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Rationale Controversy exists over the optimal dose of intravenous (iv) recombinant tissue plasminogen activator (rt-PA) and degree of blood pressure (BP) control in acute ischaemic stroke (AIS). Asian studies suggest low-dose (0·6 mg/kg) is more efficacious than standard-dose (0·9 mg/kg) iv rt-PA, and guidelines recommend reducing systolic BP to Aims The study aims to assess in thrombolysis-eligible AIS patients whether: (i) low-dose (0·6 mg/kg body weight; maximum 60 mg) iv rt-PA has non-inferior efficacy and lower risk of symptomatic intracerebral haemorrhage (sICH) compared to standard-dose (0·9 mg/kg body weight; maximum 90 mg) iv rt-PA; and (ii) early intensive BP lowering (systolic target 130–140 mmHg) has superior efficacy and lower risk of any ICH compared to guideline-recommended BP control (systolic target < 180 mmHg). Design The ENhanced Control of Hypertension And Thrombolysis strokE stuDy (ENCHANTED) trial is an independent, 2 × 2 quasi-factorial, active-comparison, prospective, randomized, open blinded endpoint (PROBE), clinical trial that is evaluating Arm [A] ‘rt-PA dose’ and/or Arm [B] ‘BP control’, using central Internet randomization and data collection in patients fulfilling local criteria for thrombolysis and clinician uncertainty over the study treatments. The treatment arms will be analyzed separately. Study outcomes The primary study outcome in both trial Arms is death or disability according to the modified Rankin scale (mRS, scores 2–6) assessed at 90 days. Secondary outcomes include sICH, any ICH, a shift (‘improvement’) in function across mRS scores, separately on death and disability, early neurological deterioration, recurrent major vascular events, health-related quality of life, length of hospital stay, need for permanent residential care, and health care costs. Results Following launch of the trial in February 2012, the study has recruited more than 2500 patients across a global network of approximately 100 sites in 15 countries. The required sample sizes are 3300 for Arm [A] and 2300 for Arm [B], which will provide >90% power to detect non-inferiority of low-dose iv rt-PA and superiority of intensive BP lowering on the primary clinical outcome, respectively. Conclusions Low-dose iv rt-PA and early intensive BP lowering could provide more affordable and safer use of thrombolysis treatment for patients with AIS worldwide.

A fatal case of late-onset graft infection of the thoracic aorta due to group C b-hemolytic streptococcus is described. A 37-year-old male patient, who had a history of total aortic arch replacement for acute aortic dissection 8 years before, was admitted to the department. He suffered from toxic shock syndrome, disseminated intravascular coagulation (DIC), and acute renal failure. Group C b-hemolytic streptococcus was detected from his blood; however, echocardiography, computed tomography (CT), and magnetic resonance imaging (MRI) failed to detect the focus of the infection. In spite of intensive care, including antibiotic therapy, artificial ventilation, and continuous hemodiafiltration, he died on the 18th day of hospitalization. Autopsy revealed that a small abscess was present at the proximal anastomotic segments of the patient’s graft. A bite inflicted by his dog, 14 days before admission, was suspected to be the source of this bacterium. A rare case of graft infection of thoracic aorta in terms of causative organism, long period from graft replacement to graft infection, and site of infection is presented and discussed.

1. Only limited information is available concerning the changes in the electrocardiogram in primary aldosteronism. The aim of the present study was to determine factors influencing the QTc interval in patients with primary aldosteronism. 2. Nineteen patients with primary aldosteronism caused by a Conn's adenoma and 69 patients with essential hypertension, in whom all possible causes of secondary hypertension had been excluded, were included in the present study. Before and 10-20 days after adrenalectomy, blood and electrocardiographic examinations were conducted. 3. Systolic and diastolic blood pressures in primary aldosteronism were found to be comparable to those in essential hypertension. However, the QTc interval was significantly prolonged and serum potassium concentrations were significantly decreased in patients with primary aldosteronism compared with patients with essential hypertension (492.7+/-20.3 vs 428.5+/-3.1 msec for QTc interval, respectively (P

Background and purpose As uncertainty persists over the prognostic significance of low estimated glomerular filtration rate (eGFR) in acute stroke, the effects of low eGFR on death/disability amongst participants with acute stroke in China were determined. Methods Nanjing First Hospital stroke registry was a prospective cohort study of stroke patients. Patients with acute stroke (brain infarction, intracerebral hemorrhage or subarachnoid hemorrhage) within 7 days of onset were recruited consecutively from 2004 to 2008. Baseline eGFR was estimated using the Chronic Kidney Disease Epidemiology Collaboration equation. Outcomes were death/disability, defined by scores 3–6 on the modified Rankin Scale at 90 days. Results A total of 1909 participants were included in the present analyses. Of them, 112 (5.9%) had baseline moderate to severe decrease in eGFR (G3b-4) and increasing risk of higher National Institutes of Health Stroke Scale (NIHSS) scores. Low eGFR was associated with increasing risk of death/disability at 90 days [G3b-4, odds ratio 2.58 (95% confidence interval 1.71–3.91); G3a, 1.86 (1.35–2.56); G2, 1.21 (0.96–1.52); P trend

Objective: The INTERACT2 trial demonstrated beneficial effects of early intensive blood pressure (BP) lowering in intracerebral hemorrhage (ICH). However, concerns persist over harms associated with the treatment, particularly in patients with cerebral small vessel disease (CSVD) (ie white matter lesions [WML], lacunes and atrophy) and renal failure. We determined associations of CSVD, and renal failure, on outcomes in INTERACT2 participants. Design and Method: There were 2069/2839 patients with baseline brain CT ( 90 mL/min/1.73 m2), mild (60–90 mL/min/1.73 m2), and moderate-severe ( Results: WML and brain atrophy were associated with death/disability (mRS score 3–6) at 90 days: adjusted ORs for WML (grade 3 and 4 vs. 1), FR and TSD (most vs. least severe atrophy quartile) were 1.42 (95%CI 1.02–0.98), 1.47 (1.08–1.99) and 1.64 (1.21–2.22), respectively (P trend Conclusions: Patients with CSVD manifestations of WML and brain atrophy, and renal failure, have significantly worse outcome in acute ICH. However, intensive BP lowering provides similar treatment effects irrespective of degree of CSVD or renal failure.

Background and Purpose— The slowdown of a steeply declining trend in cardiovascular mortality has been reported in Japan, but precise reasons for this trend are uncertain. Methods— We established 3 study cohorts of Hisayama residents aged ≥40 years without a history of stroke or myocardial infarction in 1961 (1618 subjects, first cohort), 1974 (2038 subjects, second cohort), and 1988 (2637 subjects, third cohort). We followed up with each cohort for 12 years, comparing the incidence, mortality, and survival rate of cardiovascular disease. Results— The age-adjusted incidence of cerebral infarction significantly declined by 37% for men and by 32% for women from the first to the second cohort. It continued to decline by 29% for men, but the decline decelerated for women in the third cohort. The incidence of cerebral hemorrhage steeply declined by 61% from the first to the second cohort in men only, while it was sustained for both sexes in the third cohort. Stroke mortality continuously declined as a result of these incidence changes and significant improvement of survival. In contrast, the incidence and mortality rate of coronary heart disease were unchanged except for the increasing incidence in the elderly. The prevalence of severe hypertension and current smoking significantly decreased, while that of glucose intolerance, hypercholesterolemia, and obesity greatly increased among the cohorts. Conclusions— Our data suggest that the decline in stroke incidence is slowing down and that the incidence of coronary heart disease has been increasing in the elderly in recent years. Insufficient control of hypertension and the increase in metabolic disorders may contribute to these trends.

To determine whether the beneficial effects of alcohol on lipid concentrations are mediated by insulin levels, we performed a cross-sectional analysis in 2103 nondiabetic men and women aged 40 to 79 years from a general Japanese population in Hisayama. The multivariate-adjusted sum of fasting and 2-hour postloading insulin levels and the insulin resistance index significantly decreased with elevating alcohol intake levels in men (P < 0.01 for the trend) but not in women. No dose-response relations between alcohol intake and glucose levels were observed. In both sexes, high-density lipoprotein cholesterol (HDLC) significantly increased with elevated alcohol intake (P < 0.01), whereas total cholesterol and low-density lipoprotein cholesterol (LDLC) were inversely correlated with alcohol intake (P < 0.01). In contrast, triglycerides (TGs) levels in men showed a J-shaped relation to alcohol dose, with moderate drinkers (10-29 g/d) having the lowest levels. Estimates using regression models indicated that for men, 10% of the alcohol-induced increase in HDLC and 2% of the alcohol-induced decrease in LDLC were insulin mediated. It was also estimated for male subjects that 36% of the reduction in TGs due to low to moderate alcohol intake was mediated by low levels of insulin and that this insulin-mediated pathway reduced the positive alcohol-TG relation by 13% in cases of moderate to heavy drinking. Our data suggest that regular alcohol consumption dose-dependently increased insulin sensitivity among male nondiabetics, but the insulin-mediated beneficial effects of alcohol on lipid concentrations were relatively small.

Background and Purpose— The INTEnsive blood pressure Reduction in Acute Cerebral hemorrhage Trial (INTERACT) pilot study showed that early intensive blood pressure-lowering can attenuate hematoma growth in acute intracerebral hemorrhage. The present analysis aimed to determine the treatment effects on hematoma growth by time from intracerebral hemorrhage onset to randomization. Methods— Patients (N=404) with acute intracerebral hemorrhage and elevated systolic blood pressure were randomly assigned to intensive or guideline-based blood pressure management. Baseline and repeat CT (24 and 72 hours) were performed and changes in hematoma volume were assessed using generalized estimating equations. Results— Among 296 patients with all 3 CT scans available for analysis, reductions in proportional hematoma growth produced by randomized intensive blood pressure-lowering treatment over 72 hours decreased progressively with delays in initiation of study treatment: 22%, 17%, 9%, and 3% for quartile groups defined by time from onset to randomization of P trend=0.001). There were also smaller absolute reductions in hematoma growth with delays in initiation of study treatment (6.5 mL, 3.3 mL, 0.9 mL, and 0.6 mL), although the trend did not reach statistical significance ( P trend=0.12). Conclusions— Earlier initiation of intensive blood pressure-lowering treatment is likely to provide greater protection against hematoma growth in acute intracerebral hemorrhage. Clinical Trial Registration Information— http://www.clinicaltrials.gov , NCT002226096.

Background and Purpose— Observational studies demonstrate strong associations between blood pressure and bleeding complications of antithrombotic therapy. The objective was to determine whether blood pressure lowering reduces risks of bleeding in patients on antithrombotic therapy. Methods— This is a subsidiary analysis of the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) trial, a randomized, placebo-controlled trial. A total of 6105 patients with cerebrovascular disease were randomly assigned to either active treatment (perindopril±indapamide) or placebo(s). The outcomes were intracranial and extracranial bleeding. Results— There were 4876 (80%) patients on antithrombotic therapy at baseline. Over a mean follow-up of 3.9 years, 119 intracranial and 123 extracranial bleeding events were observed. Among patients with and without antithrombotic therapy, active treatment lowered blood pressure by 8.9/4.0 and 9.3/3.8 mm Hg and reduced the risks of intracranial bleeding by 46% (95% CI, 7%–69%) and 70% (39%–85%), respectively. However, active treatment did not reduce the risks of extracranial bleeding significantly in either group. Among patients on antithrombotic therapy, the lowest risk of intracranial bleeding was observed in participants with the lowest follow-up systolic blood pressure levels (median, 113 mm Hg). Conclusions— Blood pressure lowering provides protection against intracranial bleeding among patients with cerebrovascular disease including those receiving antithrombotic therapy. Clinical Trial Registration Information— This trial was not registered because patients were enrolled before July 1, 2005.

Insulin resistance may be a factor in the etiology of hypertension, and habitual alcohol intake may modify this relationship. We prospectively examined this hypothesis in 1,133 nonhypertensive, nondiabetic Japanese subjects, aged 40–79 years. Alcohol drinkers were more frequent among men than women at baseline (57.7 vs. 8.2%). The age-adjusted incidence of hypertension significantly increased with the elevating baseline insulin levels in women (P = .003 for trend), but not in men. The age- and sex-adjusted insulin levels and insulin resistance index decreased with elevating alcohol intake, while fasting glucose levels remained unchanged, suggesting that alcohol improves insulin sensitivity. Among nondrinkers, the age-adjusted incidence of hypertension significantly increased with elevating insulin tertiles in both sexes (P = .048 and .002 for trend in men and women, respectively), but not among drinkers. Our findings suggest a close association between insulin resistance and the incidence of hypertension in Japanese. However, alcohol modified and reduced this relationship.

Moderately elevated plasma total homocyst(e)ine (tHcy) levels have been linked with cardiovascular disease. However, the findings of previous studies regarding the relationship between tHcy levels and subtypes of cerebral infarction (CI) have been conflicting. The aim of the present study was to examine this issue in a community-based case-control study performed in Hisayama Town in Japan. Fasting tHcy levels were compared among 75 CI cases, of which 43 were lacunar (LI), 24 atherothrombotic (ATI) and 8 cardioembolic infarctions (CEI), and 248 age- and sex-matched healthy controls. The mean tHcy concentrations were higher in CI than in controls (13.0 vs. 11.8 µmol/l; p = 0.018). LI and CEI also had significantly higher tHcy levels than did the corresponding controls (12.3 vs. 11.3 µmol/l for LI; p = 0.037 and 16.3 vs. 12.7 µmol/l for CEI; p = 0.036). The same tendency was also observed for ATI, but the difference was only marginally significant probably due to the small number of the cases (13.4 vs. 11.9 µmol/l; p = 0.087). After adjustment for age, sex, hypertension, serum creatinine, total protein, folate and vitamin B12 levels, the risk of LI was not significant in the second tertile of the tHcy distribution, but significantly increased in the third compared with the first tertile (adjusted odds ratio, AOR, 3.4; 95% confidence limits, CL, 1.3–8.9; p = 0.015), while the risk of ATI was significant even in the second tertile (AOR, 5.0; 95% CL, 1.0–23.7; p = 0.042) and higher in the third tertile (AOR, 7.5; 95% CL, 1.5–38.3; p = 0.015). However, the odds ratios for CEI could not be estimated, as there was no case of CEI in the first tertile. These findings suggest that elevated tHcy is an independent risk factor for all subtypes of CI, but that its impact is higher in ATI and probably in CEI than in LI.

The results of the SCAST study did not demonstrate any benefit on vascular or functional outcomes from lowering blood pressure in patients with acute stroke, but the findings were not definitive. We hope that other ongoing large-scale trials will resolve this area of clinical equipoise.

Background There is uncertainty surrounding the differences in outcomes after intracerebral haemorrhage (ICH) between men and women. This study aimed to investigate the sex differences in clinical characteristics, severity and outcomes of Chinese ICH patients. Methods The Nanjing First Hospital stroke registry was a hospital-based registry of stroke patients with 1-year prospective follow-up. From 2004 to 2008, a total of 651 consecutively recruited patients with acute ICH were enrolled. Primary outcome was death or dependency defined as a modified Rankin Scale score of 3–6 at 12 months. Multivariable logistic regression analyses were performed to determine whether there were sex differences in clinical outcomes after ICH. Clinically important and biologically plausible risk factors of death or dependency were selected from available variables. Results A total of 615 ICH patients were enrolled. There was no significant difference in age (63.5 ± 14.0 vs. 62.7 ± 12.7, p = 0.500) between women and men. At baseline, men were more likely to be current smokers (46.1% vs. 3.6%, P < 0.001) or current drinkers (35.4% vs. 3.6%, P < 0.001), but women had higher admission National Institute of Health Stroke Scale (NIHSS) scores than men (10 vs. 8, P = 0.039). Women also had higher rates of death or dependency at 3, 6, and 12 months (61.2% vs. 46.8%, P = 0.001; 56.7% vs. 45.3%, P = 0.009; and 51.8% vs. 44.1%, P = 0.065; respectively). After adjustment for age, existing hypertension and diabetes, prior stroke, previous ischemic heart disease, previous atrial fibrillation, current smoking and alcohol consumption status, pre-stroke dependency, onset-to-door time, admission NIHSS score, admission systolic blood pressure and location of bleeding, the association between the female gender and death or dependency remained statistical significant at 3 months [odds ratio (OR): 1.76; 95% confidence interval (CI): 1.07-2.89], but did not reach statistical significance at 6 months (OR: 1.59; 95% CI: 0.99-2.54) and 12 months (OR: 1.22; 95% CI: 0.77-1.95). Conclusions In a Chinese population, women are more likely to be dead or dependent early after ICH than men. However, this gender difference gradually attenuates over the period of 12 months.

Objective To provide an epidemiological perspective of the clinical profile, frequency, and determinants of poststroke hemiplegic shoulder pain. Design A prospective population-based study of an inception cohort of participants with a 12-month follow-up period. Setting General community and hospital within a geographically defined metropolitan region. Participants Multiple ascertainment techniques were used to identify 318 confirmed stroke events in 301 individuals. Among adults with stroke, data on shoulder pain were available for 198 (83% of the survivors) at baseline and for 156 and 148 at 4 and 12 months, respectively. Interventions Not applicable. Main Outcome Measures Subjective reports of onset, severity, and aggravating factors for pain and 3 passive range-of-motion measures were collected at baseline and at 4- and 12-month follow-up. Results A total of 10% of the participants reported shoulder pain at baseline, whereas 21% reported pain at each follow-up assessment. Overall, 29% of all assessed participants reported shoulder pain during 12-month follow-up, with the median pain score (visual analog scale score=40) highest at 4 months and more often associated with movement at later time points. Objective passive range-of-motion tests elicited higher frequencies of pain than did self-report and predicted later subjective shoulder pain (crude relative risk of 3.22 [95% confidence interval, 1.01–10.27]). Conclusions The frequency of poststroke shoulder pain is almost 30%. Peak onset and severity of hemiplegic shoulder pain in this study was at 4 months, outside of rehabilitation admission time frames. Systematic use of objective assessment tools may aid in early identification and management of stroke survivors at risk of this common complication of stroke.

Background As no human data exist, we aimed to determine the relation between ambient temperature and volume of perihematomal ‘cerebral’ edema in acute spontaneous intracerebral haemorrhage (ICH) among Chinese participants of the pilot phase, Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT1). Methods INTERACT1 was a multicenter, open, blind outcome assessed, randomized controlled trial of intensive (systolic target Results A total of 250 of all 384 Chinese participants had complete data that showed positive associations between ambient temperature (mean and minimum temperatures) and edema volumes at each time point over 72 h after hospital admission (all P < 0·05). All temperature parameters except diurnal temperature range were positively associated with edema volume after adjustment for confounding variables (all P < 0·02). Conclusion An apparent positive association exists between ambient temperature and perihematomal edema volume in acute spontaneous ICH.

To investigate the association between genetic variations of matrix metalloproteinase 9 (MMP9) gene and intracerebral hemorrhage (ICH) susceptibility in Chinese Han population.The clinical data and peripheral blood samples from the patients with ICH and hypertension, and controlled subjects with hypertension only, were collected. MassARRAY Analyzer was used to genotype the tagger single nucleotide polymorphism (SNP) of MMP9 gene. Haploview4.2 and Unphased3.1.7 were employed to construct haplotypes and to analyze the association between genetic variations (alleles, genotypes and haplotypes) of MMP9 gene and ICH susceptibility.181 patients with ICH and hypertension, and 197 patients with hypertension only, were recruited between Sep 2009 and Oct 2010. Patients in the ICH group were younger (61.80 ± 13.27 vs. 72.44 ± 12.71 years, p0.05). Other conventional risk factors between the ICH and control groups were similar. There were 6 Tagger SNPs and 4 haplotypes of MMP9 gene in our sample population. Our logistical regression analysis showed that there were no significant associations between genetic variations of the MPP9 gene and ICH susceptibility (all p0.05).The genetic variations of MMP9 gene were not significantly associated with ICH susceptibility in the Chinese Han population.

OBJECTIVE There is no consensus on the importance of visit-to-visit glycemic variability in diabetes. Therefore, we assessed the effects of visit-to-visit variability (VVV) in HbA1c and fasting glucose on major outcomes in the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation) trial. RESEARCH DESIGN AND METHODS ADVANCE was a factorial randomized controlled trial of intensive glucose control and blood pressure lowering in patients with type 2 diabetes. VVV in the intensive glucose treatment group was defined using the SD of five measurements of HbA1c and glucose taken 3–24 months after randomization. Outcomes were combined macro- and microvascular events and all-cause mortality occurring post 24 months. Sensitivity analyses were performed using other indices of variability and in the standard glucose treatment group. RESULTS Among 4,399 patients in the intensive group, an increase in VVV of HbA1c was associated with an increased risk of vascular events (P = 0.01) and with mortality (P < 0.001): highest versus lowest tenth hazard ratio (95% CI) 1.64 (1.05–2.55) and 3.31 (1.57–6.98), respectively, after multivariable adjustment. A clear association was also observed between VVV of fasting glucose and increased risk of vascular events (P < 0.001; 2.70 [1.65–4.42]). HbA1c variability was positively associated with the risk of macrovascular events (P = 0.02 for trend), whereas glucose variability was associated with both macro- and microvascular events (P = 0.005 and P < 0.001 for trend, respectively). Sensitivity analyses using other indices, and patients in the standard glucose treatment group, were broadly consistent with these results. CONCLUSIONS Consistency of glycemic control is important to reduce the risks of vascular events and death in type 2 diabetes.

Objective: There is ongoing controversy regarding a 'J-curve' phenomenon such that low and high blood pressure (BP) levels are associated with increased risks of recurrent stroke. We aimed to determine whether large treatment-related BP reductions are associated with increased risks of recurrent stroke. Design: Data are from the PROGRESS trial, where 6105 patients with cerebrovascular disease were randomly assigned to either active treatment ( perindopril ±indapamide) or placebo(s). There were no BP criteria for entry. BP was measured at every visit, and participant groups defined by reduction in systolic BP (SBP) from baseline were used for the analyses. Outcome was recurrent stroke. Results: During a mean follow-up of 3.9 years, 727 recurrent strokes were observed. There were clear associations between the magnitude of SBP reduction and the risk of recurrent stroke. After adjustment for cardiovascular risk factors and randomised treatment, annual incidence was 2.08%, 2.10%, 2.31% and 2.96% for participant groups defined by SBP reductions of ≥20, 10-19, 0-9 and

The objective of the present analysis was to determine the effects of a fixed combination of perindopril and indapamide in combination with calcium channel blockers (CCBs) in patients with type 2 diabetes mellitus. The Action in Diabetes and Vascular Disease: Preterax and Diamicron Controlled Evaluation (ADVANCE) trial was a factorial randomized controlled trial. A total of 11 140 patients with type 2 diabetes mellitus were randomly assigned to fixed combination of perindopril–indapamide (4/1.25 mg) or placebo. Effects of randomized treatment on mortality and major cardiovascular outcomes were examined in subgroups defined by baseline use of CCBs. Patients on CCB at baseline (n=3427) constituted a higher risk group compared with those not on CCB (n=7713), with more extensive use of antihypertensive and other protective therapies. Active treatment reduced the relative risk of death by 28% (95% confidence interval, 10%–43%) among patients with CCB at baseline compared with 5% (−12% to 20%) among those without CCB ( P homogeneity=0.02) and 14% (2%–25%) for the whole population. Similarly, the relative risk reduction for major cardiovascular events was 12% (−8% to 28%) versus 6% (−10% to 19%) for those with and without CCB at baseline although the difference was not statistically significant ( P homogeneity=0.38). There was no detectable increase in adverse effects in those receiving CCB. The combination of perindopril and indapamide with CCBs seems to provide further protection against mortality in patients with type 2 diabetes mellitus.

Background and Purpose —We estimated the incidence of first-ever cerebral infarction in regard to its subtypes and analyzed their risk factors separately in a community-based prospective cohort study in Japan. Methods —Stroke-free subjects (n=1621) aged ≥40 years were followed up for 32 years from 1961. During this period, 298 cerebral infarctions occurred and were divided into 167 lacunar, 62 atherothrombotic, 56 cardioembolic, and 13 undetermined subtypes of infarction on the basis of clinical information including brain imaging and autopsy findings. Results —The age-adjusted incidence of lacunar infarction (3.8 per 1000 person-years for men and 2.0 for women) was higher than that of atherothrombotic infarction (1.2, 0.7) and cardioembolic infarction (1.3, 0.5) in both sexes. Time-dependent Cox’s proportional hazard analysis revealed systolic blood pressure as well as age to be independent risk factors for all subtypes of cerebral infarction except for cardioembolic infarction in men. Additionally, ST depression on ECG, glucose intolerance, and smoking in men and left ventricular hypertrophy on ECG and body mass index in women remained significant risk factors for lacunar infarction. ST depression was also significantly related to events of atherothrombotic infarction in women. The risk of atrial fibrillation for cardioembolic infarction was outstandingly high in both sexes, and left ventricular hypertrophy and lower total cholesterol were additional risk factors for cardioembolic infarction in women. Conclusions —In this Japanese population, lacunar infarction was the most common subtype of cerebral infarction and had a greater variety of risk factors, including not only hypertension but also ECG abnormalities, diabetes, obesity, and smoking, than did atherothrombotic infarction or cardioembolic infarction.

Background: Patients with acute ischemic stroke (AIS) have impaired vasomotor reactivity, especially in the affected cerebral hemisphere, such that they may depend directly on systemic blood pressure to maintain perfusion to vulnerable ‘at risk' penumbral tissue. As the sitting up position may affect cerebral perfusion by decreasing cerebral blood flow (CBF) in salvageable tissue, positioning AIS patients with their head in a lying flat position could increase CBF through collateral circulation or gravitational force. We wished to quantify the effect of different head positions on mean flow velocity (MFV) by transcranial Doppler ultrasonography (TCD) in AIS patients to assess the potential for benefit (or harm) of head positioning in a clinical trial. Methods: We performed a systematic review and meta-analysis of observational studies with TCD to evaluate differences in cerebral MFV between the lying flat and sitting up head positions in AIS. For each study and each comparison, we obtained the mean value of changes in MFV and its variance. Results: A total of 303 studies were identified, but 298 were excluded for varying reasons; 4 papers met the inclusion criteria and 57 patients were included in the meta-analysis for calculation of the overall mean difference in MFV. We found a significant increase in MFV from a bed angle of 30 to 15° (4.6 cm/s, 95% confidence interval, CI, 2.9-6.2, p < 0.001) and from 30 to 0° (8.3 cm/s, 95% CI 5.3-11.3, p < 0.001) in the affected hemisphere but not on the normal side in AIS patients. Conclusions: In AIS patients, MFV increased significantly in the side affected by the stroke but not in the unaffected side when they were positioned in a lying flat head position at 0 or 15° compared to an upright head position at 30°. The clinical significance of these findings is now undergoing further randomized evaluation in the international multicenter Head Position in Acute Stroke Trial (HeadPoST).

Background— Recent evidence suggests that visit-to-visit variability in systolic blood pressure (SBP) and maximum SBP are predictors of cardiovascular disease. However, it remains uncertain whether these parameters predict the risks of macrovascular and microvascular complications in patients with type 2 diabetes mellitus. Methods and Results— The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) was a factorial randomized controlled trial of blood pressure lowering and blood glucose control in patients with type 2 diabetes mellitus. The present analysis included 8811 patients without major macrovascular and microvascular events or death during the first 24 months after randomization. SBP variability (defined as standard deviation) and maximum SBP were determined during the first 24 months after randomization. During a median 2.4 years of follow-up from the 24-month visit, 407 major macrovascular (myocardial infarction, stroke, or cardiovascular death) and 476 microvascular (new or worsening nephropathy or retinopathy) events were observed. The association of major macrovascular and microvascular events with SBP variability was continuous even after adjustment for mean SBP and other confounding factors (both P Conclusion— Visit-to-visit variability in SBP and maximum SBP were independent risk factors for macrovascular and microvascular complications in type 2 diabetes mellitus. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique Identifier: NCT00145925.

Background: Intracerebral haemorrhage (ICH) rates increase in winter months. We aimed to determine associations of ambient temperature with clinical severity and haematoma size in acute ICH among Chinese participants in the Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT1). Methods: INTERACT1 was a randomised controlled trial of early intensive blood pressure lowering in 404 patients with acute ICH. Among 304 (79%) Chinese participants, data on ambient temperature (average, minimum, maximum and range) on the day of ICH onset obtained from the China Meteorological Data Sharing Service System were linked to measures of clinical severity: elevated National Institute of Health Stroke Scale score (>10), low Glasgow Coma Scale score (Results: No significant associations were evident between temperature parameters and clinical parameters and haematoma volume (with and without IVH), even after adjustment for key prognostic factors. Conclusions: No relationship was evident between ambient temperature and severity in acute ICH.

Background and Purpose— To determine incidence and risks of subarachnoid hemorrhage in China. Methods— A prospective, population-based, 1:2 matched case–control study in Baotou, Inner Mongolia (≈2 million population) in 2009–2011. Multiple variable models used to determine relative risk and population-attributable risks for exposures. Results— For a total of 226 patients (mean age, 59 years; 65% women; 434 controls), crude annual incidence (per 100 000) of subarachnoid hemorrhage was 6.2 (95% confidence intervals, 5.4–7.0); 4.3 (3.3–5.2) for men and 8.2 (6.9–9.6) for women. Compared with nonsmokers, adjusted relative risk of subarachnoid hemorrhage in current smokers was 2.31 (95% confidence interval, 1.31–4.09) but was 4.00 (1.62–9.89) in women. Population-attributable risk for smoking, hypertension, and low income were 18%, 36% and 59%, respectively. Conclusions— The incidence of subarachnoid hemorrhage in China is slightly lower than in Western countries and is related to smoking, hypertension, and poor socioeconomic status.

Background: It has not been fully elucidated whether antihypertensive medication adherence affects blood pressure (BP) control in hypertension cases. Aim: To investigate the association of adherence to antihypertensive drug regimens and BP control using data from the Combination Pill of Losartan Potassium and Hydrochlorothiazide for Improvement of Medication Compliance Trial (COMFORT) study. Design: An observational analysis from a randomized controlled trial. Methods: A total of 203 hypertensive subjects were randomly assigned to a daily regimen of a combination pill (losartan 50 mg/hydrochlorothiazide 12.5 mg) or two pills, an angiotensin II receptor blocker and a thiazide diuretic. Medication adherence calculated based on pill counts and BPs was evaluated at 1, 3 and 6 months after randomization. Results: The subjects were divided into three groups according to their adherence, i.e. relatively low-adherence (

Background and Purpose— To determine the interrelationships between baseline Mini-Mental State Examination (MMSE) score and risk of overall dementia, post-recurrent stroke dementia, and dementia without recurrent stroke among patients with a history of stroke. Methods— Prospective cohort study among participants enrolled in the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) for whom baseline MMSE score was available. Baseline MMSE score was divided into 4 categories: 30, 29–27, 26–24, and Results— Of the 6080 participants included in this analysis, 2493 had an MMSE score of 30, 1768 had a score of 29–28, 1369 had a score of 26–24, and 450 had a score of Conclusions— Patients with stroke with low MMSE scores are at high risk of dementia over time, even in the absence of a recurrent stroke, and should therefore be followed closely for further cognitive decline.

Background and Purpose— On the basis of combined measurements of clinic blood pressure (CBP) and home blood pressure (HBP), blood pressure status can be divided into normotension, white-coat hypertension (WCHT), masked hypertension (MHT), and sustained hypertension (SHT). Despite the clear impact of MHT and SHT on clinical and subclinical arterial disease, uncertainty about the influence of WCHT remains. The objective of this study was to investigate the associations of WCHT, MHT, and SHT with carotid atherosclerosis in a general population. Methods— This is a cross-sectional survey of 2915 community-dwelling Japanese aged ≥40 years. Normotension was defined as CBP Results— There were 1374 subjects (47.1%) with normotension, 200 (6.9%) with WCHT, 639 (21.9%) with MHT, and 702 (24.1%) with SHT. The geometric average of mean intima-media thickness was significantly higher among subjects with WCHT (0.73 mm), MHT (0.77 mm), and SHT (0.77 mm) than those with normotension (0.67 mm; all P Conclusions— WCHT, as well as MHT, and SHT were associated with carotid atherosclerosis in a general Japanese population.

The International Society of Hypertension (ISH) surveyed trends in the management of hypertension worldwide, as reported by its affiliated societies.A formal questionnaire was emailed in December 2011 to 90 national and regional societies affiliated with the ISH, from 77 countries. Responses received by June 2012 were analysed.Thirty-one societies responded (nine high-income, 17 upper-middle-income, five lower-middle/low-income countries). Twenty-one reported use of national guidelines, three used regional and 17 used 'international guidelines', two-thirds used mercury, aneroid and semi-automatic sphygmomanometers and half used ambulatory blood pressure monitoring. Exercise, salt restriction and weight reduction were recommended by 31, 27 and 26 nations, respectively, but less for other diets, smoking cessation and alcohol restriction. Almost all nations used angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), calcium channel blockers and diuretics. β Blockers were only recommended for patients with coronary disease. ACEI and ARB were preferred for patients with diabetes, renal disease and metabolic syndrome. Combination treatment was recommended by all, for initiation of treatment by most, and in fixed-dose formulation by half. Most used a threshold of 140/90 mmHg to initiate drug treatment in uncomplicated patients but only half retained the threshold of 130/80 mmHg for high-risk patients. Differences in treatment patterns across regions or across high, middle and low-income countries were minimal.There was surprising consistency across countries from different regions and with varying degrees of affluence. There was a trend towards more conservative thresholds and targets than those recommended by JNC7 or ESH/ESC 2007. Combination therapy was favoured by all, but β blockers were restricted to patients with coronary heart disease.

Background: A recent observational analysis of a large-scale randomized controlled trial identified a “J-curve” phenomenon such that low and high blood pressure (BP) levels are associated with increased risks of recurrent stroke among patients with recent ischemic stroke. The objective of the present analysis was to determine whether larger reduction in BP associated with treatment increases the risks of recurrent stroke among patients with cerebrovascular disease. Methods: This is a subsidiary analysis of the PROGRESS trial, a randomized, placebo-controlled trial that established the beneficial effects of BP lowering in secondary prevention of stroke. A total of 6105 patients with prior stroke or transient ischemic attack were randomly assigned to either active treatment (perindopril ± indapamide) or matching placebo(s). There were no BP criteria for entry. BP was measured at every visit and groups of participants defined by reduction in systolic BP (SBP) from baseline ( Results: During a mean follow-up of 3.9 years, 111 hemorrhagic stroke and 565 ischemic stroke events were observed. There were clear inverse associations between SBP reduction and the risk of hemorrhagic stroke even after adjustment for age, sex, region, baseline SBP, diabetes, current smoking and randomized treatment: adjusted annual incidence rates were 0.08%, 0.06%, 0.05% and 0.03% for participant groups defined by reduction in SBP levels of Conclusions: The present analysis provided no evidence of increase in recurrent stroke associated with larger reduction in SBP produced by BP lowering treatment among patients with cerebrovascular disease.

Background Hypertension is a major risk factor for death and cardiovascular disease (CVD) in patients undergoing chronic haemodialysis (HD), but there is uncertainty surrounding the effects of blood pressure (BP) lowering on this high-risk patient group. Methods In a multicenter, prospective, randomized, open-label, blinded-endpoint trial, 469 patients with chronic HD and elevated BP (140-199/90-99 mmHg) were assigned to receive the angiotensin receptor blockade (ARB) olmesartan (at a dose of 10-40 mg daily; n = 235) or another treatment that does not include angiotensin receptor blockers and angiotensin-converting enzyme (ACE) inhibitors (n = 234). The primary outcomes were the following: (i) composite of death, nonfatal stroke, nonfatal myocardial infarction and coronary revascularization and (ii) all-cause death. Results During a mean follow-up of 3.5 years, the mean BP was 0.9/0.0 mmHg lower in the olmesartan group than in the control group (not significant). A total of 68 patients (28.9%) in the olmesartan group and 67 patients (28.6%) in the control group had subsequent primary composite endpoints [hazard ratio (HR) in the olmesartan group 1.00, 95% confidence interval (CI) 0.71-1.40, P = 0.99]. All-cause deaths occurred in 38 patients (16.2%) in the olmesartan group and 39 (16.7%) in the control group (HR, 0.97; 95% CI, 0.62-1.52, P = 0.91). Olmesartan did not alter the risks of serious adverse events. Conclusions BP-lowering treatment with an ARB did not significantly lower the risks of major cardiovascular events or death among patients with hypertension on chronic HD. (Cochrane Renal Group Prospective Trial Register number CRG010600030).

Objectives: We aimed to study the effectiveness of shoulder taping and conventional treatment vs sham taping and conventional treatment in prevention of shoulder injuries in patients with acute stroke. Methods: This study was a multicenter, interventional, prospective, randomized, outcome-blinded trial (PROBE design). All first-ever stroke patients were included within 48 hours of stroke onset (August 2009–October 2011). The treatment group included shoulder taping and conventional treatment, and the control group received sham taping and conventional treatment. Primary outcomes were changes in visual analog scale (VAS) and shoulder pain and disability index (SPADI), and secondary outcomes were changes in shoulder range of motion (flexion and abduction) at days 14 and 30. Clinical trials registration no. NCT 01062308. Results: There were 80 patients in the treatment arm and 82 in the control arm. There was a better reduction of VAS (on day 14: mean difference 3.7 mm, p = 0.45; on day 30: 11.9 mm, p = 0.03) and SPADI scores (on day 14: mean difference 3.5, p = 0.33; on day 30: 9.3, p = 0.04) in the treatment arm. Conclusions: Although there was a trend toward pain reduction and functional improvement associated with shoulder taping for 2 weeks after acute stage of stroke, this did not reach statistical significance. The long-term effects of taping need to be studied in large trials. Classification of evidence: This study provided Class III evidence that tri-pull shoulder taping was ineffective in significantly reducing shoulder pain in patients with acute stoke.

The Statistical analysis plan (SAP) for the second INTEnsive blood pressure Reduction in Acute Cerebral hemorrhage Trial (INTERACT2).

Background: Endpoint adjudication committees (EPAC) are widely used in clinical trials. The aim of the present analysis is to assess the effects of the endpoint adjudication process on the main findings of the ADVANCE trial (Trial registration: ClinicalTrials.gov NCT00145925). Methods and Findings: The ADVANCE trial was a multicentre, 2×2 factorial randomised controlled trial of blood pressure lowering and intensive blood glucose control in 11140 patients with type 2 diabetes. Primary outcomes were major macrovascular (nonfatal myocardial infarction, nonfatal stroke and cardiovascular death) and microvascular (new or worsening nephropathy and retinopathy) events. Suspected primary outcomes were initially reported by the investigators at the 215 sites with subsequent adjudication by the EPAC. The EPAC also adjudicated upon potential events identified directly by ongoing screening of all reported events. Over a median follow-up of 5 years, the site investigators reported one or more primary outcomes among 2443 participants. After adjudication these events were confirmed for 2077 (85%) with 48 further events added through the EPAC-led database screening process. The estimated relative risk reductions (95% confidence intervals) in the primary outcome for the blood pressure lowering comparison were 8% (-1 to 15%) based on the investigator-reported events and 9% (0 to 17%) based on the EPAC-based events (P for homogeneity = 0.70). The corresponding findings for the glucose comparison were 8% (1 to 15%) and 10% (2% to 18%) (P for homogeneity = 0.60). The effect estimates were also highly comparable when studied separately for macrovascular events and microvascular events for both comparisons (all P for homogeneity>0.6). Conclusions: The endpoint adjudication process had no discernible impact on the main findings in ADVANCE. These data highlight the need for careful consideration of the likely impact of an EPAC on the findings and conclusions of clinical trials prior to their establishment. © 2013 Hata et al.

Background The risk of stroke is high in men among both Asian and non-Asian populations, despite differences in risk factor profiles; whether risk factors act similarly in these populations is unknown. Aim To study the associations between five major risk factors and stroke risk, comparing Asian with non-Asian men. Methods We obtained data from the Asia Pacific Cohort Studies Collaboration, a pooled analysis of individual participant data from 44 studies involving 386 411 men with 9·4 years follow-up. Using cohorts from Asia and Australia/New Zealand Cox models were fitted to estimate risk factor associations for ischemic and haemorrhagic stroke. Results We identified significant, positive associations between all five risk factors and risk of ischemic stroke. The associations between body mass index, smoking, and diabetes with ischemic stroke were comparable for men from Asia and Australia/New Zealand. The association between systolic blood pressure and ischemic stroke was stronger for Asian than Australia/New Zealand cohorts, whereas the reverse was true for total cholesterol. For haemorrhagic stroke, only systolic blood pressure and smoking were associated with increased risk, although the relationship with systolic blood pressure was significantly stronger for men from Asia than Australia/New Zealand ( Pinteraction = 0·03), whereas the reverse was true for smoking ( Pinteraction = 0·001). There was an inverse trend of total cholesterol with haemorrhagic stroke, significant only for Asian men. Conclusions Men from the Asia-Pacific region share common risk factors for stroke. Strategies aimed at lowering population levels of systolic blood pressure, total cholesterol, body mass index, smoking, and diabetes are likely to be beneficial in reducing stroke risk, particularly for ischemic stroke, across the region.