Impact of the Approval of Intravenous Recombinant Tissue Plasminogen Activator Therapy on the Processes of Acute Stroke Management in Japan
The Stroke Unit Multicenter Observational (SUMO) Study
Background and Purpose— The Ministry of Health, Labor, and Welfare of Japan approved the use of recombinant tissue-type plasminogen activator (rt-PA) for the treatment of acute ischemic stroke in October 2005. The impact of the regulatory approval of rt-PA on the processes of acute stroke management was examined.
Methods— A prospective, multicenter, observational study was conducted between December 2004 and December 2005 in 84 Japanese institutes, including 24 institutes with a stroke unit. We enrolled 4620 consecutive patients who were hospitalized within 72 hours after the onset of completed ischemic stroke; 1089 of them were hospitalized after rt-PA was approved. The patients’ characteristics and the processes of stroke management were compared before and after rt-PA approval.
Results— Age, gender, stroke subtype, time from onset to hospital visit, and National Institutes of Health Stroke Scale score on admission were similar between the 2 periods. With approval, the percentage of patients treated with intravenous rt-PA therapy increased from 0.7% to 2.6% (P<0.001). The rate increased from 0.9% to 5.2% in institutes with a stroke unit (P<0.001) but did not increase in other institutes (P=0.587). Within 24 hours of stroke onset, conventional MRI (P=0.003), diffusion-weighted MRI (P<0.001), magnetic resonance angiography (P=0.001), carotid ultrasound (P=0.004), measurement of prothrombin time or activated partial thromboplastin time (P=0.034), and measurement of blood sugar (P=0.015) were performed more frequently after rt-PA approval.
Conclusions— The present results indicate that the approval of intravenous rt-PA therapy resulted in dramatic changes in the processes of management for acute stroke patients.
In the early 1990s, randomized controlled clinical trials performed in Japan showed that intravenous recombinant tissue-type plasminogen activator (rt-PA) therapy using duteplase improved clinical outcomes in ischemic stroke patients treated within 6 hours of symptom onset.1,2 However, the development of duteplase was aborted because of a patent issue. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study using alteplase subsequently demonstrated the clinical benefit of intravenous rt-PA therapy within the initial 3 hours of symptom onset.3 A prospective, multicenter, single-arm, open-label trial using 0.6 mg/kg of alteplase (Japan Alteplase Clinical Trial [J-ACT]) demonstrated that its clinical efficacy and safety were comparable to the results reported from the National Institute of Neurological Disorders and Stroke Study.4 On that basis, the Ministry of Health, Labor, and Welfare of Japan approved the use of rt-PA as a therapy for acute ischemic stroke within 3 hours of onset on October 11, 2005.
Some studies5–10 have sought changes in the processes of acute stroke management after the approval of intravenous rt-PA therapy. To the best of our knowledge, however, no previous report has evaluated changes in the frequency of intravenous thrombolytic therapy and in the processes of acute stroke management in comparison of hospitals with stroke unit (SU) and those without SU. Therefore, we investigated this issue using data from the Stroke Unit Multicenter Observational (SUMO) study.
Patients and Methods
The patient samples for this study were derived from the SUMO study. The SUMO study was a prospective cohort study conducted between December 2004 and December 2005 to identify the processes of acute stroke care that were effective for improving clinical outcome in Japan. Eighty-four representative acute institutes participated in the SUMO study. A total of 6815 consecutive stroke patients who were hospitalized within 72 hours after symptom onset were registered. Of these, 2186 patients with hemorrhagic stroke diagnosed and 9 patients who had inadequate data were ineligible and were excluded from the present study. The study was approved by each institutional Ethics and Hospital Management Committee. Written informed consent to participate in the study was obtained from the patient whenever possible; assent from a relative was obtained if patients could not consent themselves.
Common data forms were prepared. Survey elements included: (1) baseline characteristics including age, gender, history, and vascular risk factors; (2) information relating to acute diagnostic examinations, medical treatment, and clinical care process for the medical treatment; (3) stroke subtype; (4) severity of neurological symptom on admission estimated using the National Institutes of Health stroke scale score; and (5) clinical outcome based on the modified Rankin scale and place of residence 3 months after the onset of stroke. Clinical processes within 24 hours after admission were monitored prospectively on a daily basis by reviewing clinical records and patient observation schedules. Information was gathered primarily by attending doctors in each hospital.
The subjects of this study were divided into 2 groups: patients hospitalized from December 1, 2004 to October 10, 2005 (the preapproval group), and those hospitalized from October 11, 2005 to December 31, 2005 (the postapproval group). According to the meta-analysis by the Stroke Unit Trialists’ Collaboration, service organizations were classified into a 5-category hierarchy in descending order as follows: acute SU, comprehensive SU, mixed rehabilitation ward, mobile stroke team, and general medical ward.11 We categorized the hospitals into 2 groups on the basis of self-certification. Hospitals that had acute SU or comprehensive SU were categorized as hospitals with SU (SU group), and the other hospitals were categorized as hospitals without SU (non-SU group).
Immediately after the approval, the Japan Stroke Society published “A Guideline for Intravenous Application of rt-PA (Alteplase)”.12,13 The institutes participating in the SUMO study have adhered to this guideline in principle.
Statistical analysis was performed using the SPSS 11.0J statistical software package (SPSS Inc). Baseline clinical characteristics were compared using χ2 tests and unpaired t tests, as appropriate. Comparisons of National Institutes of Health stroke scale scores and modified Rankin scale scores were analyzed using the Mann-Whitney U test. P<0.05 was considered as significant.
A total of 4620 patients met the criteria and were included in this analysis. The mean age of these patients was 72±12 years, and 59.9% were men. Of these patients, 1089 (23.6%) were hospitalized after the approval of rt-PA. The proportion of patients treated in SU was 45.0% in the preapproval group and 42.7% in postapproval group. The characteristics of the patients in the preapproval group and the postapproval group are listed in Table 1. None of the demographic and clinical characteristics differed significantly between the 2 groups, except for the frequency of hypertension.
The frequencies of the various processes of acute stroke management before and after rt-PA approval are shown in Table 2. After the approval of rt-PA, the frequencies of conventional MRI (P=0.003), diffusion-weighted MRI (P<0.001), MRA (P=0.001), and carotid ultrasonography (P=0.004) were significantly increased, whereas those of cerebral angiography (P=0.002) and single-photon emission computed tomography (P=0.012) were significantly decreased. Similarly, after the approval of rt-PA, there were significant increases in the rate of measurement of blood sugar (P=0.015), prothrombin time or activated partial thromboplastin time (P=0.034), thrombin-antithrombin III complex (P<0.001), and D-dimer (P=0.003). The frequencies of the processes of acute stroke management before and after rt-PA approval are shown separately divided into SU and non-SU groups in Table 3. There was similar tendency of change in the processes after the approval between the SU and non-SU groups.
The rate of intravenous thrombolytic therapy increased from 0.7% before approval to 2.6% after approval of rt-PA (P<0.001), whereas the rate of intra-arterial thrombolytic therapy was not significantly changed. As shown in the Figure, the rate of intravenous thrombolytic therapy increased from 0.9% to 5.2% in the SU group (P<0.001) but did not increase in the non-SU group (P=0.587).
In this multicenter observational study, we found that the proportion of patients receiving intravenous rt-PA therapy increased after the approval of rt-PA. The increase in the frequency of intravenous rt-PA therapy was notable in institutes having an SU. In addition, this study demonstrated that the approval of rt-PA resulted in changes in the processes of acute stroke management within 24 hours of onset, with increased use of diagnostic imaging and certain laboratory tests.
Weimar et al5 reported that the rate of intravenous thrombolytic therapy in patients with acute ischemic stroke significantly increased from 4.8% before approval to 7.9% after regulatory approval of rt-PA in Germany. Our data are consistent with their report. However, they simply focused on the frequency of thrombolytic therapy. The present study revealed remarkable changes not only in the frequency of thrombolytic therapy but also in the processes of acute stroke management using the data of the prospective study.
A number of diagnostic tests, such as brain imaging (CT or MRI), blood glucose, serum electrolytes, renal function, ECG, markers of cardiac ischemia, complete blood count, prothrombin time, activated partial thromboplastin time, and oxygen saturation, are considered necessary in all patients with suspected ischemic stroke.14 The results of these diagnostic tests have an impact on the diagnosis and the choice of therapeutic options, including thrombolysis. The results of the present study suggest that there have been greater tendencies to make a proper diagnosis and initiate appropriate treatment in the initial 24 hours of hospitalization after approval of rt-PA. Specifically, invasive or time-consuming diagnostic imaging techniques (eg, cerebral angiography, single-photon emission computed tomography) have been replaced by noninvasive or simple techniques (eg, MRA, ultrasonography).
The percentage of intravenous rt-PA therapy increased from 0.9% to 5.2% in the SU group, whereas there was no change in the non-SU group. A previous study reported that patients admitted to an SU had a higher rate of thrombolytic therapy than those treated elsewhere.15 The Japan Stroke Society recommended that it was desirable to perform intravenous rt-PA therapy in institutes with an SU.12,16 The institutes participating in the SUMO study appear to have been following this recommendation.
This study demonstrated that the frequency of hypertension in the postapproval group was significantly higher than that in preapproval group. This result may be associated with better documentation after approval of rt-PA, because this is an important consideration in deciding on treatment.
This study had some limitations. We used a prospective, time series design with no control or randomization. The data may reflect changes in stroke management during the interval of ≈1 year before and after the approval of rt-PA. Although these secular trends are always a concern with such a study design, they would not explain the profound changes observed. The postapproval period was short (3 months) and no allowances for lag times to effect policy change were included. Therefore, these results may be an underestimate of the use of rt-PA in Japan. Another limitation is the fact that we categorized the hospitals into SU and non-SU groups on the basis of self-certification. The American Stroke Association guidelines have suggested that certifications of stroke centers and SU were best performed by an external body or agency.14 In Japan, there is neither a clear definition of SU nor certification system for SU. Therefore, we were obliged to use self-certification.
In conclusion, our results suggest that the approval of intravenous rt-PA therapy resulted in dramatic changes in the processes of acute stroke management and in an increase in the frequency of intravenous rt-PA therapy, particularly in institutes having an SU.
K. Minematsu, National Cardiovascular Center.
Central Trial Office
Y. Hasegawa, T. Uehara, S. Sato, K. Toyoda, National Cardiovascular Center.
Investigators and Institutions
K. Minematsu and H. Naritomi, National Cardiovascular Center; N. Yasui, Research Institute for Brain and Blood Vessels Akita; T. Hata and T. Ueda, Yokohama Stroke and Brain Center; Y. Okada, National Hospital Organization Kyushu Medical Center; A. Toyota, Chugoku Rosai General Hospital; J. Nakagawara, Nakamura Memorial Hospital; Y. Yasumoto, Matsumura General Hospital; M. Amagasa, Yamagata City Hospital Saiseikan; B. Mihara, Institute of Brain and Blood Vessels Mihara Memorial Hospital; Y. Ayuha, Flash Hospital; H. Nikaido, Saitama Ken-oh Hospital; T. Ogawa, Joto Hospital; M. Hokama, Shinonoi General Hospital; T. Seguchi, Seguchi Neurosurgical Hospital; S. Tomida, Sassa General Hospital; K. Okada, Haruyama Surgical Hospital; I. Suzuki, Japanese Red Cross Medical Center; M. Takagi, Tokyo Saiseikai Central Hospital; M. Maruyama, Kawasaki Social Insurance Hospital; I. Imafuku, Yokohama Rosai Hospital; K. Yamaguchi, Shonan Hospital; T. Fujita, Fujita Shinkeinaika Hospital; H. Yamagami, Kobe City Medical Center, General Hospital; T. Morimura, Utano National Hospital; M. Nawata, Kyoto Yawata Hospital; M. Hirai, Kyoto Kujo Hospital; K. Wada, Houwa Hospital; Y. Yamamoto, Tomidahama Hospital; Y. Otsuka, Toki General Hospital; A. Miyasaki, Ichinomiyanishi Hospital; J. Ochiai, Nagoya Ekisaikai Hospital; K. Kimura, Kawasaki Medical School Hospital; T. Arisawa, Fukuyama City Hospital; H. Ito, Vi-hara Hananosato Hospital; Y. Ueda, Shuto General Hospital; M. Takemoto, Saijo City Shuso Hospital; I. Nakahara, Kokura Memorial Hospital; T. Ishitsuka, Kyushu Rosai Hospital; H. Nakane, National Fukuoka-Higashi Medical Center; Y. Kawano, Kawano Neurosurgery Hospital; S. Sakata, Saga Prefectural Hospital Koseikan; S. Uemura, Amakusa Medical Center; K. Ata, Aisenkai Nichinan Hospital; K. Kawazoe, Kagoshima Red Cross Hospital; T. Katabami, Daiichi Hospital; N. Fukawa, Kinki University School of Medicine Hospital; R. Kanemaru, Kanemaru Neurosurgery Hospital; M. Abe, Saga Medical School Hospital; H. Goto, National Hospital Organization Nagasaki Medical Center of Neurology; Y. Unno, Kawakita General Hospital; Y. Yoshida, Eishokai Yoshida Hospital; Y. Kuroda, Emergency Medical Center; Y. Tashiro, Maizuru Municipal Hospital; E. Oogami, Sawara Hospital; K. Nobuhara, Kubo Naika Hospital; M. Murase, Tomei Hospital; H. Seki, Iwate Prefectural Central Hospital; M. Kaminogo, Sasebo Municipal General Hospital; N. Aoki, Yamanashi Kosei Hospital; Y. Tokunaga, Nagasaki Prefectural Shimabara Hospital; K. Arai, Tochigi-kennan General Hospital; H. Nakagaki, Kitakyushu Municipal Medical Center; K. Watanabe, Kaiseikai Ohnishi Hospital; T. Yamada, Aso Corporation Iizuka Hospital; T. Hidaka, Hachinohe Red Cross Hospital; Y. Tamura, Osaka Medical Callege; Y. Konta, Hirosaki Stroke Center, Reimeikyo Rehabilitation Hospital; T. Urabe, Juntendo University School of Medicine; H. Kobata, Osaka Mishima Emergency and Critical Care Medical Center; K. Fukiyama, Japan Seamen’s Relief Association Moji Hospital; K. Suzuki, Matsushita Memorial Hospital; M. Hosoe, Ena Municipal Hospital; Y. Uesaka, International Medical Center of Japan; J. Taguchi, Takarazuka Daiichi Hospital; M. Kawakami, Ohta General Hospital Foundation Ohta Nishinouchi Hospital; T. Kurimoto, Kansai Medical University Rakusai Newtown Hospital; T. Kimura, St. Luke’s International Hospital; S. Jinkawa, Yasuda Hospital; T. Fujita, Hitachi General Hospital; T. Koizumi, Ohtsu Municipal Hospital; S. Nakagawa, Azumi General Hospital; T. Shingu, Sanyudo Hospital; H. Ohtaka, Higashi Yamato Hospital; K. Shimozono, Saiseikai Misumi Hospital; T. Yokoe, Tosei General Hospital; T. Iwamoto, Chidoribashi Hospital; K. Suzuki, Mie Prefectural General Medical Center; T. Kusuhara, Sankoukai Obama Hospital; Y. Nishimura, National Hospital Organization Toyohashi Medical Center; K. Hirahara, Kagoshima City Hospital; H. Joshita, Saitama Cardiovascular and Respiratory Center; H. Hara, Yodogawa Christian Hospital; K. Sugiyama, Asai Hospital; I. Nakano and E. Watanabe, Jichi Medical University Hospital; K. Nakahara, Takagi Hospital; T. Hori and H. Ujiie, Tokyo Women’s Medical University; K. Matsumoto, Iseikai Hospital.
Sources of Funding
This study was supported in part by grants-in-aid from the Ministry of Health, Labor, and Welfare of Japan (H16-Junkanki-Chiho-Kossetsu-023 and H18-Junkanki-Ippan-044).
- Received May 5, 2008.
- Accepted May 28, 2008.
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