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Although stroke is the second leading cause of death worldwide, no comprehensive and comparable assessment of incidence, prevalence, mortality, disability, and epidemiological trends has been estimated for most regions. We used data from the Global Burden of Diseases, Injuries, and Risk Factors Study 2010 (GBD 2010) to estimate the global and regional burden of stroke during 1990–2010. We searched Medline, Embase, LILACS, Scopus, PubMed, Science Direct, Global Health Database, the WHO library, and WHO regional databases from 1990 to 2012 to identify relevant studies published between 1990 and 2010. We applied the GBD 2010 analytical technique (DisMod-MR), based on disease-specific, pre-specified associations between incidence, prevalence, and mortality, to calculate regional and country-specific estimates of stroke incidence, prevalence, mortality, and disability-adjusted life-years (DALYs) lost by age group (<75 years, ≥75 years, and in total) and country income level (high-income, and low-income and middle-income) for 1990, 2005, and 2010. We included 119 studies (58 from high-income countries and 61 from low-income and middle-income countries). From 1990 to 2010, the age-standardised incidence of stroke significantly decreased by 12% (95% CI 6–17) in high-income countries, and increased by 12% (–3 to 22) in low-income and middle-income countries, albeit non-significantly. Mortality rates decreased significantly in both high income (37%, 31–41) and low-income and middle-income countries (20%, 15–30). In 2010, the absolute numbers of people with first stroke (16·9 million), stroke survivors (33 million), stroke-related deaths (5·9 million), and DALYs lost (102 million) were high and had significantly increased since 1990 (68%, 84%, 26%, and 12% increase, respectively), with most of the burden (68·6% incident strokes, 52·2% prevalent strokes, 70·9% stroke deaths, and 77·7% DALYs lost) in low-income and middle-income countries. In 2010, 5·2 million (31%) strokes were in children (aged <20 years old) and young and middle-aged adults (20–64 years), to which children and young and middle-aged adults from low-income and middle-income countries contributed almost 74 000 (89%) and 4·0 million (78%), respectively, of the burden. Additionally, we noted significant geographical differences of between three and ten times in stroke burden between GBD regions and countries. More than 62% of new strokes, 69·8% of prevalent strokes, 45·5% of deaths from stroke, and 71·7% of DALYs lost because of stroke were in people younger than 75 years. Although age-standardised rates of stroke mortality have decreased worldwide in the past two decades, the absolute number of people who have a stroke every year, stroke survivors, related deaths, and the overall global burden of stroke (DALYs lost) are great and increasing. Further study is needed to improve understanding of stroke determinants and burden worldwide, and to establish causes of disparities and changes in trends in stroke burden between countries of different income levels. Bill & Melinda Gates Foundation.

The antiplatelet drug cilostazol is efficacious for prevention of stroke recurrence compared with placebo. We designed the second Cilostazol Stroke Prevention Study (CSPS 2) to establish non-inferiority of cilostazol versus aspirin for prevention of stroke, and to compare the efficacy and safety of cilostazol and aspirin in patients with non-cardioembolic ischaemic stroke. Patients aged 20–79 years who had had a cerebral infarction within the previous 26 weeks were enrolled at 278 sites in Japan and allocated to receive 100 mg cilostazol twice daily or 81 mg aspirin once daily for 1–5 years. Patients were allocated according to a computer-generated randomisation sequence by means of a dynamic balancing method using patient information obtained at registration. All patients, study personnel, investigators, and the sponsor were masked to treatment allocation. The primary endpoint was the first occurrence of stroke (cerebral infarction, cerebral haemorrhage, or subarachnoid haemorrhage). The predefined margin of non-inferiority was an upper 95% CI limit for the hazard ratio of 1·33. Analyses were by full-analysis set. This trial is registered with ClinicalTrials.gov, number NCT00234065. Between December, 2003, and October, 2006, 2757 patients were enrolled and randomly allocated to receive cilostazol (n=1379) or aspirin (n=1378), of whom 1337 on cilostazol and 1335 on aspirin were included in analyses; mean follow-up was 29 months (SD 16). The primary endpoint occurred at yearly rates of 2·76% (n=82) in the cilostazol group and 3·71% (n=119) in the aspirin group (hazard ratio 0·743, 95% CI 0·564–0·981; p=0·0357). Haemorrhagic events (cerebral haemorrhage, subarachnoid haemorrhage, or haemorrhage requiring hospital admission) occurred in fewer patients on cilostazol (0·77%, n=23) than on aspirin (1·78%, n=57; 0·458, 0·296–0·711; p=0·0004), but headache, diarrhoea, palpitation, dizziness, and tachycardia were more frequent in the cilostazol group than in the aspirin group. Cilostazol seems to be non-inferior, and might be superior, to aspirin for prevention of stroke after an ischaemic stroke, and was associated with fewer haemorrhagic events. Therefore, cilostazol could be used for prevention of stroke in patients with non-cardioembolic stroke. Otsuka Pharmaceutical.

Background: Different aspects of acute stroke management and strategies for stroke prevention derive from two viewpoints: specific traditional and historical backgrounds and evidence-based medicine from modern randomized controlled trials (RCTs), meta-analysis and authorized clinical practice guidelines (GLs). Regarding stroke, GLs have been published by national and international organizations in different languages, most frequently in English. Cerebrovascular Diseases published the European GLs for the management of ischemic stroke and transient ischemic attacks in 2003, with an update in 2008. At about the same time (in 2004), the first Japanese GLs for the management of stroke appeared in Japanese. The first English version of the updated Japanese GLs was published only in 2011 and included differently approved drugs and drug dosages as compared with other American or European countries. Methods: Since 2011, the authors have met repeatedly and have compared the latest versions of published European and Japanese GLs for ischemic and hemorrhagic strokes. Many aspects have only been addressed in one but left out in the other GLs, which consequently founded the basis for the comparison. Classification of evidence levels and recommendation grades defined by the individual committees differed between both original GLs. Results: Aspects of major importance were surprisingly similar and hence did not need extensive interpretation. Other aspects of ischemic stroke management differed significantly, e.g. the dosage of recombinant tissue plasminogen activator approved in Japan is lower (0.6 mg/kg) than in Europe (0.9 mg/kg), which derived from different practices in cardiovascular treatment prior to the design of acute ischemic stroke RCTs. Furthermore, comedication with neuroprotective agents (edaravone), intravenous anticoagulants (argatroban) or antiplatelet agents within 1-2 days after stroke onset is recommended in Japan but not in Europe. For cardioembolic stroke prevention, a major difference consists in a higher international normalized ratio target (2.0-3.0) in younger subjects versus in those >70 years (1.6-2.6), without age restrictions in Europe. Conclusion: This brief survey - when compared with the lengthy original recommendations - provides a stimulating basis for an extended interest among Japanese and European stroke clinicians to learn from their individual experiences and to strengthen efforts for joint cooperation in treating and preventing stroke all around the globe.

We have previously reported that the phosphodiesterase inhibitor cilostazol, an antiplatelet agent, is effective and safe for secondary prevention of recurrent cerebral infarction (Cilostazol Stroke Prevention Study; CSPS). We now report the efficacy of this drug in the prevention of pneumonia in the chronic stage of cerebral infarction as a part of our CSPS subgroup analysis. The analysis was conducted in 1,049 subjects; 524 in the cilostazol group and 525 in the placebo group. The incidences of pneumonia during the 3.3-year follow-up were 2.86% (15 in 525 patients) in the placebo group and 0.57% (3 in 524 patients) in the cilostazol group, with a significant reduction in the cilostazol group. The rates of complications and pneumonia risk factors showed no difference between the two groups. We conclude that the administration of cilostazol to patients with cerebral infarction in the chronic stage does not only reduce the recurrence of infarction but also the incidence of pneumonia at least in Japanese patients.

Background: Edaravone, a free radical scavenger approved by the Japanese Ministry of Health, Labor and Welfare in 2001 for treating acute ischemic stroke, was recommended by the Japanese Guidelines for the Management of Stroke 2004. While edaravone also has a neuroprotective profile, there is no other recognized drug that can verify its effect in clinical trials despite the need for neuroprotection. We performed a postmarketing clinical trial to provide further reliable evidence concerning edaravone in patients with acute ischemic stroke. Methods: We conducted a multicenter randomized parallel-group open-label trial of edaravone intravenously and a control drug, sodium ozagrel (ozagrel), a thromboxane A 2 synthase inhibitor, intravenously in acute noncardioembolic ischemic stroke. The primary endpoint was the modified Rankin Scale at 3 months after treatment initiation. Results: In total, 401 patients were initially enrolled. The rate of ‘grade 0–1’ on the modified Rankin Scale, as assessed at 3 months, was 57.1 and 50.3% in the edaravone and ozagrel groups, respectively. The intergroup difference was 6.8% (95% confidence interval = –3.1 to 16.7), indicating noninferiority of edaravone to ozagrel, since the lower limit of the confidence interval did not exceed –11.4%. There were no particular concerns over the safety of edaravone. Conclusion: This trial verified that edaravone was not inferior to ozagrel. Edaravone was at least as effective as ozagrel for the treatment of acute noncardioembolic ischemic stroke.

Background: Different aspects of acute stroke management and strategies for stroke prevention derive from two viewpoints: specific traditional and historical backgrounds and evidence-based medicine from modern randomized controlled trials (RCTs), meta-analysis and authorized clinical practice guidelines (GLs). Regarding intracerebral hemorrhage (ICH), Cerebrovascular Diseases published the 2006 European stroke initiative recommendations for the management of ICH. In 2009, the revised Japanese GLs for the management of stroke, including that of ICH, appeared in Japanese. Whereas GLs for the prevention and treatment of ischemic stroke were presented in detail, recommendations with regard to ICH are relatively rare both in Japan and Europe. Methods: Since 2011, the authors have met repeatedly and have compared the latest versions of published European and Japanese GLs for ischemic and hemorrhagic strokes. Many aspects have only been addressed in one but left out in the other GLs, which consequently founded the basis for the comparison. Classification of evidence levels and recommendation grades defined by the individual committees differed between both original GLs. Results: Aspects of major importance were similar and hence did not need extensive interpretation, mostly due to a lack of evidence from appropriate RCTs worldwide. The target level to which systolic blood pressure should be lowered is quite high; <170 mm Hg for patients with known hypertension in Europe and <180 mm Hg in Japan. The results of ongoing clinical trials are awaited for the optimal target level and optimal medications. Concerning ICH associated with oral anticoagulant therapy, both guidelines give similar recommendations, namely that anticoagulation should be discontinued and the international normalized ratio of prothrombin time should be normalized with prothrombin complex concentrate or fresh-frozen plasma and additional vitamin K. Patients with ICH were treated surgically, often based on individual decisions - more frequently in Japan, depending on the association with hypertension. Patients with large or intraventricular bleedings were only treated if a life-saving performance was considered, irrespective of the neurological outcome. Infra- and supratentorial differences were similarly addressed in both GLs. Conclusion: This brief survey - when compared with the lengthy original recommendations - provides a stimulating basis for an extended interest among Japanese and European stroke clinicians to learn from their individual experiences and to strengthen efforts for joint cooperation in treating and preventing stroke all around the globe.

Background and Purpose: The number of chronic-stage ischemic stroke patients in Japan continues to increase, because of decreasing mortality. This study was designed to ascertain health-related quality of life (HRQOL) in ischemic stroke patients and to analyze in detail factors affecting HRQOL. Methods: 2,069 outpatients (1,226 males, 843 females; mean age: 71 years; median duration after onset: 20.5 months) with chronic-stage ischemic stroke visiting 150 institutions in Japan were enrolled. HRQOL was evaluated using the second version of the patient self-administered Medical Outcome Study 36-Item Short-Form Health Survey (SF-36v2) questionnaire. Results: All 8 domain scores and the physical component summary (PCS) score of SF-36v2 in stroke patients were significantly lower than those of Japanese national norms (JNN). The PCS score (36.6 ± 16.1) and mental component summary (MCS) score (50.0 ± 10.2) were lower than those of age-matched JNN (p < 0.001). Age, modified Rankin Scale (mRS), duration after onset and Japan Stroke Scale Depression score (JSS-D) were significantly correlated with PCS, as were role limitation because of physical problem, bodily pain, vitality and role limitation because of emotional problem scores; duration after onset and JSS-D were significantly correlated with MCS. Negative factors for PCS were older age, higher mRS, presence of subjective symptoms, neurological signs, rehabilitation and concomitant antidepressants. Negative factors for MCS were presence of subjective symptoms, psychiatric signs and concomitant antidepressants. Conclusions: HRQOL scores in ischemic stroke patients (chronic stage) are significantly correlated with not only age, mRS, duration after onset and JSS-D, but also presence of subjective symptoms and neurological/psychiatric signs, which could be targets for treatment.

Background and Purpose: Although antiplatelets are known to be effective for secondary prevention of cerebral infarction, the number needed to treat is rather large and the effects in stroke patients with complications such as hypertension or diabetes are inadequately defined. This study was conducted to examine the effect of such complications on recurrence of cerebral infarction, and to assess the effect of cilostazol, an antiplatelet agent, in these high-risk subjects. Methods: A post hoc subgroup analysis of the already reported Cilostazol Stroke Prevention Study, which was a placebo-controlled double-blind trial, has been carried out to clarify the influence of various complications on recurrence in the placebo group and the effects of cilostazol in 1,095 patients with noncardioembolic ischemic cerebrovascular disease. Treatment continued for an average of 1.8 ± 1.3 years (maximum 4.8 years). Results: The recurrence rate of the diabetic stroke patients was significantly higher compared with the nondiabetics in the placebo group (9.4 vs. 4.7%/year, p = 0.01). Furthermore, our study showed that the relative risk reduction (RRR) for recurrence of infarction was 41.7% with cilostazol. This treatment provided a significant benefit in patients with lacunar infarction (RRR 43.4%, p = 0.04), with diabetes (RRR 64.4%, p = 0.008), or with hypertension (RRR 58.0%, p = 0.003). Conclusions: Diabetic patients are particularly at risk for recurrence of cerebral infarction. Cilostazol is useful for the prevention of the recurrence of vascular events in patients with lacunar infarction, and is probably effective in high-risk patients with diabetes and/or hypertension.

Background: Global stroke epidemiology is changing rapidly. Although age-standardized rates of stroke mortality have decreased worldwide in the past 2 decades, the absolute numbers of people who have a stroke every year, and live with the consequences of stroke or die from their stroke, are increasing. Regular updates on the current level of stroke burden are important for advancing our knowledge on stroke epidemiology and facilitate organization and planning of evidence-based stroke care. Objectives: This study aims to estimate incidence, prevalence, mortality, disability-adjusted life years (DALYs) and years lived with disability (YLDs) and their trends for ischemic stroke (IS) and hemorrhagic stroke (HS) for 188 countries from 1990 to 2013. Methodology: Stroke incidence, prevalence, mortality, DALYs and YLDs were estimated using all available data on mortality and stroke incidence, prevalence and excess mortality. Statistical models and country-level covariate data were employed, and all rates were age-standardized to a global population. All estimates were produced with 95% uncertainty intervals (UIs). Results: In 2013, there were globally almost 25.7 million stroke survivors (71% with IS), 6.5 million deaths from stroke (51% died from IS), 113 million DALYs due to stroke (58% due to IS) and 10.3 million new strokes (67% IS). Over the 1990-2013 period, there was a significant increase in the absolute number of DALYs due to IS, and of deaths from IS and HS, survivors and incident events for both IS and HS. The preponderance of the burden of stroke continued to reside in developing countries, comprising 75.2% of deaths from stroke and 81.0% of stroke-related DALYs. Globally, the proportional contribution of stroke-related DALYs and deaths due to stroke compared to all diseases increased from 1990 (3.54% (95% UI 3.11-4.00) and 9.66% (95% UI 8.47-10.70), respectively) to 2013 (4.62% (95% UI 4.01-5.30) and 11.75% (95% UI 10.45-13.31), respectively), but there was a diverging trend in developed and developing countries with a significant increase in DALYs and deaths in developing countries, and no measurable change in the proportional contribution of DALYs and deaths from stroke in developed countries. Conclusion: Global stroke burden continues to increase globally. More efficient stroke prevention and management strategies are urgently needed to halt and eventually reverse the stroke pandemic, while universal access to organized stroke services should be a priority.

Purpose: There have not been many discussions on the differences between the guidelines for the management of stroke used in eastern and western countries. The purpose of this paper was to examine whether or not there are substantial differences between western countries and Japan in the prevalence of stroke and the frequencies of stroke subtypes, as well as in the recommended therapy for secondary prevention of ischemic stroke. Results and Conclusions: Although there are racial differences and differences in approved drugs between the East and West, the prevalence of stroke and the frequencies of stroke subtypes tend to converge throughout the world. However, the ratio of stroke to ischemic heart disease is still different between the East and West. Comparison of various countries’ guidelines shows that recommendations on antiplatelet therapy for secondary prevention of ischemic stroke are fundamentally similar in the East and West, but the recommended doses of antiplatelets, especially aspirin and ticlopidine, are smaller in Japan. Furthermore, Japanese guidelines only recommend the use of antiplatelets (particularly cilostazol) for patients with lacunar infarction with evidence.