WAKE-UP Trial Summary
The WAKE-UP trial aimed to investigate the potential benefits of intravenous alteplase, a thrombolytic agent, in treating acute stroke patients with an unknown time of onset. Current guidelines recommend intravenous thrombolysis only if the time since symptom onset is less than 4.5 hours. However, the trial sought to determine whether patients with stroke who exhibited features of recent cerebral infarction on magnetic resonance imaging (MRI) but had an unknown time of onset could still benefit from thrombolysis.
In this multicenter trial, patients with stroke of unknown onset time were randomly assigned to receive either intravenous alteplase or placebo. All patients had an ischemic lesion visible on MRI diffusion-weighted imaging but no parenchymal hyperintensity on fluid-attenuated inversion recovery (FLAIR), indicating that the stroke likely occurred within the previous 4.5 hours. Patients scheduled for thrombectomy were excluded from the study. The primary outcome measure was a favorable outcome defined as a score of 0 or 1 on the modified Rankin scale, which assesses neurologic disability, at 90 days. A secondary outcome measure was the likelihood of alteplase leading to lower ordinal scores on the modified Rankin scale compared to placebo (shift analysis).
The trial was halted prematurely due to funding discontinuation after enrolling 503 patients out of the planned 800. Among the enrolled patients, 254 were randomly assigned to the alteplase group, while 249 received placebo. At 90 days, a favorable outcome was observed in 131 of 246 patients (53.3%) in the alteplase group and in 102 of 244 patients (41.8%) in the placebo group (adjusted odds ratio, 1.61; 95% confidence interval [CI], 1.09 to 2.36; P=0.02). The median score on the modified Rankin scale at 90 days was 1 in the alteplase group and 2 in the placebo group (adjusted common odds ratio, 1.62; 95% CI, 1.17 to 2.23; P=0.003). The alteplase group experienced 10 deaths (4.1%), whereas the placebo group had 3 deaths (1.2%) (odds ratio, 3.38; 95% CI, 0.92 to 12.52; P=0.07). The rate of symptomatic intracranial hemorrhage was 2.0% in the alteplase group and 0.4% in the placebo group (odds ratio, 4.95; 95% CI, 0.57 to 42.87; P=0.15).
In conclusion, the WAKE-UP trial demonstrated that in patients with acute stroke and an unknown time of onset, intravenous alteplase guided by a mismatch between diffusion-weighted imaging and FLAIR in the ischemic region resulted in significantly improved functional outcomes at 90 days compared to placebo. However, it should be noted that there were slightly more instances of intracranial hemorrhage in the alteplase group. These findings suggest that alteplase may be beneficial in this patient population, but careful consideration of the risk-benefit profile is warranted when deciding on thrombolytic therapy.