Xanthine oxidase inhibition and white matter hyperintensity progression following ischaemic stroke and transient ischaemic attack (XILO-FIST): a multicentre, double-blinded, randomised, placebo-controlled trial.

Background: People who experience an ischaemic stroke are at risk of recurrent vascular events, progression of cerebrovascular disease, and cognitive decline. We assessed whether allopurinol, a xanthine oxidase inhibitor, reduced white matter hyperintensity (WMH) progression and blood pressure (BP) following ischaemic stroke or transient ischaemic attack (TIA). Methods: In this multicentre, prospective, randomised, double-blinded, placebo-controlled trial conducted in 22 stroke units in the United Kingdom, we randomly assigned participants within 30-days of ischaemic stroke or TIA to receive oral allopurinol 300 mg twice daily or placebo for 104 weeks. All participants had brain MRI performed at baseline and week 104 and ambulatory blood pressure monitoring at baseline, week 4 and week 104. The primary outcome was the WMH Rotterdam Progression Score (RPS) at week 104. Analyses were by intention to treat. Participants who received at least one dose of allopurinol or placebo were included in the safety analysis. This trial is registered with ClinicalTrials.gov, NCT02122718. Findings: Between 25th May 2015 and the 29th November 2018, 464 participants were enrolled (232 per group). A total of 372 (189 with placebo and 183 with allopurinol) attended for week 104 MRI and were included in analysis of the primary outcome. The RPS at week 104 was 1.3 (SD 1.8) with allopurinol and 1.5 (SD 1.9) with placebo (between group difference -0.17, 95% CI -0.52 to 0.17, p = 0.33). Serious adverse events were reported in 73 (32%) participants with allopurinol and in 64 (28%) with placebo. There was one potentially treatment related death in the allopurinol group. Interpretation: Allopurinol use did not reduce WMH progression in people with recent ischaemic stroke or TIA and is unlikely to reduce the risk of stroke in unselected people. Funding: The British Heart Foundation and the UK Stroke Association.

Platelet function following acute cerebral ischemia.

BACKGROUND: Studies have previously identified increased levels of platelet activation following acute ischemic stroke. In order to evaluate new antiplatelet agents and their combinations, there is a need for accurate measures of platelet activation. METHODS: Blood was taken from 17 patients within 24 hours of an acute ischemic stroke, and then at 3, 7, 14 and 42 days. For comparison, a group of 18 stable arteriopaths had identical tests performed. Platelet aggregation was measured using a free platelet counting technique, and platelet surface P-selectin and monocyte platelet aggregates (MPAs) were measured using flow cytometry. Soluble P-selectin and D-dimers were measured by an enzyme linked immune assay. RESULTS: The initial level of MPAs was significantly raised in the stroke patients compared with the stable patients (p = 0.04, 14.2% vs. 9.3%); however, this difference was not significantly higher than later study points (14.2%, 10.1%, 9.3%, 11.9%, 11.3%; days 1, 3, 7, 14 and 42 respectively. Day 1 vs. day 7 p = 0.07 ANOVA). No changes in P-selectin or platelet aggregation were identified. D-dimer levels were significantly higher on day 7 than day 42 (p < 0.01), and fibrinogen levels were elevated on both days 3 and 14 compared with day 42. Fibrinogen levels were not elevated compared with stable patients. CONCLUSIONS: MPA levels are elevated following an acute ischemic stroke compared to stable patients, but no significant change was seen with other platelet markers. This study suggests MPAs are a more sensitive marker of platelet activation than either P-selectin or aggregation.

Soluble but not platelet P-selectin correlates with spontaneous platelet aggregation: a pilot study.

BACKGROUND: P-selectin (PS) is a marker of platelet activation measured on the platelet surface as platelet PS (pPS) or in serum as soluble PS (sPS). Controversy remains over the exact relationship between sPS, pPS, and other markers such as spontaneous platelet aggregation (SPA). OBJECTIVE: To investigate correlations between pPS, sPS, and SPA in patients with peripheral arterial disease. METHODS: SPA, pPS, and sPS levels were measured in venous blood sampled from patients following intermittent claudication (n = 18) or an acute stroke (n = 18). RESULTS: SPA and sPS correlated significantly in the claudicants (Pearson correlation coefficient, r = 0.661; P = .0020) and stroke patients (r = 0.514; P = .020). No significant correlation was identified between pPS and SPA, or sPS and pPS. CONCLUSIONS: The 2 methods of assessing PS are not comparable. Although pPS is accepted as a platelet activation marker, sPS may be a better indicator of aggregation represented by SPA.

The Recognition of Stroke in the Emergency Room (ROSIER) scale: development and validation of a stroke recognition instrument.

BACKGROUND: In patients with acute stroke, rapid intervention is crucial to maximise early treatment benefits. Stroke patients commonly have their first contact with medical staff in the emergency room (ER). We designed and validated a stroke recognition tool-the Recognition of Stroke in the Emergency Room (ROSIER) scale-for use by ER physicians. METHODS: We prospectively collected data for 1 year (development phase) on the clinical characteristics of patients with suspected acute stroke who were admitted to hospital from the ER. We used logistic regression analysis and clinical reasoning to develop a stroke recognition instrument for application in this setting. Patients with suspected transient ischaemic attack (TIA) with no symptoms or signs when assessed in the ER were excluded from the analysis. The instrument was assessed using the baseline 1-year dataset and then prospectively validated in a new cohort of ER patients admitted over a 9-month period. FINDINGS: In the development phase, 343 suspected stroke patients were assessed (159 stroke, 167 non-stroke, 32 with TIA [17 with symptoms when seen in ER]). Common stroke mimics were seizures (23%), syncope (23%), and sepsis (10%). A seven-item (total score from -2 to +5) stroke recognition instrument was constructed on the basis of clinical history (loss of consciousness, convulsive fits) and neurological signs (face, arm, or leg weakness, speech disturbance, visual field defect). When internally validated at a cut-off score greater than zero, the instrument showed a diagnostic sensitivity of 92%, specificity of 86%, positive predictive value (PPV) of 88%, and negative predictive value (NPV) of 91%. Prospective validation in 173 consecutive suspected stroke referrals (88 stroke, 59 non-stroke, 26 with TIA [13 with symptoms]) showed sensitivity of 93% (95% CI 89-97), specificity 83% (77-89), PPV 90% (85-95), and NPV 88% (83-93). The ROSIER scale had greater sensitivity than existing stroke recognition instruments in this population. INTERPRETATION: The ROSIER scale was effective in the initial differentiation of acute stroke from stroke mimics in the ER. Introduction of the instrument improved the appropriateness of referrals to the stroke team.