Safety and efficacy of factor XIa inhibition with milvexian for secondary stroke prevention (AXIOMATIC-SSP): a phase 2, international, randomised, double-blind, placebo-controlled, dose-finding trial.

BACKGROUND: People with factor XI deficiency have lower rates of ischaemic stroke than the general population and infrequent spontaneous bleeding, suggesting that factor XI has a more important role in thrombosis than in haemostasis. Milvexian, an oral small-molecule inhibitor of activated factor XI, added to standard antiplatelet therapy, might reduce the risk of non-cardioembolic ischaemic stroke without increasing the risk of bleeding. We aimed to estimate the dose-response of milvexian for recurrent ischaemic cerebral events and major bleeding in patients with recent ischaemic stroke or transient ischaemic attack (TIA). METHODS: AXIOMATIC-SSP was a phase 2, randomised, double-blind, placebo-controlled, dose-finding trial done at 367 hospitals in 27 countries. Eligible participants aged 40 years or older, with acute (<48 h) ischaemic stroke or high-risk TIA, were randomly assigned by a web-based interactive response system in a 1:1:1:1:1:2 ratio to receive one of five doses of milvexian (25 mg once daily, 25 mg twice daily, 50 mg twice daily, 100 mg twice daily, or 200 mg twice daily) or matching placebo twice daily for 90 days. All participants received clopidogrel 75 mg daily for the first 21 days and aspirin 100 mg daily for the first 90 days. Investigators, site staff, and participants were masked to treatment assignment. The primary efficacy endpoint was the composite of ischaemic stroke or incident covert brain infarct on MRI at 90 days, assessed in all participants allocated to treatment who completed a follow-up MRI brain scan, and the primary analysis assessed the dose-response relationship with Multiple Comparison Procedure-Modelling (MCP-MOD). The main safety outcome was major bleeding at 90 days, assessed in all participants who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov (NCT03766581) and the EU Clinical Trials Register (2017-005029-19). FINDINGS: Between Jan 27, 2019, and Dec 24, 2021, 2366 participants were randomly allocated to placebo (n=691); milvexian 25 mg once daily (n=328); or twice-daily doses of milvexian 25 mg (n=318), 50 mg (n=328), 100 mg (n=310), or 200 mg (n=351). The median age of participants was 71 (IQR 62-77) years and 859 (36%) were female. At 90 days, the estimates of the percentage of participants with either symptomatic ischaemic stroke or covert brain infarcts were 16·8 (90·2% CI 14·5-19·1) for placebo, 16·7 (14·8-18·6) for 25 mg milvexian once daily, 16·6 (14·8-18·3) for 25 mg twice daily, 15·6 (13·9-17·5) for 50 mg twice daily, 15·4 (13·4-17·6) for 100 mg twice daily, and 15·3 (12·8-19·7) for 200 mg twice daily. No significant dose-response was observed among the five milvexian doses for the primary composite efficacy outcome. Model-based estimates of the relative risk with milvexian compared with placebo were 0·99 (90·2% CI 0·91-1·05) for 25 mg once daily, 0·99 (0·87-1·11) for 25 mg twice daily, 0·93 (0·78-1·11) for 50 mg twice daily, 0·92 (0·75-1·13) for 100 mg twice daily, and 0·91 (0·72-1·26) for 200 mg twice daily. No apparent dose-response was observed for major bleeding (four [1%] of 682 participants with placebo, two [1%] of 325 with milvexian 25 mg once daily, two [1%] of 313 with 25 mg twice daily, five [2%] of 325 with 50 mg twice daily, five [2%] of 306 with 100 mg twice daily, and five [1%] of 344 with 200 mg twice daily). Five treatment-emergent deaths occurred, four of which were considered unrelated to the study drug by the investigator. INTERPRETATION: Factor XIa inhibition with milvexian, added to dual antiplatelet therapy, did not substantially reduce the composite outcome of symptomatic ischaemic stroke or covert brain infarction and did not meaningfully increase the risk of major bleeding. Findings from our study have informed the design of a phase 3 trial of milvexian for the prevention of ischaemic stroke in patients with acute ischaemic stroke or TIA. FUNDING: Bristol Myers Squibb and Janssen Research & Development.

Long-term stroke risk in Moyamoya disease.

BACKGROUND: Moyamoya disease (MMD) is considered a progressive disease with an ongoing risk of recurrent stroke. However, there is a lack of long-term observational data to quantify the extent of the stroke risk. METHODS: This study aimed to provide insight into the long-term stroke risk in MMD and explore possible risk factors for stroke. Records from all patients diagnosed with MMD in 13 clinical departments from 6 different Danish hospitals between 1994 and 2017 were retrospectively reviewed until 2021. RESULTS: The cohort comprised 50 patients (33 females and 17 males). Patients were followed up for a median of 9.4 years, with more than 10 years of follow-up for 24 patients. Ten patients had 11 new stroke events-6 ischemic strokes and 5 brain hemorrhages. Events occurred at a median of 7 years and up to 25 years after diagnosis. The overall Kaplan-Meier 5-year stroke risk was 10%. Patients with bypass performed had significantly fewer events than conservatively treated patients (HR 0.25, 95% confidence interval (CI) 0.07-0.91, p < 0.05). All but one event occurred in females, a difference that reached statistical significance. CONCLUSIONS: The study provides data on the extent of the risk of recurrent stroke in MMD. Bypass surgery patients had fewer stroke events than those treated conservatively. There was a trend toward a higher stroke risk in females. DATA ACCESS STATEMENT: The data supporting this study's findings are available from the corresponding author upon reasonable request.

Transport Strategy in Patients With Suspected Acute Large Vessel Occlusion Stroke: TRIAGE-STROKE, a Randomized Clinical Trial.

BACKGROUND: When patients with acute ischemic stroke present with suspected large vessel occlusion in the catchment area of a primary stroke center (PSC), the benefit of direct transport to a comprehensive stroke center (CSC) has been suggested. Equipoise remains between transport strategies and the best transport strategy is not well established. METHODS: We conducted a national investigator-driven, multicenter, randomized, assessor-blinded clinical trial. Patients eligible for intravenous thrombolysis (IVT) who were suspected for large vessel occlusion were randomized 1:1 to admission to the nearest PSC (prioritizing IVT) or direct CSC admission (prioritizing endovascular therapy). The primary outcome was functional improvement at day 90 for all patients with acute ischemic stroke, measured as shift towards a lower score on the modified Rankin Scale score. RESULTS: From September 2018 to May 2022, we enrolled 171 patients of whom 104 had acute ischemic stroke. The trial was halted before full recruitment. Baseline characteristics were well balanced. Primary analysis of shift in modified Rankin Scale (ordinal logistic regression) revealed an odds ratio for functional improvement at day 90 of 1.42 (95% CI, 0.72-2.82, P=0.31). Onset to groin time for patients with large vessel occlusion was 35 minutes (P=0.007) shorter when patients were transported to a CSC first, whereas onset to needle (IVT) was 30 minutes (P=0.012) shorter when patients were transported to PSC first. IVT was administered in 67% of patients in the PSC group versus 78% in the CSC group and EVT was performed in 53% versus 63% of the patients, respectively. CONCLUSIONS: This trial investigated the benefit of bypassing PSC. We included only IVT-eligible patients presenting <4 hours from onset and with suspected large vessel occlusion. Lack of power prevented the results from showing effect on functional outcome for patients going directly to CSC. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03542188.

Remote Ischemic Conditioning for Acute Stroke: The RESIST Randomized Clinical Trial.

Importance: Despite some promising preclinical and clinical data, it remains uncertain whether remote ischemic conditioning (RIC) with transient cycles of limb ischemia and reperfusion is an effective treatment for acute stroke. Objective: To evaluate the effect of RIC when initiated in the prehospital setting and continued in the hospital on functional outcome in patients with acute stroke. Design, Setting, and Participants: This was a randomized clinical trial conducted at 4 stroke centers in Denmark that included 1500 patients with prehospital stroke symptoms for less than 4 hours (enrolled March 16, 2018, to November 11, 2022; final follow-up, February 3, 2023). Intervention: The intervention was delivered using an inflatable cuff on 1 upper extremity (RIC cuff pressure, ≤200 mm Hg [n = 749] and sham cuff pressure, 20 mm Hg [n = 751]). Each treatment application consisted of 5 cycles of 5 minutes of cuff inflation followed by 5 minutes of cuff deflation. Treatment was started in the ambulance and repeated at least once in the hospital and then twice daily for 7 days among a subset of participants. Main Outcomes and Measures: The primary end point was improvement in functional outcome measured as a shift across the modified Rankin Scale (mRS) score (range, 0 [no symptoms] to 6 [death]) at 90 days in the target population with a final diagnosis of ischemic or hemorrhagic stroke. Results: Among 1500 patients who were randomized (median age, 71 years; 591 women [41%]), 1433 (96%) completed the trial. Of these, 149 patients (10%) were diagnosed with transient ischemic attack and 382 (27%) with a stroke mimic. In the remaining 902 patients with a target diagnosis of stroke (737 [82%] with ischemic stroke and 165 [18%] with intracerebral hemorrhage), 436 underwent RIC and 466 sham treatment. The median mRS score at 90 days was 2 (IQR, 1-3) in the RIC group and 1 (IQR, 1-3) in the sham group. RIC treatment was not significantly associated with improved functional outcome at 90 days (odds ratio [OR], 0.95; 95% CI, 0.75 to 1.20, P = .67; absolute difference in median mRS score, -1; -1.7 to -0.25). In all randomized patients, there were no significant differences in the number of serious adverse events: 169 patients (23.7%) in the RIC group with 1 or more serious adverse events vs 175 patients (24.3%) in the sham group (OR, 0.97; 95% CI, 0.85 to 1.11; P = .68). Upper extremity pain during treatment and/or skin petechia occurred in 54 (7.2%) in the RIC group and 11 (1.5%) in the sham group. Conclusions and Relevance: RIC initiated in the prehospital setting and continued in the hospital did not significantly improve functional outcome at 90 days in patients with acute stroke. Trial Registration: ClinicalTrials.gov Identifier: NCT03481777.

Patient-Centered Outcomes in a Randomized Trial Investigating a Multimodal Prevention Program After Transient Ischemic Attack or Minor Stroke: The INSPiRE-TMS Trial.

BACKGROUND: The INSPiRE-TMS trial (Intensified Secondary Prevention Intending a Reduction of Recurrent Events in Transient Ischemic Attack and Minor Stroke Patients) investigated effects of a multicomponent support program in patients with nondisabling stroke or transient ischemic attack. Although secondary prevention targets were achieved more frequently in the intensified care group, no significant differences were seen in rates of recurrent major vascular events. Here, we present the effects on prespecified patient-centered outcomes. METHODS: In a multicenter trial, we randomized patients with modifiable risk factors either to the intensified or conventional care alone program. Intensified care was provided by stroke specialists and used feedback and motivational interviewing strategies (≥8 outpatient visits over 2 years) aiming to improve adherence to secondary prevention targets. We measured physical fitness, disability, cognitive function and health-related quality of life by stair-climbing test, modified Rankin Scale, Montreal Cognitive Assessment, and European Quality of Life 5 Dimension 3 Level during the first 3 years of follow-up. RESULTS: Of 2072 patients (mean age: 67.4years, 34% female) assessed for the primary outcome, patient-centered outcomes were collected in 1,771 patients (877 intensified versus 894 conventional care group). Physical fitness improved more in the intensified care group (mean between-group difference in power (Watt): 24.5 after 1 year (95% CI, 5.5-43.5); 36.1 after 2 years (95% CI, 13.1-59.7) and 29.6 (95% CI, 2.0-57.3 after 3 years). At 1 year, there was a significant shift in ordinal regression analysis of modified Rankin Scale in favor of the intensified care group (common odds ratio, 1.23 [95% CI, 1.03-1.47]) but not after 2 (odds ratio, 1.17 [95% CI, 0.96-1.41]) or 3 years (odds ratio, 1.16 [95% CI, 0.95-1.43]) of follow-up. However, Montreal Cognitive Assessment and European Quality of Life 5 Dimension scores showed no improvement in the intensified intervention arm after 1, 2, or 3 years of follow-up. CONCLUSIONS: Patients of the intensified care program group had slightly better results for physical fitness and modified Rankin Scale after 1 year, but none of the other patient-centered outcomes was significantly improved. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01586702.

Vagus Nerve Cross-Sectional Area in Patients With Parkinson's Disease-An Ultrasound Case-Control Study.

Background: Vagal parasympathetic neurons are prone to degeneration in Parkinson's disease (PD). High-resolution ultrasound can precisely estimate the cross-sectional (CSA) area of peripheral nerves. Here, we tested the hypothesis that vagus CSA is reduced in PD. Methods: We included 56 healthy controls (HCs) and 63 patients with PD. Using a high-end ultrasound system equipped with a high-frequency transducer, five images were obtained of each nerve. The hypoechoic neuronal tissue was delineated offline with dedicated software and the CSA extracted. Results: In the initial PD vs. HC comparison, no statistically significant differences were observed in mean left vagus CSA (HC: 1.97 mm2, PD: 1.89 mm2, P = 0.36) nor in mean right vagus CSA (HC: 2.37 mm2, PD: 2.23 mm2, P = 0.17). The right vagus CSA was significantly larger than the left vagus CSA in both groups (P < 0.0001). Females were overrepresented in the HC group and presented with generally smaller vagus CSAs. Consequently, sex-adjusted CSA was significantly smaller for the right vagus nerve of the PD group (P = 0.041), but not for the left. Conclusion: A small but significant reduction in sex-adjusted right vagus CSA was observed in patients with PD. The left vagus CSA was not significantly reduced in patients with PD. Ultrasound may not be a suitable method to detecting vagal axonal loss in individual patients.

Endovascular Treatment of Intracerebral Giant Cell Arteritis.

Background: Giant cell arteritis (GCA) is the most common primary systemic vasculitis predominantly affecting large and medium sized vessels. In rare cases, the vasculitis can affect the vessels of the brain. Results: We describe four cases of GCA with involvement of the cerebral vessels causing stroke. These cases were unresponsive to aggressive immunosuppression and we opted to treat with endovascular balloon dilatation of the stenotic areas. The procedure was safe. The four patients were treated in nine sessions and a total of 16 vessels were treated. We observed two dissections with no clinical influence on the patients. Discussion: In patients with stroke due to progressive GCA that is non-responsive to immunosuppression, endovascular therapy is feasible.

A support programme for secondary prevention in patients with transient ischaemic attack and minor stroke (INSPiRE-TMS): an open-label, randomised controlled trial.

BACKGROUND: Patients with recent stroke or transient ischaemic attack are at high risk for a further vascular event, possibly leading to permanent disability or death. Although evidence-based treatments for secondary prevention are available, many patients do not achieve recommended behavioural modifications and pharmaceutical prevention targets in the long-term. We aimed to investigate whether a support programme for enhanced secondary prevention can reduce the frequency of recurrent vascular events. METHODS: INSPiRE-TMS was an open-label, multicentre, international randomised controlled trial done at seven German hospitals with acute stroke units and a Danish stroke centre. Patients with non-disabling stroke or transient ischaemic attack within 2 weeks from study enrolment and at least one modifiable risk factor (ie, arterial hypertension, diabetes, atrial fibrillation, or smoking) were included. Computerised randomisation was used to allocate patients (1:1) either to the support programme in addition to conventional care or to conventional care alone. The support programme used feedback and motivational interviewing strategies with eight outpatient visits over 2 years aiming to improve adherence to secondary prevention targets. The primary outcome was the composite of major vascular events consisting of stroke, acute coronary syndrome, and vascular death, assessed in the intention-to-treat population (all patients who underwent randomisation, did not withdraw study participation, and had at least one follow-up). Outcomes were assessed at annual follow-ups using time-to-first-event analysis. All-cause death was monitored as a safety outcome. This trial is registered with ClinicalTrials.gov, NCT01586702. FINDINGS: From Aug 22, 2011, to Oct 30, 2017, we enrolled 2098 patients. Of those, 1048 (50·0%) were randomly assigned to the support programme group and 1050 (50·0%) patients were assigned to the conventional care group. 1030 (98·3%) patients in the support group and 1042 (99·2%) patients in the conventional care group were included in the intention-to-treat analysis. The mean age of analysed participants was 67·4 years and 700 (34%) were women. After a mean follow-up of 3·6 years, the primary outcome of major vascular events had occurred in 163 (15·8%) of 1030 patients of the support programme group and in 175 (16·8%) of 1042 patients of the conventional care group (hazard ratio [HR] 0·92, 95% CI 0·75-1·14). Total major vascular event numbers were 209 for the support programme group and 225 for the conventional care group (incidence rate ratio 0·93, 95% CI 0·77-1·12; p=0·46) and all-cause death occurred in 73 (7·1%) patients in the support programme group and 85 (8·2%) patients in the conventional care group (HR 0·85, 0·62-1·17). More patients in the support programme group achieved secondary prevention targets (eg, in 1-year-follow-up 52% vs 42% [p<0·0001] for blood pressure, 62% vs 54% [p=0·0010] for LDL, 33% vs 19% [p<0·0001] for physical activity, and 51% vs 34% [p=0·0010] for smoking cessation). INTERPRETATION: Provision of an intensified secondary prevention programme in patients with non-disabling stroke or transient ischaemic attack was associated with improved achievement of secondary prevention targets but did not lead to a significantly lower rate of major vascular events. Further research is needed to investigate the effects of support programmes in selected patients who do not achieve secondary prevention targets soon after discharge. FUNDING: German Federal Ministry of Education and Research, Pfizer, and German Stroke Foundation.

Bypass strategies for common carotid artery occlusion.

BACKGROUND: Common carotid artery occlusion (CCA-occlusion) is a rare condition where standard revascularization is not feasible. Here, we analyzed our experience with surgical revascularization of CCA-occlusion to develop an algorithm for selection of the most suitable bypass strategy according to the Riles classification. METHODS: During a 10-year period, 16 out of 288 patients with cerebrovascular disease and compromised hemodynamic reserve underwent revascularization for unilateral CCA-occlusion. The utilized bypass strategies included (1) a saphenous vein graft from the subclavian artery (SA) to the internal carotid artery (ICA), (2) a radial artery graft from the V3 segment of the vertebral artery (VA) to a superficial branch of the middle cerebral artery (MCA), or (3) a saphenous vein graft from the SA to a deep branch of the MCA. RESULTS: In CCA-occlusion with maintained external carotid artery (ECA)/ICA patency (Riles type 1A), an SA-ICA bypass was performed (25%). In cases without ECA/ICA patency (Riles type 1B or 2) but suitable VA, a VA-MCA bypass was grafted (31%). In cases with unsuitable VA, a long SA-MCA interposition bypass was performed (38%). Transient postoperative neurological deficits occurred in 5 patients (31%) with 1 patient (6%) suffering permanent neurological worsening and 1 mortality (6%). Overall, no difference was found between the median preoperative mRS (2; range, 1-4) and the mRS at the time point of the last follow-up (2; range, 1-6; p = 0.75). The long-term graft patency was 94%. CONCLUSIONS: Although surgical revascularization for CCA-occlusion is feasible, it is associated with a higher risk than standard bypass grafting. Considering the poor natural history of CCA-occlusion, however, this risk may be justified in carefully selected patients.

Decreased GABA levels in the symptomatic hemisphere in patients with transient ischemic attack.

Transient ischemic attack (TIA) is an ischemic episode of neurologic dysfunction characterized by a spontaneous clinical resolution of symptoms within 24 hours. Mechanisms of this remarkable recovery are not yet well understood. In patients with permanent brain injury caused by a stroke cortical levels of γ-Aminobutyric acid (GABA) are decreased. In this study, we aimed to investigate, whether similar alterations of cortical GABA are also present in patients with TIA. Ten first-time TIA patients with temporary unilateral motor symptoms from upper limb and 10 control subjects underwent Magnetic Resonance Spectroscopy (MRS) with SPECIAL technique. GABA:creatine (GABA:CR) ratios were measured in the hand area of the primary motor cortex in both hemispheres. GABA:CR ratios were significantly lower in the symptomatic hemisphere of TIA patients when compared with healthy subjects. Whether reduced GABA is induced directly by transient ischemia or is a secondary compensatory mechanism, which facilitate re-establishment of normal function remains to be elucidated. Further research investigating our findings in larger samples will aid in understanding of the clinical significance of GABA alterations in TIA patients. GABA MRS may provide vital information about mechanisms involved in recovery after transient ischemia, which may have crucial importance for development of new neuroprotective strategies in stroke.

Low Morbidity after Extracranial-Intracranial Bypass Operation. The Danish Extracranial-Intracranial Bypass Study: A Nationwide Survey.

BACKGROUND: Patients with symptomatic atherosclerotic carotid artery occlusion (SACAO) have a high risk of a recurrent stroke. Extracranial-intracranial bypass (EC-IC bypass) has been shown not to improve outcome compared with medical treatment alone because long-term prevention of recurrent stroke in operated patients was offset by high perioperative stroke rates. We report our experience with EC-IC bypass operated at an experienced high-volume centre. METHODS: We conducted a nationwide observational study of EC-IC bypass patients operated in the years 2007-2016 due to SACAO with ongoing clinical symptoms or progression on MRI and severe haemodynamic failure (SHF). Perioperative stroke and death within 30 days after the operation, ipsilateral stroke, bypass patency, transient ischaemic attack, and all-stroke events and deaths during long-term follow-up were registered prospectively. RESULTS: EC-IC bypass was performed in 48 patients with SHF and SACAO. The mean age was 64 (45-83) years. The mean follow-up was 3.6 years. The stroke rate after 30 days was 4.2%. No further ipsilateral strokes occurred during follow-up. Clinical symptoms arrested in all patients. Bypass patency rate was 94%. CONCLUSIONS: The perioperative stroke rate in EC-IC bypass operation, performed at a highly experienced centre, was low. During long-term follow-up, no ipsilateral stroke occurred. Consequently, EC-IC-bypass should still be considered for selected patients with SACAO, if operation can be carried out in experienced centres with low perioperative morbidity.

Effects of centralizing acute stroke services: A prospective cohort study.

OBJECTIVE: To investigate the effects of centralizing the acute stroke services in the Central Denmark Region (CDR). METHODS: The CDR (1.3 million inhabitants) centralized acute stroke care from 6 to 2 designated acute stroke units with 7-day outpatient clinics. We performed a prospective "before-and-after" cohort study comparing all strokes from the CDR with strokes in the rest of Denmark to discover underlying general trends, adopting a difference-in-differences approach. The population comprised 22,141 stroke cases hospitalized from May 2011 to April 2012 and May 2013 to April 2014. RESULTS: Centralization was associated with a significant reduction in length of acute hospital stay from a median of 5 to 2 days with a length-of-stay ratio of 0.53 (95% confidence interval 0.38-0.75, data adjusted) with no corresponding change seen in the rest of Denmark. Similarly, centralization led to a significant increase in strokes with same-day admission (mainly outpatients), whereas this remained unchanged in the rest of Denmark. We observed a significant improvement in quality of care captured in 11 process performance measures in both the CDR and the rest of Denmark. Centralization was associated with a nonsignificant increase in thrombolysis rate. We observed a slight increase in readmissions at day 30, but this was not significantly different from the general trend. Mortality at days 30 and 365 remained unchanged, as in the rest of Denmark. CONCLUSIONS: Centralizing acute stroke care in the CDR significantly reduced the length of acute hospital stay without compromising quality. Readmissions and mortality stayed comparable to the rest of Denmark.

[Dissection of the cervical arteries]. / Dissektion af halskar.

Dissection of the cervical arteries is an important cause of stroke in young adults. A haematoma in the wall of the cervical vessel leads to stenosis or occlusion and thereby risk of stroke. The most frequent local symptoms in carotid-artery dissection are head- and neck pain accompanied by Horner's syndrome, while typical symptoms in vertebral-artery dissection are pain in the back of the neck and head. The mural haematoma is best visualized by magnetic resonance imaging. Antithrombotic versus anticoagulation treatment to prevent stroke have recently shown to be equally effective.

Remote ischemic perconditioning as an adjunct therapy to thrombolysis in patients with acute ischemic stroke: a randomized trial.

BACKGROUND AND PURPOSE: Remote ischemic preconditioning is neuroprotective in models of acute cerebral ischemia. We tested the effect of prehospital rPerC as an adjunct to treatment with intravenous alteplase in patients with acute ischemic stroke. METHODS: Open-label blinded outcome proof-of-concept study of prehospital, paramedic-administered rPerC at a 1:1 ratio in consecutive patients with suspected acute stroke. After neurological examination and MRI, patients with verified stroke receiving alteplase treatment were included and received MRI at 24 hours and 1 month and clinical re-examination after 3 months. The primary end point was penumbral salvage, defined as the volume of the perfusion-diffusion mismatch not progressing to infarction after 1 month. RESULTS: Four hundred forty-three patients were randomized after provisional consent, 247 received rPerC and 196 received standard treatment. Patients with a nonstroke diagnosis (n=105) were excluded from further examinations. The remaining patients had transient ischemic attack (n=58), acute ischemic stroke (n=240), or hemorrhagic stroke (n=37). Transient ischemic attack was more frequent (P=0.006), and National Institutes of Health Stroke Scale score on admission was lower (P=0.016) in the intervention group compared with controls. Penumbral salvage, final infarct size at 1 month, infarct growth between baseline and 1 month, and clinical outcome after 3 months did not differ among groups. After adjustment for baseline perfusion and diffusion lesion severity, voxelwise analysis showed that rPerC reduced tissue risk of infarction (P=0.0003). CONCLUSIONS: Although the overall results were neutral, a tissue survival analysis suggests that prehospital rPerC may have immediate neuroprotective effects. Future clinical trials should take such immediate effects, and their duration, into account. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00975962.

Extra-intracranial standard bypass in the elderly: perioperative risk, bypass patency and outcome.

BACKGROUND: Patients with chronic atherosclerotic vessel occlusion and cerebrovascular hemodynamic insufficiency may benefit from extra-intracranial (EC-IC) bypass surgery. Due to demographic changes, an increasing number of elderly patients presents with cerebrovascular hemodynamic insufficiency. So far, little data for EC-IC bypass surgery in elderly patients suffering occlusive cerebrovascular disease are available. We therefore designed a retrospective study to address the question whether EC-IC bypass is a safe and efficient treatment in a patient cohort ≥70 years. METHODS: 50 patients underwent EC-IC standard bypass surgery with translocation of the superficial temporal artery to an M2 segment of the medial cerebral artery. Criteria for bypass surgery were presence of symptomatic occlusive cerebrovascular disease of the anterior circulation and proof of a severely restricted or abrogated reserve capacity (detected by H2O-photon emission tomography or single photon emission computer tomography - before and after forced vessel dilatation by diamox). The incidence of perioperative neurological and surgical complications, bypass patency, bypass function and short-term outcome were retrospectively analyzed. RESULTS: The study cohort consisted of 16 patients ≥70 years (mean = 74.3 years, SE 1.3). It was compared to a cohort of 34 patients <70 years (mean = 61.2 years, SE 1.0). Both groups underwent EC-IC bypass surgery after careful preoperative work-up. Both patient groups did not differ significantly in gender, vascular pathology, previous history of diseases/comorbidity or clinical symptoms. The number of patients which underwent stenting or other endovascular treatments of the internal or common carotid artery prior to EC-IC bypass surgery was significantly higher in the group of patients ≥70 years (37.5 vs. 0%, p < 0.001). Perioperative stroke rate was 0% in both groups and mild morbidity occurred in 18.8 and 14.7%, respectively (p = 0.699). One 84-year-old female patient died due to perioperative endocarditis. Initial bypass patency was 93.8% in patients above the age of 70 years and 97.1% in the younger group (p = 0.542). Secondary occlusion rate was low in both groups (≥70 years: 0% vs. <70 years 3.7%). No new neurologic deficit occurred in patients with a patent bypass during the follow-up period (median 18 ± 13.1 months). Two patients with an initially occluded bypass and one with a secondary bypass occlusion suffered from new neurological symptoms. CONCLUSIONS: Our data show comparable safety and efficiency of EC-IC bypass surgery in patients under and above the age of 70 years due to a careful preoperative work-up and a strict indication for bypass surgery.

The role of the cerebral capillaries in acute ischemic stroke: the extended penumbra model.

The pathophysiology of cerebral ischemia is traditionally understood in relation to reductions in cerebral blood flow (CBF). However, a recent reanalysis of the flow-diffusion equation shows that increased capillary transit time heterogeneity (CTTH) can reduce the oxygen extraction efficacy in brain tissue for a given CBF. Changes in capillary morphology are typical of conditions predisposing to stroke and of experimental ischemia. Changes in capillary flow patterns have been observed by direct microscopy in animal models of ischemia and by indirect methods in humans stroke, but their metabolic significance remain unclear. We modeled the effects of progressive increases in CTTH on the way in which brain tissue can secure sufficient oxygen to meet its metabolic needs. Our analysis predicts that as CTTH increases, CBF responses to functional activation and to vasodilators must be suppressed to maintain sufficient tissue oxygenation. Reductions in CBF, increases in CTTH, and combinations thereof can seemingly trigger a critical lack of oxygen in brain tissue, and the restoration of capillary perfusion patterns therefore appears to be crucial for the restoration of the tissue oxygenation after ischemic episodes. In this review, we discuss the possible implications of these findings for the prevention, diagnosis, and treatment of acute stroke.

Intensified secondary prevention intending a reduction of recurrent events in TIA and minor stroke patients (INSPiRE-TMS): a protocol for a randomised controlled trial.

BACKGROUND: Patients with recent stroke or TIA are at high risk for new vascular events. Several evidence based strategies in secondary prevention of stroke are available but frequently underused. Support programs with multifactorial risk factor modifications after stroke or TIA have not been investigated in large-scale prospective controlled trials so far. INSPiRE-TMS is a prospective, multi-center, randomized open intervention trial for intensified secondary prevention after minor stroke and TIA. METHODS/DESIGN: Patients with acute TIA or minor stroke admitted to the participating stroke centers are screened and recruited during in-hospital stay. Patients are randomised in a 1:1 ratio to intervention (support program) and control (usual care) arms. Inclusion of 2.082 patients is planned. The support program includes cardiovascular risk factor measurement and feedback, monitoring of medication adherence, coaching in lifestyle modifications, and active involvement of relatives. Standardized motivational interviewing is used to assess and enhance patients' motivation. Primary objective is a reduction of new major vascular events defined as nonfatal stroke and myocardial infarction or vascular death. Recruitment time is planned for 3.5 years, follow up time is at least 2 years for every patient resulting in a total study time of 5 years (first patient in to last patient out). DISCUSSION: Given the high risk for vascular re-events in acute stroke and the available effective strategies in secondary prevention, the INSPIRE-TMS support program has the potential to lead to a relevant reduction of recurrent events and a prolongation of the event-free survival time. The trial will provide the basis for the decision whether an intensified secondary prevention program after stroke should be implemented into regular care. A cost-effectiveness evaluation will be performed. TRIAL REGISTRATION: clinicaltrials.gov: 01586702.

Transient ischemic attack and minor stroke are the most common manifestations of acute cerebrovascular disease: a prospective, population-based study--the Aarhus TIA study.

BACKGROUND: Severity of acute vascular illness may have changed in the last decades due to improvements in primary and secondary prevention. Population-based data on the severity of acute ischemic cerebrovascular disease are sparse. We aimed to examine incidence, characteristics and severity of acute ischemic cerebrovascular disease in a well-defined population. METHODS: All patients admitted with transient ischemic attack (TIA) or acute ischemic stroke from March 1, 2007, to February 29, 2008, with residence in the Aarhus area, were included. Incidence rates and characteristics of TIA and ischemic stroke were compared. RESULTS: TIA accounted for 30%, TIA and minor stroke combined for 65% of all acute ischemic cerebrovascular events. Age-adjusted incidence rates of TIA and ischemic stroke were 72.2/100,000 and 129.5/100,000 person-years, respectively. TIA patients were younger than stroke patients (66.3 vs. 72.7 years; p < 0.001). Atrial fibrillation, previous myocardial infarction and previous stroke were significantly more frequent in stroke patients; no differences in other baseline characteristics were found. CONCLUSIONS: Minor events are the most common in ischemic cerebrovascular disease, and may constitute a larger proportion than previously reported. TIA and stroke patients share many characteristics; however, TIA patients are younger and have fewer manifestations of atherosclerotic diseases, indicating a high potential for secondary prevention.

Extracranial posterior communicating artery bypass for revascularization of patients with common carotid artery occlusion.

BACKGROUND: Extracranial-intracranial bypass surgery provides blood flow augmentation in patients suffering from intracranial or long-distance conductance artery stenosis or occlusion that otherwise cannot be treated. The standard procedure for these cases is an anastomosis between the superficial temporal and middle cerebral arteries. However, in patients presenting with common carotid artery occlusion, the superficial temporal artery is no longer sufficiently perfused. For these patients, alternative revascularization strategies have to be applied. OBJECTIVE: To describe a novel strategy for revascularization of patients with common carotid artery occlusion, ie, the extracranial posterior communicating artery bypass. METHODS: Two patients with chronic cerebrovascular compromise resulting in transitory ischemic attacks and/or border-zone infarctions caused by common carotid artery occlusion were referred to our institution. A radial artery bypass was established between the third segment of the vertebral artery and an M3 branch of the middle cerebral artery. The vertebral artery was exposed between the vertebral lamina of C1 and occipital bone via a paramedian incision. The bypass was tunneled subcutaneously, conducted intracranially via a tailored extended burr-hole craniotomy, and anastomosed to a recipient M3 vessel. RESULTS: The postoperative course of both patients was uneventful in terms of cerebral ischemia or bleeding complications. In both patients, postoperative angiographic controls revealed an excellent bypass function with markedly improved hemispheric filling of multiple middle cerebral artery branches. The patients were discharged without new neurological symptoms. CONCLUSION: Our extracranial posterior communicating artery bypass using a radial artery transplant from the vertebral artery to the middle cerebral artery is a useful tool to treat patients suffering from hemodynamic cerebrovascular compromise caused by common carotid artery occlusion.

[Thrombolysis of apoplexy patients. A year's experience and results in Aarhus Hospital]. / Trombolyse af apopleksipatienter. Første års erfaringer og resultater på Arhus Sygehus.

INTRODUCTION: Treatment of acute stroke with thrombolysis within three hours is a challenging aspect of the organization of state-of-the-art stroke care. Indication for thrombolysis is based on studies where CT was used as a diagnostic tool. MR-based techniques are in some aspects superior to CT, though the scan times are longer. In this study, the feasibility and effectiveness of MR-based thrombolysis was examined. MATERIALS AND METHODS: Prospective registration of patient time delays, demographics, initial NIHSS (National Institute of Health Stroke Scale) and MR data for all patients referred to Aarhus Hospital with symptoms of acute stroke was done over a one-year period. For patients receiving thrombolysis, additional MR data, complications, NIHSS at follow-up (2 hours, 24 hours, 7 days and 3 months) and modified Rankin score at 3 months were recorded. Results were compared to the data in the international thrombolysis database (SITS-MOST). RESULTS: During the period, 112 patients were referred and 86 were scanned using MR techniques. 22 patients received thrombolysis (17/5 after MR/CT). 54% of patients had a good outcome at 3 months (mRS = 0-1) compared to 34% in SITS-MOST (n.s). No symptomatic haemorrhages were recorded; mortality was 9% (13% in SITS-MOST). Treatment was not delayed compared to SITS-MOST despite the longer MR scan time. CONCLUSION: Effective organization of treatment with thrombolysis using MR imaging is feasible. The MR techniques were beneficial in decision making and did not cause delay of treatment. Thrombolysis in this setup was as efficient with respect to outcome and complications as was that recorded in the SITS-MOST register.