Dabigatran vs. Aspirin for Secondary Prevention After Embolic Stroke of Undetermined Source　- Japanese Subanalysis of the RE-SPECT ESUS Randomized Controlled Trial.

BACKGROUND: The international Randomized, Double-Blind, Evaluation in Secondary Stroke Prevention Comparing the EfficaCy and Safety of the Oral Thrombin Inhibitor Dabigatran Etexilate versus Acetylsalicylic Acid in Patients with Embolic Stroke of Undetermined Source (RE-SPECT ESUS) trial did not demonstrate superiority of dabigatran over aspirin for reduction of recurrent strokes in patients with embolic strokes of undetermined source (ESUS). Based on pre-defined subanalyses, the safety and efficacy of dabigatran vs. aspirin in Japanese patients was assessed.Methods and Results:ESUS patients were randomized to receive either dabigatran (150 or 110 mg twice daily) or aspirin (100 mg once daily). Of 5,390 patients randomized, 594 were Japanese. Most Japanese patients (99.8%) underwent brain magnetic resonance imaging for trial screening, compared to 76.8% of non-Japanese (P<0.0001). In the Japanese cohort, over a 19.4-month median follow-up period, recurrent stroke as the primary outcome occurred in 20/294 patients (4.3%/year) in the dabigatran group and 38/300 (8.3%/year) in the aspirin group (hazard ratio [HR], 0.55; 95% confidence interval [CI], 0.32-0.94). Major bleeding occurred in 12 patients (2.5%/year) and 17 patients (3.5%/year), respectively (HR, 0.72; 95% CI, 0.34-1.52). In contrast, in the non-Japanese cohort, recurrent stroke occurred in 4.1%/year and 4.3%/year, respectively, showing no apparent difference in recurrent stroke for dabigatran vs. aspirin (HR, 0.91; 95% CI, 0.74-1.14). The P-interaction for treatment and region did not reach statistical significance (P=0.09). CONCLUSIONS: Dabigatran was putatively associated with a lower relative risk of recurrent stroke compared with aspirin in Japanese ESUS patients.

Effects of clazosentan on cerebral vasospasm-related morbidity and all-cause mortality after aneurysmal subarachnoid hemorrhage: two randomized phase 3 trials in Japanese patients.

OBJECTIVE: Clazosentan has been investigated globally for the prevention of cerebral vasospasm after aneurysmal subarachnoid hemorrhage (aSAH). The authors evaluated its effects on vasospasm-related morbidity and all-cause mortality following aSAH in Japanese patients. METHODS: Two similar double-blind, placebo-controlled phase 3 studies were conducted in 57 Japanese centers in patients with aSAH, after aneurysms were secured by endovascular coiling in one study and surgical clipping in the other. In each study, patients were randomly administered intravenous clazosentan (10 mg/hr) or placebo (1:1) starting within 48 hours of aSAH and for up to 15 days after aSAH. Stratified randomization based on World Federation of Neurosurgical Societies grade was performed using a centralized interactive web response system. Vasospasm-related morbidity and all-cause mortality within 6 weeks post-aSAH, including new cerebral infarcts and delayed ischemic neurological deficits as well as all-cause mortality, were the first primary endpoint in each study. The second primary endpoint was all-cause morbidity (new cerebral infarct or delayed ischemic neurological deficit from any causes) and all-cause mortality (all-cause morbidity/mortality) within 6 weeks post-aSAH. The incidence of individual components of the primary morbidity/mortality endpoints within 6 weeks and patient outcome at 12 weeks post-aSAH (including the modified Rankin Scale scores) were also evaluated. The above analyses were also performed in the population pooled from both studies. RESULTS: In each study, 221 patients were randomized and 220 were included in the full analysis set of the primary analysis (109 in each clazosentan group, 111 in each placebo group). Clazosentan significantly reduced the incidence of vasospasm-related morbidity and all-cause mortality after aneurysm coiling (from 28.8% to 13.6%; relative risk reduction 53%; 95% CI 17%-73%) and after clipping (from 39.6% to 16.2%; relative risk reduction 59%; 95% CI 33%-75%). All-cause morbidity/mortality and poor outcome (dichotomized modified Rankin Scale scores) were significantly reduced by clazosentan after preplanned study pooling. Treatment-emergent adverse events were similar to those reported previously. CONCLUSIONS: Clazosentan significantly reduced the combined incidence of vasospasm-related morbidity and all-cause mortality post-aSAH with no unexpected safety findings. Clinical trial registration nos.: JapicCTI-163368 and JapicCTI-163369 (https://www.clinicaltrials.jp).

Vertebral artery occlusion associated with blunt traumatic cervical spine injury.

AIM: Vertebral artery injury associated with blunt traumatic cervical spine injury sometimes causes severe cerebellar and brain stem infarction. No treatment guidelines for vertebral artery injury aimed at preventing stroke have been decided. We have conducted endovascular embolization in patients with up to Denver grade IV cerebrovascular injury complicated by unstable cervical spine injury before open reduction and fixation surgery. The purpose of this study was to validate the clinical course of vertebral artery injury and especially endovascular treatment for grade IV patients in our hospital. METHODS: Participants comprised of patients diagnosed as having traumatic cervical spine injury in our hospital between January 2015 and April 2018. Among these patients, we selected those with vertebral artery injury and retrospectively examined the background characteristics of the patients, details of treatment, and complications with or without stroke. RESULTS: Traumatic cervical spine injury was diagnosed in 89 patients. Among these patients, 15 (16.7%) showed a complicating vertebral artery injury. Mean age was 62.6 years, and almost 50% of the patients were injured in falls. Three types of cervical spine injury caused vertebral artery injury: subluxation, Jefferson fracture, and fracture involving the foramen transversarium. Vertebral artery injury was classified as grade IV in 12 patients, of whom nine required spinal surgery. All patients who needed spinal surgery underwent endovascular therapy before surgery, and none experienced a stroke. CONCLUSION: Endovascular embolization of the vertebral artery occlusion in patients with unstable cervical spine injury before open reduction and fixation surgery can be a treatment option to prevent stroke.

Fibrinogen level on admission is a predictor for massive transfusion in patients with severe blunt trauma: Analyses of a retrospective multicentre observational study.

INTRODUCTION: In the early phase of trauma, fibrinogen (Fbg) plays an important role in clot formation. However, to the best of our knowledge, few studies have analysed methods of predicting the need for massive transfusion (MT) based on Fbg levels using multiple logistic regression. Therefore, the present study aimed to evaluate whether Fbg levels on admission can be used to predict the need for MT in patients with trauma. METHODS: We conducted a retrospective multicentre observational study. Patients with blunt trauma with ISS ≥16 who were admitted to 15 tertiary emergency and critical care centres in Japan participating in the J-OCTET were enrolled in the present study. MT was defined as the transfusion of packed red blood cells (PRBC) ≥10 units or death caused by bleeding within 24h after admission. Patients were divided into non-MT and MT groups. Multiple logistic-regression analysis was used to assess the predictive value of the variables age, sex, vital signs, Glasgow Coma Scale (GCS) score, and Fbg levels for MT. We also evaluated the discrimination threshold of MT prediction via receiver operating characteristic curve (ROC) analysis for each variable. RESULTS: Higher heart rate (HR; per 10 beats per minutes [bpm]), systolic blood pressure (SBP; per 10mm Hg), GCS, and Fbg levels (per 10mg/dL) were independent predictors of MT (odds ratio [OR] 1.480, 95% confidence interval [CI] 1.326-1.668; OR 0.851, 95% CI 0.789-0.914; OR 0.907, 95% CI 0.855-0.962; and OR 0.931, 95% CI 0.898-0.963, respectively). The optimal cut-off values for HR, SBP, GCS, and Fbg levels were ≥100 bpm (sensitivity 62.4%, specificity 79.8%), ≤120mm Hg (sensitivity 61.5%, specificity 70.5%), ≤12 points (sensitivity 63.3%, specificity 63.6%), and ≤190mg/dL (sensitivity 55.1%, specificity 78.6%), respectively. CONCLUSIONS: Our findings suggest that vital signs, GCS, and decreased Fbg levels can be regarded as predictors of MT. Therefore, future studies should consider Fbg levels when devising models for the prediction of MT.

Gene therapy for ischemic brain diseases.

We discuss possible gene therapies for the treatment of ischemic diseases in the central nervous system (CNS). These therapies aim at the prevention of carotid artery restenosis, stimulation of angiogenesis for ischemic brain, protection of neurons against ischemia, and prevention of vasospasm due to subarachnoid hemorrhage (SAH). Carotid artery restenosis can perhaps be approached by preventing vascular smooth muscle cell proliferation via gene therapy in addition to surgical treatment. Cerebral angiogenesis therapy might be applicable to moyamoya disease. Gene therapies with VEGF and HGF to stimulate angiogenesis have been successful in muscle; however, efficacy in the CNS is unknown. Gene transfection efficiency of viral vectors has been poor in the CNS, and the safety of such vectors is questionable. Therefore, development of gene therapy is for neural protection and prevention of vasospasm due to SAH has been limited. Infusion of HVJ-AVE liposomes into monkey cerebrospinal fluid (CSF) space yielded wide-spread gene transfection. HVJ-AVE liposomes may be a promising vector for use in the human CNS. Few currently available gene therapies appear to be options for clinical treatment of cerebral ischemia despite many experimental designs. In addition to the inherent difficulties of treating the CNS, vectors and methods for introducing vectors into the CNS must be improved.