rivaroxaban and Infarction--Middle-Cerebral-Artery

The timing of anti-coagulation therapy initiation after acute cardioembolic stroke remains controversial. We investigated the effects of post-stroke administration of a factor Xa inhibitor in mice, focusing on tissue repair and functional restoration outcomes. We initiated administration of rivaroxaban, a Xa inhibitor, immediately after permanent distal middle cerebral artery occlusion (pMCAO) in CB-17 mice harboring few leptomeningeal anastomoses at baseline. Rivaroxaban initiated immediately after pMCAO hindered the recovery of blood flow in ischemic areas by inhibiting leptomeningeal anastomosis development, and led to impaired restoration of neurologic functions with less extensive peri-infarct astrogliosis. Within infarct areas, angiogenesis and fibrotic responses were attenuated in rivaroxaban-fed mice. Furthermore, inflammatory responses, including the accumulation of neutrophils and monocytes/macrophages, local secretion of pro-inflammatory cytokines, and breakdown of the blood-brain barrier, were enhanced in infarct areas in mice treated immediately with rivaroxaban following pMCAO. The detrimental effects were not found when rivaroxaban was initiated after transient MCAO or on day 7 after pMCAO. Collectively, early post-stroke initiation of a factor Xa inhibitor may suppress leptomeningeal anastomosis development and blood flow recovery in ischemic areas, thereby resulting in attenuated tissue repair and functional restoration unless occluded large arteries are successfully recanalized.

Topics: Animals; Blood-Brain Barrier; Brain Ischemia; Disease Models, Animal; Factor Xa; Factor Xa Inhibitors; Fibrinolytic Agents; Infarction, Middle Cerebral Artery; Male; Mice; Rivaroxaban; Stroke; Time Factors

The aim of this study was to assess the risk and the threshold of hemorrhagic transformation (HT) after treatment with recombinant tissue plasminogen activator (rtPA) under the novel oral anticoagulant, rivaroxaban.. Fifty-three spontaneous hypertensive rats were used in this study. We performed transient middle cerebral artery occlusion for 270 minutes. Placebo, 10 mg/kg or 20 mg/kg rivaroxaban were administered via a stomach tube 180 minutes after induction of ischemia, and rtPA (10 mg/kg) was administered just before reperfusion. Ninety minutes after rivaroxaban administration we measured the rivaroxaban plasma concentration and prothrombin time (PT). HT volume was assessed by hemoglobin spectrophotometry. Additionally, infarct volume, IgG leakage volume, and neurological outcome were assessed.. Rivaroxaban plasma concentration and PT increased in a dose dependent manner but were lower than human peak levels after a once-daily dose of 20 mg rivaroxaban. HT volume increased after treatment with 20 mg/kg rivaroxaban compared with placebo treated controls or those treated with 10 mg/kg rivaroxaban (26.5 ± 5.4, 26.8 ± 8.7, and 41.4 ± 12.6 μL in placebo, 10 mg/kg, and 20 mg/kg treated groups, respectively; P < .05).. Our results suggest that even at therapeutic plasma concentrations, rivaroxaban may increase the risk of HT after thrombolysis in some conditions, such as hypertension and/or a prolonged ischemic period.

Topics: Animals; Blood Coagulation; Disease Models, Animal; Dose-Response Relationship, Drug; Factor Xa Inhibitors; Fibrinolytic Agents; Infarction, Middle Cerebral Artery; Intracranial Hemorrhages; Male; Rats, Inbred SHR; Recombinant Proteins; Risk Factors; Rivaroxaban; Thrombolytic Therapy; Tissue Plasminogen Activator

Background The aims of the present study were to investigate the relationships between prior direct oral anticoagulant ( DOAC ) therapy and infarct volume and the site of arterial occlusion in patients with acute ischemic stroke and non-valvular atrial fibrillation. Methods and Results From March 2011 through November 2016, consecutive patients with acute ischemic stroke in the middle cerebral artery territory and non-valvular atrial fibrillation were recruited. The infarct volume was assessed semi-automatically using initial diffusion-weighted imaging, and the arterial occlusion site was evaluated on magnetic resonance angiography. The effect of prior DOAC treatment on the site of arterial occlusion was assessed by multivariate ordinal logistic regression analysis. A total of 330 patients (149 women; median age 79 [quartiles 71-86] years; median National Institutes of Health Stroke Scale score 11 [4-21]) were enrolled. Of these, 239 were on no anticoagulant, 40 were undertreated with a vitamin K antagonist ( VKA ), 22 were sufficiently treated with VKA ( PT - INR ≥1.6), and 29 were on a DOAC before the acute ischemic stroke. The infarct volume on admission differed among the groups (median 14.5 [2.0-59.8] cm

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Cerebral Angiography; Dabigatran; Diffusion Magnetic Resonance Imaging; Female; Humans; Infarction, Middle Cerebral Artery; International Normalized Ratio; Logistic Models; Magnetic Resonance Angiography; Male; Multivariate Analysis; Prothrombin Time; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Severity of Illness Index; Stroke; Thiazoles; Warfarin

Warfarin and rivaroxaban are highly effective in reducing stroke risk in patients with atrial fibrillation (AF). However, their effects on anticoagulation and neurovascular unit (NVU) change remain elusive. In this study, we assessed the risks and benefits of pre-treatment with warfarin or rivaroxaban after tissue-type plasminogen activator (tPA) thrombolysis in ischemic rat brain.. Pre-treatment with warfarin (.2 mg/kg/day), low dose rivaroxaban (60 mg/kg/day), high dose rivaroxaban (120 mg/kg/day) or vehicle was performed for 2 weeks, transient middle cerebral artery occlusion (tMCAO) was induced for 90 min, then followed by reperfusion with tPA. At 24 hours (h) after reperfusion, we observed the changes of matrix metalloproteinase-9 (MMP-9), tissue factor, caspase 3 and NVU dissociation.. Prothrombin time (PT) was significantly prolonged in the warfarin and rivaroxaban pretreated groups. MMP-9 expression greatly increased in the warfarin group, and this was reduced in the rivaroxaban groups compared with the vehicle group. Tissue factor expression remarkably decreased in the warfarin and rivaroxaban groups. The number of caspase 3-positive cells had no difference among all the groups. Marked dissociations between astrocyte foot processes and the basal lamina or pericytes were observed in the warfarin pretreated group, but such dissociations were improved in the rivaroxaban groups.. Our present study shows that pre-treatment with rivaroxaban was noninferior to warfarin in the anticoagulation, but a lower risk of NVU dysfunction and dissociation after tPA treatment in rivaroxaban. This finding could partly explain the mechanism of reducing hemorrhagic complications by rivaroxaban in clinical studies.

Topics: Animals; Anticoagulants; Body Weight; Brain; Caspase 3; Collagen; Disease Models, Animal; Drug Administration Schedule; Gene Expression Regulation; Glial Fibrillary Acidic Protein; Infarction, Middle Cerebral Artery; Male; Matrix Metalloproteinase 9; Plant Lectins; Rats; Rats, Wistar; Receptors, Platelet-Derived Growth Factor; Rivaroxaban; Warfarin

Topics: Administration, Oral; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Benzimidazoles; Biological Availability; Blood Coagulation; Dabigatran; Drug Monitoring; Drug Substitution; Factor Xa Inhibitors; Female; Humans; Infarction, Middle Cerebral Artery; Intestinal Absorption; Morpholines; Predictive Value of Tests; Pyridines; Risk Factors; Rivaroxaban; Short Bowel Syndrome; Thiophenes; Treatment Outcome

The safety of recombinant tissue plasminogen activator (rt-PA) and/or endovascular therapy for patients using the novel oral anticoagulant (NOAC) for atrial fibrillation remains unclear.. We report a patient who was treated by both rt-PA and endovascular thrombectomy who suffered from acute ischemic stroke under treatment with NOAC.. An 83-year-old woman had a medical history with ischemic stroke due to paroxysmal atrial fibrillation and was then administered 10 mg of rivaroxaban daily. Although she took rivaroxaban in the morning, ischemic stroke recurred at midnight of that day. Soon after transferring to our hospital, we confirmed right middle cerebral artery (MCA) occlusion in the patient and then initiated treatment with intravenous rt-PA. Although no hemorrhagic complication occurred, recovery of her symptoms was not seen, and endovascular thrombectomy was performed. Although the inferior branch of the MCA was recanalized, an infarct was seen in her left frontal lobe. Hemorrhagic transformation was not observed during or after these combined treatments.. Thrombolysis and/or endovascular thrombectomy might be safe for patients treated with the new anticoagulant rivaroxaban.

Topics: Aged, 80 and over; Brain Ischemia; Cerebral Revascularization; Factor Xa Inhibitors; Female; Humans; Infarction, Middle Cerebral Artery; Morpholines; Rivaroxaban; Stroke; Thiophenes; Thrombectomy; Tissue Plasminogen Activator