1. In patients who had a stroke with unknown time of onset and DWI-FLAIR or perfusion mismatch, IV alteplase resulted in better functional outcomes at 90 days compared to placebo or current standard care.
2. The prevalence of severe disability or death was lower with IV alteplase, but was also associated with increased risk of symptomatic intracranial hemorrhage and higher mortality.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Thrombolysis with intravenous alteplase is the current standard of care for acute ischemic stroke. Treatment with alteplase has traditionally been reserved for patients with known time of symptom onset, but in approximately 20-25% of patients with stroke, time of symptom onset is unknown. However, several individual trials utilizing imaging biomarkers to select patients with unknown time of stroke onset for IV thrombolysis have shown promise with net clinical benefit. This systematic review and meta-analysis included individual patient data from four randomized-controlled trials comparing IV alteplase with placebo or standard of care in adults with stroke of unknown time of onset. Patients were selected using imaging biomarkers (MRI diffusion weighted imaging-fluid attenuated inversion recovery [DWI-FLAIR] mismatch or perfusion CT/MRI based penumbral imaging) to help identify salvageable tissue. Treatment with alteplase was associated with significantly improved functional outcomes including functional independence at 90 days compared to control. Additionally, a net benefit across all functional outcomes was observed with thrombolysis despite an increased risk of symptomatic intracranial hemorrhage and higher mortality. Prevalence of severe disability or death was lower with IV alteplase. This study was limited by the overall small number of patients included in the meta-analysis allowing for limited conclusions to be drawn from sub-group analysis. Additionally, the conclusions of this meta-analysis may be driven by the results of the WAKE-UP trial which represented most patients included in the analysis.
Relevant Reading: MRI-Guided Thrombolysis for Stroke with Unknown Time of Onset
In-Depth [systematic review]: This systematic review and meta-analysis included individual patient data from four randomized-controlled trials comparing IV alteplase with placebo or standard of care in adults with stroke of unknown time of onset and imaging mismatch (perfusion-diffusion MRI, perfusion CT or MRI with DWI-FLAIR). The primary outcome was defined as a favourable score of 0-1 on the modified Rankin Scale (mRS) to identify patients with no symptoms or minimal symptoms with no functional disability at 90 days after stroke.
A total of four trials met the inclusion criteria with individual patient data for 843 patients (mean age = 68.5 years; 38% female) included in the analysis. Overall, a favorable outcome (mRS score 0-1) at 90 days was observed in 199 of 420 (47%) patients in the alteplase group and in 160 of 409 (39%) patients in the control group (adjusted odds ratio [OR] 1.49, 95% CI 1.10 to 2.03; p=0.011) with low heterogeneity across studies (I2=27%). Alteplase treatment was associated with improved functional outcomes with lower mRS scores (adjusted common OR 1.38, 95% CI 1.05 to 1.80; p=0.019) and increased proportion of patients who reached functional independence (mRS score 0-2) at 90 days (adjusted OR 1.50, 95% CI 1.06 to 2.12; p=0.022) compared to control. In the alteplase group, 21% of patients were severely disabled or died (mRS score 4-6) compared to 25% of patients in the control group (adjusted OR 0.76, 95% CI 0.52 to 1.11; p=0.14). However, overall, 6% of patients died in the alteplase group compared to 3% among controls (adjusted OR 2.06, 95% CI 1.03 to 4.09; p=0.040) Patients receiving alteplase had a higher overall prevalence of symptomatic intracranial hemorrhage compared to controls (3% vs <1%, adjusted OR 5.58, 95% CI 1.22 to 25.50; p=0.024). Overall, study findings suggest that IV alteplase in patients with a stroke of unknown time of onset (with a DWI-FLAIR or perfusion mismatch) is associated with improved functional outcomes and functional independence.
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