THrombolysis for Acute Wake-up and unclear-onset Strokes with alteplase at 0·6 mg/kg (THAWS) Trial

Masatoshi Koga, Kazunori Toyoda, Kazumi Kimura, Haruko Yamamoto, Makoto Sasaki, Toshimitsu Hamasaki, Takanari Kitazono, Junya Aoki, Kenta Seki, Kazunari Homma, Shoichiro Sato, Kazuo Minematsu, THAWS investigators, Kazuo Minematsu, Kazunori Toyoda, Kazumi Kimura, Haruko Yamamoto, Masatoshi Koga, Junya Aoki, Toshimitsu Hamasaki, Kazumi Kimura, Masatoshi Koga, Shoichiro Sato, Kazunori Toyoda, Toshimitsu Hamasaki, Toshisuke Otsuki, Wataru Shimizu, Takashi Sozu, Makoto Sasaki, Teruyuki Hirano, Kohsuke Kudo, Naomi Morita, Ken Kuwahara, Sohei Yoshimura, Shoichiro Sato, Kazunari Homma, Kenta Seki, Haruka Kanai, Azusa Tokunaga, Kazunori Toyoda, Kazuyuki Nagatsuka, Haruko Yamamoto, Masatoshi Koga, Hiroshi Yamagami, Shoichiro Sato, Kazunari Homma, Kenta Seki, Kazumi Kimura, Junya Aoki, Masafumi Ohtaki, Kamiyama Kenji, Metoki Norifumi, Eisuke Furui, Rei Kondo, Hiroshi Mochizuki, Shuichi Igarashi, Ban Mihara, Tomoaki Kameda, Norio Tanahashi, Ichiro Deguchi, Takao Urabe, Nobutaka Hattori, Yasuyuki Iguchi, Yoshikazu Uesaka, Yoshiaki Shiokawa, Denbo Norihisa, Yasuhiro Hasegawa, Shunya Takizawa, Jin Yoshii, Yasuhiro Ito, Satoshi Okuda, Yoshinari Nagakane, Shinichi Yoshimura, Nobuyuki Sakai, Kenichi Todo, Hideyuki Ohnishi, Tsuyoshi Inoue, Hideo Ohyama, Ichiro Nakahara, Shigeru Fujimoto, Kenichiro Fujii, Sohei Yoshimura, Yasushi Okada, Takeshi Uwatoko, Akira Tsujino, Toshiro Yonehara, Tadashi Terasaki, Masatoshi Koga, Kazunori Toyoda, Kazumi Kimura, Haruko Yamamoto, Makoto Sasaki, Toshimitsu Hamasaki, Takanari Kitazono, Junya Aoki, Kenta Seki, Kazunari Homma, Shoichiro Sato, Kazuo Minematsu, THAWS investigators, Kazuo Minematsu, Kazunori Toyoda, Kazumi Kimura, Haruko Yamamoto, Masatoshi Koga, Junya Aoki, Toshimitsu Hamasaki, Kazumi Kimura, Masatoshi Koga, Shoichiro Sato, Kazunori Toyoda, Toshimitsu Hamasaki, Toshisuke Otsuki, Wataru Shimizu, Takashi Sozu, Makoto Sasaki, Teruyuki Hirano, Kohsuke Kudo, Naomi Morita, Ken Kuwahara, Sohei Yoshimura, Shoichiro Sato, Kazunari Homma, Kenta Seki, Haruka Kanai, Azusa Tokunaga, Kazunori Toyoda, Kazuyuki Nagatsuka, Haruko Yamamoto, Masatoshi Koga, Hiroshi Yamagami, Shoichiro Sato, Kazunari Homma, Kenta Seki, Kazumi Kimura, Junya Aoki, Masafumi Ohtaki, Kamiyama Kenji, Metoki Norifumi, Eisuke Furui, Rei Kondo, Hiroshi Mochizuki, Shuichi Igarashi, Ban Mihara, Tomoaki Kameda, Norio Tanahashi, Ichiro Deguchi, Takao Urabe, Nobutaka Hattori, Yasuyuki Iguchi, Yoshikazu Uesaka, Yoshiaki Shiokawa, Denbo Norihisa, Yasuhiro Hasegawa, Shunya Takizawa, Jin Yoshii, Yasuhiro Ito, Satoshi Okuda, Yoshinari Nagakane, Shinichi Yoshimura, Nobuyuki Sakai, Kenichi Todo, Hideyuki Ohnishi, Tsuyoshi Inoue, Hideo Ohyama, Ichiro Nakahara, Shigeru Fujimoto, Kenichiro Fujii, Sohei Yoshimura, Yasushi Okada, Takeshi Uwatoko, Akira Tsujino, Toshiro Yonehara, Tadashi Terasaki

Abstract

Rationale: Because of lack of information regarding timing of stroke, patients who suffer stroke during sleep are generally ineligible for intravenous thrombolysis, although many of these patients could potentially recover with this treatment. Magnetic resonance image findings with positive diffusion-weighted imaging and no marked parenchymal hyperintensity on fluid-attenuated inversion recovery (negative pattern) can identify acute ischemic stroke patients within 4·5 h from symptom onset.

Aims: The THrombolysis for Acute Wake-up and unclear-onset Strokes with alteplase at 0·6 mg/kg trial aims to determine the efficacy and safety of intravenous thrombolysis with alteplase at 0·6 mg/kg body weight, the approved dose for Japanese stroke patients, using magnetic resonance image-based selection in ischemic stroke patients with unclear time of symptom onset, and compare findings with standard treatment.

Design: This is an investigator-initiated, multicenter, prospective, randomized, open-treatment, blinded-end-point clinical trial. The design is similar to the Efficacy and Safety of MRI-based Thrombolysis in Wake-up Stroke trial. Patients with unclear-onset time of stroke symptoms beyond 4·5 h and within 12 h after the time of the last-known-well period and within 4·5 h after symptom recognition, who showed a negative fluid-attenuated inversion recovery pattern, are randomized to either intravenous thrombolysis or standard treatment.

Study outcomes: The primary efficacy end-point is modified Rankin Scale 0-1 at 90 days. The safety outcome measures are symptomatic intracranial hemorrhage at 22-36 h, and major bleeding and mortality at 90 days.

Discussion: This trial may help determine if low-dose alteplase at 0·6 mg/kg should be recommended as a routine clinical strategy for ischemic stroke patients with unclear-onset time.

Trial registration: ClinicalTrials.gov NCT02002325.

Keywords: acute ischemic stroke; clinical trials; diffusion-weighted imaging; fluid-attenuated inversion recovery imaging; thrombolysis; unclear-onset time.

© 2014 World Stroke Organization.

Figures

Fig. 1
Fig. 1
Thrombolysis for Acute Wake-up and unclear-onset Strokes with alteplase at 0·6 mg/kg (THAWS) trial flow chart. AEs, adverse events; ASPECTS, the Alberta Stroke Program Early CT Score; CT, computed tomography; DWI, diffusion-weighted imaging; FLAIR, fluid-attenuated inversion recovery; i.v., intravenous; MRI, magnetic resonance imaging; NIHSS, National Institutes of Health Stroke Scale; mRS, modified Rankin Scale; rt-PA, recombinant tissue-type plasminogen activator.
Fig. 2
Fig. 2
Examples of magnetic resonance imaging (MRI) inclusion and exclusion criteria. (a) A negative fluid-attenuated inversion recovery (FLAIR) pattern shows an acute ischemic lesion clearly visible on diffusion-weighted imaging (DWI), but no marked parenchymal hyperintensity visible on fluid-attenuated inversion recovery (FLAIR) corresponding to the DWI lesion (yellow circles). (b) A positive FLAIR pattern shows an acute ischemic lesion clearly visible on DWI and clear parenchymal hyperintensity on FLAIR corresponding to the acute DWI lesion (yellow circle).

References

    1. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008;359:1317–1329.
    1. Lees KR, Bluhmki E, von Kummer R, et al. Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Lancet. 2010;375:1695–1703.
    1. Mackey J, Kleindorfer D, Sucharew H, et al. Population-based study of wake-up strokes. Neurology. 2011;76:1662–1667.
    1. Kang DW, Kwon JY, Kwon SU, Kim JS. Wake-up or unclear-onset strokes: are they waking up to the world of thrombolysis therapy? Int J Stroke. 2012;7:311–320.
    1. Koton S, Tanne D, Bornstein NM. Ischemic stroke on awakening: patients' characteristics, outcomes and potential for reperfusion therapy. Neuroepidemiology. 2012;39:149–153.
    1. Todo K, Moriwaki H, Saito K, Tanaka M, Oe H, Naritomi H. Early CT findings in unknown-onset and wake-up strokes. Cerebrovasc Dis. 2006;21:367–371.
    1. Serena J, Davalos A, Segura T, Mostacero E, Castillo J. Stroke on awakening: looking for a more rational management. Cerebrovasc Dis. 2003;16:128–133.
    1. Marsh EE, 3rd, Biller J, Adams HP, Jr, et al. Circadian variation in onset of acute ischemic stroke. Arch Neurol. 1990;47:1178–1180.
    1. Aoki J, Kimura K, Iguchi Y, Shibazaki K, Sakai K, Iwanaga T. FLAIR can estimate the onset time in acute ischemic stroke patients. J Neurol Sci. 2010;293:39–44.
    1. Thomalla G, Rossbach P, Rosenkranz M, et al. Negative fluid-attenuated inversion recovery imaging identifies acute ischemic stroke at 3 hours or less. Ann Neurol. 2009;65:724–732.
    1. Petkova M, Rodrigo S, Lamy C, et al. MR imaging helps predict time from symptom onset in patients with acute stroke: implications for patients with unknown onset time. Radiology. 2010;257:782–792.
    1. Minematsu K, Li L, Fisher M, Sotak CH, Davis MA, Fiandaca MS. Diffusion-weighted magnetic resonance imaging: rapid and quantitative detection of focal brain ischemia. Neurology. 1992;42:235–240.
    1. Ebinger M, Galinovic I, Rozanski M, Brunecker P, Endres M, Fiebach JB. Fluid-attenuated inversion recovery evolution within 12 hours from stroke onset: a reliable tissue clock? Stroke. 2009;41:250–255.
    1. Aoki J, Kimura K, Iguchi Y, et al. Intravenous thrombolysis based on diffusion-weighted imaging and fluid-attenuated inversion recovery mismatch in acute stroke patients with unknown onset time. Cerebrovasc Dis. 2011;31:435–441.
    1. Aoki J, Kimura K, Shibazaki K, Sakamoto Y. Negative fluid-attenuated inversion recovery- based intravenous thrombolysis using recombinant tissue plasminogen activator in acute stroke patients with unknown onset time. Cerebrovasc Dis Extra. 2013;3:35–45.
    1. Barreto AD, Martin-Schild S, Hallevi H, et al. Thrombolytic therapy for patients who wake-up with stroke. Stroke. 2009;40:827–832.
    1. Cho AH, Sohn S-I, Han M-K, et al. Safety and efficacy of MRI-based thrombolysis in unclear-onset stroke. Cerebrovasc Dis. 2008;25:572–579.
    1. Breuer L, Schellinger PD, Huttner HB, et al. Feasibility and safety of magnetic resonance imaging-based thrombolysis in patients with stroke on awakening: initial single-centre experience. Int J Stroke. 2010;5:68–73.
    1. Ebinger M, Scheitz JF, Kufner A, Endres M, Fiebach JB, Nolte CH. MRI-based intravenous thrombolysis in stroke patients with unknown time of symptom onset. Eur J Neurol. 2012;19:348–350.
    1. Thomalla G, Fiebach JB, Østergaard L, et al. A multicenter, randomized, double-blind, placebo-controlled trial to test efficacy and safety of magnetic resonance imaging-based thrombolysis in wake-up stroke (WAKE-UP) Int J Stroke. 2014;9:829–836.
    1. Ostrem JL, Saver JL, Alger JR, et al. Acute basilar artery occlusion: diffusion-perfusion MRI characterization of tissue salvage in patients receiving intra-arterial stroke therapies. Stroke. 2004;35:e30–34.
    1. Schulman S, Kearon C. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005;3:692–694.
    1. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;333:1581–1587.
    1. Saqqur M, Uchino K, Demchuk AM, et al. Site of arterial occlusion identified by transcranial Doppler predicts the response to intravenous thrombolysis for stroke. Stroke. 2007;38:948–954.
    1. Wahlgren N, Ahmed N, Dávalos A, et al. Thrombolysis with alteplase for acute ischaemic stroke in the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST): an observational study. The Lancet. 2007;369:275–282.
    1. Yamaguchi T, Mori E, Minematsu K, et al. Alteplase at 0.6 mg/kg for acute ischemic stroke within 3 hours of onset: Japan Alteplase Clinical Trial (J-ACT) Stroke. 2006;37:1810–1815.
    1. Toyoda K, Koga M, Naganuma M, et al. Routine use of intravenous low-dose recombinant tissue plasminogen activator in Japanese patients: general outcomes and prognostic factors from the SAMURAI register. Stroke. 2009;40:3591–3595.
    1. Kang DW, Sohn SI, Hong KS, et al. Reperfusion therapy in unclear-onset stroke based on MRI evaluation (RESTORE): a prospective multicenter study. Stroke. 2012;43:3278–3283.
    1. Chao AC, Hsu HY, Chung CP, et al. Outcomes of thrombolytic therapy for acute ischemic stroke in Chinese patients: the Taiwan Thrombolytic Therapy for Acute Ischemic Stroke (TTT-AIS) study. Stroke. 2010;41:885–890.

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