Response to Letter by Loh and Sharma
We appreciate the interest of Loh and Sharma in our multicenter observational study on low-dose intravenous (IV) recombinant tissue plasminogen activator (rtPA, 0.6 mg/kg alteplase) for Japanese patients with stroke (Stroke Acute Management with Urgent Risk-factor Assessment and Improvement [SAMURAI] rt-PA Registry).1 In addition to this SAMURAI study, several studies, including the Japan Alteplase Clinical Trial (J-ACT),2 a single-center observational study from our institute,3 and a prospective multicenter observational study (J-ACT II),4 reported that approximately ≥40% of patients with stroke had a modified Rankin Scale score ≤1 at 3 months. Thus, we are certain that low-dose IV rtPA (0.6 mg/kg) for Japanese patients is as effective as standard dose rtPA (0.9 mg/kg) for Western patients. The underlying rationale for the low-dose therapy was published on the Stroke web site for the J-ACT (Supplemental Appendix 2; available at http://stroke.ahajournals.org).2
We recently read a report by Sharma et al5 with great interest; standard dose IV rt-PA for 82 Singaporean patients brought much better 3-month outcome than low-dose IV rtPA (0.9 mg/kg, maximum dose 50 mg) for 48 patients (modified Rankin Scale score ≤1; 59% versus 35%), although a median 3-month National Institutes of Health Stroke Scale score estimated from their table was the same (6 for both) in the 2 groups. To the best of our knowledge, this is the best clinical outcome after standard dose rtPA. We should try a head-to-head comparison of the alteplase dose of 0.9 mg/kg versus 0.6 mg/kg for Japanese patients to ascertain if we could also obtain such a good clinical outcome.
In the Loh and Sharma letter, they discussed that low-dose rtPA results in lower rates of recanalization, causes delayed recanalization, and increases the risk of symptomatic intracerebral hemorrhage. We do not agree with their opinion. In the J-ACT II,4 recanalization of the middle cerebral artery was noted in 51.7% of patients receiving IV rtPA at 0.6 mg/kg on MR angiography 6 hours after stroke onset and in 69.0% on 24-hour MR angiography; these rates exceeded the predetermined value based on previous publications. After logistic regression analysis, recanalization on either 6-hour or 24-hour MR angiography as well as delayed recanalization (ie, arterial occlusion unchanged on 6-hour MR angiography but recanalized on 24-hour MR angiography) was an independent predictor for the 3-month modified Rankin Scale score ≤1. Previous studies reported comparatively low risk of symptomatic intracerebral hemorrhage after low-dose IV rtPA.1–4
As Loh and Sharma proposed, hemorrhagic complication after thrombolysis or antithrombotic therapy is a critical problem for Asian populations.6 We think that there may be much differences in ethnic features and medical circumstances even in the same Asia.
Sources of Funding
SAMURAI rt-PA Registry is supported in part by Grants-in-Aid (H20-Junkanki-Ippan-019) from the Ministry of Health, Labour and Welfare, Japan.
Toyoda K, Koga M, Naganuma M, Shiokawa Y, Nakagawara J, Furui E, Kimura K, Yamagami H, Okada Y, Hasegawa Y, Kario K, Okuda S, Nishiyama K, Minematsu K; for the Stroke Acute Management with Urgent Risk-factor Assessment and Improvement (SAMURAI) Study Investigators. 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.
Yamaguchi T, Mori E, Minematsu K, Nakagawara J, Hashi K, Saito I, Shinohara Y; Japan Alteplase Clinical Trial (J-ACT) Group. Alteplase at 0.6 mg/kg for acute ischemic stroke within 3 hours of onset: Japan Alteprase Clinical Trial. Stroke. 2006; 37: 1810–1815.
Mori E, Minematsu K, Nakagawara J, Yamaguchi T, Sasaki M, Hirano T, for the J-ACT II Group. Effects of 0.6 mg/kg intravenous alteplase on vascular and clinical outcomes in middle cerebral artery occlusion: Japan Alteplase Clinical Trial II (J-ACT II). Stroke. 2010; 41: 461–465.