Prior anticoagulation and bridging thrombolysis improve outcomes in patients with atrial fibrillation undergoing endovascular thrombectomy for anterior circulation stroke.

BACKGROUND: Where stroke occurs with pre-existing atrial fibrillation (AF)studies validating the safety and efficacy of bridging thrombolysis, and the use of endovascular thrombectomy (EVT) in the setting of prior anticoagulation, are limited to single-center reports. METHODS: In a retrospective analysis, AF patients undergoing EVT for anterior circulation large vessel occlusion stroke enrolled in a prospectively-maintained, international multicenter database (International Stroke Perfusion Imaging Registry (INSPIRE)) between 2016 and 2019 were studied. Patients were categorized by anticoagulation status: anticoagulated (warfarin/non-vitamin K oral anticoagulants) versus not anticoagulated. Patients not anticoagulated were further divided into intravenous thrombolysis versus no thrombolysis. Outcomes compared between groups included 90-day modified Rankin Scale, 90-day mortality, rates of symptomatic intracerebral hemorrhage (sICH), and good reperfusion (modified Thrombolysis In Cerebral Infarction (mTICI) 2b-3). RESULTS: Of 563 AF patients, 118 (21%) were on anticoagulation. AF patients on anticoagulation showed improved 90-day functional outcomes (adjusted odds ratio (aOR) 1.68, 95% confidence interval (95% CI) 1.00 to 2.82). Mortality (26.3% vs 23.8%), sICH (4.5% vs 3.9%), and rates of good reperfusion (91.3% vs 88.0%) were similar between those anticoagulated and those not anticoagulated. Thrombolysis before EVT in AF patients was independently associated with improved 90-day functional outcomes (aOR 1.81, 95% CI 1.18 to 2.79) and reduced mortality (aOR 0.51, 95% CI 0.31 to 0.84), with similar sICH rates (3.4% vs 4.5%). CONCLUSIONS: Anticoagulated patients with AF who underwent EVT had improved 90-day functional outcomes and similar sICH rates. Thrombolysis before EVT in AF patients was associated with improved 90-day functional outcomes and reduced mortality.

Effects of a Province-wide Triaging System for TIA: The ASPIRE Intervention.

BACKGROUND AND OBJECTIVES: Urgent transient ischemic attack (TIA) management to reduce stroke recurrence is challenging, particularly in rural and remote areas. In Alberta, Canada, despite an organized stroke system, data from 1999 to 2000 suggested that stroke recurrence after TIA was as high as 9.5% at 90 days. Our objective was to determine whether a multifaceted population-based intervention resulted in a reduction in recurrent stroke after TIA. METHODS: In this quasi-experimental health services research intervention study, we implemented a TIA management algorithm across the entire province, centered around a 24-hour physician's TIA hotline and public and health provider education on TIA. From administrative databases, we linked emergency department discharge abstracts to hospital discharge abstracts to identify incident TIAs and recurrent strokes at 90 days across a single payer system with validation of recurrent stroke events. The primary outcome was recurrent stroke; with a secondary composite outcome of recurrent stroke, acute coronary syndrome, and all-cause death. We used an interrupted time series regression analysis of age-adjusted and sex-adjusted stroke recurrence rates after TIA, incorporating a 2-year preimplementation period (2007-2009), a 15-month implementation period, and a 2-year postimplementation period (2010-2012). Logistic regression was used to examine outcomes that did not fit the time series model. RESULTS: We assessed 6,715 patients preimplementation and 6,956 patients postimplementation. The 90-day stroke recurrence rate in the pre-Alberta Stroke Prevention in TIA and mild Strokes (ASPIRE) period was 4.5% compared with 5.3% during the post-ASPIRE period. There was neither a step change (estimate 0.38; p = 0.65) nor slope change (parameter estimate 0.30; p = 0.12) in recurrent stroke rates associated with the ASPIRE intervention implementation period. Adjusted all-cause mortality (odds ratio 0.71, 95% CI 0.56-0.89) was significantly lower after the ASPIRE intervention. DISCUSSION: The ASPIRE TIA triaging and management interventions did not further reduce stroke recurrence in the context of an organized stroke system. The apparent lower mortality postintervention may be related to improved surveillance after events identified as TIAs, but secular trends cannot be excluded. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that a standardized population-wide algorithmic triage system for patients with TIA did not reduce recurrent stroke rate.

Design and synthesis of inhaled p38 inhibitors for the treatment of chronic obstructive pulmonary disease.

This paper describes the identification and optimization of a novel series of DFG-out binding p38 inhibitors as inhaled agents for the treatment of chronic obstructive pulmonary disease. Structure based drug design and "inhalation by design" principles have been applied to the optimization of the lead series exemplied by compound 1a. Analogues have been designed to be potent and selective for p38, with an emphasis on slow enzyme dissociation kinetics to deliver prolonged lung p38 inhibition. Pharmacokinetic properties were tuned with high intrinsic clearance and low oral bioavailability in mind, to minimize systemic exposure and reduce systemically driven adverse events. High CYP mediated clearance and glucuronidation were targeted to achieve high intrinsic clearance coupled with multiple routes of clearance to minimize drug-drug interactions. Furthermore, pharmaceutical properties such as stability, crystallinity, and solubility were considered to ensure compatibility with a dry powder inhaler. 1ab (PF-03715455) was subsequently identified as a clinical candidate from this series with efficacy and safety profiles confirming its potential as an inhaled agent for the treatment of COPD.