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Table of Contents
Vol. 31, No. 6, 2011
Issue release date: May 2011
Cerebrovasc Dis 2011;31:601–613
(DOI:10.1159/000327035)

The Japanese Aggrenox (Extended-Release Dipyridamole plus Aspirin) Stroke Prevention versus Aspirin Programme (JASAP) Study: A Randomized, Double-Blind, Controlled Trial

Uchiyama S.a · Ikeda Y.b · Urano Y.c · Horie Y.c · Yamaguchi T.d
aDepartment of Neurology, Tokyo Women’s Medical University, bGraduate School of Advanced Science and Engineering, Waseda University, and cNippon Boehringer Ingelheim Co. Ltd., Tokyo, and dNational Cardiovascular Center, Suita, Japan
email Corresponding Author

Abstract

Background: Despite improvements in treatment, stroke still carries a high death toll and disability in Asia. Extended-release dipyridamole (ER-DP) plus acetylsalicylic acid (ASA) has consistently been shown to be superior over conventional platelet inhibition by ASA. ER-DP plus ASA is well established in the secondary prevention of stroke in a lot of countries including the USA and Europe. DP has an established benefit in the treatment of heart disease in Japan; however, for the prevention of stroke, the fixed-dose combination of ER-DP plus ASA has only been investigated in a small number of patients in Japan. Methods: The aim of this double-blind, randomized clinical trial was to investigate the efficacy and safety of ER-DP plus ASA versus 81 mg ASA over 1 year. The primary end point of this study was the event rate of recurrent ischemic stroke (fatal or nonfatal) using the Kaplan-Meier method and Cox regression analysis. Results: Of the 1,294 enrolled patients, the primary end point was analyzed in 652 patients in the ER-DP plus ASA group and 639 in the ASA group. The incidence of ischemic stroke was 6.9% for ER-DP plus ASA and 5.0% for ASA with a hazard ratio of 1.47 (95% confidence interval 0.93–2.31) for the primary end point. The ASA treatment group was found to have a lower than expected yearly event rate, compared to other studies in Japanese stroke patients. Noninferiority of ER-DP plus ASA versus ASA could not be shown. The risks of major bleeding events and intracranial hemorrhage were found to be similar between the treatment arms. There were 4 deaths (0.6%) in the ER-DP plus ASA group and 10 (1.6%) in the ASA group. Conclusions: The results of the study are inconclusive. Noninferiority of ER-DP plus ASA versus ASA could not be established, a difference between treatments could not be shown for the primary end point. Possible reasons for this result include a small sample size, low event rates and too short a treatment duration (ClinicalTrials. gov number, NCT00311402).


 Outline


 goto top of outline Key Words

  • Aspirin
  • Clinical trials
  • Ischemic stroke
  • Antiplatelet therapy
  • Secondary prevention

 goto top of outline Abstract

Background: Despite improvements in treatment, stroke still carries a high death toll and disability in Asia. Extended-release dipyridamole (ER-DP) plus acetylsalicylic acid (ASA) has consistently been shown to be superior over conventional platelet inhibition by ASA. ER-DP plus ASA is well established in the secondary prevention of stroke in a lot of countries including the USA and Europe. DP has an established benefit in the treatment of heart disease in Japan; however, for the prevention of stroke, the fixed-dose combination of ER-DP plus ASA has only been investigated in a small number of patients in Japan. Methods: The aim of this double-blind, randomized clinical trial was to investigate the efficacy and safety of ER-DP plus ASA versus 81 mg ASA over 1 year. The primary end point of this study was the event rate of recurrent ischemic stroke (fatal or nonfatal) using the Kaplan-Meier method and Cox regression analysis. Results: Of the 1,294 enrolled patients, the primary end point was analyzed in 652 patients in the ER-DP plus ASA group and 639 in the ASA group. The incidence of ischemic stroke was 6.9% for ER-DP plus ASA and 5.0% for ASA with a hazard ratio of 1.47 (95% confidence interval 0.93–2.31) for the primary end point. The ASA treatment group was found to have a lower than expected yearly event rate, compared to other studies in Japanese stroke patients. Noninferiority of ER-DP plus ASA versus ASA could not be shown. The risks of major bleeding events and intracranial hemorrhage were found to be similar between the treatment arms. There were 4 deaths (0.6%) in the ER-DP plus ASA group and 10 (1.6%) in the ASA group. Conclusions: The results of the study are inconclusive. Noninferiority of ER-DP plus ASA versus ASA could not be established, a difference between treatments could not be shown for the primary end point. Possible reasons for this result include a small sample size, low event rates and too short a treatment duration (ClinicalTrials. gov number, NCT00311402).

Copyright © 2011 S. Karger AG, Basel


goto top of outline Introduction

Asian countries generally have a higher stroke mortality than Western countries [1]. In Japan, stroke is a greater health problem than heart disease [2]. Recently, the lifetime risk of stroke has been given as high as nearly 20% for middle-aged and older adults, underlining the major public health burden in Japan [3]. Data from the Japan Multicenter Stroke Investigators’ Collaboration study show that the death toll from cerebrovascular disease is higher than that of cardiovascular disease or even cancer after hospital discharge following ischemic stroke and transient ischemic attack (TIA) [4]. The incidence of stroke can differ within the same country; for example, a survey in China demonstrated that the percentage of patients with ischemic stroke in urban areas was more than 20% higher than that in rural areas [5], which is difficult to explain on the basis of genetic or ethnic variations, and makes conducting clinical trials challenging. Cerebrovascular disease is often seen as part of a common global atherothrombotic cardiovascular problem. However, large differences in the incidence of cerebrovascular disease in Western (USA and Europe) and Asian countries possibly suggest differences between the pathophysiology of these diseases in different parts of the world [1].

In 2009, data from the Japan Standard Stroke Registry showed that the relative frequencies of ischemic and hemorrhagic strokes in Japan were 75.4 and 24.6%, respectively [6]. The percentage of hemorrhagic strokes in East Asia is higher than in the Western world [1], even though the age-adjusted stroke mortality was reduced by about 63% in men and 43% in women between 1961 and 1986 [7]. Smoking and hypertension are more prevalent in Japan compared with other countries [8], which may lead to differences in the pathogenesis of vascular disease. Consequently, regulatory authorities have issued guidance on ethnic factors, such as differences in concomitant therapies, medical practices and food consumption, when evaluating foreign clinical data [9].

Dipyridamole (DP) was licensed in 1960 for clinical use in Japan for indications based on its coronary vasodilatory effect. DP in combination with warfarin received approval in 1982 for therapeutic use based on its antiplatelet effects, with the extended-release (ER) formulation receiving approval for these indications in 1994. ER-DP plus acetylsalicylic acid (ASA) has demonstrated a favorable efficacy and safety profile in all large, placebo-controlled, randomized stroke prevention trials, like the European Stroke Prevention Study 2 (ESPS-2) or the European/Australasian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT), with bleeding rates similar or even lower compared with other antiplatelet therapies [10,11].

Although international guidelines recommend a fixed-dose combination of ER-DP and ASA for secondary stroke prevention, the combination of ER-DP plus ASA (free or fixed dose) had not yet been approved for this indication in Japan [12,13,14]. Until now, there has been no formally conducted trial in Japan comparing ER-DP (200 mg twice daily) plus ASA (25 mg twice daily) with ASA 81 mg, one of the most commonly used dose in Japan.

The aim of the Japanese Aggrenox (ER-DP plus ASA) Stroke Prevention versus Aspirin Programme (JASAP) study (for investigators, see the Appendix) was to demonstrate the noninferiority of ER-DP plus ASA to ASA with regard to the event rate of recurrent ischemic stroke. Data from the ESPS-2 study were used to determine the clinically acceptable limit [10] as data were not available for secondary stroke prevention with ASA or ER-DP plus ASA in Japanese patients.

 

goto top of outline Methods

goto top of outline Study Design

This phase III, randomized, double-blind, parallel-group, active, controlled comparative study was conducted in 157 centers in Japan and sponsored by Boehringer Ingelheim. Patients provided written informed consent prior to participating in the trial.

The chosen noninferiority study design was the basis for the sample size calculation, which was approved by the Pharmaceuticals and Medical Devices Agency in Japan.

The study protocol was approved by the institutions’ review committee on human research from all study centers. The study was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice guidelines and local laws and regulations.

Patient Numbers
The study was scheduled to have a 1-year treatment period and, according to the calculation based on the event rate after 1 year with a significance level of 5% (two-sided) and a power of 80% using the log-rank test. A total of 1,294 patients were randomly assigned (ER-DP plus ASA: 655, ASA: 639).

An interim review of the number of events and event rate was conducted under blinded conditions in week 26 (after 500 patients had been included). Following this interim analysis, the planned number of patients was increased from 1,000 to 1,250 in order to obtain at least 75 events.

Patient Selection
Patients aged 50 years or older with an ischemic stroke (excluding cardiogenic cerebral embolism) who met the National Institute of Neurological Disorders and Stroke ad hoc committee’s diagnostic criteria of cerebrovascular disease III [15] were eligible for inclusion in the study. The onset of the ischemic stroke, including first and recurrent ischemic stroke, had to take place between 1 week and 6 months before enrollment in the study. Neurological signs and symptoms had to be considered stable by the investigator, and the responsible lesion had to be confirmed by computerized tomography (CT) or magnetic resonance imaging (MRI).

Patients had to have at least 2 of the following risk factors:

– diabetes [16];

– hypertension (systolic blood pressure ≧140 mm Hg or diastolic blood pressure ≧90 mm Hg), or being under treatment for hypertension;

– being a smoker at the time of onset of ischemic stroke;

– body mass index >25;

– previous vascular disease (stroke, myocardial infarction or peripheral arterial disease before the onset of the qualifying ischemic stroke);

– end organ damage (retinopathy, left ventricular hypertrophy or microalbuminuria);

– hyperlipidemia [17].

Patients who met the following criteria were excluded from the study: diagnosis of brain disorders with a bleeding risk; complications of cardiac disorders that may cause cerebral embolism; acute coronary syndromes <6 months before enrollment; history of peptic ulcer in the past 3 years; having undergone arterial reconstruction after developing ischemic stroke; severe disability (modified Rankin Scale 4 or 5); bleeding or bleeding tendencies; severe hypertension (systolic blood pressure ≧180 mm Hg or diastolic blood pressure ≧120 mm Hg); complications such as serious cardiac, renal or hepatic disorders; malignant tumor or having received cancer treatment in the past 5 years; pregnant or lactating women.

Outcomes
The primary end point of this study was recurrent ischemic stroke (fatal or nonfatal).

Secondary end points included: cerebral hemorrhage, subarachnoid hemorrhage, TIA, acute coronary syndromes (acute myocardial infarction, unstable angina, sudden cardiac death), other vascular events, ischemic vascular event composite end point (ischemic stroke, TIA, myocardial infarction, unstable angina or sudden death attributable to thromboembolism), stroke (composite end point of ischemic stroke, cerebral hemorrhage or subarachnoid hemorrhage).

For a post hoc analysis, the event rate of intracranial hemorrhage and the composite end point of stroke or major bleeding were evaluated for different subgroups of patients.

Safety was assessed using the end points, outcomes and definitions detailed in table 1.

TAB01
Table 1. Safety end points and definitions

All vascular events, sudden death or bleeding events were reviewed and adjudicated by a blinded Event Assessment Committee.

An independent, blinded Safety Monitoring Committee reviewed bleeding events and serious adverse events other than vascular events during the trial.

goto top of outline Statistical Considerations

The primary objective of this study was the comparison of ER-DP plus ASA and ASA to show the noninferiority of ER-DP plus ASA with regard to the event rate of recurrent ischemic stroke. The clinically acceptable limit was based on results from the ESPS-2 study [10]. Additionally, the superiority test was planned to compare the 2 treatment groups if the noninferiority was shown.

In the ESPS-2 study, the event rates of recurrent ischemic stroke in the ER-DP plus ASA and ASA groups were 6.0 and 8.5% after 1 year, and 9.9 and 12.9% after 2 years, respectively [10].

The noninferiority limit was set to 2%, which equaled 1.37 with regard to the hazard ratio, for the level to suggest noninferiority of ER-DP plus ASA to ASA. Under these conditions, 500 patients per group were regarded to be sufficient to detect the noninferiority of ER-DP plus ASA to ASA with over 80% power.

The primary analysis population for efficacy was defined as the full analysis set, which excluded patients who did not meet the inclusion criteria, who had never taken the investigational products and who had no data after drug administration.

A similar analysis was conducted for the primary end point using the per-protocol set, to ensure universality of the results. The per-protocol set excluded patients who violated the exclusion criteria, had compliance rates <80% and deviated from the rules regarding concomitant treatment.

Safety was assessed in the treated set, which excluded patients who did not meet the inclusion criteria, had never taken the investigational products and had no data after drug administration. Patients who discontinued due to headache in the run-in period were included in the ‘safety analysis in the run-in period’.

The event rates of recurrent ischemic stroke, and some of the secondary end points, were compared between ER-DP plus ASA and ASA when each treatment was given for 52 weeks or longer. The event rate was calculated using the Kaplan-Meier method, and the 2 treatment groups were compared using the Cox proportional hazard model including time from first stroke and age as covariates.

Exploratory analyses were used to assess those secondary end points based on frequencies or changes. The frequencies of major and minor bleeding in both treatment groups were compared using Fisher’s exact test.

goto top of outline Treatment Schedule

After the screening phase (–1 to –2 weeks), clinic visits took place at weeks 0, 1 and then every 4 weeks to a maximum of 124 weeks. Visits also took place just before and 2 weeks (+14 days) after patients had terminated treatment.

CT/MRI was performed if onset of stroke or TIA was suspected to confirm the recurrence of disease. The study assessments are detailed in table 2; adverse events, bleeding and vascular events were assessed once a month.

TAB02
Table 2. Study assessments

The incidence, intensity and duration of headache, and the dose of acetaminophen were recorded in a patient’s diary during the screening phase and for the first 4 weeks.

goto top of outline Randomization

Patients were randomized to a fixed-dose combination product containing ER-DP 200 mg and ASA 25 mg (ER-DP plus ASA) p.o. twice daily, or ASA 81 mg (ASA) p.o. once daily for a minimum of 52 weeks (including a 1-week run-in period), but not longer than 124 weeks, in blocks of 8, by an external enrollment center. Randomization was stratified by time from first stroke and age in order to minimize any confounding effect of these factors on the evaluation of efficacy of the tested treatment regimens.

During the 1-week run-in period to minimize potential headache with ER-DP, patients received ASA 81 mg once daily in the morning and ER-DP plus ASA once daily before bedtime.

Concomitant use of anticoagulant and antiplatelet therapies was prohibited from the run-in period until treatment discontinuation. Thrombolytic therapies, tissue plasminogen activator preparations and urokinase preparations were prohibited from week 0 until treatment discontinuation.

 

goto top of outline Results

A total of 1,294 patients were randomized and received either ER-DP plus ASA (n = 655) or ASA (n = 639). Of these 1,294 patients, 907 completed the study (n = 445 ER-DP plus ASA, n = 462 ASA). The reasons for withdrawal are included in figure 1.

FIG01
Fig. 1. Patient disposition.

There were no differences in baseline demographics or characteristics between the 2 treatment groups, given the formal inclusion criteria of 2 or more risk factors (table 3).

TAB03
Table 3. Demographics, baseline characteristics and risk factors

The majority of patients had at least 2–4 risk factors at baseline (88.4%; table 3).

The majority of patients were receiving concomitant ASA therapy (71.9%). Other concomitant antiplatelet therapies included DP (1.4%), cilostazol (18.8%), ticlopidine (total 4.9%; ER-DP plus ASA 4.7%, ASA 5.0%) and clopidogrel (total 12.9%; ER-DP plus ASA 11.8%, ASA 14.1%) for the last 12 weeks before screening.

There was an imbalance between the 2 groups for the proportion of patients receiving concomitant statin therapy (ER-DP plus ASA 32.4% vs. ASA 28.6%; p = 0.1479) before screening.

The mean treatment durations in the ER-DP plus ASA and ASA groups were 447 and 471 days, respectively.

Of the patients randomized to treatment, 3 patients in the ER-DP plus ASA group were not included in the analysis (2 took the wrong medication; 1 had no qualifying stroke). The efficacy results were therefore analyzed in a total of 1,291 patients (n = 652 ER-DP plus ASA, n = 639 ASA). The efficacy results were also analyzed in the 1,280 patients in the per-protocol population (n = 646 ER-DP plus ASA, n = 634 ASA).

goto top of outline Efficacy

Recurrent ischemic stroke occurred in 45 (6.9%) of the 652 patients in the ER-DP plus ASA group, and in 32 (5.0%) of the 639 patients in the ASA group (fig. 2; table 4). Non-inferiority of ER-DP plus ASA compared with ASA was not shown (hazard ratio 1.47; 95% confidence interval 0.93–2.31; fig. 3). These results were consistent with those in the per-protocol population (table 4; fig. 4).

TAB04
Table 4. Primary and secondary efficacy end points and post hoc analysis

FIG02
F02B
Fig. 2. Kaplan-Meier curve (a) and log-log survival (LLS) plot (b), with –log(nonevent), for recurrence of ischemic stroke. The estimated hazard ratios are based on a Cox proportional hazards model with the covariates of age and time from qualifying event to entry.

FIG03
Fig. 3. Confidence interval for recurrence of ischemic stroke (full analysis set).

FIG04
Fig. 4. Forest plot for primary and secondary efficacy end points and post hoc analysis.

The event rate of stroke was significantly higher for ER-DP plus ASA compared with ASA (table 4; fig. 4). There was no statistically significant difference between treatment groups for the other secondary end points (table 4; fig. 4).

goto top of outline Post hoc Analysis

A multivariate analysis taking into account potential confounders for recurrence of ischemic stroke but only keeping covariates with a significant contribution in the model revealed a similar result for the comparison between treatments as the primary analysis. This analysis also revealed that higher modified Rankin Scale values and established end organ damage at baseline had a deleterious effect on the primary outcome, whereas the concomitant therapy with statins had a beneficial effect (table 5).

TAB05
Table 5. Post hoc multivariate analysis of hazard ratios for the primary end point of recurrent ischemic stroke, including baseline characteristics with significant contribution to prediction of risk (p < 0.05)

Visit-to-visit variability of systolic blood pressure was found to be surprisingly large (up to ±32 mm Hg).

goto top of outline Safety

ER-DP plus ASA and ASA were well tolerated. The total number of adverse events was greater in the ER-DP plus ASA group compared with the ASA group (640 vs. 611, p = 0.04; table 6).

TAB06
Table 6. Adverse events by system organ class and preferred term with a frequency of ≥10% of the patients in either treatment group, other adverse events and mortality data

Major bleeding events and clinically relevant minor bleeding events were comparable in the ER-DP plus ASA and ASA groups (table 7).

TAB07
Table 7. Adjudicated bleeding events (numbers, with percentages in parentheses)

The difference in drug-related adverse events was mainly due to headache in the early stages of treatment with ER-DP plus ASA (table 6). More patients in the ER-DP plus ASA group discontinued treatment due to headache (table 6).

No relevant changes in laboratory parameters, vital signs and electrocardiography were noted in either treatment group.

There were 4 deaths (0.6%) in the ER-DP plus ASA group and 10 (1.6%) in the ASA group.

 

goto top of outline Discussion

In the JASAP trial, ER-DP plus ASA failed to demonstrate noninferiority over ASA for the event rate of recurrent ischemic stroke, which was the primary objective of this study. Consequently, the study could not prove superiority of one treatment over the other. The observed yearly event rates for ischemic stroke in the JASAP were smaller than expected for the sample size calculation (expected/observed event rate 8.5/3.9% in the ASA group vs. 6.0/5.4% in the ER-DP plus ASA group). The ASA arm showed a far lower event rate than in the ASA arms of other studies conducted about the same time; for example, the Sarpogrelate-Aspirin Comparative Clinical Study for Efficacy and Safety in Secondary Prevention of Cerebral Infarction [18] reported in patients with less pronounced risk profiles than in the JASAP an event rate for ASA of 4.9%/year (table 8), while in the JASAP we expected an event rate for ASA of 8.5%/year but we observed 3.9%/year. In contrast, for the ER-DP plus ASA arm, the expected event rate was 6.0%/year and was in the range of the observed event rate 5.6%/year. A retrospective power calculation revealed that, based on the actually observed lower-than-expected yearly event rates, the JASAP trial had only a 53% power to achieve its primary statistical objective that was to demonstrate noninferiority. Despite the fact that the number of enrolled patients had been increased by 125 patients in each arm and the enrollment period extended by 4 months during the conduct of the trial, the ASA incidence rates from previous trials could not be replicated. Similar underestimations have been observed in another trial conducted at the same time (CSPS 2 [19]).

TAB08
Table 8. Comparison of sample size, exposure to drug, event rate for recurrent stroke events and prevalence of risk factors in the JASAP study, the PRoFESS study, the S-ACCESS study, ESPS-2 and ESPRIT

A very early separation of the 2 Kaplan-Meier plots (within the first few days of treatment initiation) was observed in the JASAP, in the ER-DP plus ASA treatment arm (fig. 2a). This has never been observed in any other stroke prevention trials or trials with ER-DP plus ASA. These findings in the JASAP are unexplained and unexpected. Nevertheless, separation of the Kaplan-Meier curves has been observed after 6 months’ treatment in ESPS-2 [10]. Similarly, the slope of the log-log plot is consistently different in the second part of the treatment period potentially crossing at a later time (fig. 2b).

Study design and patient population differed substantially from previous and other trials as well; the JASAP enrolled patients as late as 180 days after the qualifying event, more than 50% of the patients had been recruited more than 1 month after the index stroke, approximately 19% of the patients were recruited more than 3 months after the event, compared with 3% of the patients in PRoFESS and 1.2% in ESPS-2 [10,] [20]. Early initiation of treatment has shown a clear benefit, as demonstrated in the recently published EARLY trial, which compared early (within 24 h after the event) initiation of treatment with ER-DP plus ASA (control group received ASA) with initiation after 7 days’ standard ASA treatment [21]. The benefit of the treatment with DP plus ASA was correlated with a significant reduction in innate inflammation [22], which was shown the highest immediately after stroke [23].

Compared to previous large stroke studies, this trial had the shortest patient exposure to medication (1.3 years vs. 1.4 years in ESPS-2, vs. 2.5 years in PRoFESS and vs. 3.5 years in ESPRIT) [10,11,20]. Trials investigating the prevention of a second stroke required several years of observation and follow-up in order to arrive at stable and conclusive data [11,24], strengthening the argument that in the JASAP trial, patients may have not been treated sufficiently long enough.

Concomitant treatment with irreversible platelet inhibitors (thienopyridines) was observed more frequently in the ASA arm (122 vs. 108 patients). This may have led to a confounding, irreversible inhibition of platelet function (table 3).

More patients with stroke had diabetes in the ER-DP plus ASA group (42.0 vs. 38.8%). Similar differences were observed for patients with concomitant hyperlipidemia (68.4 vs. 63.8%) and those receiving angiotensin receptor blockers (45.6 vs. 47.6%; table 3).

Even though patients with severe hypertension were excluded and concomitant antihypertensive treatment was in line with the Japanese Society of Hypertension guidelines [14], a high rate of hypertension and high visit-to-visit blood pressure differences were observed in both treatment arms. Neither excessive high blood pressure nor high instability has been reported for previous stroke prevention trials with any of the tested study medications.

A post hoc analysis of the visit-to-visit blood pressure measurements revealed a standard deviation of up to ±32 mm Hg of the mean blood pressure for individual patients. Recent publications argued that blood pressure fluctuations are even more predictive of vascular and thromboembolic complications than stable elevated blood pressure alone [25,26,27].

While direct platelet inhibitors such as ASA or thiopyridines show immediate benefit for controlling highly thrombogenic states such as after angioplasty or stenting, other preventive treatments have a protective or enhancing effect on the wall of blood vessels, such as DP, cilostazol or statins. Statins were found to not only reduce blood lipids, but through their pleiotrophic effects also positively influence antithrombotic/anti-inflammatory properties of the blood vessel walls [28,29]. However, the benefit for these approaches has only been shown after a longer period of time, typically 2.5 years and more. Reduction of inflammation has recently also been observed for DP experimentally [30,31,32] as well as clinically [22], setting this compound apart from conventional inhibitors of platelet function.

Given the high rate of diabetics in this study, it is tempting to compare these data with the diabetic subgroup of SPARCL [24]. A treatment benefit there was only shown in the later part of another trial, such as for nonfatal stroke. Both SPARCL and ESPRIT [11] showed benefit after significantly longer periods of observation. SPARCL also showed a numerical disadvantage for the active treatment of nonfatal stroke in diabetic patients in the early phase of the observation period. This is similar to the JASAP data. The JASAP then showed a convergence of the log-log plots of events, towards the end of the (short) observation period (fig. 2). One could argue that a longer duration of the study would have shown clearer results, as suggested by the extrapolation of the incidence seen in figure 2.

This study was originally designed for registration of ER-DP plus ASA in Japan, and was not of a sufficiently long duration. Modern treatment approaches, directed to restore and enhance antithrombotic functions of the blood vessel, not only require early initiation but also a longer period of treatment to produce the full benefit. This has been demonstrated with ER-DP plus ASA in EARLY and ESPRIT, and with statins in SPARCL.

The results from the JASAP are inconclusive. Neither noninferiority nor superiority of one treatment over the other was demonstrated. However, because of the frequent visits and thus good longitudinal observations in each patient, the JASAP trial highlights the importance of aggressive risk control, particularly blood pressure management, the importance of control of concomitant medication as well as the importance of very early initiation of treatment which is also capable of controlling acute inflammatory processes as well as sufficient length of the trial/treatment period to allow repair/recovery.

 

goto top of outline Conclusions

The JASAP study did not meet its primary study objective to demonstrate noninferiority of ER-DP plus ASA versus ASA 81 mg. Taken together, the favorable assessment of the combination treatment with ER-DP plus ASA over conventional platelet inhibition by ASA remains unchanged.

 

goto top of outline Appendix

The JASAP study investigators are as follows.

Steering Committee: Takenori Yamaguchi (chair), Shinichiro Uchiyama, Yasuo Ikeda (medical expert).

Protocol Committee: S. Uchiyama (chair), Kotaro Tanaka.

Statistical advisor: Hideki Origasa.

Event Assessment Committee: Masayasu Matsumoto (chair), Makoto Takagi, Yoshihiko Seino, Shinya Goto.

Safety Monitoring Committee: Masahiro Yasaka (chair), Takehiko Nagao, Haruko Yamamoto.

Principal investigators: Aiba, Ikuko; Akai, Akifumi; Akanuma, Jun; Aoki, Takeshi; Asahi, Minoru; Bundo, Masahiko; Chiba, Kei; Fujimoto, Shunichiro; Fujita, Tsuneo; Goto, Hirofumi; Harada, Kiyoshi; Hashiguchi, Kazuhide; Hashimoto, Yoshihiro; Hattori, Takeshi; Hayashi, Kazuko; Higashi, Sotaro; Hirai, Osamu; Ichihashi, Toshikazu; Imamura, Akira; Imamura, Shigehiro; Inoue, Yukiya; Irie, Shinsuke; Isaji, Takashi; Ishige, Naoki; Ishihara, Tetsuya; Isobe, Masanori; Ito, Kenjiro; Ito, Mamoru; Ito, Shotaro; Ito, Yasuhiro; Izumi, Yorimichi; Jinnouchi, Takafumi; Kaido, Misako; Kaku, Yasuhiko; Kamitani, Toshiaki; Kamiya, Ken; Kanda, Masutaro; Kaneko, Yoshiro; Kaseda, Shun; Katayama, Shinji; Kato, Kojiro; Kato, Takaaki; Kawakami, Masahisa; Kawakita, Seisaburo; Kawamoto, Takashi; Kawano, Hirokazu; Kim, Ilu; Kimura, Teruo; Kita, Yasushi; Kitazawa, Kazuo; Kiya, Katsuzo; Kobayashi, Nobuaki; Koda, Akashi; Kohno, Kazuyuki; Konno, Shu; Kotera, Minoru; Kubo, Toshiro; Kubota, Tsukasa; Kujiraoka, Yuji; Kurisaki, Hiroshi; Kurokawa, Shinichiro; Kurokawa, Tetsu; Kusuki, Tsukasa; Kuwahara, Kazuhide; Maeda, Yukio; Maruyama, Junichi; Matsui, Makoto; Matsumoto, Katsumi; Matsumoto, Masahiro; Matsumoto, Sadayuki; Matsunaga, Takashi; Mihara, Ban; Mishima, Nobuya; Miyata, Shiro; Mori, Kentaro; Mori, Satoru; Morimura, Tatsuo; Murai, Hiroyuki; Murao, Kenichi; Naka, Takashi; Naka, Yutaka; Nakagawa, Fukuo; Nakagawa, Hidemitsu; Nakagawara, Joji; Nakamura, Shigenobu; Nakamura, Yusaku; Nakane, Shunya; Nakano, Atsuhisa; Nakano, Imaharu; Nakayama, Teiji; Nishi, Shogo; Nishimura, Yasuaki; Nomura, Tatsufumi; Nozue, Mutsumi; Numazawa, Shinichi; Ochiai, Jun; Ohba, Hideki; Ohmori, Shigehiro; Ohnishi, Hideyuki; Ohyama, Hideki; Oiwa, Yoshitsugu; Oka, Kou; Oku, Takamitsu; Okuda, Satoshi; Okuma, Hirohisa; Onoda, Kimio; Orimo, Satoshi; Oshima, Shuichi; Sakai, Naoki; Sano, Motoki; Sasaki, Takahiro; Sato, Akira; Sato, Nobuyuki; Sato, Naoaki; Sato, Tsukasa; Seguchi, Tatsuya; Seki, Tadakazu; Seki, Yojiro; Shibagaki, Yasuro; Shigeno, Koji; Shimada, Kenji; Shimura, Hideki; Shindo, Naoko; Shingaki, Tatsuya; Shinozaki, Nobuaki; Shintani, Shuzo; Shirai, Kaoru; Shitamichi, Masayuki; Suda, Sumio; Suenaga, Toshihiko; Sugiyama, Makoto; Suwa, Tomonari; Tabata, Hitoshi; Tabuchi, Akira; Takahashi, Kazunori; Takahashi, Yoshitomo; Takashima, Shutaro; Takaya, Satoru; Takeda, Hidetaka; Takekawa, Mitsuru; Takenaka, Katsunobu; Takimoto, Yutaka; Takizawa, Katsumi; Tanabe, Hideki; Tanahashi, Hiromichi; Tanahashi, Norio; Tanaka, Naofumi; Tanaka, Shigeki; Tanemura, Takashi; Taniguchi, Hirokatsu; Taniwaki, Yoshihide; Tanoi, Chiharu; Tatsuoka, Yoshihisa; Terai, Tadashi; Terasaka, Shunsuke; Toda, Kazuo; Toriyama, Takanobu; Tsugu, Yasukuni; Tsuji, Tetsuro; Ueda, Yuji; Uemichi, Tomoyuki; Uenohara, Hiroshi; Urabe, Takao; Uranishi, Ryunosuke; Ushikoshi, Satoshi; Wada, Hirochiyo; Yamada, Takeshi; Yamagata, Hajime; Yamaguchi, Shuhei; Yamamoto, Toru; Yamamoto, Yasumasa; Yamasaki, Masahiro; Yamazaki, Masashi; Yanai, Yoshimi; Yaoita, Hiroyuki; Yoneda, Takeshi; Yoshida, Hideto.

 

goto top of outline Acknowledgements

The authors wish to thank all the patients and investigators involved in the study, who are listed in the Appendix. All authors contributed to the design, writing and critical appraisal of the manuscript. This study was sponsored and financed by Boehringer Ingelheim. Editorial assistance was provided by Quercus Medical Communications Ltd., UK. Funding for editorial assistance in the preparation of the manuscript was provided by Boehringer Ingelheim.

 

goto top of outline Disclosure Statement

S. Uchiyama is an advisory board member of Sanofi-Aventis KK, Nippon Boehringer Ingelheim Co. Ltd. and Bayer Yakuhin Ltd., and has received honoraria as a speaker or moderator and research funds from Sanofi-Aventis KK, Nippon Boehringer Ingelheim Co. Ltd., Daiichi Sankyo Co. Ltd. and Bayer Yakuhin Ltd.

Y. Ikeda received research grants or honoraria from Nippon Boehringer Ingelheim Co. Ltd., Chugai Pharmaceutical Co. Ltd., Daiichi Sankyo Co. Ltd., Astra Zeneca KK, Sanofi-Aventis KK, Glaxo Smith Kline KK, Kyowa Hakko Kirin Co. Ltd. and Eisai Co. Ltd.

T. Yamaguchi has provided consultancy for Nippon Boehringer Ingelheim Co. Ltd., Otsuka Pharmaceutical and Mitsubishi Tanabe Pharma; he also received honoraria for lecture from Otsuka Pharmaceutical, Sanofi-Aventis KK and a honorarium for chairmanship of public education from Bayer Yakuhin Ltd.

Y. Urano and Y. Horie are employees of Nippon Boehringer Ingelheim Co. Ltd.


 goto top of outline References
  1. Ueshima H, Sekikawa A, Miura K, Turin TC, Takashima N, Kita Y, Watanabe M, Kadota A, Okuda N, Kadowaki T, Nakamura Y, Okamura T: Cardiovascular disease and risk factors in Asia: a selected review. Circulation 2008;118:2702–2709.
  2. World Health Organization: The atlas of heart disease and stroke. 6. World tables. 2010. http://www.who.int/entity/cardiovascular_diseases/en/cvd_atlas_29_world_data_table.pdf (accessed August 2010).
  3. Turin TC, Kokubo Y, Murakami Y, Higashiyama A, Rumana N, Watanabe M, Okamura T: Lifetime risk of stroke in Japan. Stroke 2010;41:1552–1554.
  4. Kimura K, Minematsu K, Kazui S, Yamaguchi T, Japan Multicenter Stroke Investigators’ Collaboration (J-MUSIC): Mortality and cause of death after hospital discharge in 10,981 patients with ischemic stroke and transient ischemic attack. Cerebrovasc Dis 2005;19:171–178.
  5. Wang X, Jiang G, Choi BC, Wang D, Wu T, Pan Y, Boulton M: Surveillance of trend and distribution of stroke mortality by subtype, age, gender, and geographic areas in Tianjin, China, 1999–2006. Int J Stroke 2009;4:169–174.
  6. Kobayashi S: Stroke Databank 2009. Tokyo, Nakayama Shoten Co, 2009.
  7. Kubo M, Kiyohara Y, Kato I, Tanizaki Y, Arima H, Tanaka K, Nakamura H, Okubo K, Iida M: Trends in incidence, mortality, and survival rate of cardiovascular disease in a Japanese community: the Hisayama Study. Stroke 2003;34:2349–2354.
  8. World Health Organization: The atlas of heart disease and stroke. 2. Risk factors. 2010. www.who.int/entity/cardiovascular_diseases/en/cvd_atlas_03_risk_factors.pdf (accessed August 2010).
  9. European Medicines Agency (EMEA): ICH Topic E 5 (R1). Ethnic factors in the acceptability of foreign clinical data. CPMP/ICH/289/95. September 1998. www.ema.europa.eu/pdfs/human/ich/028995en.pdf (accessed July 2010).
  10. Diener H-C, Cunha L, Forbes C, Sivenius J, Smets P, Lowenthal A: European Stroke Prevention Study. 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci 1996;143:1–13.
  11. The ESPRIT Study Group: Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial. Lancet 2006;367:1665–1673.
  12. Adams RJ, Albers G, Alberts MJ, Benavente O, Furie K, Goldstein LB, Gorelick P, Halperin J, Harbaugh R, Johnston SC, Katzan I, Kelly-Hayes M, Kenton EJ, Marks M, Sacco RL, Schwamm LH, American Heart Association, American Stroke Association: Update to the AHA/ASA recommendations for the prevention of stroke in patients with stroke and transient ischemic attack. Stroke 2008;39:1647–1652.
  13. European Stroke Organization (ESO) Executive Committee, ESO Writing Committee: Guidelines for management of ischaemic stroke and transient ischaemic attack 2008. Cerebrovasc Dis 2008;25:457–507.
  14. Japanese Society of Hypertension: Guidelines for the management of hypertension (JSH 2004). Hypertens Res Clin Exp 2006;29(suppl):S1–S102.
  15. Health and Welfare Statistics Association: Annual Statistical Report of National Health Conditions (in Japanese). 2002, pp 388–389.
  16. Japan Diabetes Society: Treatment Guide for Diabetes 2006–2007. Tokyo, Bunkodo Co, 2006.
  17. Japan Atherosclerosis Society: Japan Atherosclerosis Society (JAS) guidelines for diagnosis and treatment of atherosclerotic cardiovascular diseases. 2002.
  18. Shinohara Y, Nishimaru K, Sawada T, Terashi A, Handa S, Hirai S, Hayashi K, Tohgi H, Fukuuchi Y, Uchiyama S, Yamaguchi T, Kobayashi S, Kondo K, Otomi E, Gotoh F, S-ACCESS Study Group: Sarpogrelate-aspirin comparative clinical study for efficacy and safety in secondary prevention of cerebral infarction (S-ACCESS): a randomized, double-blind, aspirin-controlled trial. Stroke 2008;39:1827–1833.
  19. Shinohara Y, Katayama Y, Uchiyama S, Yamaguchi T, Handa S, Matsuoka K, Ohashi Y, Tanahashi N, Yamamoto H, Genka C, Kitagawa Y, Kusuoka H, Nishimaru K, Tsushima M, Koretsune Y, Sawada T, Hamada C, CSPS 2 group: Cilostazol for prevention of secondary stroke (CSPS 2): an aspirin-controlled, double-blind, randomised non-inferiority trial. Lancet Neurol 2010;9:959–968.
  20. Sacco RL, Diener H-C, Yusuf S, Cotton D, Ôunpuu S, Lawton WA, Palesch Y, Martin RH, Albers GW, Bath P, Bornstein N, Chan BPL, Chen S-T, Cunha L, Dahlöf B, De Keyser J, Donnan GA, Estol C, Gorelick P, Gu V, Hermansson K, Hilbirch L, Kaste M, Lu C, Machig T, Pais P, Roberts R, Skvortsova V, Teal P, Toni D, Van der Maelen C, Voigt T, Weber M, Yoon B-W, the PRoFESS Study Group: Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke. N Engl J Med 2008;359:1238–1251.
  21. Dengler R, Diener HC, Schwartz A, Grond M, Schumacher H, Machnig T, Eschenfelder CC, Leonard J, Weissenborn K, Kastrup A, Haberl R, the EARLY investigators: Early treatment with aspirin plus extended-release dipyridamole for transient ischaemic attack or ischaemic stroke within 24 h of symptom onset (EARLY trial): a randomised, open-label, blinded-endpoint trial. Lancet Neurol 2010;9:159–166.
  22. Worthmann H, Lichtinghagen R, Dengler R, et al: Relationship between inflammatory biomarkers, acute treatment and clinical outcome after ischaemic stroke and TIA: a substudy of the EARLY trial (poster presentation). Cerebrovasc Dis 2010;29(suppl 2):12.
  23. Worthmann H, Tryc AB, Goldbecker A, Ma YT, Tountopoulou A, Hahn A, Denger R, Lichtinghagen R, Weissenborn K: The temporal profile of inflammatory markers and mediators in blood after acute ischemic stroke differs depending on stroke outcome. Cerebrovasc Dis 2010;30:85–92.
  24. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators: High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med 2006;355:549–559.
  25. Rothwell PM: Limitations of the usual blood-pressure hypothesis and importance of variability, instability, and episodic hypertension. Lancet 2010;375:938–948.
  26. Rothwell PM, Howard SC, Dolan E, O’Brien E, Dobson JE, Dahlöf B, Sever PS, Poulter NR: Prognostic significance of visit-to-visit variability, maximum systolic blood pressure, and episodic hypertension. Lancet 2010;375:895–905.
  27. Rothwell PM, Howard SC, Dolan E, O’Brien E, Dobson JE, Dahlöf B, Poulter NR, Sever PS, ASCOT-BPLA and MRC Trial Investigators: Effects of beta-blockers and calcium channel blockers on within-individual variability in blood pressure and risk of stroke. Lancet Neurol 2010;9:469–480.
  28. Mays ME, Dujovne CA: Pleiotropic effects: should statins be considered an essential component in the treatment of dyslipidemia? Curr Atheroscler Res 2008;10:45–52.
  29. Örem C, Uydu HA, Yilmaz R, Gökçe M, Baykan M, Eminağaoğlu S, Örem A: The effects of atorvastatin treatment on the fibrinolytic system in dyslipidemic patients. Jpn Heart J 2004;45:977–987.
  30. Kim HH, Liao JK: Translational therapeutics of dipyridamole. Arterioscler Thromb Vasc Biol 2008;28:s39–s42.
  31. Venkatesh PK, Pattillo CB, Branch B, Hood J, Thoma S, Illum S, Pardue S, Teng X, Patel RP, Kevil CG: Dipyridamole enhances ischaemia-induced arteriogenesis through an endocrine nitrate/nitric oxide-dependent pathway. Cardiovasc Res 2010;85:661–670.
  32. Weyrich AS, Denis MM, Kuhlmann-Eyre JR, Spencer ED, Dixon DA, Marathe GK, McIntrye TM, Zimmerman GA, Prescott SM: Dipyridamole selectively inhibits inflammatory gene expression in platelet-monocyte aggregates. Circulation 2005;111:633–642.

 goto top of outline Author Contacts

Prof. Shinichiro Uchiyama
Department of Neurology, Tokyo Women’s Medical University
8-1 Kawada-cho, Shinjuku-ku
Tokyo 162-8666 (Japan)
Tel. +81 3 3353 8111, E-Mail suchiyam@nij.twmu.ac.jp


 goto top of outline Article Information

The reported study was presented in part at the Japanese Stroke Society meeting on April 10, 2010, and the World Stroke Congress on October 14, 2010.

Received: October 26, 2010
Accepted: March 3, 2011
Published online: April 19, 2011
Number of Print Pages : 13
Number of Figures : 4, Number of Tables : 8, Number of References : 32


 goto top of outline Publication Details

Cerebrovascular Diseases

Vol. 31, No. 6, Year 2011 (Cover Date: May 2011)

Journal Editor: Hennerici M.G. (Mannheim)
ISSN: 1015-9770 (Print), eISSN: 1421-9786 (Online)

For additional information: http://www.karger.com/CED


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

Background: Despite improvements in treatment, stroke still carries a high death toll and disability in Asia. Extended-release dipyridamole (ER-DP) plus acetylsalicylic acid (ASA) has consistently been shown to be superior over conventional platelet inhibition by ASA. ER-DP plus ASA is well established in the secondary prevention of stroke in a lot of countries including the USA and Europe. DP has an established benefit in the treatment of heart disease in Japan; however, for the prevention of stroke, the fixed-dose combination of ER-DP plus ASA has only been investigated in a small number of patients in Japan. Methods: The aim of this double-blind, randomized clinical trial was to investigate the efficacy and safety of ER-DP plus ASA versus 81 mg ASA over 1 year. The primary end point of this study was the event rate of recurrent ischemic stroke (fatal or nonfatal) using the Kaplan-Meier method and Cox regression analysis. Results: Of the 1,294 enrolled patients, the primary end point was analyzed in 652 patients in the ER-DP plus ASA group and 639 in the ASA group. The incidence of ischemic stroke was 6.9% for ER-DP plus ASA and 5.0% for ASA with a hazard ratio of 1.47 (95% confidence interval 0.93–2.31) for the primary end point. The ASA treatment group was found to have a lower than expected yearly event rate, compared to other studies in Japanese stroke patients. Noninferiority of ER-DP plus ASA versus ASA could not be shown. The risks of major bleeding events and intracranial hemorrhage were found to be similar between the treatment arms. There were 4 deaths (0.6%) in the ER-DP plus ASA group and 10 (1.6%) in the ASA group. Conclusions: The results of the study are inconclusive. Noninferiority of ER-DP plus ASA versus ASA could not be established, a difference between treatments could not be shown for the primary end point. Possible reasons for this result include a small sample size, low event rates and too short a treatment duration (ClinicalTrials. gov number, NCT00311402).



 goto top of outline Author Contacts

Prof. Shinichiro Uchiyama
Department of Neurology, Tokyo Women’s Medical University
8-1 Kawada-cho, Shinjuku-ku
Tokyo 162-8666 (Japan)
Tel. +81 3 3353 8111, E-Mail suchiyam@nij.twmu.ac.jp


 goto top of outline Article Information

The reported study was presented in part at the Japanese Stroke Society meeting on April 10, 2010, and the World Stroke Congress on October 14, 2010.

Received: October 26, 2010
Accepted: March 3, 2011
Published online: April 19, 2011
Number of Print Pages : 13
Number of Figures : 4, Number of Tables : 8, Number of References : 32


 goto top of outline Publication Details

Cerebrovascular Diseases

Vol. 31, No. 6, Year 2011 (Cover Date: May 2011)

Journal Editor: Hennerici M.G. (Mannheim)
ISSN: 1015-9770 (Print), eISSN: 1421-9786 (Online)

For additional information: http://www.karger.com/CED


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Ueshima H, Sekikawa A, Miura K, Turin TC, Takashima N, Kita Y, Watanabe M, Kadota A, Okuda N, Kadowaki T, Nakamura Y, Okamura T: Cardiovascular disease and risk factors in Asia: a selected review. Circulation 2008;118:2702–2709.
  2. World Health Organization: The atlas of heart disease and stroke. 6. World tables. 2010. http://www.who.int/entity/cardiovascular_diseases/en/cvd_atlas_29_world_data_table.pdf (accessed August 2010).
  3. Turin TC, Kokubo Y, Murakami Y, Higashiyama A, Rumana N, Watanabe M, Okamura T: Lifetime risk of stroke in Japan. Stroke 2010;41:1552–1554.
  4. Kimura K, Minematsu K, Kazui S, Yamaguchi T, Japan Multicenter Stroke Investigators’ Collaboration (J-MUSIC): Mortality and cause of death after hospital discharge in 10,981 patients with ischemic stroke and transient ischemic attack. Cerebrovasc Dis 2005;19:171–178.
  5. Wang X, Jiang G, Choi BC, Wang D, Wu T, Pan Y, Boulton M: Surveillance of trend and distribution of stroke mortality by subtype, age, gender, and geographic areas in Tianjin, China, 1999–2006. Int J Stroke 2009;4:169–174.
  6. Kobayashi S: Stroke Databank 2009. Tokyo, Nakayama Shoten Co, 2009.
  7. Kubo M, Kiyohara Y, Kato I, Tanizaki Y, Arima H, Tanaka K, Nakamura H, Okubo K, Iida M: Trends in incidence, mortality, and survival rate of cardiovascular disease in a Japanese community: the Hisayama Study. Stroke 2003;34:2349–2354.
  8. World Health Organization: The atlas of heart disease and stroke. 2. Risk factors. 2010. www.who.int/entity/cardiovascular_diseases/en/cvd_atlas_03_risk_factors.pdf (accessed August 2010).
  9. European Medicines Agency (EMEA): ICH Topic E 5 (R1). Ethnic factors in the acceptability of foreign clinical data. CPMP/ICH/289/95. September 1998. www.ema.europa.eu/pdfs/human/ich/028995en.pdf (accessed July 2010).
  10. Diener H-C, Cunha L, Forbes C, Sivenius J, Smets P, Lowenthal A: European Stroke Prevention Study. 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci 1996;143:1–13.
  11. The ESPRIT Study Group: Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial. Lancet 2006;367:1665–1673.
  12. Adams RJ, Albers G, Alberts MJ, Benavente O, Furie K, Goldstein LB, Gorelick P, Halperin J, Harbaugh R, Johnston SC, Katzan I, Kelly-Hayes M, Kenton EJ, Marks M, Sacco RL, Schwamm LH, American Heart Association, American Stroke Association: Update to the AHA/ASA recommendations for the prevention of stroke in patients with stroke and transient ischemic attack. Stroke 2008;39:1647–1652.
  13. European Stroke Organization (ESO) Executive Committee, ESO Writing Committee: Guidelines for management of ischaemic stroke and transient ischaemic attack 2008. Cerebrovasc Dis 2008;25:457–507.
  14. Japanese Society of Hypertension: Guidelines for the management of hypertension (JSH 2004). Hypertens Res Clin Exp 2006;29(suppl):S1–S102.
  15. Health and Welfare Statistics Association: Annual Statistical Report of National Health Conditions (in Japanese). 2002, pp 388–389.
  16. Japan Diabetes Society: Treatment Guide for Diabetes 2006–2007. Tokyo, Bunkodo Co, 2006.
  17. Japan Atherosclerosis Society: Japan Atherosclerosis Society (JAS) guidelines for diagnosis and treatment of atherosclerotic cardiovascular diseases. 2002.
  18. Shinohara Y, Nishimaru K, Sawada T, Terashi A, Handa S, Hirai S, Hayashi K, Tohgi H, Fukuuchi Y, Uchiyama S, Yamaguchi T, Kobayashi S, Kondo K, Otomi E, Gotoh F, S-ACCESS Study Group: Sarpogrelate-aspirin comparative clinical study for efficacy and safety in secondary prevention of cerebral infarction (S-ACCESS): a randomized, double-blind, aspirin-controlled trial. Stroke 2008;39:1827–1833.
  19. Shinohara Y, Katayama Y, Uchiyama S, Yamaguchi T, Handa S, Matsuoka K, Ohashi Y, Tanahashi N, Yamamoto H, Genka C, Kitagawa Y, Kusuoka H, Nishimaru K, Tsushima M, Koretsune Y, Sawada T, Hamada C, CSPS 2 group: Cilostazol for prevention of secondary stroke (CSPS 2): an aspirin-controlled, double-blind, randomised non-inferiority trial. Lancet Neurol 2010;9:959–968.
  20. Sacco RL, Diener H-C, Yusuf S, Cotton D, Ôunpuu S, Lawton WA, Palesch Y, Martin RH, Albers GW, Bath P, Bornstein N, Chan BPL, Chen S-T, Cunha L, Dahlöf B, De Keyser J, Donnan GA, Estol C, Gorelick P, Gu V, Hermansson K, Hilbirch L, Kaste M, Lu C, Machig T, Pais P, Roberts R, Skvortsova V, Teal P, Toni D, Van der Maelen C, Voigt T, Weber M, Yoon B-W, the PRoFESS Study Group: Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke. N Engl J Med 2008;359:1238–1251.
  21. Dengler R, Diener HC, Schwartz A, Grond M, Schumacher H, Machnig T, Eschenfelder CC, Leonard J, Weissenborn K, Kastrup A, Haberl R, the EARLY investigators: Early treatment with aspirin plus extended-release dipyridamole for transient ischaemic attack or ischaemic stroke within 24 h of symptom onset (EARLY trial): a randomised, open-label, blinded-endpoint trial. Lancet Neurol 2010;9:159–166.
  22. Worthmann H, Lichtinghagen R, Dengler R, et al: Relationship between inflammatory biomarkers, acute treatment and clinical outcome after ischaemic stroke and TIA: a substudy of the EARLY trial (poster presentation). Cerebrovasc Dis 2010;29(suppl 2):12.
  23. Worthmann H, Tryc AB, Goldbecker A, Ma YT, Tountopoulou A, Hahn A, Denger R, Lichtinghagen R, Weissenborn K: The temporal profile of inflammatory markers and mediators in blood after acute ischemic stroke differs depending on stroke outcome. Cerebrovasc Dis 2010;30:85–92.
  24. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators: High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med 2006;355:549–559.
  25. Rothwell PM: Limitations of the usual blood-pressure hypothesis and importance of variability, instability, and episodic hypertension. Lancet 2010;375:938–948.
  26. Rothwell PM, Howard SC, Dolan E, O’Brien E, Dobson JE, Dahlöf B, Sever PS, Poulter NR: Prognostic significance of visit-to-visit variability, maximum systolic blood pressure, and episodic hypertension. Lancet 2010;375:895–905.
  27. Rothwell PM, Howard SC, Dolan E, O’Brien E, Dobson JE, Dahlöf B, Poulter NR, Sever PS, ASCOT-BPLA and MRC Trial Investigators: Effects of beta-blockers and calcium channel blockers on within-individual variability in blood pressure and risk of stroke. Lancet Neurol 2010;9:469–480.
  28. Mays ME, Dujovne CA: Pleiotropic effects: should statins be considered an essential component in the treatment of dyslipidemia? Curr Atheroscler Res 2008;10:45–52.
  29. Örem C, Uydu HA, Yilmaz R, Gökçe M, Baykan M, Eminağaoğlu S, Örem A: The effects of atorvastatin treatment on the fibrinolytic system in dyslipidemic patients. Jpn Heart J 2004;45:977–987.
  30. Kim HH, Liao JK: Translational therapeutics of dipyridamole. Arterioscler Thromb Vasc Biol 2008;28:s39–s42.
  31. Venkatesh PK, Pattillo CB, Branch B, Hood J, Thoma S, Illum S, Pardue S, Teng X, Patel RP, Kevil CG: Dipyridamole enhances ischaemia-induced arteriogenesis through an endocrine nitrate/nitric oxide-dependent pathway. Cardiovasc Res 2010;85:661–670.
  32. Weyrich AS, Denis MM, Kuhlmann-Eyre JR, Spencer ED, Dixon DA, Marathe GK, McIntrye TM, Zimmerman GA, Prescott SM: Dipyridamole selectively inhibits inflammatory gene expression in platelet-monocyte aggregates. Circulation 2005;111:633–642.