Alteplase Is Beneficial in Patients With Unknown Stroke Onset


A net benefit was observed for all functional outcomes across the entire range of the modified Rankin Scale despite an increased risk of symptomatic intracranial hemorrhage.

Gotz Thomalla, MD

Results from a systematic review and meta-analysis of individual patient data from 4 trials demonstrated that intravenous alteplase resulted in better functional outcome at 90 days compared with placebo or standard care in patients who have had a stroke with unknown time of onset.

Lead author Gotz Thomalla, MD, department of neurology, University Medical Center Hamburg-Eppendorf, and colleagues documented that favorable outcome, defined as a score of 0–1 on the modified Rankin Scale (mRS) occurred in 199 (47%) of 420 patients treated with alteplase compared to 160 (39%) of 409 controls (adjusted odds ratio [aOR], 1.49; 95% CI, 1.10–2.03).

"This individual patient data meta-analysis extends the evidence from individual trials and supports the use of imaging biomarkers to guide treatment with intravenous alteplase in patients with stroke with an unknown time of onset,” Thomalla et al concluded.

Investigators pulled data from the WAKE-UP (NCT01525290), EXTEND (NCT01580839), THAWS (NCT02002325), and ECASS-4 trials, all of which compared intravenous alteplase versus standard of care or placebo in adults with stroke with unknown time of onset using perfusion-diffusion magnetic resonance imaging (MRI), perfusion computerized tomography (CT), or MRI with diffusion weighted imaging-fluid attenuated inversion recovery (DWI-FLAIR) mismatch.

READ MORE: Reperfusion Benefits for Stroke Are Consistent Across Time Windows

In their effort to establish whether intravenous alteplase is safe and effective in such patients, Thomalla and colleagues found the treatment to be associated with a significant shift towards better functional outcome (common aOR, 1.38; 95% CI, 1.05–1.80), and a higher odds of independent outcome (aOR, 1.50; 95% CI, 1.06–2.12; P = .022).

The proportion of patents who reached functional independence (mRS score 0–2) at 90 days was also significantly higher in the alteplase group than in the control group (aOR, 1.50; 95% CI, 1.06–2.12; P = .022).

Safety outcomes included death, severe disability or death (mRS score 4–6), and symptomatic intracranial hemorrhage. Severe disability or death occurred in 90 (21%) patients in the alteplase group, compared with 102 (25%) patients in the control group (aOR, 0.76; 95% CI, 0.52–1.11; P = .15).

At 90 days, death was reported in 27 (6%) patients in the alteplase group compared with 14 (3%) patients in the control group (aOR, 2.06; 95% CI, 1.03–4.09; P = .040). Symptomatic intracranial hemorrhage, recurrent or progressive stroke, and unknown cause represented 7, 4, and 2 of the deaths in the alteplase group, respectively. The remaining 14 were attributable to non-neurological cause and unrelated to treatment or index stroke. In the control group, all 14 deaths were of non-neurological cause and unrelated to treatment or index stroke.

The investigators noted that the prevalence of symptomatic intracranial hemorrhage was higher in the alteplase group than among controls (11 [3%] vs 2 [<1%]; aOR, 5.58; 95% CI, 1.22–25.50; P = .024).

There was no observed evidence of heterogeneity of treatment effect across any of the subgroups for mortality. This included variables such as dose of alteplase (0.9 vs 0.6 mg/kg bodyweight), age (≤60 years vs >60 years), sex, baseline stroke severity, any vessel occlusion, large vessel occlusion, imaging modality (CT vs MRI), history of atrial fibrillation, previous antiplatelet use, delay from symptom recognition to treatment (≤3 hours vs >3 hours), penumbral mismatch present, or DWI-FLAIR mismatch present.

Researchers did not conduct a subgroup analysis on symptomatic intracranial hemorrhage and parenchymal hemorrhage type 2 due to the overall small numbers.

The mean age of patients within the combined data was 68.5 years (standard deviation, 12.5). Waking from overnight sleep was the reason for unknown symptom onset in 751 patients (89%), and the median time from last seen well to symptom recognition was 7.0 hours (interquartile range, 5.0–9.0).

The meta-analysis did have notable limitations. Drawing inference on the possible effects of the different dose of alteplase cannot be done, as the THAWS trial was the only trial that used the lower dose of 0.6 mg/kg bodyweight. Therefore, investigators could not separate a possible interaction of treatment effect with alteplase dose from overall trial effects.

Thomalla G, Boutitie F, Ma H, et al. intravenous alteplase for stroke with unknown time of onset guided by advanced imaging: systematic review and meta-analysis of individual patient data. Lancet Neurol. Published online November 8, 2020. doi: 10.1016/S0140-6736(20)32161-2
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