Amrou Sarraj

Design of a prospective, dose-escalation study evaluating the Safety of Pioglitazone for Hematoma Resolution in Intracerebral Hemorrhage (SHRINC).

Rationale Preclinical work demonstrates that the transcription factor peroxisome proliferator-activated receptor gamma plays an important role in augmenting phagocytosis while modulating oxidative stress and inflammation. We propose that targeted stimulation of phagocytosis to promote efficient removal of the hematoma without harming surrounding brain cells may be a therapeutic option for intracerebral hemorrhage. Aims The primary objective is to assess the safety of the peroxisome proliferator-activated receptor gamma agonist, pioglitazone, in increasing doses for three-days followed by a maintenance dose, when administered to patients with spontaneous intracerebral hemorrhage within 24 h of symptom onset compared with standard care. We will determine the maximum tolerated dose of pioglitazone. Study Design This is a prospective, randomized, blinded, placebo-controlled, dose-escalation safety trial in which patients with spontaneous intracerebral hemorrhage are randomly allocated to placebo or treatment. The Continual Reassessment Method for dose finding is used to determine the maximum tolerated dose of pioglitazone. Hematoma and edema resolution is evaluated with serial magnetic resonance imaging (MRI) at specified time points. Functional outcome will be evaluated at three- and six-months. Outcomes The primary safety outcome is mortality at discharge. Secondary safety outcomes include mortality at three-months and six-months, symptomatic cerebral edema, clinically significant congestive heart failure, edema, hypoglycemia, anemia, and hepatotoxicity. Radiographic outcomes will explore the time frame for resolution of 25%, 50%, and 75% of the hematoma. Clinical outcomes are measured by the National Institutes of Health Stroke Scale (NIHSS), the Barthel Index, modified Rankin Scale, Stroke Impact Scale-16, and EuroQol at three- and six-months.

Endovascular therapy for acute ischemic stroke with occlusion of the middle cerebral artery M2 segment

Importance Randomized clinical trials have shown the superiority of endovascular therapy (EVT) compared with best medical management for acute ischemic strokes with large vessel occlusion (LVO) in the anterior circulation. However, of 1287 patients enrolled in 5 trials, 94 with isolated second (M2) segment occlusions were randomized and 51 of these received EVT, thereby limiting evidence for treating isolated M2 segment occlusions as reflected in American Heart Association guidelines. Objective To evaluate EVT safety and effectiveness in M2 occlusions in a cohort of patients with acute ischemic stroke. Design, Setting, and Participants This multicenter retrospective cohort study pooled patients with acute ischemic strokes and LVO isolated to M2 segments from 10 US centers. Patients with acute ischemic strokes and LVO in M2 segments presenting within 8 hours from their last known normal clinical status (LKN) from January 1, 2012, to April 30, 2015, were divided based on their treatment into EVT and medical management groups. Logistic regression was used to compare the 2 groups. Univariate and multivariate analyses evaluated associations with good outcome in the EVT group. Main Outcomes and Measures The primary outcome was the 90-day modified Rankin Scale score (range, 0-6; scores of 0-2 indicate a good outcome); the secondary outcome was symptomatic intracerebral hemorrhage. Results A total of 522 patients (256 men [49%]; 266 women [51%]; mean [SD] age, 68 [14.3] years) were identified, of whom 288 received EVT and 234 received best medical management. Patients in the medical management group were older (median [interquartile range] age, 73 [60-81] vs 68 [56-78] years) and had higher rates of intravenous tissue plasminogen activator treatment (174 [74.4%] vs 172 [59.7%]); otherwise the 2 groups were balanced. The rate of good outcomes was higher for EVT (181 [62.8%]) than for medical management (83 [35.4%]). The EVT group had 3 times the odds of a good outcome as the medical management group (odds ratio [OR], 3.1; 95% CI, 2.1-4.4; P < .001) even after adjustment for age, National Institute of Health Stroke Scale (NIHSS) score, Alberta Stroke Program Early Computed Tomographic Score (ASPECTS), intravenous tissue plasminogen activator treatment, and time from LKN to arrival in the emergency department (OR, 3.2; 95% CI, 2-5.2; P < .001). No statistical difference in symptomatic intracerebral hemorrhage was found (5.6% vs 2.1% for the EVT group vs the medical management group; P = .10). The treatment effect did not change after adjusting for center (OR, 3.3; 95% CI, 1.9-5.8; P < .001). Age, NIHSS score, ASPECTS, time from LKN to reperfusion, and successful reperfusion score of at least 2b (range, 0 [no perfusion] to 3 [full perfusion with filling of all distal branches]) were independently associated with good outcome of EVT. A linear association was found between good outcome and time from LKN to reperfusion. Conclusions and Relevance Although a randomized clinical trial is needed to confirm these findings, available data suggest that EVT is reasonable, safe, and effective for LVO of the M2 segment relative to best medical management.

Optimizing Prediction Scores for Poor Outcome After Intra-Arterial Therapy in Anterior Circulation Acute Ischemic Stroke

Background and Purpose— Intra-arterial therapy (IAT) promotes recanalization of large artery occlusions in acute ischemic stroke. Despite high recanalization rates, poor clinical outcomes are common. We attempted to optimize a score that combines clinical and imaging variables to more accurately predict poor outcome after IAT in anterior circulation occlusions. Methods— Patients with acute ischemic stroke undergoing IAT at University of Texas (UT) Houston for large artery occlusions (middle cerebral artery or internal carotid artery) were reviewed. Independent predictors of poor outcome (modified Rankin Scale, 4–6) were studied. External validation was performed on IAT-treated patients at Emory University. Results— A total of 163 patients were identified at UT Houston. Independent predictors of poor outcome (P⩽0.2) were identified as score variables using sensitivity analysis and logistic regression. Houston Intra-Arterial Therapy 2 (HIAT2) score ranges 0 to 10: age (⩽59=0, 60–79=2, ≥80 years=4), glucose (<150=0, ≥150=1), National Institute Health Stroke Scale (⩽10=0, 11–20=1, ≥21=2), the Alberta Stroke Program Early CT Score (8–10=0, ⩽7=3). Patients with HIAT2≥5 were more likely to have poor outcomes at discharge (odds ratio, 6.43; 95% confidence interval, 2.75–15.02; P<0.001). After adjusting for reperfusion (Thrombolysis in Cerebral Infarction score ≥2b) and time from symptom onset to recanalization, HIAT2≥5 remained an independent predictor of poor outcome (odds ratio, 5.88; 95% confidence interval, 1.96–17.64; P=0.02). Results from the cohort of Emory (198 patients) were consistent; patients with HIAT2 score ≥5 had 6× greater odds of poor outcome at discharge and at 90 days. HIAT2 outperformed other previously published predictive scores. Conclusions— The HIAT2 score, which combines clinical and imaging variables, performed better than all previous scores in predicting poor outcome after IAT for anterior circulation large artery occlusions.

Posterior circulation stroke is associated with prolonged door-to-needle time

Background Lack of recognition of early symptoms of acute posterior circulation ischaemic stroke might delay timely diagnosis and treatment with tissue plasminogen activator. Aims and hypothesis We hypothesized that patients with posterior circulation stroke receive delayed thrombolytic treatment in comparison to anterior circulation stroke. We investigated the differences in times to evaluation or treatment between patients with anterior circulation ischaemic stroke and posterior circulation stroke in our aim to understand the barriers that might have caused these delays. Methods A cross-sectional study was conducted using consecutive patients presenting to our tertiary academic centre with acute ischaemic stroke who were treated with intravenous tissue plasminogen activator within 4·5 h from symptom onset. We compared demographics, stroke severity, symptoms and signs, and time intervals among onset, emergency department arrival, emergency department physician evaluation, neurologist evaluation, brain imaging, and tissue plasminogen activator treatment in patients with anterior circulation stroke and posterior circulation stroke. Results Among 252 patients treated with intravenous tissue plasminogen activator, 12% had posterior circulation stroke. Patients with posterior circulation stroke had significantly lower median baseline the National Institutes of Health and Stroke Scale (NIHSS) score (P = 0·01), higher frequency of nausea (P < 0·01), vomiting (P < 0·01), dizziness (P < 0·01), and lower frequency of aphasia (P = 0·002) or neglect (P = 0·048). The emergency department physician evaluation-to-neurologist evaluation and door-to-needle intervals were significantly longer for posterior circulation stroke patients compared with anterior circulation stroke patients. The neurologist-to-needle time, however, was similar in the two groups. The presence of nausea and vomiting was associated with a longer time from emergency department evaluation to neurology evaluation and had a significant association with delayed treatment. Conclusions Posterior circulation stroke patients had a delay in neurology evaluation after initial emergency department evaluation and a delay in intravenous tissue plasminogen activator administration compared with anterior circulation stroke patients. There may be difficulties in rapidly recognizing the symptoms of posterior circulation stroke, in contrast to anterior circulation stroke, in the emergency department.

Prospective, open-label safety study of intravenous recombinant tissue plasminogen activator in wake-up stroke.

It is estimated that one of four ischemic strokes are noticed upon awakening and are not candidates for intravenous recombinant tissue plasminogen activator (rtPA) because their symptoms are >3 hours from last seen normal (LSN). We tested the safety of rtPA in a multicenter, single‐arm, prospective, open‐label study (NCT01183533) in patients with wake‐up stroke (WUS).

Prospective, open‐label safety study of intravenous rtPA in wake‐up stroke

It is estimated that one of four ischemic strokes are noticed upon awakening and are not candidates for intravenous recombinant tissue plasminogen activator (rtPA) because their symptoms are >3 hours from last seen normal (LSN). We tested the safety of rtPA in a multicenter, single‐arm, prospective, open‐label study (NCT01183533) in patients with wake‐up stroke (WUS).

Agreement Among Stroke Faculty and Fellows in Treating Ischemic Stroke Patients With Tissue-Type Plasminogen Activator and Thrombectomy

Background and Purpose— The aim of this study is to determine agreement among vascular neurology fellows and faculty in treating patients with acute ischemic stroke with intravenous tissue-type plasminogen activator and intra-arterial thrombectomy (IAT). Methods— Patients were evaluated simultaneously by at least 2 vascular neurology. Agreement was determined using kappa (&kgr;) and intraclass correlation coefficients. Results— In 60 patients, agreement was substantial for tissue-type plasminogen activator (&kgr;=0.75 [95% confidence interval, 0.57–0.92]) and IAT (&kgr;=0.63 [95% confidence interval, 0.30–0.96]), with no difference between fellow–fellow versus fellow–faculty. Intraclass correlation coefficient for National Institutes of Health Stroke Scale was 0.94 (95% confidence interval, 0.90–0.97) and &kgr; for Alberta Stroke Program Early CT Score was 0.53 (95% confidence interval, 0.20–0.78). Rapidly improving or mild deficits caused disagreement for both tissue-type plasminogen activator and IAT, whereas interpretation of computed tomographic perfusion led to disagreement for IAT. Conclusions— We found substantial agreement between vascular neurology fellows and faculty in treating with tissue-type plasminogen activator or IAT. Areas for improvement include recognition of stroke mimics, consensus on treating less severe strokes, and use/interpretation of imaging.

Telemedicine-guided remote enrollment of patients into an acute stroke trial

Enrollment into acute stroke clinical trials is limited to experienced tertiary centers with emergency research infrastructure. Feasibility of remote enrollment via telemedicine into an acute thrombolytic clinical trial has never been demonstrated.

Endovascular Treatment for Ischemic Strokes With Large Vessel Occlusion: Proven Therapy and Bright Future

Intravenous tissue-type plasminogen activator (tPA) has been the mainstay and only therapy with proven clinical benefit in patients with acute ischemic stroke for the nearly 20 years.1 Patients harboring a large vessel occlusions (LVOs) seemed to be recalcitrant to intravenous thrombolysis that portended a poor neurological recovery.2 Catheter-based treatments offered a promise of higher recanalization rates and better outcomes. Over 2 decades, there has been increasing operator experience and advances in technology allowing for efficient and effective removal of the offending thrombus. Three randomized controlled trials published in February 2013 failed to demonstrate the benefit of intra-arterial therapy (IAT) but had slow rates of recruitment, absence of mandating the presence of an LVO, prolonged times to IAT and use of older generation thrombectomy devices.3–5 This led to an initial dampening of enthusiasm followed by a resolve of the stroke community to press forward with clinical trials. The Multicenter Randomized Clinical Trial of Endovascular Treatment of Acute Ischemic Stroke in the Netherlands (MR CLEAN)6 addressed several of the weaknesses of previous trials by enrolling only patients with a proven LVO in the anterior circulation, enrolling a high proportion of patients with more proximal occlusions of the carotid terminus and M1 MCA (91%) and achieving higher TICI 2b or 3 reperfusion rates as compared with recent studies. With 500 enrolled patients, 233 in the intervention (IAT) arm and 267 in the control (medical management of which almost 90% received IV tPA), the study showed a significantly higher proportion of patients achieving a good functional outcome with IAT as compared with medical management only, resulting in a 13.5% absolute difference points in …

Higher prehospital blood pressure prolongs door to needle thrombolysis times: A target for quality improvement?

BACKGROUND Per the American Heart Association guidelines, blood pressure (BP) should be less than 185/110 to be eligible for stroke thrombolysis. No studies have focused on prehospital BP and its impact on door to needle (DTN) times. We hypothesized that DTN times would be longer for patients with higher prehospital BP. METHODS We conducted a retrospective review of acute ischemic stroke patients who presented between January 2010 and December 2010 to our emergency department (ED) through emergency medical services within 3 hours of symptom onset. Patients were categorized into 2 groups: prehospital BP greater than or equal to 185/110 (group 1) and less than 185/110 (group 2). Blood pressure records were abstracted from emergency medical services run sheets. Primary outcome measure was DTN time, and secondary outcome measures were modified Rankin Score at discharge, symptomatic intracranial hemorrhage, length of stay in stroke unit, and discharge disposition. RESULTS A total of 107 consecutive patients were identified. Of these, 75 patients (70%) were thrombolysed. Mean DTN times were significantly higher in group 1 (adjusted mean [95% confidence interval], 86minutes [76-97] vs 56minutes [45-68]; P<.0001). A greater number of patients required antihypertensive medications before thrombolysis in the ED in group 1 compared to group 2 (54% vs 27%; P=.02). CONCLUSION Higher prehospital BP is associated with prolonged DTN times and DTN time remains prolonged if prehospital BP greater than or equal to 185/110 is untreated before ED arrival. Prehospital BP control could be a potential area for improvement to reduce DTN times in patients with acute ischemic stroke.