Plaque Composition as a Predictor of Plaque Ulceration in Carotid Artery Atherosclerosis: The Plaque At RISK Study.

BACKGROUND AND PURPOSE: Plaque ulceration is a marker of previous plaque rupture. We studied the association between atherosclerotic plaque composition at baseline and plaque ulceration at baseline and follow-up. MATERIALS AND METHODS: We included symptomatic patients with a carotid stenosis of <70% who underwent MDCTA and MR imaging at baseline (n = 180). MDCTA was repeated at 2 years (n = 73). We assessed the presence of ulceration using MDCTA. Baseline MR imaging was used to assess the vessel wall volume and the presence and volume of plaque components (intraplaque hemorrhage, lipid-rich necrotic core, and calcifications) and the fibrous cap status. Associations at baseline were evaluated with binary logistic regression and reported with an OR and its 95% CI. Simple statistical testing was performed in the follow-up analysis. RESULTS: At baseline, the prevalence of plaque ulceration was 27% (49/180). Increased wall volume (OR = 12.1; 95% CI, 3.5-42.0), higher relative lipid-rich necrotic core (OR = 1.7; 95% CI, 1.3-2.2), higher relative intraplaque hemorrhage volume (OR = 1.7; 95% CI, 1.3-2.2), and a thin-or-ruptured fibrous cap (OR = 3.4; 95% CI, 1.7-6.7) were associated with the presence of ulcerations at baseline. In 8% (6/73) of the patients, a new ulcer developed. Plaques with a new ulceration at follow-up had at baseline a larger wall volume (1.04 cm3 [IQR, 0.97-1.16 cm3] versus 0.86 cm3 [IQR, 0.73-1.00 cm3]; P = .029), a larger relative lipid-rich necrotic core volume (23% [IQR, 13-31%] versus 2% [IQR, 0-14%]; P = .002), and a larger relative intraplaque hemorrhage volume (14% [IQR, 8-24%] versus 0% [IQR, 0-5%]; P < .001). CONCLUSIONS: Large atherosclerotic plaques and plaques with intraplaque hemorrhage and lipid-rich necrotic cores were associated with plaque ulcerations at baseline and follow-up.

Cognitive and physical impairment and the risk of stroke - A prospective cohort study.

The manifestation of cognitive and physical impairment in stroke patients before the acute event suggests accumulating subclinical vascular pathology in the brain. We investigated whether impairments in cognitive and physical functioning were associated with an increased stroke risk. Between 2002 and 2008, 8,519 stroke-free non-demented participants from the population-based Rotterdam Study underwent cognition and physical assessments including Mini-Mental State Examination, 15-word learning test, Stroop test, letter-digit substitution test, verbal fluency test, Purdue pegboard test and questionnaires on basic and instrumental activities of daily living (BADL; IADL). Principal component analysis was used to derive global cognition (G-factor). Incident stroke was assessed through continuous monitoring of medical records until 2016. Among 8,519 persons (mean age 66.0 years; 57.8% women), 489 suffered a stroke during mean follow-up of 8.7 years (SD: 2.9). Worse G-factor was associated with higher stroke risk (Hazard Ratio 1.21, 95% CI: 1.06-1.38), largely driven by unspecified stroke. Likewise, worse scores on 15-word learning test, Stroop test, Purdue pegboard test, IADL, and BADL were associated with higher risk of stroke. Thus both worse cognitive and physical functioning were associated with a higher stroke risk, in particular unspecified stroke and persons with worse memory, information processing, executive function, and motor function.

Association between fibrinogen and fibrinogen γ' and atherosclerotic plaque morphology and composition in symptomatic carotid artery stenosis: Plaque-At-RISK study.

INTRODUCTION: Von Willebrand Factor (VWF), ADAMTS13, fibrinogen and fibrinogen γ' are associated with an increased risk of ischemic stroke. Carotid atherosclerosis is an important risk factor for ischemic stroke. Characteristics of the vulnerable plaque; intraplaque hemorrhage (IPH), plaque ulceration and lipid-rich necrotic core (LRNC) can be visualized with imaging techniques. Since atherosclerosis might attribute to the association between coagulation factors and ischemic stroke risk, the aim of this study is to investigate the association between coagulation factors and atherosclerotic plaque characteristics in more detail. MATERIALS AND METHODS: In 182 patients of the Plaque-At-RISK study (prospective multicenter cohort study) with a recent transient ischemic attack (TIA) or ischemic stroke and a symptomatic mild-to-moderate carotid artery stenosis, we measured VWF antigen (VWF:Ag), ADAMTS13 activity, fibrinogen (Clauss), and fibrinogen γ'. Presence of plaque ulceration, IPH volume and LRNC volume were determined by Multidetector-Row Computed Tomography (MDCTA, n = 160) and Magnetic Resonance Imaging (MRI, n = 172). Linear regression analysis was used to assess the association between imaging biomarkers and coagulation factors. RESULTS: VWF:Ag or ADAMTS13 levels were not significantly associated with plaque ulceration, IPH and LRNC. We found an inverse association between fibrinogen and fibrinogen γ' and IPH volume (B = -23.40 mm3/g/L, p = 0.01 and B = -161.73 mm3/g/L, p = 0.01) and between fibrinogen and fibrinogen γ' and LRNC volume (B = -38.89 mm3 g/L, p < 0.01 and B = -227.06 mm3 g/L, p = 0.01). Additional adjustments for C-reactive protein (CRP) did not change the results. CONCLUSIONS: Fibrinogen and fibrinogen γ' are inversely associated with IPH volume and LRNC volume, independent of inflammation. CLINICAL TRIAL REGISTRATION: clinicaltrials.govNCT01208025.

Professional occupation and the risk of Parkinson's disease.

BACKGROUND AND PURPOSE: Creativity in Parkinson's disease (PD) is strongly related to dopaminergic activity and medication. We hypothesized that patients with PD, including those who are in the pre-diagnostic phase of PD, are prone to choose highly structured 'conventional' professional occupations and avoid highly creative 'artistic' occupations. METHODS: At baseline of the population-based Rotterdam Study, we asked 12 147 individuals aged ≥45 years about their latest occupation and categorized occupations according to the RIASEC model. Participants underwent baseline and follow-up (median 11 years) examinations for PD. We determined associations of artistic (versus any other occupation) and conventional (versus any other occupation) occupations with PD. Additionally, we pooled our results with a recently published case-control study (Radboud Study). RESULTS: At baseline, conventional occupations were common [n = 4356 (36%)], whereas artistic occupations were rare [n = 137 (1%)]. There were 217 patients with PD, including 91 with prevalent PD and 126 with incident PD. The risk of PD varied substantially across occupational categories (chi-square, 14.61; P = 0.01). The penalized odds ratio (OR) of artistic occupations for PD was 0.19 [95% confidence interval (CI), 0.00-1.31; P = 0.11], whereas the OR of conventional occupations for PD was 1.23 (95% CI, 0.95-1.66; P = 0.10). The direction and magnitude of ORs were similar in cross-sectional and longitudinal subsamples. Pooled ORs across the Rotterdam and Radboud Studies were 0.20 (95% CI, 0.08-0.52; P < 0.001) for artistic and 1.23 (95% CI, 0.92-1.67; P = 0.08) for conventional occupations. CONCLUSIONS: The risk of PD varies substantially by choice of professional occupation. Our findings suggest that dopaminergic degeneration affects choice of occupation, which may start in the pre-diagnostic phase of PD.

Impaired fasting glucose is associated with unfavorable outcome in ischemic stroke patients treated with intravenous alteplase.

OBJECTIVES: Hyperglycemia on admission and diabetes mellitus type II are associated with unfavorable outcome in stroke patients. We studied whether impaired fasting glucose (IFG) is associated with unfavorable outcome in ischemic stroke patients treated with intravenous alteplase as well and if IFG is a stronger prognostic factor than hyperglycemia on admission. METHODS: We studied 220 consecutive patients with ischemic stroke treated with intravenous alteplase. In all nondiabetic patients, fasting glucose was determined on day 2-5. IFG was defined as fasting glucose level of ≥ 5.6 mmol/L, hyperglycemia on admission as glucose levels ≥ 7.9 mmol/L. The primary effect measure was the adjusted common odds ratio (acOR) for a shift in the direction of worse outcome on the modified Rankin Scale at 3 months, estimated with ordinal logistic regression, and adjusted for common prognostic factors. RESULTS: The fasting glucose levels were available in 194 and admission glucose levels in 215 patients. Sixty-three (32.5%) had IFG, 58 (27%) hyperglycemia on admission and 32 (14.6%) pre-existent diabetes. Patients with IFG showed a shift towards worse functional outcome compared with patients with normal fasting glucose levels (acOR 2.77; 95% CI 1.54-4.97), which was stronger than hyperglycemia on admission (acOR 1.75; 95% CI 0.91-3.4). CONCLUSIONS: IFG is associated with unfavorable outcome after treatment with intravenous alteplase for acute ischemic stroke. IFG predicts unfavorable outcome better than hyperglycemia on admission.

Glucose in prediabetic and diabetic range and outcome after stroke.

OBJECTIVES: Newly diagnosed disturbed glucose metabolism is highly prevalent in patients with stroke. Limited data are available on their prognostic value on outcome after stroke. We aimed to assess the association of glucose in the prediabetic and diabetic range with unfavourable short-term outcome after stroke. MATERIALS AND METHODS: We included 839 consecutive patients with ischemic stroke and 168 patients with intracerebral haemorrhage. In all nondiabetic patients, fasting glucose levels were determined on day 2-4. Prediabetic range was defined as fasting glucose of 5.6-6.9 mmol/L, diabetic range as ≥7.0 mmol/L, pre-existent diabetes as the use of anti-diabetic medication prior to admission. Outcome measures were poor functional outcome or death defined as modified Rankin Scale (mRS) score >2 and discharge not to home. The association of prediabetic range, diabetic range and pre-existent diabetes (versus normal glucose) with unfavourable outcome was expressed as odds ratios, estimated with multiple logistic regression, with adjustment for prognostic factors. RESULTS: Compared with normal glucose, prediabetic range (aOR 1.8; 95%CI 1.1-2.8), diabetic range (aOR 2.5; 95%CI 1.3-4.9) and pre-existent diabetes (aOR 2.6; 95%CI 1.6-4.0) were associated with poor functional outcome or death. Patients in the prediabetic range (aOR 0.6; 95%CI 0.4-0.9), diabetic range (aOR 0.4; 95%CI 0.2-0.9) and pre-existent diabetes (aOR 0.6; 95%CI 0.4-0.9) were more likely not to be discharged to home. CONCLUSIONS: Patients with glucose in the prediabetic and diabetic range have an increased risk of unfavourable short-term outcome after stroke. These findings illustrate the potential impact of early detection and treatment of these patients.

Increased admission and fasting glucose are associated with unfavorable short-term outcome after intra-arterial treatment of ischemic stroke in the MR CLEAN pretrial cohort.

BACKGROUND: Limited data are available on the impact of fasting glucose on outcome after intra-arterial treatment (IAT). We studied whether hyperglycemia on admission and impaired fasting glucose (IFG) are associated with unfavorable outcome after IAT in acute ischemic stroke. METHODS: Patients were derived from the pretrial registry of the MR CLEAN-trial. Hyperglycemia on admission was defined as glucose>7.8mmol/L, IFG as fasting glucose>5.5mmol/L in the first week of admission. Primary effect measure was the adjusted common odds ratio (acOR) for a shift in the direction of worse outcome on the modified Rankin Scale at discharge, estimated with ordinal logistic regression, adjusted for common prognostic factors. RESULTS: Of the 335 patients in which glucose on admission was available, 86 (26%) were hyperglycemic, 148 of the 240 patients with available fasting glucose levels (62%) had IFG. Median admission glucose was 6.8mmol/L (IQR 6-8). Increased admission glucose (acOR 1.2, 95%CI 1.1-1.3), hyperglycemia on admission (acOR 2.6, 95%CI 1.5-4.6) and IFG (acOR 2.8, 95%CI 1.4-5.6) were associated with worse functional outcome at discharge. CONCLUSION: Increased glucose on admission and IFG in the first week after stroke onset are associated with unfavorable short-term outcome after IAT of acute ischemic stroke.

Cerebrovascular disease.

With 16.9 million people who suffered a first-ever stroke in 2010 worldwide, stroke is a very common vascular disease. Epidemiologic studies have played an essential role in assessing this burden and in detecting the risk factors for stroke. Primary prevention of these risk factors, primarily hypertension, smoking, diabetes, and atrial fibrillation, has reduced the incidence in high-income countries. However, stroke remains a major cause of death and disability, and therefore research should be continued. Subarachnoid hemorrhages are less prevalent than strokes but have an even higher risk of death. Similar to stroke, epidemiologic studies identified smoking and hypertension as its most important risk factors, together with excessive alcohol intake. Although rare, arterial dissections, CADASIL, arteriovenous malformations, venous sinus thrombosis, moyamoya disease, and vasculitis can lead to serious symptoms. The burden and risk factors of those rare diseases are more challenging to assess. Whenever possible, they should be recognized in a timely manner for their increased risk of stroke, but most often they are diagnosed only at the time of stroke. Some cerebrovascular abnormalities do not result in immediate symptoms. This subclinical cerebrovascular disease includes silent infarcts, white-matter lesions, and microbleeds, and is incidentally found by neuroimaging. These lesions are not innocent, as several epidemiologic studies have associated subclinical cerebrovascular disease with an increased risk of stroke, cognitive decline, dementia, and death.

Intraplaque Hemorrhage and the Plaque Surface in Carotid Atherosclerosis: The Plaque At RISK Study (PARISK).

BACKGROUND AND PURPOSE: An important characteristic of vulnerable plaque, intraplaque hemorrhage, may predict plaque rupture. Plaque rupture can be visible on noninvasive imaging as a disruption of the plaque surface. We investigated the association between intraplaque hemorrhage and disruption of the plaque surface. MATERIALS AND METHODS: We selected the first 100 patients of the Plaque At RISK study, an ongoing prospective noninvasive plaque imaging study in patients with mild-to-moderate atherosclerotic lesions in the carotid artery. In carotid artery plaques, disruption of the plaque surface (defined as ulcerated plaques and/or fissured fibrous cap) and intraplaque hemorrhage were assessed by using MDCTA and 3T MR imaging, respectively. We used a χ(2) test and multivariable logistic regression to assess the association between intraplaque hemorrhage and disrupted plaque surface. RESULTS: One hundred forty-nine carotid arteries in 78 patients could be used for the current analyses. Intraplaque hemorrhage and plaque ulcerations were more prevalent in symptomatic compared with contralateral vessels (hemorrhage, 38% versus 11%; P < .001; and ulcerations, 27% versus 7%; P = .001). Fissured fibrous cap was more prevalent in symptomatic compared with contralateral vessels (13% versus 4%; P = .06). After adjustment for age, sex, diabetes mellitus, and degree of stenosis, intraplaque hemorrhage was associated with disrupted plaque surface (OR, 3.13; 95% CI, 1.25-7.84) in all vessels. CONCLUSIONS: Intraplaque hemorrhage is associated with disruption of the plaque surface in patients with a carotid artery stenosis of <70%. Serial studies are needed to investigate whether intraplaque hemorrhage indeed increases the risk of plaque rupture and subsequent ischemic stroke during follow-up.

N-terminal pro-B-type natriuretic peptide and the risk of stroke and transient ischaemic attack: the Rotterdam Study.

BACKGROUND AND PURPOSE: Amino-terminal pro-B-type natriuretic peptide (NT-proBNP) is a predictor of heart disease. It has also been related to stroke, but its association with transient ischaemic attacks (TIAs) is unclear. Moreover, it is unknown how clinical heart disease influences this relation. Within the prospective population-based Rotterdam Study, the association of NT-proBNP with stroke and TIA was examined and the role of heart disease on this association was investigated. METHODS: NT-proBNP was measured in 1997-2001 in 5611 participants (mean age 68.7 years; 57.7% women) without a history of stroke, TIA or heart failure. Follow-up for stroke and TIA finished in 2012. Models were adjusted for age and cardiovascular risk factors, and were stratified by sex. RESULTS: During 22 058 person-years 195 men suffered a stroke and 118 a TIA. During 31 825 person-years 230 women suffered a stroke and 187 a TIA. Higher NT-proBNP was associated with a higher risk of stroke in men [hazard ratio (HR) per SD increase 1.50; 95% confidence interval (CI) 1.29-1.76] and in women (HR 1.24; 95% CI 1.05-1.46). Associations with TIA were only present in women (HR 1.51; 95% CI 1.26-1.82) but not in men (HR 1.02; 95% CI 0.83-1.26). Excluding persons with a history of clinical coronary heart disease, heart failure or atrial fibrillation and censoring for clinical heart disease during follow-up did not change the associations. CONCLUSIONS: Higher NT-proBNP is associated with incident stroke in men and women and with incident TIA only in women. These associations are independent of clinical heart disease preceding cerebrovascular disease.

Plaque At RISK (PARISK): prospective multicenter study to improve diagnosis of high-risk carotid plaques.

BACKGROUND: Patients with symptomatic carotid artery stenosis are at high risk for recurrent stroke. To date, the decision to perform carotid endarterectomy in patients with a recent cerebrovascular event is mainly based on degree of stenosis of the ipsilateral carotid artery. However, additional atherosclerotic plaque characteristics might be better predictors of stroke, allowing for more precise selection of patients for carotid endarterectomy. AIMS AND HYPOTHESIS: We investigate the hypothesis that the assessment of carotid plaque characteristics with magnetic resonance imaging, multidetector-row computed tomography angiography, ultrasonography, and transcranial Doppler, either alone or in combination, may improve identification of a subgroup of patients with < 70% carotid artery stenosis with an increased risk of recurrent stroke. METHODS: The Plaque At RISK (PARISK) study is a prospective multicenter cohort study of patients with recent (<3 months) neurological symptoms due to ischemia in the territory of the carotid artery and < 70% ipsilateral carotid artery stenosis who are not scheduled for carotid endarterectomy or stenting. At baseline, 300 patients will undergo magnetic resonance imaging, multidetector-row computed tomography angiography, and ultrasonography examination of the carotid arteries. In addition, magnetic resonance imaging of the brain, ambulatory transcranial Doppler recording of the middle cerebral artery and blood withdrawal will be performed. After two-years, imaging will be repeated in 150 patients. All patients undergo a follow-up brain magnetic resonance imaging, and there will be regular clinical follow-up until the end of the study. STUDY OUTCOMES: The combined primary end-point contains ipsilateral recurrent ischemic stroke or transient ischemic attack or new ipsilateral ischemic brain lesions on follow-up brain magnetic resonance imaging.

Is isolated aphasia a typical presentation of presumed cardioembolic transient ischemic attack or stroke?

BACKGROUND: Previous studies have suggested that patients with a transient ischemic attack (TIA) or minor ischemic stroke and isolated aphasia should be carefully screened for a potential cardiac source of embolism. Most of these publications, however, were case reports or small-series. The purpose of this study was to assess the relationship between isolated aphasia and atrial fibrillation (AF) as the cause of presumed cardioembolic TIA or stroke within the setting of 2 large multicenter trials. METHODS: The frequency of isolated aphasia was compared between patients with a TIA or minor ischemic stroke either with AF [European Atrial Fibrillation Trial (EAFT), n = 1,001] or without AF [Dutch TIA Trial (DTT), n = 3,150]. We analyzed data with univariable and multivariable logistic regression. Isolated aphasia was defined as aphasia without dysarthria, visual-field defects or motor or sensory deficits of the arm, leg or face. Because dysarthria can be difficult to detect in aphasic patients, a second analysis was done without excluding dysarthric patients. In a third analysis, we excluded patients with a symptomatic lacunar infarct from the DTT, as these patients were overrepresented due to the exclusion of patients with AF. Subgroup analysis was performed for patients presenting with TIA and minor stroke. RESULTS: Of 4,151 patients, 210 (5.1%) had isolated aphasia, 109 from the EAFT and 101 from the DTT, crude odds ratio (OR) 3.69, 95% confidence interval (CI) 2.79-4.89. Patients with isolated aphasia were older (mean age 70.3 vs. 66.8 years, p < 0.01), more often female (OR 1.87, 95% CI 1.41-2.46), and more often had diabetes (OR 1.73, 95% CI 1.16-2.59) and hypercholesterolemia (OR 1.83, 95% CI 1.11-3.03) than those without aphasia. After simultaneous adjustment for age, sex, diabetes and hypercholesterolemia, patients with isolated aphasia still had AF more often than patients without isolated aphasia (adjusted OR 2.94, 95% CI 2.16-4.01). Both after inclusion of patients with dysarthria in the group of patients with isolated aphasia and after exclusion of patients with a symptomatic lacunar infarct, essentially the results remained the same. Patients presenting with isolated aphasia due to a TIA tended to have AF more often than patients with a minor ischemic stroke. CONCLUSIONS: Isolated aphasia is an independent sign of AF in patients with a TIA or minor ischemic stroke. Careful cardiac screening seems warranted in patients with isolated aphasia, as secondary prevention is different in patients with a cardiac source of embolism.

Structural and diffusion MRI measures of the hippocampus and memory performance.

Hippocampal atrophy on MRI and changes in diffusion tensor imaging (DTI) measures of the hippocampus have been reported in patients with Alzheimer's disease. We examined the association between hippocampal volumes, DTI measures of the hippocampus and memory performance in 892 non-demented persons (age ≥ 55 years) across different age groups. Hippocampal volume was segmented on 3D volumetric MRI scans. The segmentations were co-registered to mean diffusivity (MD) and fractional anisotropy (FA) maps to yield mean hippocampal MD and FA measurements. Higher MD of the hippocampus was associated with impaired verbal memory performance. In all persons ≥ 55 years, a higher MD of the hippocampus was associated with a worse memory performance. Hippocampal volumes were very weakly positively associated with delayed recall and only in persons > 65 years. FA of the hippocampus was not associated with memory performance. Follow-up studies will be needed to determine whether higher MD of hippocampus at younger ages could be an earlier marker of incident Alzheimer's disease than hippocampal volume.

Is dementia incidence declining?: Trends in dementia incidence since 1990 in the Rotterdam Study.

OBJECTIVE: To investigate whether dementia incidence has changed over the last 2 decades. METHODS: We compared dementia incidence in 2 independent subcohorts of persons aged 60-90 years from the Rotterdam Study, a population-based cohort study. The first subcohort started in 1990 (n = 5,727), the second in 2000 (n = 1,769). Participants were dementia-free at baseline and followed for at maximum 5 years. We calculated age-adjusted dementia incidence rates for the 2 subcohorts in total, in 10-year age strata, and for men and women separately. We also compared mortality rates, differences in prevalence of vascular risk factors, and medication use. Finally, we compared brain volumes and the extent of cerebral small vessel disease in participants who underwent brain imaging 5 years after the baseline examinations. RESULTS: In the 1990 subcohort (25,696 person-years), 286 persons developed dementia, and in the 2000 subcohort (8,384 person-years), 49 persons. Age-adjusted dementia incidence rates were consistently, yet nonsignificantly, lower in the 2000 subcohort in all strata, reaching borderline significance in the overall analysis (incidence rate ratio 0.75, 95% confidence interval [CI] 0.56-1.02). Mortality rates were also lower in the 2000 subcohort (rate ratio 0.63, 95% CI 0.52-0.77). The prevalence of hypertension and obesity significantly increased between 1990 and 2000. This was paralleled by a strong increase in use of antithrombotics and lipid-lowering drugs. Participants in 2005-2006 had larger total brain volumes (p < 0.001) and less cerebral small vessel disease (although nonsignificant in men) than participants in 1995-1996. CONCLUSIONS: Although the differences in dementia incidence were nonsignificant, our study suggests that dementia incidence has decreased between 1990 and 2005.

Genetic determinants of von Willebrand factor plasma levels and the risk of stroke: the Rotterdam Study.

BACKGROUND: High von Willebrand factor (VWF) plasma levels are associated with an increased risk of stroke. VWF levels are strongly heritable. A previous meta-analysis of five large genome-wide association studies identified single-nucleotide polymorphisms (SNPs) within eight genetic loci as determinants of VWF levels. Whether these SNPs are associated with stroke risk is not known. The aim of our study was to investigate the association between genetic determinants of VWF levels and stroke risk. METHODS: The study was part of the Rotterdam Study, a large population-based cohort study among subjects aged ≥ 55 years. A total of 5763 participants for whom DNA was available, and who were free of stroke at baseline, were eligible for analysis. VWF antigen (VWF:Ag) levels were measured in 3379 eligible participants. Within each of the eight loci, one top SNP was defined. The association between the eight SNPs and the risk of stroke was analyzed. Then, a genetic score, based on these eight SNPs, was constructed, and its total contribution to VWF plasma levels and stroke risk was investigated. RESULTS: None of the eight SNPs was individually associated with stroke risk. A higher genetic score was significantly associated with a higher VWF:Ag level, but was not associated with an increased risk of stroke. CONCLUSION: Eight SNPs that strongly determine VWF levels are not associated with stroke risk, either individually, or combined in a genetic score.

Effects of high-dose paracetamol on blood pressure in acute stroke.

BACKGROUND: Early administration of paracetamol may improve outcome of patients with acute stroke and a baseline body temperature of 37°C or above by lowering body temperature and preventing fever. Besides its antipyretic effects, paracetamol may affect blood pressure through cyclooxygenase-2 inhibition. We therefore aimed to assess the effect of high-dose paracetamol on blood pressure in patients with acute stroke. METHODS: We analyzed data of 540 patients admitted within 24 h of stroke onset who were randomized to treatment with either paracetamol (6 g daily) or placebo. Blood pressures were measured at 12, 24, and 48 h from the start of treatment. Changes in blood pressure from baseline in the two treatment groups and corresponding 95% confidence intervals (CI) were calculated with linear regression analysis. Adjustments for potential confounders were made with a multiple linear regression model. RESULTS: Treatment with high-dose paracetamol was associated with a significant reduction in systolic blood pressure of 4.5 mm Hg (95% CI 0.6-8.5) at 12 h from the start of treatment. This effect was no longer present after 24 and 48 h. CONCLUSION: High-dose paracetamol reduces not only body temperature but also systolic blood pressure in the first 12 h after start of treatment. Both effects may improve functional outcome after stroke, but this needs further study.

Tiotropium Handihaler and the risk of cardio- or cerebrovascular events and mortality in patients with COPD.

BACKGROUND: Tiotropium has been associated with an increased risk of mortality and/or cardiovascular events. Recent data from RCTs suggests tiotropium Handihaler to be safe, but its safety has not yet been fully investigated under real-life circumstances. METHODS: We conducted 2 nested case-control studies in a COPD cohort from the Dutch IPCI database. In the first case-control study, cases had a cardiovascular or cerebrovascular endpoint (CCVE): stroke and transient ischemic attack (TIA), myocardial infarction, heart failure and/or ventricular arrhythmia. In the second, cases were all patients who died. Cases were matched to controls on age, sex and index date. Conditional logistic regression analysis was used to calculate adjusted odds ratios (OR(adj)) with 95% confidence intervals (CI) for tiotropium vs. long-acting beta-agonists (LABA). RESULTS: Within a cohort of 6788 COPD patients, 784 CCVE's and 1032 deaths were reported. Compared to current LABA use, use of tiotropium Handihaler was neither associated with an increased risk of a CCVE (OR(adj) 0.89, 95% 0.55-1.44) nor with an increased risk of death (OR(adj) 0.79, 95% CI 0.49-1.28). CONCLUSIONS: In real life, use of tiotropium Handihaler in COPD patients is not associated with an increased risk of a CCVE or mortality compared to LABA.