MILAN, Italy — A Japanese trial of low-dose thrombolysis — alteplase (tPA 0.6mg/kg) — has shown neutral results in patients with an unknown time of acute stroke, a so-called "wake-up" stroke, who were selected with imaging patterns suggesting recent onset.
The THAWS study showed no evidence of benefit but also no evidence of harm with use of the 0.6mg/kg dose of alteplase — the dose recommended in Japan.
However, the trial was stopped early due to the positive results of the WAKE-UP trial, reported last year, which showed better outcomes with the regular 0.9mg/kg dose of alteplase in acute stroke patients with unknown time of onset also identified by suitable imaging.
The THAWS trial results were presented at last week's 5th European Stroke Organisation Conference (ESOC) 2019 in Milan by Manabu Inoue, MD, of the National Cerebral and Cardiovascular Center in Osaka, Japan.
"The early halt of THAWS with less than half the number of patients planned precludes any definitive conclusions being drawn," Inoue said.
"But several factors may account for differences in results between the WAKE-UP trial and the THAWS trial," Inoue commented to Medscape Medical News.
"In addition to the premature termination, in THAWS antithrombotic medication was given straight after randomization in the control arm whereas this was not the case in WAKE-UP. The positive late thrombectomy trials also had a large impact in Japan and we believe a number of potential THAWS trial candidates were taken to the cath lab," he said. "And there is obviously the different doses of alteplase used."
Inoue explained that alteplase 0.6mg/kg is the recommended dose of alteplase for stroke in Japan based on a single-arm open-label study, and subsequently the 0.6mg/kg dose showed similar efficacy to the 0.9mg/kg dose in the ENCHANTED study.
"From the last year's WAKE-UP trial results, the Japanese stroke guidelines already list the use of wake-up tPA as class 3 evidence (no harm but no domestic evidence yet) before we got the results for THAWS, so it is possible to use wake-up tPA in Japan."
"But our trial has shown safety of the 0.6mg/kg dose in wake-up population so I think the Japanese strategy will be to extrapolate the WAKE UP trial results to the 0.6mg/kg dose."
The THAWS trial was an investigator-initiated, multicenter, randomized, open label, blinded endpoint study in patients with unknown time of stroke onset but with diffusion-weighted imaging (DWI) fluid-attenuated inversion recovery (FLAIR) mismatch.
DWI-FLAIR mismatch means that an acute ischemic lesion is visible on DWI, but not on FLAIR images, which is believed to correlate with a high likelihood that the stroke occurred within the therapeutic time window (4.5 hours) for thrombolysis.
The THAWS trial planned to randomize 300 such patients to treatment with alteplase (0.6mg/kg) or standard medical treatment (control). Inoue noted that standard medical treatment comprised one to three antithrombotic drugs including aspirin, clopidogrel, argatroban, and heparin.
The trial was prematurely stopped after 131 patients (44% of the planned total) were enrolled.
Results showed no difference in functional outcome scores at 3 months. Favorable outcomes (mRS 0 - 2) occurred in 59% of the alteplase group versus 60% of the control group (odds ratio, 0.97; P = .862).
In terms of safety, symptomatic ICH occurred in one patient in the alteplase group and zero in the control group (P = 1.0). There were two deaths in each group (P = 1.0).
Support for Efficacy
Commenting on the study for Medscape Medical News was Bruce Campbell, MD, University of Melbourne, Australia, who was involved in the recent EXTEND trial of late thrombolysis in stroke.
"I think it is reasonable for the Japanese to use alteplase in wake-up patients based on the WAKE-UP trial," Campbell said. "Their trial didn't show support for efficacy but unfortunately that's what often happens when trials are stopped early."
On the issue of the dosage, Campbell said: "There have been studies comparing alteplase doses of 0.6mg/kg and 0.9mg/kg, and while these have formally not met noninferiority criteria, they have shown generally similar results, so I would not suspect that is the reason for the difference in results between THAWS and WAKE-UP."
European Stroke Organisation Conference (ESOC) 2019: MRI-Guided Thrombolysis With Alteplase at 0.6mg/Kg for Stroke With Unknown Time of Onset: THAWS Randomized Controlled Trial. Presented May 22, 2019.
Medscape Medical News © 2019
Cite this: Sue Hughes. THAWS: Neutral Result in 'Wake-up' Stroke With Low-Dose tPA - Medscape - May 29, 2019.