Recruitment to trials of late thrombolysis: Lessons from the EXTEND study

To increase the percentage of acute stroke patients benefiting from thrombolysis, the utility of expanding the time window of treatment beyond 4.5 hours after stroke onset needs to be investigated. We aimed to identify the target population and the challenges of recruitment of patients for the time window beyond 4.5 hours. Extending the time for Thrombolysis in Emergency Neurological Deficits (EXTEND), a multicentre randomised controlled trial testing the efficacy of thrombolytic therapy in patients with clinically significant ischaemic penumbra between 4.5 to 9 hours after stroke onset, was used as a model to evaluate inclusion and exclusion criteria for late thrombolysis trials. Data from all stroke patients admitted to Austin Health over a 1 year period were retrospectively analysed. Case notes were examined to determine potential trial eligibility. Of 556 patients assessed, 95 (17%) presented during the EXTEND time window. Sixty-seven of these (70.5%) were wake-up strokes (WUS) and 28 (29.5%) arrived between 4.5 and 9 hours after symptoms onset. At least one exclusion criterion was found for 78 (82%) of them. Hence, 17 (3%) patients arrived within an appropriate time frame for the study without any exclusion criteria. Most of these (13) arrived outside routine MRI hours. The number of patients recruited would have increased more than three-fold if imaging had been available 24 hours, 7 days a week. A significant proportion (17%) of ischaemic stroke patients presented between 4.5 and 9 hours after stroke onset. The majority of these were WUS. The major challenge identified for patient recruitment was imaging availability

Acute Stroke Biomarkers: Are We There Yet?

Background: Distinguishing between stroke subtypes and knowing the time of stroke onset are critical in clinical practice. Thrombolysis and thrombectomy are very effective treatments in selected patients with acute ischemic stroke. Neuroimaging helps decide who should be treated and how they should be treated but is expensive, not always available and can have contraindications. These limitations contribute to the under use of these reperfusion therapies. Aim: An alternative approach in acute stroke diagnosis is to identify blood biomarkers which reflect the body's response to the damage caused by the different types of stroke. Specific blood biomarkers capable of differentiating ischemic from hemorrhagic stroke and mimics, identifying large vessel occlusion and capable of predicting stroke onset time would expedite diagnosis and increase eligibility for reperfusion therapies. Summary of Review: To date, measurements of candidate biomarkers have usually occurred beyond the time window for thrombolysis. Nevertheless, some candidate markers of brain tissue damage, particularly the highly abundant glial structural proteins like GFAP and S100β and the matrix protein MMP-9 offer promising results. Grouping of biomarkers in panels can offer additional specificity and sensitivity for ischemic stroke diagnosis. Unbiased "omics" approaches have great potential for biomarker identification because of greater gene, protein, and metabolite coverage but seem unlikely to be the detection methodology of choice because of their inherent cost. Conclusion: To date, despite the evolution of the techniques used in their evaluation, no individual candidate or multimarker panel has proven to have adequate performance for use in an acute clinical setting where decisions about an individual patient are being made. Timing of biomarker measurement, particularly early when decision making is most important, requires urgent and systematic study