Routine Use of Intravenous Low-Dose Recombinant Tissue Plasminogen Activator in Japanese Patients
General Outcomes and Prognostic Factors From the SAMURAI Register
Background and Purpose— A retrospective, multicenter, observational study was conducted to document clinical outcomes and to identify outcome predictors in patients treated with low-dose intravenous recombinant tissue plasminogen activator (0.6 mg/kg alteplase), which was approved in Japan in 2005, within 3 hours of stroke onset.
Methods— Consecutive patients with stroke treated with recombinant tissue plasminogen activator in 10 Japanese stroke centers were included.
Results— A total of 600 patients (377 men, 72±12 years old) were studied. Median National Institutes of Health Stroke Scale scores decreased from 13 before recombinant tissue plasminogen activator to 8 at 24 hours later. Symptomatic intracerebral hemorrhage within 36 hours with a ≥1-point increase from the baseline National Institutes of Health Stroke Scale score developed in 23 patients (3.8%; 95% CI, 2.6% to 5.7%). At 3 months, 43 patients had died (7.2%; 5.4% to 9.5%), and 199 patients (33.2%; 29.5% to 37.0%) had a modified Rankin Scale score ≤1. Analysis of 399 patients with a premorbid modified Rankin Scale score ≤1 who met the criteria of the European license (≤80 years old, an initial National Institutes of Health Stroke Scale score ≤24, etc) showed that 40.6% (35.9% to 45.5%) had a 3-month modified Rankin Scale score ≤1. After multivariate adjustment, younger age, lower initial National Institutes of Health Stroke Scale score, absence of internal carotid artery occlusion, higher Alberta Stroke Program Early CT Score on CT, and absence of intravenous antihypertensives just before recombinant tissue plasminogen activator were independently related to a 3-month modified Rankin Scale score ≤1. Congestive heart failure and hyperglycemia were independently related to mortality.
Conclusions— Three-month outcomes of patients receiving low-dose intravenous recombinant tissue plasminogen activator therapy in the present study were similar to those from postmarketing surveys using 0.9 mg/kg alteplase.
- acute stroke
- cerebral infarction
- recombinant tissue plasminogen activator
- stroke outcome
In 2005, intravenous (IV) alteplase therapy at a dose of 0.6 mg/kg was approved in Japan after a dose comparison study using duteplase1 and a multicenter study using a single dose of alteplase (Japan Alteplase Clinical Trial [J-ACT]),2 although a head-to-head comparison of the alteplase dose of 0.9 mg/kg versus 0.6 mg/kg has not been done. A postmarketing survey from our single stroke center found that 36 (46%) of 78 patients receiving low-dose recombinant tissue plasminogen activator (rtPA) therapy had a favorable 3-month outcome corresponding to a modified Rankin Scale (mRS) score ≤1.3
Based on the large population of patients included in Western randomized, controlled trials and postmarketing studies, several predictors of stroke outcome after rtPA have been identified, including advanced age, stroke severity, initial hyperglycemia, and high acute blood pressure.4–7⇓⇓⇓ Low-dose rtPA therapy may, in principle, share the same predictors. Because MRI is widely available in Japan, studies on low-dose rtPA were often based on MRI and MR angiography. In the above study from our center, occlusion of the internal carotid artery (ICA) and early ischemic signs on diffusion-weighted MRI (DWI), defined as an Alberta Stroke Program Early CT Score (ASPECTS) ≤6, were independently predictive of an mRS ≥2 at 3 months.3 Kimura et al8 reported that ASPECTS on DWI ≤5 was predictive of a National Institutes of Health Stroke Scale (NIHSS) score≥20 at 7 days. Chronic outcomes of low-dose rtPA therapy as well as the factors affecting the outcomes should be ascertained using a larger population with a multicenter design.
To determine appropriate risk factor control in acute stroke, a multicenter study group (Stroke Acute Management with Urgent Risk-factor Assessment and Improvement [SAMURAI] Study Group) was formed. A retrospective observational study was conducted to identify the effects of risk factors and other patient characteristics on the outcome of IV alteplase at a dose of 0.6 mg/kg. This article reports the overall general results.
Patients and Methods
The SAMURAI Study Group was composed of 10 Japanese stroke centers that were balanced regionally. In this study, all consecutive patients with ischemic stroke or transient ischemic attack who received IV rtPA therapy in these 10 centers between October 2005 (when IV alteplase therapy was approved in Japan) and July 2008 were registered. Patient eligibility for alteplase therapy was determined based primarily on Japanese guidelines for IV rtPA therapy,9 which follow the inclusion and exclusion criteria used in the National Institute of Neurological Disorders and Stroke (NINDS) study and J-ACT.2,10⇓ Each local ethics committee approved the retrospective collection of clinical data from the database and submission of the data to our central office.
Each patient received a single alteplase dose of 0.6 mg/kg (not exceeding 60 mg) IV with 10% given as a bolus within 3 hours of stroke onset followed by a continuous IV infusion of the remainder over 1 hour. Like in the NINDS study,10 use of antithrombotic agents was prohibited in principle for 24 hours after onset, blood pressure was maintained at <180/105 mm Hg, and neurological signs and symptoms were frequently monitored.
Before rtPA therapy, all patients underwent brain noncontrast CT or DWI. The ASPECTS was calculated on both CT and DWI; it is a 10-point quantitative topographical scoring method of the early ischemic signs, originally developed for CT, which divides the middle cerebral arterial territory into 10 regions of interest.11,12⇓ To identify arterial occlusion sites, MR angiography, CT angiography, or ultrasound was performed. The baseline characteristics listed in Tables 1 and 2⇓ were studied.
The outcomes were: completely independent activity of daily living at 3 months corresponding to an mRS ≤1; death at 3 months; any intracerebral hemorrhage (ICH) defined as CT evidence of new ICH within the initial 36 hours; and symptomatic ICH with neurological deterioration corresponding to an increase of ≥1 point from the baseline NIHSS score. Symptomatic ICH was also defined according to the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST)13 protocol as parenchymal hemorrhage Type II combined with an increase of ≥4 points from the baseline NIHSS score. Outcomes at 3 months were assessed by clinical examination at a hospital clinic (or by phone survey for patients whose neurological deficits were too severe to visit the clinic). The examiners at the clinics were familiar with patients’ stroke features in some hospitals and not in others. For patients who were lost to follow-up at 3 months, mRS at hospital discharge was assessed instead.
All calculations were performed using JMP 7 software (SAS Institute Inc). A probability value <0.05 was considered significant. The proportions and 95% CIs of patients with ICH and mRS ≤1 as well as mortality were calculated for all patients as well as for patients who met the criteria of the European license (patients ≤80 years old with an initial NIHSS score ≤24 and without any history of prior stroke and concomitant diabetes). Multivariate analyses were performed to find predictors for an mRS ≤1 and death at 3 months based on the characteristics in Tables 1 and 2⇑. For each outcome, a backward selection procedure was performed using P>0.10 of the likelihood ratio test for exclusion. We assessed the main effects of each characteristic and did not assess bivariable interaction of characteristics. Multivariate analyses were also done simply with adjustment for sex, age, and initial NIHSS score.
A total of 600 patients with stroke (377 men, 72±12 years old) were registered. During the same period, a domestic survey estimated that approximately 13 500 Japanese patients with stroke received IV rtPA therapy. Thus, the present patients accounted for approximately 4.4% of the rtPA-treated patients in Japan during that time period. Of these 600 patients, 422 (70.3%) met the criteria of the European license (patients ≤80 years old with an initial NIHSS score ≤24 and without any history of prior stroke and concomitant diabetes).
The baseline characteristics of the 600 patients as well as their stroke features and process measures are listed in Tables 1 and 2⇑. The leading risk factor was hypertension (61.0%) followed by atrial fibrillation (43.4%). MR angiography was performed in 479 patients, CT angiography was performed in 15, and ultrasound was performed in 369. The leading site of arterial occlusion was the trunk of the middle cerebral artery (29.1%) followed by its branch (19.8%). The leading stroke subtype was cardioembolism (63.3%).
The median NIHSS score decreased from 13 (interquartile range, 7.25 to 19) before rtPA to 8 (interquartile range, 3 to 16) 24 hours later. ICH developed in 119 patients (19.8%; 16.8% to 23.2%); of these, 30 showed parenchymal hemorrhage Type I (5.0%) and 21 showed parenchymal hemorrhage Type II (3.5%). Symptomatic ICH within 36 hours developed in 23 patients (3.8%; 2.6% to 5.7%). Symptomatic ICH within 36 hours per the SITS-MOST definition developed in 8 patients (1.3%; 0.7% to 2.6%); 7 of these met the criteria of the European license (7 of 422 [1.7%; 0.8% to 3.4%]).
Vital prognosis at 3 months was available for all 600 patients, but the mRS scores for 5 patients were not available. mRS scores at hospital discharge in these 5 patients were 2, 4, 4, 5, and 5, and their durations of hospitalization were 38, 30, 33, 18, and 37 days, respectively.
Of the total 600 patients, 199 patients (33.2%; 95% CI, 29.5% to 37.0%) had an mRS score ≤1 at 3 months, when the score at hospital discharge was used for 5 patients who were lost to follow-up at 3 months (Figure). When 65 patients with a premorbid mRS score ≥2 were excluded from the analysis, 199 (37.2%; 33.2% to 41.4%) of 535 patients had an mRS score ≤1. In addition, when patients who did not meet the criteria of the European license were excluded, 162 (40.6%; 35.9% to 45.5%) of 399 patients had a score ≤1.
At 3 months, 43 patients (7.2%; 95% CI, 5.4% to 9.5%) died, including 7 with symptomatic ICH. Nineteen patients died within the initial week of stroke. Fifteen patients died directly of stroke, 7 died of heart disease (5 heart failure, one heart rupture, and one infective endocarditis) and 6 died of pneumonia. Of 422 patients who met the criteria of the European license, 20 died (4.7%; 3.1% to 7.2%).
Multivariate regression analysis using a backward selection method indicated that younger age, lower initial NIHSS score, absence of ICA occlusion, higher ASPECTS on CT, and absence of IV antihypertensives just before rtPA were independently related to an mRS ≤1 at 3 months (Table 3). In addition, hypertension (P=0.013), higher initial systolic blood pressure (P=0.046), and higher initial glucose level (P=0.034) were inversely related, and cardioembolism (P=0.034) was positively related to an mRS ≤1 after simple adjustment for sex, age, and the initial NIHSS score.
After multivariate regression analysis using a backward selection method, congestive heart failure and higher initial glucose level were independently related to death at 3 months (Table 3). In addition, older age (P=0.048), higher initial NIHSS score (P<0.001), ischemic heart disease (P<0.001), prior use of anticoagulants (P=0.047), prior use of antihypertensives (P=0.016), lower body weight (P=0.032), and ICA occlusion (P<0.001) were positively related, and use of the IV free radical scavenger, edaravone (which was approved for clinical use in Japan in 2001 after a multicenter randomized clinical trial),14 was inversely related to death (P=0.002) after adjustment for sex, age, and the NIHSS score.
The first major finding of this study was that 33.2% (95% CI, 29.5% to 37.0%) of patients with stroke in our cohort had an mRS ≤1 at 3 months after receiving low-dose (0.6 mg/kg) IV alteplase therapy, a therapeutic strategy that has only been approved in Japan. When patients who did not meet the criteria of the European license as well as those with a premorbid mRS score ≥2 were excluded, like in SITS-MOST,13 40.6% (35.9% to 45.5%) had a score ≤1. These percentages were similar to the percentage of patients with an mRS score ≤1 in J-ACT2 (37%) and those in Western postmarketing surveys using 0.9 mg/kg alteplase (35% in Standard Treatment with Alteplase to Reverse Stroke [STARS]; 37% in Canadian Alteplase for Stroke Effectiveness Study [CASES]; 38.9%, 37.7 to 40.1% in SITS-MOST).13,15,16⇓⇓ In addition, the frequency of symptomatic ICH in our study (3.8%; 2.6% to 5.7%) was relatively low compared with that in the NINDS study (6.4%)10 and CASES (4.6%; 3.4% to 6.0%)16 and similar to that in SITS-MOST (1.3%; 0.7% to 2.6% in ours versus 1.7%; 1.4% to 2.0% in SITS-MOST using the SITS-MOST definition).13 Our definition for symptomatic ICH was similar to the others; accordingly, this low frequency suggests a true reduction in risk of ICH by low-dose rtPA. Our mortality rate at 3 months (4.7%; 3.1% to 7.2%, for patients meeting the criteria of the European license) was also lower than that in SITS-MOST (11.3%; 10.5% to 12.1%)13 and CASES (22.3%; 20.0% to 25.0%).16 Because our result was from experienced centers, it might be better than the overall results in Japan. At the very least, low-dose IV rtPA given to Japanese patients in experienced centers resulted in relatively good efficacy and safety compared with regular-dose therapy in Western patients.
The second major finding was that age, initial neurological severity, ICA occlusion, ASPECTS on CT, and IV antihypertensives just before rtPA were related to long-term independence, and congestive heart failure and initial glucose level were related to mortality after low-dose rtPA; some of these are known predictors.4–6⇓⇓ Of these, admission hyperglycemia was reported to be associated with a poor recanalization rate of the occluded artery and increased risk of death, symptomatic ICH, and poor functional status.6,17,18⇓⇓ High acute blood pressure is associated with poor outcome after rtPA.4,6,7,19⇓⇓⇓ In a multivariate analysis from Safe Implementation of Thrombolysis in Stroke-International Stroke Thrombolysis Register (SITS-ISTR) involving 11 080 patients, a high average systolic blood pressure at 2 to 24 hours was associated with high mortality, high rates of symptomatic ICH, and low rates of functional independence.7 However, the effect of emergent IV antihypertensives on stroke outcome is being disputed; a recent study found no effect.20 A major advance in our data set was that we had pretreatment MR angiography information. In addition to our MR angiography studies,3 some studies using transcranial Doppler showed ICA occlusion to be resistant to IV rtPA.21,22⇓ We should note that our patients with ICA occlusion had much higher initial median NIHSS scores than those without ICA occlusion (18 versus 12, P<0.001), although the inverse association between ICA occlusion and long-term independence was significant after adjustment for the NIHSS score. An association of lower body weight with mortality after adjustment for sex, age, and the NIHSS score suggests that alteplase at a dose of 0.6 mg/kg was insufficient for lightweight patients, because a dose in proportional to body weight may be inadequate in such patients due to the plasma distribution and activation of alteplase.
The limitations of the present study include missing data of 3-month mRS scores for 5 patients as well as missing data for some baseline characteristics; these affected the data on chronic outcomes and limited the number of patients available for the multivariate analyses. Second, this was an observational study, and patient eligibility for rtPA was determined according to each patient’s situation, although the determination was principally based on the Japanese guidelines.9 We did not collect data for patients with stroke who visited our centers within 3 hours after onset and did not receive thrombolysis. Third, some continuous variables might have been re-evaluated as categorized factors for proper statistical analyses. Our previous studies indicated that ASPECTS on DWI beyond threshold values was indicative of poor stroke outcome,3,8⇓ but the present study using ASPECTS as a continuous variable did not. Detailed analyses on outcome predictors should be explored in further subanalyses.
In conclusion, chronic outcomes and the factors affecting chronic outcomes were determined in Japanese patients with stroke receiving low-dose IV rtPA therapy. In future studies, we plan to determine the contribution of each risk factor and other patient characteristics to the outcomes.
Sources of Funding
This study was supported in part by Grants-in-Aid (H20-Junkanki-Ippan-019, chief investigator: Kazunori Toyoda) from the Ministry of Health, Labour and Welfare, Japan.
- Received July 15, 2009.
- Accepted August 14, 2009.
- ↵Yamaguchi T, Kikuchi H, Hayakawa T; Japanese Thrombolysis Study Group. Clinical efficacy and safety of intravenous tissue plasminogen activator in acute embolic stroke: a randomized, double-blind, dose comparison study of duteplase. In: Yamaguchi T, Mori E, Minematsu K, del Zoppo GJ, eds. Thrombolytic Therapy in Acute Ischemic Stroke III. Tokyo: Springer-Verlag; 1995: 223–229.
- ↵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.
- ↵Nakashima T, Toyoda K, Koga M, Matsuoka H, Nagatsuka K, Takada T, Naritomi H, Minematsu K. Arterial occlusion sites on MRA influence the efficacy of intravenous low-dose (0.6 mg/kg) alteplase therapy for ischemic stroke. Int J Stroke. 2009;4: In press.
- ↵Kent DM, Selker HP, Ruthazer R, Bluhmki E, Hacke W. The stroke-thrombolytic predictive instrument: a predictive instrument for intravenous thrombolysis in acute ischemic stroke. Stroke. 2006; 37: 2957–2962.
- ↵Wahlgren N, Ahmed N, Eriksson N, Aichner F, Bluhmki E, Dávalos A, Erilä T, Ford GA, Grond M, Hacke W, Hennerici MG, Kaste M, Köhrmann M, Larrue V, Lees KR, Machnig T, Roine RO, Toni D, Vanhooren G; Safe Implementation of Thrombolysis in Stroke-MOnitoring STudy Investigators. Multivariable analysis of outcome predictors and adjustment of main outcome results to baseline data profile in randomized controlled trials: Safe Implementation of Thrombolysis in Stroke-MOnitoring STudy (SITS-MOST). Stroke. 2008; 39: 3316–3322.
- ↵Ahmed N, Wahlgren N, Brainin M, Castillo J, Ford GA, Kaste M, Lees KR, Toni D; SITS Investigators. Relationship of blood pressure, antihypertensive therapy, and outcome in ischemic stroke treated with intravenous thrombolysis. Retrospective analysis from Safe Implementation of Thrombolysis in Stroke-International Stroke Thrombolysis Register (SITS-ISTR). Stroke. 2009; 40: 2442–2449.
- ↵Kimura K, Iguchi Y, Shibazaki K, Terasawa Y, Inoue T, Uemura J, Aoki J. Large ischemic lesions on diffusion-weighted imaging done before intravenous tissue plasminogen activator thrombolysis predicts a poor outcome in patients with acute stroke. Stroke. 2008; 39: 2388–2391.
- ↵Guideline Committee for Intravenous rt-PA (alteplase) in Acute Ischemic Stroke. Guidelines for intravenous application of rt-PA (alteplase) [in Japanese]. Jpn J Stroke. 2005; 26: 327–354.
- ↵Barber PA, Hill MD, Eliasziw M, Demchuk AM, Pexman JH, Hudon ME, Tomanek A, Frayne R, Buchan AM; ASPECTS Study Group. Imaging of the brain in acute ischaemic stroke: comparison of computed tomography and magnetic resonance diffusion-weighted imaging. J Neurol Neurosurg Psychiatry. 2005; 76: 1528–1533.
- ↵Wahlgren N, Ahmed N, Dávalos A, Ford GA, Grond M, Hacke W, Hennerici MG, Kaste M, Kuelkens S, Larrue V, Lees KR, Roine RO, Soinne L, Toni D, Vanhooren G; SITS-MOST investigators. Thrombolysis with alteplase for acute ischaemic stroke in the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST): an observational study. Lancet. 2007; 369: 275–282.
- ↵Hill MD, Buchan AM; Canadian Alteplase for Stroke Effectiveness Study (CASES) Investigators. Thrombolysis for acute ischemic stroke: results of the Canadian Alteplase for Stroke Effectiveness Study. CMAJ. 2005; 172: 1307–1312.
- ↵Ribo M, Molina C, Montaner J, Rubiera M, Delgado-Mederos R, Arenillas JF, Quintana M, Alvarez-Sabín J. Acute hyperglycemia state is associated with lower tPA-induced recanalization rates in stroke patients. Stroke. 2005; 36: 1705–1709.
- ↵Poppe AY, Majumdar SR, Jeerakathil T, Ghali W, Buchan AM, Hill MD; Canadian Alteplase for Stroke Effectiveness Study Investigators. Admission hyperglycemia predicts a worse outcome in stroke patients treated with intravenous thrombolysis. Diabetes Care. 2009; 32: 617–622.
- ↵Yong M, Kaste M. Association of characteristics of blood pressure profiles and stroke outcomes in the ECASS-II trial. Stroke. 2008; 39: 366–372.
- ↵Rubiera M, Ribo M, Delgado-Mederos R, Santamarina E, Delgado P, Montaner J, Alvarez-Sabín J, Molina CA. Tandem internal carotid artery/middle cerebral artery occlusion: an independent predictor of poor outcome after systemic thrombolysis. Stroke. 2006; 37: 2301–2305.
- ↵Saqqur M, Uchino K, Demchuk AM, Molina CA, Garami Z, Calleja S, Akhtar N, Orouk FO, Salam A, Shuaib A, Alexandrov AV; CLOTBUST Investigators. Site of arterial occlusion identified by transcranial Doppler predicts the response to intravenous thrombolysis for stroke. Stroke. 2007; 38: 948–954.