Sohei Yoshimura, MD, PhD

Koga M, Yamamoto H, Inoue M, Asakura K, Aoki J, Hamasaki T, Kanzawa T, Kondo R, Ohtaki M, Itabashi R, et al. Thrombolysis With Alteplase at 0.6 mg/kg for Stroke With Unknown Time of Onset: A Randomized Controlled Trial. Stroke. 2020;51:1530–1538.

The guidelines of the American Heart Association/American Stroke Association recommend MRI to identify diffusion-positive FLAIR-negative lesions (DWI-FLAIR mismatch) for selecting patients who can benefit from IV alteplase in acute ischemic stroke (AIS) patients who awake with stroke symptoms or have unclear time of onset > 4.5 hours from last known well.1 The efficacy and safety of IV alteplase for these patients was revealed by the WAKE-UP trial.2

In the WAKE-UP trial, a favorable outcome defined by mRS 0 to 1 at 90 days was achieved in 53.3% in the alteplase group and 41.8% in the placebo group (adjusted odds ratio, 1.61; 95% confidence interval [CI], 1.09 to 2.36; P = 0.02). The trial was stopped early for lack of funding, and there was numerically more death (4.1% vs 1.2%, P=0.07) and significantly more symptomatic intracranial hemorrhage (sICH) (2.0% vs. 0.4%, P= 0.15). So, there still have been some concerns about safety of the therapy.

In Japan, a different alteplase dose of 0.6 mg/kg is only available for patients with AIS. The THAWS trial was conducted to test whether the low-dose IV alteplase is effective and safe in patients with AIS with an unknown time of onset who had DWI-FLAIR mismatch. Following the early stop and positive results of the WAKE-UP trial, this trial was prematurely terminated. In contrast to the WAKE-UP trial, favorable outcome was comparable between the alteplase group and the control group (47.1% vs. 48.3%; relative risk [RR], 0.97 [95% CI, 0.68–1.41]; P=0.892), and the proportion of sICH and death did not differ between groups.

The differences of study design between WAKE-UP and THAWS include blind method and alteplase dose. Open treatment design of the THAWS trial allowed early initiation of antithrombotic therapy for the control group, that might cause a better-than-expected outcome for the control group. Actually, antithrombotic therapy was initiated in 13% of alteplase treated patients versus 85% of control patients within the initial 24 hours. Regarding the safety outcome, low-dose of 0.6 mg/kg alteplase might be superior to that at 0.9mg/kg.

One of the clinical implications of their findings is that alteplase at 0.6 mg/kg for MRI-selected AIS patients with unknown time of onset was safe. However, efficacy of low-dose alteplase for these patients is still uncertain. Currently, meta-analysis of individual patient data of 4 randomized trials (WAKE-UP, EXTEND, THAWS, ECASS-4) enrolling patients with unknown onset stroke is being conducted. The results are eagerly awaited.

Another intriguing issue is adding endovascular therapy with this therapy. During the registration period of the THAWS trial, mechanical thrombectomy became standard treatment for AIS with large vessel occlusion. Thereafter, patients with major artery occlusion might be excluded at the initial assessment, and neurological severity of enrolled patients might shift to a milder population. Clinical practice data and well-designed trials are needed to identify the efficacy of the combination therapy.


1) Powers WJ, et al. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2019 Dec;50(12):e344-e418. doi: 10.1161/STR.0000000000000211. Epub 2019 Oct 30.

2) Thomalla G, et al; WAKE-UP Investigators. MRI-Guided thrombolysis for stroke with unknown time of onset. N Engl J Med. 2018;379:611–622. doi: 10.1056/NEJMoa1804355