance is emerging as a significant factor in effective secondary stroke prevention. Prevalence of aspirin and clopidogrel resistance is dependent upon laboratory test and remains contentious. Large studies in cardiovascular disease populations have demonstrated worse ischemic outcomes in patients with antiplatelet resistance, particularly in patients with coronary stents. Thromboembolism is a complication of neurointerventional procedures that leads to stroke. Stroke rates related to aneurysm coiling range from 2 to 10% and may be higher when considering silent ischemia. Stroke associated with carotid stenting is a major cause of morbidity. Antiplatelet use in the periprocedure setting varies among different centers. No guidelines exist for use of antiplatelet regimens in neurointerventional procedures. Incidence of stroke in patients post procedure may be partly explained by resistance to antiplatelet agents. Further research is required to establish the incidence of stroke in patients with antiplatelet resistance undergoing neurointerventional procedures.

Glasgow Coma Scale Does Not Predict Outcome Post-Intra-Arterial Treatment for Basilar Artery Thrombosis

When is it too late to treat patients with basilar artery thrombosis? The common sense answer is usually “never” because the prognosis is so poor in these patients if nothing is done. Can the Glasgow Coma Scale be used for this purpose? Does a low GCS score predict a poor outcome and negate the need for treatment? The authors addressed these questions by studying 40 patients with basilar artery thrombosis treated intra-arterially. Interventions were done on average 7 hours after onset of clinical symptoms in patients with median GCS of 9 and recanalization was accomplished in 82%. There was no correlation between the initial GCS score and modified Rankin Scale at 90 days. Thus, it is not appropriate to exclude patients with low initial GCS scores from intra-arterial treatment of a thrombosed basilar artery. BACKGROUND AND PURPOSE: Evidence to guide patient selection for IA therapy in acute basilar artery thrombosis is lacking. The GCS is frequently used as a selection criterion, based on the view that higher GCS correlates with better neurologic outcome. This view has not been systematically studied. We hypothesize that low GCS does not correlate with poor outcome and that it should not preclude IA therapy. MATERIALS AND METHODS: We included 40 consecutive patients with basilar artery thrombosis treated with IA therapy. Clinical characteristics, GCS, time to intervention, and postprocedural TIMI scores were collected. Recanalization was defined as TIMI grade 2 or 3; clinical outcome was measured by 90-day mRS. RESULTS: Median patient age was 63.5 years. Most presented with gaze palsies (67.5%) or hemiparesis (45%). Median GCS was 9, the median time to intervention was 7.2 hours, and recanalization rate was 82.5%. Good neurologic outcome (mRS ≤ 1) occurred in 30%. There was no correlation between GCS and 90-day mRS (Spearman ρ − 0.174, P = .283). Equal numbers of patients with good neurologic outcome of mRS ≤ 1 (n = 12) had a GCS of ≤6 or >6. In those with GCS ≤ 6 for >3 hours, 33.3% had good neurologic outcome—a similar rate to that of the overall cohort. Statistical significance was demonstrated between time to IA therapy within 6 hours and mRS ≤ 2. CONCLUSIONS: Low GCS score did not correlate with poor neurologic outcome in patients with acute basilar artery thrombosis managed with IA therapy. It is not appropriate to exclude patients from IA therapy on the basis of low GCS.