Rationale and Design of the Statins Use in Intracerebral Hemorrhage Patients (SATURN) Trial.

INTRODUCTION: The benefits and risks of HMG-CoA reductase inhibitor (statin) drugs in survivors of intracerebral hemorrhage (ICH) are unclear. Observational studies suggest an association between statin use and increased risk of lobar ICH, particularly in patients with apolipoprotein-E (APOE) ε2 and ε4 genotypes. There are no randomized controlled trials (RCTs) addressing the effects of statins after ICH leading to uncertainty as to whether statins should be used in patients with lobar ICH who are at high risk for ICH recurrence. The SATURN trial aims to evaluate the effects of continuation versus discontinuation of statin on the risk of ICH recurrence and ischemic major adverse cerebro-cardio-vascular events (MACCE) in patients with lobar ICH. Secondary aims include the assessment of whether the APOE genotype modifies the effects of statins on ICH recurrence, functional and cognitive outcomes and quality of life. METHODS: The SATURN trial is a multi-center, pragmatic, prospective, randomized, open-label, Phase III clinical trial with blinded end-point assessment. A planned total of 1456 patients with lobar ICH will be recruited from 140 sites in the United States, Canada and Spain. Patients presenting within seven days of a spontaneous lobar ICH that occurred while taking a statin, will be randomized (1:1) to continuation (control) vs. discontinuation (intervention) of the same statin drug and dose that they were using at ICH onset. The primary outcome is the time to recurrent symptomatic ICH within a two-year follow-up period. The primary safety outcome is the occurrence of ischemic MACCE. CONCLUSION: The results will help to determine the best strategy for statin use in survivors of lobar ICH and may help to identify if there is a subset of patients who would benefit from statins.

Stroke Prevention in Atrial Fibrillation: Our Current Failures and Required Research.

Nonvalvular atrial fibrillation is a common rhythm disorder of middle-aged to older adults that can cause ischemic strokes and systemic embolism. Lifelong use of oral anticoagulants reduces the risk of these ischemic events but increases the risk of major and clinically relevant hemorrhages. These medications also require strict compliance for efficacy, and they have nontrivial failure rates in higher-risk patients. Left atrial appendage closure is a nonpharmacological method to prevent ischemic strokes in atrial fibrillation without the need for lifelong anticoagulant use, but this procedure has the potential for complications and residual embolic events. This workshop of the Roundtable of Academia and Industry for Stroke Prevention discussed future research needed to further decrease the ischemic and hemorrhagic risks among patients with atrial fibrillation. A direct thrombin inhibitor, factor Xa inhibitors, and left atrial appendage closure are FDA-approved approaches whereas factor XIa inhibitors are currently being studied in phase 3 randomized controlled trials for stroke prevention. The benefits, risks, and shortcomings of these treatments and future research required in different high-risk patient populations are reviewed in this consensus statement.

Recombinant factor VIIa for hemorrhagic stroke treatment at earliest possible time (FASTEST): Protocol for a phase III, double-blind, randomized, placebo-controlled trial.

INTRODUCTION: Intracerebral hemorrhage is the deadliest form of stroke. Hematoma expansion, growth of the hematoma between the baseline computed tomography scan and a follow-up computed tomography scan at 24 ± 6 h, predicts long-term disability or death. Recombinant factor VIIa (rFVIIa) has reduced hematoma expansion in previous clinical trials with a variable effect on clinical outcomes, with the greatest impact on hematoma expansion and potential benefit when administered within 2 h of symptom onset. METHODS: Factor VIIa for Hemorrhagic Stroke Treatment at Earliest Possible Time (FASTEST, NCT03496883) is a randomized controlled trial that will enroll 860 patients at ∼100 emergency departments and mobile stroke units in five countries. Patients are eligible for enrollment if they have acute intracerebral hemorrhage within 2 h of symptom onset confirmed by computed tomography, a hematoma volume of 2 to 60 mL, no or small volumes of intraventricular hemorrhage, do not take anticoagulant medications or concurrent heparin/heparinoids (antiplatelet medications are permissible), and are not deeply comatose. Enrolled patients will receive rFVIIa 80 µg/kg or placebo intravenously over 2 min. The primary outcome measure is the distribution of the ordinal modified Rankin Scale at 180 days. FASTEST is monitored by a Data Safety Monitoring Board. Safety endpoints include thrombotic events (e.g. myocardial infarction). Human subjects research is monitored by an external Institutional Review Board in participating countries. DISCUSSION: In the US, FASTEST will be first NIH StrokeNet Trial with an Exception from Informed Consent which allows enrollment of non-communicative patients without an immediately identifiable proxy.

Intense Arm Rehabilitation Therapy Improves the Modified Rankin Scale Score: Association Between Gains in Impairment and Function.

OBJECTIVE: To evaluate the effect of intensive rehabilitation on the modified Rankin Scale (mRS), a measure of activities limitation commonly used in acute stroke studies, and to define the specific changes in body structure/function (motor impairment) most related to mRS gains. METHODS: Patients were enrolled >90 days poststroke. Each was evaluated before and 30 days after a 6-week course of daily rehabilitation targeting the arm. Activity gains, measured using the mRS, were examined and compared to body structure/function gains, measured using the Fugl-Meyer (FM) motor scale. Additional analyses examined whether activity gains were more strongly related to specific body structure/function gains. RESULTS: At baseline (160 ± 48 days poststroke), patients (n = 77) had median mRS score of 3 (interquartile range, 2-3), decreasing to 2 [2-3] 30 days posttherapy (p < 0.0001). Similarly, the proportion of patients with mRS score ≤2 increased from 46.8% at baseline to 66.2% at 30 days posttherapy (p = 0.015). These findings were accounted for by the mRS score decreasing in 24 (31.2%) patients. Patients with a treatment-related mRS score improvement, compared to those without, had similar overall motor gains (change in total FM score, p = 0.63). In exploratory analysis, improvement in several specific motor impairments, such as finger flexion and wrist circumduction, was significantly associated with higher likelihood of mRS decrease. CONCLUSIONS: Intensive arm motor therapy is associated with improved mRS in a substantial fraction (31.2%) of patients. Exploratory analysis suggests specific motor impairments that might underlie this finding and may be optimal targets for rehabilitation therapies that aim to reduce activities limitations. CLINICAL TRIAL: Clinicaltrials.gov identifier: NCT02360488. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients >90 days poststroke with persistent arm motor deficits, intensive arm motor therapy improved mRS in a substantial fraction (31.2%) of patients.

The multiarm optimization of stroke thrombolysis phase 3 acute stroke randomized clinical trial: Rationale and methods.

BACKGROUND: Intravenous recombinant tissue plasminogen activator is the only proven effective medication for the treatment of acute ischemic stroke. Two approaches that may augment recombinant tissue plasminogen activator thrombolysis and prevent arterial reocclusion are direct thrombin inhibition with argatroban and inhibition of the glycoprotein 2b/3a receptor with eptifibatide. AIM: The multi-arm optimization of stroke thrombolysis trial aims to determine the safety and efficacy of intravenous therapy with argatroban or eptifibatide as compared with placebo in acute ischemic stroke patients treated with intravenous recombinant tissue plasminogen activator within 3 h of symptom onset. SAMPLE SIZE ESTIMATE: A maximum of 1200 randomized subjects to test the superiority of argatroban or eptifibatide to placebo in improving 90-day modified Rankin scores. METHODS AND DESIGN: Multiarm optimization of stroke thrombolysis is a multicenter, multiarm, adaptive, single blind, randomized controlled phase 3 clinical trial conducted within the National Institutes of Health StrokeNet clinical trial network. Patients treated with 0.9 mg/kg intravenous recombinant tissue plasminogen activator within 3 h of stroke symptom onset are randomized to receive intravenous argatroban (100 µg/kg bolus followed by 3 µg/kg/min for 12 h), intravenous eptifibatide (135 µg/kg bolus followed by 0.75 µg/kg/min infusion for 2 h) or IV placebo. Patients may receive endovascular thrombectomy per usual care. STUDY OUTCOMES: The primary efficacy outcome is improved modified Rankin score assessed at 90 days post-randomization. DISCUSSION: Multiarm optimization of stroke thrombolysis is an innovative and collaborative project that is the culmination of many years of dedicated efforts to improve outcomes for stroke patients.

Intensive vs Standard Treatment of Hyperglycemia and Functional Outcome in Patients With Acute Ischemic Stroke: The SHINE Randomized Clinical Trial.

Importance: Hyperglycemia during acute ischemic stroke is common and is associated with worse outcomes. The efficacy of intensive treatment of hyperglycemia in this setting remains unknown. Objectives: To determine the efficacy of intensive treatment of hyperglycemia during acute ischemic stroke. Design, Setting, and Participants: The Stroke Hyperglycemia Insulin Network Effort (SHINE) randomized clinical trial included adult patients with hyperglycemia (glucose concentration of >110 mg/dL if had diabetes or ≥150 mg/dL if did not have diabetes) and acute ischemic stroke who were enrolled within 12 hours from stroke onset at 63 US sites between April 2012 and August 2018; follow-up ended in November 2018. The trial included 1151 patients who met eligibility criteria. Interventions: Patients were randomized to receive continuous intravenous insulin using a computerized decision support tool (target blood glucose concentration of 80-130 mg/dL [4.4-7.2 mmol/L]; intensive treatment group: n = 581) or insulin on a sliding scale that was administered subcutaneously (target blood glucose concentration of 80-179 mg/dL [4.4-9.9 mmol/L]; standard treatment group: n = 570) for up to 72 hours. Main Outcomes and Measures: The primary efficacy outcome was the proportion of patients with a favorable outcome based on the 90-day modified Rankin Scale score (a global stroke disability scale ranging from 0 [no symptoms or completely recovered] to 6 [death]) that was adjusted for baseline stroke severity. Results: Among 1151 patients who were randomized (mean age, 66 years [SD, 13.1 years]; 529 [46%] women, 920 [80%] with diabetes), 1118 (97%) completed the trial. Enrollment was stopped for futility based on prespecified interim analysis criteria. During treatment, the mean blood glucose level was 118 mg/dL (6.6 mmol/L) in the intensive treatment group and 179 mg/dL (9.9 mmol/L) in the standard treatment group. A favorable outcome occurred in 119 of 581 patients (20.5%) in the intensive treatment group and in 123 of 570 patients (21.6%) in the standard treatment group (adjusted relative risk, 0.97 [95% CI, 0.87 to 1.08], P = .55; unadjusted risk difference, -0.83% [95% CI, -5.72% to 4.06%]). Treatment was stopped early for hypoglycemia or other adverse events in 65 of 581 patients (11.2%) in the intensive treatment group and in 18 of 570 patients (3.2%) in the standard treatment group. Severe hypoglycemia occurred only among patients in the intensive treatment group (15/581 [2.6%]; risk difference, 2.58% [95% CI, 1.29% to 3.87%]). Conclusions and Relevance: Among patients with acute ischemic stroke and hyperglycemia, treatment with intensive vs standard glucose control for up to 72 hours did not result in a significant difference in favorable functional outcome at 90 days. These findings do not support using intensive glucose control in this setting. Trial Registration: ClinicalTrials.gov Identifier: NCT01369069.

Efficacy of Home-Based Telerehabilitation vs In-Clinic Therapy for Adults After Stroke: A Randomized Clinical Trial.

IMPORTANCE: Many patients receive suboptimal rehabilitation therapy doses after stroke owing to limited access to therapists and difficulty with transportation, and their knowledge about stroke is often limited. Telehealth can potentially address these issues. OBJECTIVES: To determine whether treatment targeting arm movement delivered via a home-based telerehabilitation (TR) system has comparable efficacy with dose-matched, intensity-matched therapy delivered in a traditional in-clinic (IC) setting, and to examine whether this system has comparable efficacy for providing stroke education. DESIGN, SETTING, AND PARTICIPANTS: In this randomized, assessor-blinded, noninferiority trial across 11 US sites, 124 patients who had experienced stroke 4 to 36 weeks prior and had arm motor deficits (Fugl-Meyer [FM] score, 22-56 of 66) were enrolled between September 18, 2015, and December 28, 2017, to receive telerehabilitation therapy in the home (TR group) or therapy at an outpatient rehabilitation therapy clinic (IC group). Primary efficacy analysis used the intent-to-treat population. INTERVENTIONS: Participants received 36 sessions (70 minutes each) of arm motor therapy plus stroke education, with therapy intensity, duration, and frequency matched across groups. MAIN OUTCOMES AND MEASURES: Change in FM score from baseline to 4 weeks after end of therapy and change in stroke knowledge from baseline to end of therapy. RESULTS: A total of 124 participants (34 women and 90 men) had a mean (SD) age of 61 (14) years, a mean (SD) baseline FM score of 43 (8) points, and were enrolled a mean (SD) of 18.7 (8.9) weeks after experiencing a stroke. Among those treated, patients in the IC group were adherent to 33.6 of the 36 therapy sessions (93.3%) and patients in the TR group were adherent to 35.4 of the 36 assigned therapy sessions (98.3%). Patients in the IC group had a mean (SD) FM score change of 8.36 (7.04) points from baseline to 30 days after therapy (P < .001), while those in the TR group had a mean (SD) change of 7.86 (6.68) points (P < .001). The covariate-adjusted mean FM score change was 0.06 (95% CI, -2.14 to 2.26) points higher in the TR group (P = .96). The noninferiority margin was 2.47 and fell outside the 95% CI, indicating that TR is not inferior to IC therapy. Motor gains remained significant when patients enrolled early (<90 days) or late (≥90 days) after stroke were examined separately. CONCLUSIONS AND RELEVANCE: Activity-based training produced substantial gains in arm motor function regardless of whether it was provided via home-based telerehabilitation or traditional in-clinic rehabilitation. The findings of this study suggest that telerehabilitation has the potential to substantially increase access to rehabilitation therapy on a large scale. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02360488.

A randomized 500-subject open-label phase 3 clinical trial of minimally invasive surgery plus alteplase in intracerebral hemorrhage evacuation (MISTIE III).

RATIONALE AND HYPOTHESIS: Surgical removal of spontaneous intracerebral hemorrhage may reduce secondary destruction of brain tissue. However, large surgical trials of craniotomy have not demonstrated definitive improvement in clinical outcomes. Minimally invasive surgery may limit surgical tissue injury, and recent evidence supports testing these approaches in large clinical trials. METHODS AND DESIGN: MISTIE III is an investigator-initiated multicenter, randomized, open-label phase 3 study investigating whether minimally invasive clot evacuation with thrombolysis improves functional outcomes at 365 days compared to conservative management. Patients with supratentorial intracerebral hemorrhage clot volume ≥ 30 mL, confirmed by imaging within 24 h ofknown symptom onset,and intact brainstem reflexes were screened with a stability computed tomography scan at least 6 h after diagnostic scan. Patients who met clinical and imaging criteria (no ongoing coagulopathy; no suspicion of aneurysm, arteriovenous malformation, or any other vascular anomaly; and stable hematoma size on consecutive scans) were randomized to either minimally invasive surgery plus thrombolysis or medical therapy. The sample size of 500 was based on findings of a phase 2 study. STUDY OUTCOMES: The primary outcome measure is dichotomized modified Rankin Scale 0-3 vs. 4-6 at 365 days adjusting for severity variables. Clinical secondary outcomes include dichotomized extended Glasgow Outcome Scale and all-cause mortality at 365 days; rate and extent of parenchymal blood clot removal; patient disposition at 365 days; efficacy at 180 days; type and intensity of ICU management; and quality of life measures. Safety was assessed at 30 days and throughout the study.

Impact of Baseline Features and Risk Factor Control on Cognitive Function in the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis Trial.

BACKGROUND: Cerebrovascular disease is an important cause of cognitive impairment. The aim of this study is to report the relationship between cognitive function and risk factors at baseline and during follow-up in the Stenting and Aggressive Medical Management for Preventing Recurrent stroke in Intracranial Stenosis (SAMMPRIS) trial. METHODS: Subjects in the SAMMPRIS trial were included in this study. In order to have an assessment of cognitive function independent of stroke, patients with a stroke as a qualifying event whose deficits included aphasia or neglect were excluded from these analyses as were those with a cerebrovascular event during follow-up. The Montreal Cognitive Assessment (MoCA) score was used to assess cognitive impairment at baseline, 4 months, 12 months and closeout. Cognitive impairment was defined as MoCA < 26. A multivariate analysis was performed to determine what risk factors were independent predictors of cognitive function at baseline, 12 months and closeout. Among patients randomized to aggressive medical management only, the percentage of patients with cognitive impairment was compared between patients in versus out of target for each risk factor at 12 months and closeout. RESULTS: Of the 451 patients in SAMMPRIS, 371 patients met the inclusion criteria. MoCA < 26 was present in 55% at baseline. Older age and physical inactivity were associated with cognitive impairment at baseline. Older age, non-white race, lower baseline body mass index, and baseline cognitive impairment were associated with cognitive impairment at 12 months. In the aggressive medical management group, at 12 months, physical inactivity during follow-up was the strongest risk factor associated with cognitive impairment. CONCLUSION: Cognitive impairment is common in patients with severe symptomatic intracranial atherosclerosis. Physical inactivity at baseline and during follow-up is a strong predictor of cognitive impairment.

Efficacy and safety of minimally invasive surgery with thrombolysis in intracerebral haemorrhage evacuation (MISTIE III): a randomised, controlled, open-label, blinded endpoint phase 3 trial.

BACKGROUND: Acute stroke due to supratentorial intracerebral haemorrhage is associated with high morbidity and mortality. Open craniotomy haematoma evacuation has not been found to have any benefit in large randomised trials. We assessed whether minimally invasive catheter evacuation followed by thrombolysis (MISTIE), with the aim of decreasing clot size to 15 mL or less, would improve functional outcome in patients with intracerebral haemorrhage. METHODS: MISTIE III was an open-label, blinded endpoint, phase 3 trial done at 78 hospitals in the USA, Canada, Europe, Australia, and Asia. We enrolled patients aged 18 years or older with spontaneous, non-traumatic, supratentorial intracerebral haemorrhage of 30 mL or more. We used a computer-generated number sequence with a block size of four or six to centrally randomise patients to image-guided MISTIE treatment (1·0 mg alteplase every 8 h for up to nine doses) or standard medical care. Primary outcome was good functional outcome, defined as the proportion of patients who achieved a modified Rankin Scale (mRS) score of 0-3 at 365 days, adjusted for group differences in prespecified baseline covariates (stability intracerebral haemorrhage size, age, Glasgow Coma Scale, stability intraventricular haemorrhage size, and clot location). Analysis of the primary efficacy outcome was done in the modified intention-to-treat (mITT) population, which included all eligible, randomly assigned patients who were exposed to treatment. All randomly assigned patients were included in the safety analysis. This study is registered with ClinicalTrials.gov, number NCT01827046. FINDINGS: Between Dec 30, 2013, and Aug 15, 2017, 506 patients were randomly allocated: 255 (50%) to the MISTIE group and 251 (50%) to standard medical care. 499 patients (n=250 in the MISTIE group; n=249 in the standard medical care group) received treatment and were included in the mITT analysis set. The mITT primary adjusted efficacy analysis estimated that 45% of patients in the MISTIE group and 41% patients in the standard medical care group had achieved an mRS score of 0-3 at 365 days (adjusted risk difference 4% [95% CI -4 to 12]; p=0·33). Sensitivity analyses of 365-day mRS using generalised ordered logistic regression models adjusted for baseline variables showed that the estimated odds ratios comparing MISTIE with standard medical care for mRS scores higher than 5 versus 5 or less, higher than 4 versus 4 or less, higher than 3 versus 3 or less, and higher than 2 versus 2 or less were 0·60 (p=0·03), 0·84 (p=0·42), 0·87 (p=0·49), and 0·82 (p=0·44), respectively. At 7 days, two (1%) of 255 patients in the MISTIE group and ten (4%) of 251 patients in the standard medical care group had died (p=0·02) and at 30 days, 24 (9%) patients in the MISTIE group and 37 (15%) patients in the standard medical care group had died (p=0·07). The number of patients with symptomatic bleeding and brain bacterial infections was similar between the MISTIE and standard medical care groups (six [2%] of 255 patients vs three [1%] of 251 patients; p=0·33 for symptomatic bleeding; two [1%] of 255 patients vs 0 [0%] of 251 patients; p=0·16 for brain bacterial infections). At 30 days, 76 (30%) of 255 patients in the MISTIE group and 84 (33%) of 251 patients in the standard medical care group had one or more serious adverse event, and the difference in number of serious adverse events between the groups was statistically significant (p=0·012). INTERPRETATION: For moderate to large intracerebral haemorrhage, MISTIE did not improve the proportion of patients who achieved a good response 365 days after intracerebral haemorrhage. The procedure was safely adopted by our sample of surgeons. FUNDING: National Institute of Neurological Disorders and Stroke and Genentech.

The AtRial Cardiopathy and Antithrombotic Drugs In prevention After cryptogenic stroke randomized trial: Rationale and methods.

RATIONALE: Recent data suggest that a thrombogenic atrial substrate can cause stroke in the absence of atrial fibrillation. Such an atrial cardiopathy may explain some proportion of cryptogenic strokes. AIMS: The aim of the ARCADIA trial is to test the hypothesis that apixaban is superior to aspirin for the prevention of recurrent stroke in subjects with cryptogenic ischemic stroke and atrial cardiopathy. SAMPLE SIZE ESTIMATE: 1100 participants. METHODS AND DESIGN: Biomarker-driven, randomized, double-blind, active-control, phase 3 clinical trial conducted at 120 U.S. centers participating in NIH StrokeNet. POPULATION STUDIED: Patients ≥ 45 years of age with embolic stroke of undetermined source and evidence of atrial cardiopathy, defined as ≥ 1 of the following markers: P-wave terminal force >5000 µV × ms in ECG lead V1, serum NT-proBNP > 250 pg/mL, and left atrial diameter index ≥ 3 cm/m2 on echocardiogram. Exclusion criteria include any atrial fibrillation, a definite indication or contraindication to antiplatelet or anticoagulant therapy, or a clinically significant bleeding diathesis. Intervention: Apixaban 5 mg twice daily versus aspirin 81 mg once daily. Analysis: Survival analysis and the log-rank test will be used to compare treatment groups according to the intention-to-treat principle, including participants who require open-label anticoagulation for newly detected atrial fibrillation. STUDY OUTCOMES: The primary efficacy outcome is recurrent stroke of any type. The primary safety outcomes are symptomatic intracranial hemorrhage and major hemorrhage other than intracranial hemorrhage. DISCUSSION: ARCADIA is the first trial to test whether anticoagulant therapy reduces stroke recurrence in patients with atrial cardiopathy but no known atrial fibrillation.

Thrombolytic removal of intraventricular haemorrhage in treatment of severe stroke: results of the randomised, multicentre, multiregion, placebo-controlled CLEAR III trial.

BACKGROUND: Intraventricular haemorrhage is a subtype of intracerebral haemorrhage, with 50% mortality and serious disability for survivors. We aimed to test whether attempting to remove intraventricular haemorrhage with alteplase versus saline irrigation improved functional outcome. METHODS: In this randomised, double-blinded, placebo-controlled, multiregional trial (CLEAR III), participants with a routinely placed extraventricular drain, in the intensive care unit with stable, non-traumatic intracerebral haemorrhage volume less than 30 mL, intraventricular haemorrhage obstructing the 3rd or 4th ventricles, and no underlying pathology were adaptively randomly assigned (1:1), via a web-based system to receive up to 12 doses, 8 h apart of 1 mg of alteplase or 0·9% saline via the extraventricular drain. The treating physician, clinical research staff, and participants were masked to treatment assignment. CT scans were obtained every 24 h throughout dosing. The primary efficacy outcome was good functional outcome, defined as a modified Rankin Scale score (mRS) of 3 or less at 180 days per central adjudication by blinded evaluators. This study is registered with ClinicalTrials.gov, NCT00784134. FINDINGS: Between Sept 18, 2009, and Jan 13, 2015, 500 patients were randomised: 249 to the alteplase group and 251 to the saline group. 180-day follow-up data were available for analysis from 246 of 249 participants in the alteplase group and 245 of 251 participants in the placebo group. The primary efficacy outcome was similar in each group (good outcome in alteplase group 48% vs saline 45%; risk ratio [RR] 1·06 [95% CI 0·88-1·28; p=0·554]). A difference of 3·5% (RR 1·08 [95% CI 0·90-1·29], p=0·420) was found after adjustment for intraventricular haemorrhage size and thalamic intracerebral haemorrhage. At 180 days, the treatment group had lower case fatality (46 [18%] vs saline 73 [29%], hazard ratio 0·60 [95% CI 0·41-0·86], p=0·006), but a greater proportion with mRS 5 (42 [17%] vs 21 [9%]; RR 1·99 [95% CI 1·22-3·26], p=0·007). Ventriculitis (17 [7%] alteplase vs 31 [12%] saline; RR 0·55 [95% CI 0·31-0·97], p=0·048) and serious adverse events (114 [46%] alteplase vs 151 [60%] saline; RR 0·76 [95% CI 0·64-0·90], p=0·002) were less frequent with alteplase treatment. Symptomatic bleeding (six [2%] in the alteplase group vs five [2%] in the saline group; RR 1·21 [95% CI 0·37-3·91], p=0·771) was similar. INTERPRETATION: In patients with intraventricular haemorrhage and a routine extraventricular drain, irrigation with alteplase did not substantially improve functional outcomes at the mRS 3 cutoff compared with irrigation with saline. Protocol-based use of alteplase with extraventricular drain seems safe. Future investigation is needed to determine whether a greater frequency of complete intraventricular haemorrhage removal via alteplase produces gains in functional status. FUNDING: National Institute of Neurological Disorders and Stroke.

Is There Benefit from Stenting on Cognitive Function in Intracranial Atherosclerosis?

BACKGROUND: Revascularization of stenotic cerebral arteries is hypothesized to improve cognition by increasing cerebral perfusion. AIMS: We compared cognition impairment among patients treated with percutaneous angioplasty and stenting (PTAS) and aggressive medical management (AMM) versus AMM alone in the Stenting versus Aggressive Medical Therapy for Intracranial Arterial Stenosis (SAMMPRIS) Trial. METHODS: In SAMMPRIS, 451 patients with recent transient ischemic attack or stroke attributed to 70-99% intracranial stenosis were randomized to PTAS plus AMM or AMM alone. Patients who had stroke as the qualifying event with National Institutes of Health Stroke Scale indicating aphasia or neglect were excluded from these analyses. Patients with a cerebrovascular event (ischemic stroke, cerebral infarct with temporary signs or intracranial hemorrhage) during follow-up were excluded from follow-up visit analyses. The Montreal Cognitive Assessment (MoCA) score was used to assess cognition impairment at baseline, 4 months, 12 months and closeout. Cognitive impairment was defined as MoCA <26. Mean MoCA scores and the percentage of patients with cognitive impairment were compared between treatment groups at each time point using t tests and chi-square tests. Differences in MoCA mean at baseline and follow-up time points were compared using mixed model repeated measures ANOVA and Tukey-Kramer tests. RESULTS: There were no significant differences between the treatment groups for mean MoCA at any time point. Mean MoCA scores improved in both groups. The percentage of patients with cognitive impairment in the AMM versus PTAS groups was not significantly different at any time point. CONCLUSIONS: Revascularization with PTAS showed no improvement in cognitive impairment over AMM alone among patients who did not have recurrent cerebrovascular events during follow-up.

Safety and efficacy of minimally invasive surgery plus alteplase in intracerebral haemorrhage evacuation (MISTIE): a randomised, controlled, open-label, phase 2 trial.

BACKGROUND: Craniotomy, according to the results from trials, does not improve functional outcome after intracerebral haemorrhage. Whether minimally invasive catheter evacuation followed by thrombolysis for clot removal is safe and can achieve a good functional outcome is not known. We investigated the safety and efficacy of alteplase, a recombinant tissue plasminogen activator, in combination with minimally invasive surgery (MIS) in patients with intracerebral haemorrhage. METHODS: MISTIE was an open-label, phase 2 trial that was done in 26 hospitals in the USA, Canada, the UK, and Germany. We used a computer-generated allocation sequence with a block size of four to centrally randomise patients aged 18-80 years with a non-traumatic (spontaneous) intracerebral haemorrhage of 20 mL or higher to standard medical care or image-guided MIS plus alteplase (0·3 mg or 1·0 mg every 8 h for up to nine doses) to remove clots using surgical aspiration followed by alteplase clot irrigation. Primary outcomes were all safety outcomes: 30 day mortality, 7 day procedure-related mortality, 72 h symptomatic bleeding, and 30 day brain infections. This trial is registered with ClinicalTrials.gov, number NCT00224770. FINDINGS: Between Feb 2, 2006, and April 8, 2013, 96 patients were randomly allocated and completed follow-up: 54 (56%) in the MIS plus alteplase group and 42 (44%) in the standard medical care group. The primary outcomes did not differ between the standard medical care and MIS plus alteplase groups: 30 day mortality (four [9·5%, 95% CI 2·7-22.6] vs eight [14·8%, 6·6-27·1], p=0·542), 7 day mortality (zero [0%, 0-8·4] vs one [1·9%, 0·1-9·9], p=0·562), symptomatic bleeding (one [2·4%, 0·1-12·6] vs five [9·3%, 3·1-20·3], p=0·226), and brain bacterial infections (one [2·4%, 0·1-12·6] vs zero [0%, 0-6·6], p=0·438). Asymptomatic haemorrhages were more common in the MIS plus alteplase group than in the standard medical care group (12 [22·2%; 95% CI 12·0-35·6] vs three [7·1%; 1·5-19·5]; p=0·051). INTERPRETATION: MIS plus alteplase seems to be safe in patients with intracerebral haemorrhage, but increased asymptomatic bleeding is a major cautionary finding. These results, if replicable, could lead to the addition of surgical management as a therapeutic strategy for intracerebral haemorrhage. FUNDING: National Institute of Neurological Disorders and Stroke, Genentech, and Codman.

Factors Associated With Recurrent Ischemic Stroke in the Medical Group of the SAMMPRIS Trial.

IMPORTANCE: The Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) Trial showed that aggressive medical therapy was more effective than stenting for preventing stroke in patients with symptomatic intracranial stenosis. However, 15% of patients in the medical group still experienced a primary end point during a median follow-up of 32.7 months. OBJECTIVE: To determine baseline features that were associated with a high rate of a primary end point in the medical arm of the SAMMPRIS Trial. DESIGN, SETTING, AND PARTICIPANTS: A post hoc analysis of patients in the medical arm only of the SAMMPRIS trial. Enrollment occurred between October 2008 and April 2013 and included 227 patients randomized to medical management alone. Baseline demographic features, vascular risk factors, qualifying event, brain imaging, and angiographic features were analyzed. Bivariate and multivariable proportional hazard regression modeling was performed to relate baseline features to the time until a primary end point. The post hoc analysis was conducted from November 2014 to June 2015. INTERVENTIONS: The SAMMPRIS Trial compared stenting with aggressive medical management in patients with a stroke or transient ischemic attack attributed to 70% to 99% stenosis of a major intracranial artery. MAIN OUTCOMES AND MEASURES: The primary outcome was any of the following: stroke or death within 30 days of enrollment, ischemic stroke in the territory of the symptomatic intracranial artery beyond 30 days after enrollment, or any stroke or death within 30 days after stenting a patient in the medical group during follow-up. RESULTS: A total of 227 patients were included in the study, 82 of whom were female, and the mean (SD) age was 59.5 (11.8) years. Being female (hazard ratio [HR], 1.9; 95% CI, 0.96-3.7), having diabetes mellitus (HR, 1.8; 95% CI, 0.9-3.5), not taking a statin at enrollment (HR, 2.6; 95% CI, 1.2-5.7), stroke as the qualifying event (HR, 2.5; 95% CI, 1.03-6.0), Rankin grade of 1 or greater (HR, 2.3; 95% CI, 0.9-5.5), old infarct in the territory of the stenotic artery (HR, 2.6; 95% CI, 1.3-5.1), and greater than 80% stenosis (HR, 1.9; 95% CI, 0.9-3.7) were associated (P < .10) with higher risk on bivariate analysis. Factors that were significantly associated with a primary end point on multivariable analyses were old infarct in the territory (HR, 2.6; 95% CI, 1.3-5.3; P = .006), stroke as the qualifying event (HR, 3.0; 95% CI, 1.1-7.7; P = .03), and no statin use at enrollment (HR, 2.4; 95% CI, 1.1-5.2; P = .03). CONCLUSIONS AND RELEVANCE: Old infarct in the territory of the stenosis, new stroke presentation, and absence of statin use at enrollment were independently associated with high rates of the primary end point in the medical group in the SAMMPRIS Trial. These features may be useful for selecting high-risk patients for future clinical trials evaluating alternative therapies for intracranial stenosis. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00576693.

Enrollment volume effect on risk factor control and outcomes in the SAMMPRIS trial.

OBJECTIVE: The role of physician experience and patient volumes on the outcome of surgical or endovascular procedures has been well-studied but there are limited data on how these factors affect the outcome of medical therapy. METHODS: In the stenting and medical cohorts of the Stenting and Aggressive Medical Management for the Prevention of Recurrent Ischemic Stroke (SAMMPRIS) trial, we compared Kaplan-Meier (K-M) curves for the primary endpoint (any stroke or death within 30 days of enrollment or ischemic stroke in the territory beyond 30 days) using the log-rank test and the percentages of patients achieving target levels for primary and secondary risk factors during the study using Fisher exact test between patients at high-enrolling (≥12 patients) vs low-enrolling (<12 patients) sites. RESULTS: In the stenting group, the K-M curves for the primary endpoint were similar at high-enrolling sites and low-enrolling sites (p = 0.93) with rates of 13.5% vs 14.7% at 30 days and 19.0% vs 20.6% at 2 years. In the medical group, the K-M curves differed between high-enrolling sites and low-enrolling sites (p = 0.0005) with rates of 1.8% vs 9.8% at 30 days and 7.3% vs 20.9% at 2 years. The percentages of patients who achieved targets for low-density lipoprotein cholesterol and systolic blood pressure at high- vs low-enrolling sites in both treatment groups combined were 64% vs 49% (p = 0.003) and 70% vs 59% (p = 0.026), respectively. CONCLUSIONS: High-enrolling sites in SAMMPRIS achieved better control of primary risk factors and much lower rates of the primary endpoint than low-enrolling sites in the medical group, suggesting that experience with medical management is an important determinant of patient outcome.