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

Abstract

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.

IV thrombolysis for treatment of patients with stroke upon awakening

“…In a study evaluating the safety and efficacy of IV thrombolysis for patients with wake-up stroke, Hill et al 26 were able to enroll only 20 of 89 screened patients; 19 patients were excluded because well-defined strokes were already present on the initial CT scan. Based on the experience at one EXTEND center, Dagonnier et al 27 found that 70.5% of the 95 patients screened for the trial had wake-up strokes, but only 17 patients had no other exclusion criterion for treatment. Based on these experiences and that of the AbESTT-II, researchers should anticipate that the rates of recruitment in the trials will be slower than expected.…”

Are the current MRI criteria using the DWI-FLAIR mismatch concept for selection of patients with wake-up stroke to thrombolysis excluding too many patients?

“…Ongoing trials selecting patients either with WUS (WAKE-UP trial) or beyond the 4.5 time window (EXTEND trial) based on identification of significant salvageable brain tissue may further contribute to better select patients profiting from IVT [ 24 , 25 ].…”