Prediabetes is associated with proteinuria development but not with glomerular filtration rate decline: A longitudinal observational study.

AIMS: Diabetes is recognized as the leading cause of chronic kidney disease (CKD); however, the association of prediabetes with CKD remains unclear, in particular, the independent effect of prediabetes on proteinuria or estimated glomerular filtration rate (eGFR) has not been evaluated. This study aimed to investigate the associations of prediabetes with the proteinuria development and with eGFR decline separately in the Japanese general population without CKD. METHODS: Participants who underwent health check-ups in 2014 and had adequate data after 2 years were retrospectively analysed. A total of 405,487 participants without CKD (eGFR, ≥60 ml min-1  1.73 m-2 , with negative or trace urinary protein) at baseline were categorized according to fasting plasma glucose as having diabetes (≥126 mg/dl [7.0 mmol/l]), prediabetes (100-125 mg/dl [5.6-6.9 mmol/l]) or normal glucose level (˂100 mg/dl [5.6 mmol/l]). Logistic regression analysis was used to analyse the effects of prediabetes (vs. normal glucose level) on the proteinuria development (urinary protein of ≥1+) and eGFR decline (˂60 ml min-1  1.73 m-2 ) after 2 years. RESULTS: After 2 years, 7037 participants (1.7%) developed proteinuria alone, 19,015 (4.7%) presented eGFR decline alone and 636 (0.2%) showed both proteinuria and eGFR decline. Compared to normal glucose level and adjusting for prognostic factors, prediabetes was independently associated with the proteinuria development (odds ratio [OR] 1.233; 95% confidence interval [CI] 1.170-1.301], whereas prediabetes was not associated with eGFR decline (OR 0.981; 95% CI 0.947-1.017). CONCLUSIONS: Prediabetes is associated with the proteinuria development but not with eGFR decline in the general population.

Stroke Care during the COVID-19 Pandemic: International Expert Panel Review.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has placed a tremendous strain on healthcare services. This study, prepared by a large international panel of stroke experts, assesses the rapidly growing research and personal experience with COVID-19 stroke and offers recommendations for stroke management in this challenging new setting: modifications needed for prehospital emergency rescue and hyperacute care; inpatient intensive or stroke units; posthospitalization rehabilitation; follow-up including at-risk family and community; and multispecialty departmental developments in the allied professions. SUMMARY: The severe acute respiratory syndrome coronavirus 2 uses spike proteins binding to tissue angiotensin-converting enzyme (ACE)-2 receptors, most often through the respiratory system by virus inhalation and thence to other susceptible organ systems, leading to COVID-19. Clinicians facing the many etiologies for stroke have been sobered by the unusual incidence of combined etiologies and presentations, prominent among them are vasculitis, cardiomyopathy, hypercoagulable state, and endothelial dysfunction. International standards of acute stroke management remain in force, but COVID-19 adds the burdens of personal protections for the patient, rescue, and hospital staff and for some even into the postdischarge phase. For pending COVID-19 determination and also for those shown to be COVID-19 affected, strict infection control is needed at all times to reduce spread of infection and to protect healthcare staff, using the wealth of well-described methods. For COVID-19 patients with stroke, thrombolysis and thrombectomy should be continued, and the usual early management of hypertension applies, save that recent work suggests continuing ACE inhibitors and ARBs. Prothrombotic states, some acute and severe, encourage prophylactic LMWH unless bleeding risk is high. COVID-19-related cardiomyopathy adds risk of cardioembolic stroke, where heparin or warfarin may be preferable, with experience accumulating with DOACs. As ever, arteritis can prove a difficult diagnosis, especially if not obvious on the acute angiogram done for clot extraction. This field is under rapid development and may generate management recommendations which are as yet unsettled, even undiscovered. Beyond the acute management phase, COVID-19-related stroke also forces rehabilitation services to use protective precautions. As with all stroke patients, health workers should be aware of symptoms of depression, anxiety, insomnia, and/or distress developing in their patients and caregivers. Postdischarge outpatient care currently includes continued secondary prevention measures. Although hoping a COVID-19 stroke patient can be considered cured of the virus, those concerned for contact safety can take comfort in the increasing use of telemedicine, which is itself a growing source of patient-physician contacts. Many online resources are available to patients and physicians. Like prior challenges, stroke care teams will also overcome this one. Key Messages: Evidence-based stroke management should continue to be provided throughout the patient care journey, while strict infection control measures are enforced.

Healthy lifestyle reduces incidence of trace/positive proteinuria and rapid kidney function decline after 2 years: from the Japan Ningen Dock study.

BACKGROUND: Lifestyle modification is recommended for subjects with trace proteinuria during health checkups. However, whether overall healthy lifestyle reduces the incidence of trace/positive proteinuria or rapid decline in estimated glomerular filtration rate (eGFR) is not clarified. METHODS: A total of 451 534 people (277 494 men and 174 040 women) ages 20-79 years with negative proteinuria were included. The number of three healthy lifestyle factors (LFs) was assessed: noncurrent smoking, healthy eating habits (late dinner, snacking and skipping breakfast <3 times/week) and body mass index <25. The incidence of trace (±) and positive (≥1+) proteinuria by the dipstick method and eGFR decline ≥20% over 2 years were compared with the number of healthy LFs. RESULTS: The incidence of trace/positive proteinuria and rapid eGFR decline decreased with an increasing number of healthy LFs as follows: odds ratios (ORs) for trace proteinuria, 0.91 [95% confidence interval (CI) 0.86-0.96], 0.82 (0.78-0.87) and 0.72 (0.68-0.77); ORs for positive proteinuria, 0.76 (95% CI 0.67-0.86), 0.56 (0.50-0.63) and 0.46 (0.40-0.53); and ORs for an eGFR decline ≥20%, 0.93 (95% CI 0.82-1.05), 0.90 (0.79-1.02) and 0.81 (0.70-0.93) for those with one, two and three healthy LFs compared with those with none of the three healthy LFs, respectively. Overall, subjects with a healthy lifestyle showed 28, 54 and 19% reduced risk of developing trace proteinuria, positive proteinuria and eGFR decline ≥20%, respectively, compared with those with an unhealthy lifestyle after 2 years. This association was similarly observed even among subjects without hypertension (HT) or diabetes mellitus (DM). CONCLUSIONS: Subjects with an overall healthy lifestyle showed a lower incidence of trace/positive proteinuria by dipstick test and rapid eGFR decline over 2 years in a nationwide general population. Thus lifestyle modification should be recommended for subjects with trace proteinuria during health checkups, even for subjects without HT or DM.

The Japan Statin Treatment Against Recurrent Stroke (J-STARS): A Multicenter, Randomized, Open-label, Parallel-group Study.

BACKGROUND: Although statin therapy is beneficial for the prevention of initial stroke, the benefit for recurrent stroke and its subtypes remains to be determined in Asian, in whom stroke profiles are different from Caucasian. This study examined whether treatment with low-dose pravastatin prevents stroke recurrence in ischemic stroke patients. METHODS: This is a multicenter, randomized, open-label, blinded-endpoint, parallel-group study of patients who experienced non-cardioembolic ischemic stroke. All patients had a total cholesterol level between 4.65 and 6.21 mmol/L at enrollment, without the use of statins. The pravastatin group patients received 10 mg of pravastatin/day; the control group patients received no statins. The primary endpoint was the occurrence of stroke and transient ischemic attack (TIA), with the onset of each stroke subtype set to be one of the secondary endpoints. FINDING: Although 3000 patients were targeted, 1578 patients (491 female, age 66.2 years) were recruited and randomly assigned to pravastatin group or control group. During the follow-up of 4.9 ± 1.4 years, although total stroke and TIA similarly occurred in both groups (2.56 vs. 2.65%/year), onset of atherothrombotic infarction was less frequent in pravastatin group (0.21 vs. 0.64%/year, p = 0.0047, adjusted hazard ratio 0.33 [95%CI 0.15 to 0.74]). No significant intergroup difference was found for the onset of other stroke subtypes, and for the occurrence of adverse events. INTERPRETATION: Although whether low-dose pravastatin prevents recurrence of total stroke or TIA still needs to be examined in Asian, this study has generated a hypothesis that it may reduce occurrence of stroke due to larger artery atherosclerosis. FUNDING: This study was initially supported by a grant from the Ministry of Health, Labour and Welfare, Japan. After the governmental support expired, it was conducted in collaboration between Hiroshima University and the Foundation for Biomedical Research and Innovation.

Benefit of cilostazol in patients with high risk of bleeding: subanalysis of cilostazol stroke prevention study 2.

BACKGROUND: The Cilostazol Stroke Prevention Study 2 (CSPS 2) showed that cilostazol significantly reduced the risk of stroke by 25.7% relative to aspirin, with significantly fewer hemorrhagic events, in patients with prior ischemic stroke, excluding cardioembolic stroke. However, whether the benefit of cilostazol is sustained in patients with a high risk of bleeding has not been examined. METHODS: We conducted a subanalysis of CSPS 2 to examine whether known risk factors for hemorrhagic stroke, such as stroke subtype and systolic blood pressure (SBP), influence the efficacy of the study drugs on hemorrhagic stroke. The relative risk reduction of hemorrhagic stroke was determined from the incidences calculated by the person-year method. The cumulative incidence rates of ischemic stroke and hemorrhagic stroke were estimated and plotted using the Kaplan-Meier method. Incidences of serious hemorrhage and hemorrhage requiring hospital admission were also evaluated in the two treatment groups. Hazard ratios (HR) and 95% confidence intervals (95% CI) calculated by the Cox proportion hazard model for cilostazol versus aspirin were assessed, and a log-rank test was used for the comparison between treatments. RESULTS: The incidence of hemorrhagic stroke was significantly lower in the cilostazol group than in the aspirin group among patients with prior lacunar stroke (0.36 vs. 1.20% in person-year, HR 0.35, 95% CI 0.18-0.70, p < 0.01), but not among those with prior atherothrombotic stroke (0.31 vs. 0.59% in person-year, HR 0.53, 95% CI 0.14-2.0, p = 0.34). The incidence of hemorrhagic stroke was significantly lower in the cilostazol group than in the aspirin group throughout all SBP categories (Poisson regression model including time-dependent covariates, p < 0.01) including SBP above 140 mm Hg (cilostazol 0.45% vs. aspirin 1.44% in person-year; Poisson regression model including time-dependent covariates, p = 0.02). Cilostazol, compared with aspirin, significantly reduced the incidence of cerebral hemorrhage (HR 0.36, 95% CI 0.19-0.70, p < 0.01), overall hemorrhage requiring hospital admission (HR 0.53, 95% CI 0.29-0.97, p = 0.04), and gastrointestinal (GI) bleeding requiring hospital admission (HR 0.44, 95% CI 0.21-0.90, p = 0.03). CONCLUSIONS: Hemorrhagic stroke was less frequent in the cilostazol group than in the aspirin group among patients with lacunar stroke as well as those with increased blood pressure levels. As for extracranial hemorrhage requiring hospitalization, GI bleeding was also less frequent in the cilostazol than in the aspirin group. Cilostazol is supposed to be a therapeutic option to replace aspirin for secondary stroke prevention, especially in these subgroups with high risks for hemorrhagic events.

Global and regional burden of stroke during 1990-2010: findings from the Global Burden of Disease Study 2010.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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 nonsignificantly. 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 fi rst 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. INTERPRETATION: 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. FUNDING: Bill & Melinda Gates Foundation.

Rationale, design, and baseline features of a randomized controlled trial to assess the effects of statin for the secondary prevention of stroke: the Japan Statin Treatment Against Recurrent Stroke (J-STARS).

BACKGROUND: Although statin therapy is beneficial for preventing first strokes, the benefit for recurrent stroke and its sub-types remains unknown in Asian populations. The aim of this study is to examine the role of pravastatin in the secondary prevention of stroke in Japanese patients. METHODS: This is a multicenter, randomized, open-label, parallel group study of patients with noncardioembolic ischemic stroke (atherothrombotic infarction, lacunar infarction, and infarction of undetermined etiology). All patients were diagnosed with hyperlipidemia and with a total cholesterol level between 180 and 240 mg/dl at enrollment. Patients in the treatment group receive 10 mg/day of pravastatin, and those in the control group receive no statin treatment. The primary end-point is the recurrence of stroke, including transient ischemic attack. The secondary end-points include the onset of respective stroke sub-types and functional outcomes related to stroke. The patients were enrolled for five-years and will be followed up for five-years. RESULTS: A total of 1578 eligible patients (age: 66·2 years, men: 68·8%), including 64·2% with lacunar infarction, 25·4% with atherothrombotic infarction, and 10·4% with infarction of undetermined etiology were included in this study. Lipid levels were generally well controlled (total cholesterol: 210·0 mg/dl, low density lipoprotein cholesterol: 129·5 mg/dl) at baseline. In addition, the disability of patients was relatively mild, and cognitive function was preserved in the majority of patients. CONCLUSION: This article reports the rationale, design, and baseline features of a randomized controlled trial to assess the effects of statin for the secondary prevention of stroke. Follow-ups of patients are in progress and will end in 2014.

Comparison of the European and Japanese guidelines for the management of 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 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.

Comparison of the European and Japanese guidelines for the acute management of intracerebral hemorrhage.

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.

Global and regional burden of first-ever ischaemic and haemorrhagic stroke during 1990-2010: findings from the Global Burden of Disease Study 2010.

BACKGROUND: The burden of ischaemic and haemorrhagic stroke varies between regions and over time. With differences in prognosis, prevalence of risk factors, and treatment strategies, knowledge of stroke pathological type is important for targeted region-specific health-care planning for stroke and could inform priorities for type-specific prevention strategies. 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 first-ever ischaemic and haemorrhagic stroke during 1990-2010. METHODS: We searched Medline, Embase, LILACS, Scopus, PubMed, Science Direct, Global Health Database, the WHO library, and regional databases from 1990 to 2012 to identify relevant studies published between 1990 and 2010. We applied the GBD 2010 analytical technique (DisMod-MR) to calculate regional and country-specific estimates for ischaemic and haemorrhagic stroke incidence, mortality, mortality-to-incidence ratio, and disability-adjusted life-years (DALYs) lost, by age group (aged <75 years, ≥ 75 years, and in total) and country income level (high-income and low-income and middle-income) for 1990, 2005, and 2010. FINDINGS: We included 119 studies (58 from high-income countries and 61 from low-income and middle-income countries). Worldwide, the burden of ischaemic and haemorrhagic stroke increased significantly between 1990 and 2010 in terms of the absolute number of people with incident ischaemic and haemorrhagic stroke (37% and 47% increase, respectively), number of deaths (21% and 20% increase), and DALYs lost (18% and 14% increase). In the past two decades in high-income countries, incidence of ischaemic stroke reduced significantly by 13% (95% CI 6-18), mortality by 37% (19-39), DALYs lost by 34% (16-36), and mortality-to-incidence ratios by 21% (10-27). For haemorrhagic stroke, incidence reduced significantly by 19% (1-15), mortality by 38% (32-43), DALYs lost by 39% (32-44), and mortality-to-incidence ratios by 27% (19-35). By contrast, in low-income and middle-income countries, we noted a significant increase of 22% (5-30) in incidence of haemorrhagic stroke and a 6% (-7 to 18) non-significant increase in the incidence of ischaemic stroke. Mortality rates for ischaemic stroke fell by 14% (9-19), DALYs lost by 17% (-11 to 21%), and mortality-to-incidence ratios by 16% (-12 to 22). For haemorrhagic stroke in low-income and middle-income countries, mortality rates reduced by 23% (-18 to 25%), DALYs lost by 25% (-21 to 28), and mortality-to-incidence ratios by 36% (-34 to 28). INTERPRETATION: Although age-standardised mortality rates for ischaemic and haemorrhagic stroke have decreased in the past two decades, the absolute number of people who have these stroke types annually, and the number with related deaths and DALYs lost, is increasing, with most of the burden in low-income and middle-income countries. Further study is needed in these countries to identify which subgroups of the population are at greatest risk and who could be targeted for preventive efforts.

Cost-effectiveness analysis of the neuroprotective agent edaravone for noncardioembolic cerebral infarction.

BACKGROUND: The free radical scavenger edaravone has been reported useful for improvement in activities of daily living and for prevention of recurrent stroke in the edaravone versus sodium ozagrel in acute noncardioembolic ischemic stroke (EDO) trial. The aim of this report was to evaluate the cost-effectiveness of edaravone compared to the intravenous antiplatelet drug ozagrel sodium (ozagrel) for noncardioembolic stroke (non-CES) based on the EDO trial data. METHODS: A cost-effectiveness analysis was performed using the Markov model, which also incorporated the long-term course after the acute stage of non-CES. From the perspective of a health care payer, direct medical costs and nursing care costs were taken into account in the cost analysis. The quality-adjusted life year (QALY) served as an indicator of effectiveness. Simulation at 5 and 10 years after the onset of non-CES was carried out. The study involved 68-year-old patients with non-CES, selected against the EDO trial subject selection criteria. A 14-day treatment with edaravone 60 mg/day or ozagrel 160 mg/day was assumed as acute treatment for non-CES. RESULTS: The use of edaravone was associated with a reduction in total costs (0.51 million yen [$6,374] at 5 years and 0.64 million yen [$8,039]) at 10 years after the onset of non-CES) and improvement in QALYs (0.23 at 5 years and 0.38 at 10 years). Compared to ozagrel therapy, edaravone therapy was a cost-saving strategy for treating non-CES. CONCLUSIONS: Compared to ozagrel therapy, edaravone therapy for non-CES is not only useful from a clinical viewpoint, but also valuable from a socioeconomic perspective.

Post-stroke pneumonia prevention by angiotensin-converting enzyme inhibitors: results of a meta-analysis of five studies in Asians.

INTRODUCTION: Angiotensin-converting enzyme inhibitors (ACEIs) are reported to reduce the incidence of aspiration pneumonia in hypertensive patients. In this study, a metaanalysis was conducted to obtain statistically more reliable estimates of outcome. METHODS: The MEDLINE and JMEDICINE databases were searched and the following study selection criteria were applied: (1) comparative controlled studies identified with the following keywords: drug therapy, ACEI, hypertension, swallowing function, dysphagia, stroke, and pneumonia; (2) a minimum follow-up period of 6 months; and (3) a minimum number of patients of more than 100. Patients with hypertension and a history of stroke or transient ischemic attack (TIA) in five controlled studies that reported the incidence of pneumonia were included in the analysis. RESULTS: A total of 8,693 post-stroke patients were given ACEIs with another antihypertensive agent or placebo as a control. In all studies, ACEIs, particularly imidapril, exhibited preventive effects equating to a relative risk that ranged from 0.32 to 0.81 compared with controls. In the combined studies the overall relative risk of ACEI-treated patients versus controls was 0.61 (95% confidence intervals [CI] 0.51-0.75; P < 0.001). Among Asian patients, the relative risk was 0.42 (95% CI 0.32-0.56; P < 0.001). Among Japanese patients, an even greater preventive effect was found for ACEIs versus other antihypertensives (relative risk: 0.38 [95% CI 0.27-0.54; P < 0.001]). CONCLUSION: ACEIs appear to be more effective than other antihypertensive agents or placebo in reducing pneumonia risk in post-stroke patients, especially in Asian populations.

Safety of the novel protease-activated receptor-1 antagonist vorapaxar in Japanese patients with a history of ischemic stroke.

BACKGROUND: Vorapaxar, formerly SCH 530348, is a novel, orally active, potent thrombin receptor inhibitor selective for the protease-activated receptor-1 (PAR-1). Previous phase II studies of patients undergoing urgent or scheduled percutaneous coronary intervention treated with vorapaxar plus aspirin and clopidogrel or ticlopidine showed a trend toward reducing major adverse cardiac events, particularly myocardial infarction, without increasing bleeding risk. The present study evaluated the safety of vorapaxar in Japanese patients with a history of ischemic stroke receiving aspirin. METHODS: Ninety patients with previous ischemic stroke (≥14 days to <1 year before randomization) were randomized to receive vorapaxar (1 or 2.5 mg) or placebo once daily for 60 days. All patients received aspirin (75-150 mg/day). The primary endpoint was overall incidence of adverse events during the protocol-defined treatment phase (60 days). RESULTS: Addition of vorapaxar to aspirin did not significantly increase the overall incidence of adverse events, including serious adverse events. None of the patients treated with vorapaxar plus aspirin experienced thrombolysis in myocardial infarction major or minor bleeding versus 1 patient treated with placebo. Nonfatal stroke occurred in 1 patient allocated to placebo and 1 patient allocated to vorapaxar. CONCLUSIONS: Vorapaxar used in combination with standard doses of aspirin was safe and well tolerated in Japanese subjects with a history of ischemic stroke.