Thrombolysis With Alteplase at 0.6 mg/kg for Stroke With Unknown Time of Onset: A Randomized Controlled Trial

Masatoshi Koga, Haruko Yamamoto, Manabu Inoue, Koko Asakura, Junya Aoki, Toshimitsu Hamasaki, Takao Kanzawa, Rei Kondo, Masafumi Ohtaki, Ryo Itabashi, Kenji Kamiyama, Toru Iwama, Taizen Nakase, Yusuke Yakushiji, Shuichi Igarashi, Yoshinari Nagakane, Shunya Takizawa, Yasushi Okada, Ryosuke Doijiri, Akira Tsujino, Yasuhiro Ito, Hideyuki Ohnishi, Takeshi Inoue, Yasushi Takagi, Yasuhiro Hasegawa, Yoshiaki Shiokawa, Nobuyuki Sakai, Masato Osaki, Yoshikazu Uesaka, Shinichi Yoshimura, Takao Urabe, Toshihiro Ueda, Masafumi Ihara, Takanari Kitazono, Makoto Sasaki, Akira Oita, Sohei Yoshimura, Mayumi Fukuda-Doi, Kaori Miwa, Kazumi Kimura, Kazuo Minematsu, Kazunori Toyoda, THAWS Trial Investigators, Masatoshi Koga, Haruko Yamamoto, Manabu Inoue, Koko Asakura, Junya Aoki, Toshimitsu Hamasaki, Takao Kanzawa, Rei Kondo, Masafumi Ohtaki, Ryo Itabashi, Kenji Kamiyama, Toru Iwama, Taizen Nakase, Yusuke Yakushiji, Shuichi Igarashi, Yoshinari Nagakane, Shunya Takizawa, Yasushi Okada, Ryosuke Doijiri, Akira Tsujino, Yasuhiro Ito, Hideyuki Ohnishi, Takeshi Inoue, Yasushi Takagi, Yasuhiro Hasegawa, Yoshiaki Shiokawa, Nobuyuki Sakai, Masato Osaki, Yoshikazu Uesaka, Shinichi Yoshimura, Takao Urabe, Toshihiro Ueda, Masafumi Ihara, Takanari Kitazono, Makoto Sasaki, Akira Oita, Sohei Yoshimura, Mayumi Fukuda-Doi, Kaori Miwa, Kazumi Kimura, Kazuo Minematsu, Kazunori Toyoda, THAWS Trial Investigators

Abstract

Background and Purpose- We assessed whether lower-dose alteplase at 0.6 mg/kg is efficacious and safe for acute fluid-attenuated inversion recovery-negative stroke with unknown time of onset. Methods- This was an investigator-initiated, multicenter, randomized, open-label, blinded-end point trial. Patients met the standard indication criteria for intravenous thrombolysis other than a time last-known-well >4.5 hours (eg, wake-up stroke). Patients were randomly assigned (1:1) to receive alteplase at 0.6 mg/kg or standard medical treatment if magnetic resonance imaging showed acute ischemic lesion on diffusion-weighted imaging and no marked corresponding hyperintensity on fluid-attenuated inversion recovery. The primary outcome was a favorable outcome (90-day modified Rankin Scale score of 0-1). Results- Following the early stop and positive results of the WAKE-UP trial (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke), this trial was prematurely terminated with 131 of the anticipated 300 patients (55 women; mean age, 74.4±12.2 years). Favorable outcome was comparable between the alteplase group (32/68, 47.1%) and the control group (28/58, 48.3%; relative risk [RR], 0.97 [95% CI, 0.68-1.41]; P=0.892). Symptomatic intracranial hemorrhage within 22 to 36 hours occurred in 1/71 and 0/60 (RR, infinity [95% CI, 0.06 to infinity]; P>0.999), respectively. Death at 90 days occurred in 2/71 and 2/60 (RR, 0.85 [95% CI, 0.06-12.58]; P>0.999), respectively. Conclusions- No difference in favorable outcome was seen between alteplase and control groups among patients with ischemic stroke with unknown time of onset. The safety of alteplase at 0.6 mg/kg was comparable to that of standard treatment. Early study termination precludes any definitive conclusions. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT02002325.

Keywords: control groups; informed consent; intracranial hemorrhages; magnetic resonance imaging; stroke, acute; tissue-type plasminogen activator.

Figures

Figure 1.
Figure 1.
Screening and randomization of patients. FLAIR indicates fluid-attenuated inversion recovery.
Figure 2.
Figure 2.
Distribution of scores on 90-d modified Rankin Scale (intention-to-treat population).
Figure 3.
Figure 3.
Prespecified (A) and additional (B) subgroup analyses: relative risks and 95% CIs for favorable outcome. ASPECTS indicates Alberta Stroke Program Early CT Score; FLAIR, fluid-attenuated inversion recovery; MRA, magnetic resonance angiography; and NIHSS, National Institutes of Health Stroke Scale.

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Source: PubMed

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