Risk of Stroke in Chronic Heart Failure Patients Without Atrial Fibrillation: Analysis of the Controlled Rosuvastatin in Multinational Trial Heart Failure (CORONA) and the Gruppo Italiano per lo Studio della Sopravvivenza nell'Insufficienza Cardiaca-Heart Failure (GISSI-HF) Trials.

BACKGROUND: Our aim was to describe the incidence and predictors of stroke in patients who have heart failure without atrial fibrillation (AF). METHODS AND RESULTS: We pooled 2 contemporary heart failure trials, the Controlled Rosuvastatin in Multinational Trial Heart Failure (CORONA) and the Gruppo Italiano per lo Studio della Sopravvivenza nell'Insufficienza cardiaca-Heart Failure trial (GISSI-HF). Of the 9585 total patients, 6054 did not have AF. Stroke occurred in 165 patients (4.7%) with AF and in 206 patients (3.4%) without AF (rates 16.8/1000 patient-years and 11.1/1000 patient-years, respectively). Using Cox proportional-hazards models, we identified the following independent predictors of stroke in patients without AF (ranked by χ(2) value): age (hazard ratio, 1.34; 95% confidence interval, 1.18-1.63 per 10 years), New York Heart Association class (1.60, 1.21-2.12 class III/IV versus II), diabetes mellitus treated with insulin (1.87, 1.22-2.88), body mass index (0.74, 0.60-0.91 per 5 kg/m(2) up to 30), and previous stroke (1.81, 1.19-2.74). N-terminal pro B-type natriuretic peptide (available in 2632 patients) was also an independent predictor of stroke (hazard ratio, 1.31; 1.11-1.57 per log unit) when added to this model. With the use of a risk score formulated from these predictors, we found that patients in the upper third of risk had a rate of stroke that approximated the risk in patients with AF. CONCLUSIONS: A small number of demographic and clinical variables identified a subset of patients who have heart failure without AF at a high risk of stroke.

National institutes of health stroke scale item profiles as predictor of patient outcome: external validation on independent trial data.

BACKGROUND AND PURPOSE: National Institutes of Health Stroke Scale (NIHSS) item profiles that were recently proposed may prove useful both clinically and for research studies. We aimed to validate the NIHSS item profiles in an acute cohort. METHODS: We conducted a retrospective analysis on pooled data from randomized clinical trials. We applied the latent class analysis probabilities of profile membership developed from the derivation study to obtain symptom grouping, a-NIHSS item profiles. We implemented an independent latent class analysis to derive secondary symptom grouping, b-NIHSS item profiles. Validation was performed by assessing the associations with outcomes and evaluating both sets of NIHSS item profiles' discrimination and calibration to the data. The outcomes evaluated included modified Rankin Scale (mRS; using the full distribution and dichotomized, mRS, 0-1) at day 90 and mortality by 90 days. RESULTS: We identified 10 271 patients. Ordinal analysis of mRS confirmed increased odds of better outcome across the profiles in a stepwise manner, adjusted for age and thrombolysis treatment, for each set of NIHSS item profiles. Similar patterns were observed for mRS 0 to 1, and inverse patterns were seen for mortality. The c-statistics of a-NIHSS and b-NIHSS item profiles for mRS 0 to 1 were similar at 0.71 (95% confidence interval, 0.70-0.72) and for mortality, 0.74 (0.73-0.75) and 0.75 (0.73-0.76), respectively. Calibration was good. CONCLUSIONS: These NIHSS item profiles identified using latent class analysis offer a reliable approach to capture the true response patterns that are associated with functional and outcome and mortality post stroke. This approach has the potential to enhance the clinical value of the overall NIHSS score.

National Institutes of Health Stroke Scale Item Profiles as Predictor of Patient Outcome: External Validation on Safe Implementation of Thrombolysis in Stroke-Monitoring Study Data.

BACKGROUND AND PURPOSE: National Institutes of Health Stroke Scale (NIHSS) item profiles that were recently proposed and validated may prove useful for clinical prognostication and research studies. We aimed to validate the NIHSS item profiles in hyper-acute stroke patients who received thrombolysis treatment (tissue-type plasminogen activator). METHODS: We applied the latent class analysis probabilities of the profile membership generated from the derivation study onto NIHSS data from the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST). We separately considered NIHSS data collected within 3 hours and at ≈24 hours after stroke onset to obtain 2 sets of symptom groupings. The discrimination and calibration of both sets of symptom profiles were assessed from their association with outcomes. The outcome measures included modified Rankin Scale (mRS; using full distribution and dichotomized, mRS 0-1 or back to baseline) at day 90 and mortality by 90 days. RESULTS: We obtained data for 6843 patients. Ordinal analysis of mRS showed odds of better outcome across the profiles, for each set of symptom profiles, adjusted for age, sex, and prestroke mRS. Dichotomized outcomes mirrored the ordinal findings. There were significant differences in prognostic discrimination ability for the dichotomized outcome measures between the 2 sets of symptom profiles, with the latter set (ie, 24-hour symptom profiles) performing better. CONCLUSIONS: The NIHSS item profiles are individually associated with functional outcome and mortality in acute stroke patients treated with tissue-type plasminogen activator. Considering profiles of NIHSS subscores rather than only the total score is informative for prognostication, particularly for assessments collected 24 hours after stroke onset.

Risk Factors of Ischemic Stroke and Subsequent Outcome in Patients Receiving Hemodialysis.

BACKGROUND AND PURPOSE: End-stage renal disease (ESRD) requiring hemodialysis carries up to a 10-fold greater risk of stroke than normal renal function. Knowledge on risk factors and management strategies derived from the general population may not be applicable to those with ESRD. We studied a large ESRD population to identify risk factors and outcomes for stroke. METHODS: All adult patients receiving hemodialysis for ESRD from January 1, 2007, to December 31, 2012, were extracted from the electronic patient record. Variables associated with stroke were identified by survival analysis; demographic, clinical, imaging, and dialysis-related variables were assessed, and case-fatality was determined. Follow-up was until December 31, 2013. RESULTS: A total of 1382 patients were identified (mean age, 60.5 years; 58.5% men). The prevalence of atrial fibrillation was 21.2%, and 59.4% were incident hemodialysis patients. One hundred and sixty patients (11.6%) experienced a stroke during 3471 patient-years of follow-up (95% ischemic). Stroke incidence was 41.5/1000 patient-years in prevalent and 50.1/1000 patient-years in incident hemodialysis patients. Factors associated with stroke on regression analysis were prior stroke, diabetes mellitus, and age at starting renal replacement therapy. Atrial fibrillation was not significantly associated with stroke, and warfarin did not affect stroke risk in warfarin-treated patients. Fatality was 18.8% at 7 days, 26.9% at 28 days, and 56.3% at 365 days after stroke. CONCLUSIONS: Incidence of stroke is high in patients with ESRD on hemodialysis with high case-fatality. Incident hemodialysis patients had the highest stroke incidence. Many, but not all, important risk factors commonly associated with stroke in the general population were not associated with stroke in patients receiving hemodialysis.

Characteristic adverse events and their incidence among patients participating in acute ischemic stroke trials.

BACKGROUND AND PURPOSE: Adverse events (AE) in trial populations present a major burden to researchers and patients, yet most events are unrelated to investigational treatment. We aimed to develop a coherent list of expected AEs, whose incidence can be predicted by patient characteristics that will inform future trials and perhaps general poststroke care. METHODS: We analyzed raw AE data from patients participating in acute ischemic stroke trials. We identified events that occurred with a lower 99% confidence bound greater than nil. Among these, we applied receiver operating characteristic principles to select the fewest types of events that together represented the greatest number of reports. Using ordinal logistic regression, we modeled the incidence of these events as a function of patient age, sex, baseline National Institutes of Health Stroke Scale, and multimorbidity status, defining P<0.05 as statistically significant. RESULTS: We analyzed 5775 placebo-treated patients, reporting 21 217 AEs. Among 756 types of AEs, 132 accounted for 82.7%, of which 80% began within 10 days after stroke. Right hemisphere (odds ratio [OR], 1.67), increasing baseline National Institutes of Health Stroke Scale (OR, 1.11), multimorbidity status (OR, 1.09 per disease), patient age (OR, 1.01 per year), height (OR, 1.01 per centimeter), diastolic blood pressure (OR, 0.99 per mm Hg), and smoking (OR, 0.82) were independently associated with developing more AEs but together explained only 13% of the variation. CONCLUSIONS: A list of 132 expected AEs after acute ischemic stroke may be used to simplify interpretation and reporting of complications. AEs can be modestly predicted by patient characteristics, facilitating stratification of patients by risk for poststroke complications.

Transcranial laser therapy in acute stroke treatment: results of neurothera effectiveness and safety trial 3, a phase III clinical end point device trial.

BACKGROUND AND PURPOSE: On the basis of phase II trials, we considered that transcranial laser therapy could have neuroprotective effects in patients with acute ischemic stroke. METHODS: We studied transcranial laser therapy in a double-blind, sham-controlled randomized clinical trial intended to enroll 1000 patients with acute ischemic stroke treated ≤24 hours after stroke onset and who did not undergo thrombolytic therapy. The primary efficacy measure was the 90-day functional outcome as assessed by the modified Rankin Scale, with hierarchical Bayesian analysis incorporating relevant previous data. Interim analyses were planned after 300 and 600 patients included. RESULTS: The study was terminated on recommendation by the Data Monitoring Committee after a futility analysis of 566 completed patients found no difference in the primary end point (transcranial laser therapy 140/282 [49.6%] versus sham 140/284 [49.3%] for good functional outcome; modified Rankin Scale, 0-2). The results remained stable after inclusion of all 630 randomized patients (adjusted odds ratio, 1.024; 95% confidence interval, 0.705-1.488). CONCLUSIONS: Once the results of the interim futility analysis became available, all study support was immediately withdrawn by the capital firms behind PhotoThera, and the company was dissolved. Proper termination of the trial was difficult but was finally achieved through special efforts by former employees of PhotoThera, the CRO Parexel and members of the steering and the safety committees. We conclude that transcranial laser therapy does not have a measurable neuroprotective effect in patients with acute ischemic stroke when applied within 24 hours after stroke onset. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01120301.

How well do standard stroke outcome measures reflect quality of life? A retrospective analysis of clinical trial data.

BACKGROUND AND PURPOSE: Quality of life (QoL) is important to stroke survivors yet is often recorded as a secondary measure in acute stroke randomized controlled trials. We examined whether commonly used stroke outcome measures captured aspects of QoL. METHODS: We examined primary outcomes by National Institutes of Health Stroke Scale (NIHSS), Barthel Index (BI) and modified Rankin Scale (mRS), and QoL by Stroke Impact Scale (SIS) and European Quality of Life Scale (EQ-5D) from the Virtual International Stroke Trials Archive (VISTA). Using Spearman correlations and logistic regression, we described the relationships between QoL mRS, NIHSS, and BI at 3 months, stratified by respondent (patient or proxy). Using χ2 analyses, we examined the mismatch between good primary outcome (mRS ≤1, NIHSS ≤5, or BI ≥95) but poor QoL, and poor primary outcome (mRS ≥3, NIHSS ≥20, or BI ≤60) but good QoL. RESULTS: Patient-assessed QoL had a stronger association with mRS (EQ-5D weighted score n=2987, P<0.0001, r=-0.7, r2=0.53; SIS recovery n=2970, P<0.0001, r=-0.71, r2=0.52). Proxy responses had a stronger association with BI (EQ-5D weighted score n=837, P<0.0001, r=0.78, r2=0.63; SIS recovery n=867, P<0.0001, r=0.68, r2=0.48). mRS explained more of the variation in QoL (EQ-5D weighted score=53%, recovery by SIS v3.0=52%) than NIHSS or BI and resulted in fewer mismatches between good primary outcome and poor QoL (P<0.0001, EQ-5D weighted score=8.5%; SIS recovery=10%; SIS-16=4.4%). CONCLUSIONS: The mRS seemed to align closely with stroke survivors' interests, capturing more information on QoL than either NIHSS or BI. This further supports its recommendation as a primary outcome measure in acute stroke randomized controlled trials.

Characterization and treatment of chronic active Epstein-Barr virus disease: a 28-year experience in the United States.

Chronic active EBV disease (CAEBV) is a lymphoproliferative disorder characterized by markedly elevated levels of antibody to EBV or EBV DNA in the blood and EBV RNA or protein in lymphocytes in tissues. We present our experience with CAEBV during the last 28 years, including the first 8 cases treated with hematopoietic stem cell transplantation in the United States. Most cases of CAEBV have been reported from Japan. Unlike CAEBV in Japan, where EBV is nearly always found in T or natural killer (NK) cells in tissues, EBV was usually detected in B cells in tissues from our patients. Most patients presented with lymphadenopathy and splenomegaly; fever, hepatitis, and pancytopenia were common. Most patients died of infection or progressive lymphoproliferation. Unlike cases reported from Japan, our patients often showed a progressive loss of B cells and hypogammaglobulinemia. Although patients with CAEBV from Japan have normal or increased numbers of NK cells, many of our patients had reduced NK-cell numbers. Although immunosuppressive agents, rituximab, autologous cytotoxic T cells, or cytotoxic chemotherapy often resulted in short-term remissions, they were not curative. Hematopoietic stem cell transplantation was often curative for CAEBV, even in patients with active lymphoproliferative disease that was unresponsive to chemotherapy. These studies are registered at http://www.clinicaltrials.gov as NCT00032513 for CAEBV, NCT00062868 and NCT00058812 for EBV-specific T-cell studies, and NCT00578539 for the hematopoietic stem cell transplantation protocol.

Seven-day NIHSS is a sensitive outcome measure for exploratory clinical trials in acute stroke: evidence from the Virtual International Stroke Trials Archive.

BACKGROUND AND PURPOSE: Clinical trials in stroke typically measure outcome after 90 days. Earlier outcome assessment would reduce costs and may increase power. We aimed to compare the sensitivity of 4 end points (modified Rankin Scale [mRS] at 30 and 90 days, and National Institutes of Health Stroke Scale (NIHSS) at 7 and 90 days, analyzed as ordinal measures) to detect the established treatment effect of recombinant tissue-type plasminogen activator (rtPA). METHODS: Within the Virtual International Stroke Trials Archive, we compared rtPA-treated patients with untreated control subjects using a multiple resampling approach. From our total sample we drew 10 000 random samples of unique patients, constraining the sample sizes in treated and untreated groups to be equal. In each of these samples we tested for the treatment effect of rtPA by each of the 4 studied end points. The percentage of samples yielding significant results approximates the power of each end point at a given sample size. This process was repeated across a range of sample sizes, to determine the relationship between sample size and power for each of the 4 end points. RESULTS: For our 4 end points of mRS at 30 and 90 days, and NIHSS at 7 and 90 days the smallest sample sizes required to generate statistical power >80% were 620, 480, 370, and 420, respectively, making 7-day NIHSS the most sensitive end point. These results were supported by dichotomized analyses. CONCLUSIONS: Seven-day NIHSS score appears a sensitive end point that should be validated in randomized trial datasets for use in exploratory stroke trials.

Impact of atrial fibrillation on outcome in thrombolyzed patients with stroke: evidence from the Virtual International Stroke Trials Archive (VISTA).

BACKGROUND AND PURPOSE: Atrial fibrillation has been considered a risk factor for poor outcome from acute stroke and may influence response to thrombolysis, although supporting data are limited due to potential confounding with age and stroke severity. METHOD: We assessed the association of atrial fibrillation and thrombolysis exposure with the modified Rankin Scale score distribution at 90 days among patients registered in a trials archive. We used an age and baseline National Institutes of Health Stroke Scale-adjusted Cochran-Mantel-Haenszel test to test significance (P) followed by proportional odds logistic regression analysis to estimate the ORs for improved modified Rankin Scale score. RESULTS: Data were available for 7091 patients, of whom 3027 were thrombolyzed. A total of 1631 patients had a history of atrial fibrillation, of whom 639 were thrombolyzed. Among patients with atrial fibrillation, baseline severity was greater (median baseline National Institutes of Health Stroke Scale, 14 versus 12; P<0.001) and age was higher (mean age, 74.0 versus 66.5; P<0.001). An association of treatment with outcome was seen independently and was of similar magnitude within patients with atrial fibrillation (OR, 1.44; 95% CI, 1.12-1.73; P<0.001) and without atrial fibrillation (OR, 1.53; 95% CI, 1.39-1.69; P<0.001). No association of atrial fibrillation and overall stroke outcome could be found (OR, 0.93; 95% CI, 0.84-1.03; P=0.409). CONCLUSIONS: In this nonrandomized comparison, presence of atrial fibrillation had no independent impact on stroke outcome and compared with untreated comparators, the patients who received thrombolysis experienced an advantage in outcomes that was of equal magnitude whether in the presence or absence of atrial fibrillation.

Response of blood pressure and blood glucose to treatment with recombinant tissue-type plasminogen activator in acute ischemic stroke: evidence from the virtual international stroke trials archive.

BACKGROUND AND PURPOSE: Elevations in blood pressure (BP) and blood glucose are common during stroke and may represent a stress response secondary to the acute neurological deficit. If so, they should settle more completely in recombinant tissue-type plasminogen activator (rtPA)-treated patients in association with improved neurological status. METHODS: We performed a controlled comparison of 24-hour declines in BP and glucose in rtPA-treated and control patients from the Virtual Stroke International Stroke Trial Archive (VISTA) database. Twenty-four-hour falls in BP and glucose were compared using multiple regression to account for baseline imbalances. The logarithmic transformation of glucose was used and 24-hour differences expressed as ratios of 24 hours to admission geometric means. Two-way analysis of variance was used to test for interaction between rtPA and early improvement for 24-hour falls in BP and blood glucose. RESULTS: BP analysis included 5406 patients (rtPA=41%) and glucose analysis 4288 (rtPA=37%). rtPA-treated patients were younger, less likely to have a history of hypertension or diabetes, and had more severe strokes on admission. BP and glucose were lower at baseline in rtPA-treated patients than control subjects. On regression, rtPA predicted significantly greater 24-hour falls in systolic BP (ß=3.9; 95% CI, 2.8-5.0), diastolic BP (ß=3.1; 95% CI, 2.4-3.9), and glucose (ß=0.97; 95% CI, 0.95-0.99). rtPA did not interact with early neurological improvement for 24-hour falls in systolic BP (P=0.72), diastolic BP (P=0.79), or blood glucose (P=0.51). CONCLUSIONS: A stress response does not appear to be the principal cause of elevations in BP and glucose during stroke.

Contemporary outcome measures in acute stroke research: choice of primary outcome measure.

BACKGROUND AND PURPOSE: The diversity of available outcome measures for acute stroke trials is challenging and implies that the scales may be imperfect. To assist researchers planning trials and to aid interpretation, this article reviews and makes recommendations on the available choices of scales. The aim is to identify an approach that will be universally accepted and that should be included in most acute trials, without seeking to restrict options for special circumstances. METHODS: The article considers outcome measures that have been widely used or are currently advised. It examines desirable properties for outcome measures such as validity, relevance, responsiveness, statistical properties, availability of training, cultural and language issues, resistance to comorbidity, as well as potential weaknesses. Tracking and agreement among outcomes are covered. RESULTS: Typical ranges of scores for the common scales are described, along with their statistical properties, which in turn influence optimal analytic techniques. The timing of recovery on scores and usual practice in trial design are considered. CONCLUSIONS: The preferred outcome measure for acute trials is the modified Rankin Scale, assessed at 3 months after stroke onset or later. The interview should be conducted by a certified rater and should involve both the patient and any relevant caregiver. Incremental benefits at any level of the modified Rankin Scale may be acceptable. The modified Rankin Scale is imperfect but should be retained in its present form for comparability with existing treatment comparisons. No second measure should be required, but correlations with supporting scales may be used to confirm consistency in direction of effects on other measures.

Kinetics of serum cytokines after primary or repeat vaccination with the smallpox vaccine.

BACKGROUND: The smallpox vaccine is associated with more serious adverse events than any other live attenuated vaccine in use today. Although studies have examined serum cytokine levels in primary vaccine recipients at 1 and 3-5 weeks after vaccination with the smallpox vaccine, serial measurements have not been performed, and studies in revaccinated subjects have not been conducted. METHODS: We analyzed cytokine responses in both primary vaccine recipients and revaccinated subjects every other day for 2 weeks after vaccination. RESULTS: Primary vaccine recipients had maximal levels of granulocyte-colony-stimulating factor on days 6-7 after vaccination; peak levels of tumor necrosis factor (TNF)-alpha, soluble TNF receptor 1, interferon (IFN)-gamma, IFN-inducible protein-10 (IP-10), interleukin (IL)-6, and tissue inhibitor of metalloproteinases-1 on days 8-9 after vaccination; peak levels of soluble TNF receptor 2 and monokine induced by IFN-gamma (MIG) on days 10-11 after vaccination; and peak levels of granulocyte-macrophage-colony-stimulating factor on days 12-13 after vaccination. Primary vaccine recipients were significantly more likely to have higher peak levels of IFN-gamma, IP-10, and MIG after vaccination than were revaccinated subjects. Primary vaccine recipients were significantly more likely to have fatigue, lymphadenopathy, and headache, as well as a longer duration of these symptoms and more hours missed from work, compared with revaccinated subjects. CONCLUSIONS: The increased frequency and duration of symptoms observed in primary vaccine recipients, compared with revaccinated subjects, paralleled the increases in serum cytokine levels in these individuals. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT00325975.

End-user perceptions of a patient- and family-centred intervention to improve nutrition intake among oncology patients: a descriptive qualitative analysis.

BACKGROUND: People with cancer are at high risk of malnutrition. Nutrition education is an effective strategy to improve patient outcomes, however, little is known regarding the impact of family and/or carer involvement in nutrition education and requires investigation. The purpose of the study was to evaluate PIcNIC (Partnering with families to promote nutrition in cancer care) intervention acceptability from the perspective of patients, families and health care providers. METHODS: A descriptive qualitative study was undertaken at an inpatient and an outpatient hospital setting in Australia and an outpatient/home setting in Hong Kong. A patient-and-family centred intervention including nutrition education, goals setting/nutrition plans, and food diaries, was delivered to patients and/or families in the inpatient, outpatient or home setting. Semi-structured interviews were used to explore perceptions of the intervention. 64 participants were interviewed; 20 patients, 15 family members, and 29 health care professionals. Data were analysed using deductive and inductive content analysis. RESULTS: Two categories were identified; 1) 'context and intervention acceptability'; and 2) 'benefits of patient- and family-centred nutrition care'. Within each category redundant concepts were identified. For category 1 the redundant concepts were: the intervention works in outpatient settings, the food diary is easy but needs to be tailored, the information booklet is a good resource, and the intervention should be delivered by a dietitian, but could be delivered by a nurse. The redundant concepts for category 2 were: a personalised nutrition plan is required, patient and family involvement in the intervention is valued and the intervention has benefits for patients and families. Converging and diverging perceptions across participant groups and settings were identified. CONCLUSIONS: In this paper we have described an acceptable patient- and family-centred nutrition intervention, which may be effective in increasing patient and family engagement in nutrition care and may result in improved nutrition intakes. Our study highlights important contextual considerations for nutrition education; the outpatient and home setting are optimal for engaging patients and families in learning opportunities.

Mortality in intensive care: The impact of bacteremia and the utility of systemic inflammatory response syndrome.

BACKGROUND: The purpose of this study was to determine the impact of bacteremia on intensive care unit (ICU) mortality and to develop a bacteremia prediction tool using systemic inflammatory response syndrome (SIRS) criteria. METHODS: Patients included those aged >18 years who had blood cultures taken in the ICU from January 1, 2011-December 31, 2013. Eligible patients were identified from microbiology records of the Glasgow Royal Infirmary, Scotland. Clinical and outcome data were gathered from ICU records. Patients with clinically significant bacteremia were matched to controls using propensity scores. SIRS criteria were gathered and used to create decision rules to predict the absence of bacteremia. The main outcome was mortality at ICU discharge. The utility of the decision tools was measured using sensitivity and specificity. RESULTS: One hundred patients had a clinically significant positive blood culture and were matched to 100 controls. Patients with bacteremia had higher ICU mortality (odds ratio [OR], 2.35; P = .001) and longer ICU stay (OR, 17.0 vs 7.8 days; P ≤ .001). Of 1,548 blood culture episodes, 1,274 met ≥2 SIRS criteria (106 significant positive cultures and 1,168 negative cultures). There was no association between SIRS criteria and positive blood cultures (P = .11). A decision rule using 3 SIRS criteria had optimal predictive performance (sensitivity, 56%; specificity, 50%) but low accuracy. CONCLUSIONS: ICU patients with bacteremia have increased mortality and length of ICU stay. SIRS criteria cannot be used to identify patients at low risk of bacteremia.

Acetaminophen use and risk of myocardial infarction and stroke in a hypertensive cohort.

Recent data suggest that self-reported acetaminophen use is associated with increased risk of cardiovascular events and that acetaminophen causes a modest blood pressure rise. There are no randomized trials or studies using verified prescription data of this relationship. We aimed to assess the relationship between verified acetaminophen prescription data and risk of myocardial infarction or stroke in patients with hypertension. We performed a retrospective data analysis using information contained within the UK Clinical Research Practice Datalink. Multivariable Cox proportional hazard models were used to estimate hazard ratios for myocardial infarction (primary end point), stroke, and any cardiovascular event (secondary end points) associated with acetaminophen use during a 10-year period. Acetaminophen exposure was a time-dependent variable. A propensity-matched design was also used to reduce potential for confounding. We included 24,496 hypertensive individuals aged ≥ 65 years. Of these, 10,878 were acetaminophen-exposed and 13,618 were not. There was no relationship between risk of myocardial infarction, stroke, or any cardiovascular event and acetaminophen exposure on adjusted analysis (hazard ratio, 0.98; 95% confidence interval, 0.76-1.27; hazard ratio, 1.09; 95% confidence interval, 0.86-1.38; and hazard ratio, 1.17; 95% confidence interval, 0.99-1.37; respectively). Results in the propensity-matched sample (n=4000 per group) and when men and women were analyzed separately were similar. High-frequency users (defined as receiving a prescription for >75% of months) were also not at increased risk. After allowance for potentially confounding variables, the use of acetaminophen was not associated with an increased risk of myocardial infarction or stroke in a large cohort of hypertensive patients.

Selection for delayed intravenous alteplase treatment based on a prognostic score.

BACKGROUND AND PURPOSE: Approved use of intravenous alteplase for ischemic stroke offers net benefit. Pooled randomized controlled trial analysis suggests additional patients could benefit but others be harmed with treatment initiated beyond 4·5 h after stroke onset. We proposed prognostic scoring methods to identify a strategy for patient selection. METHODS: We selected 500 patients treated by intravenous alteplase and 500 controls from Virtual International Stroke Trials Archive, matching modified Rankin score outcomes to those from pooled randomized controlled trial 4·5-6 h data. We ranked patients by prognostic score. We chose limits to optimize our sample for a net treatment benefit significant at P = 0·01 by Cochran-Mantel-Haenszel test and by ordinal regression. For validation, we had these applied to the pooled randomized controlled trial data for 4·5-6 h, testing for net benefit by Cochran-Mantel-Haenszel test, ordinal regression, and also by dichotomized outcomes: modified Rankin score 0-1, mortality and parenchymal hemorrhage type 2 bleeds. All analyses were adjusted for age and National Institutes of Health Stroke Scale. RESULTS: In the training dataset, limits of 56-95 on a prognostic score retained 714 patients in whom there was net benefit significant at P = 0·01. When applied to the 1120 patients in the pooled randomized controlled trial 4·5-6 h dataset, score limits of 56-95 retained 711 patients and gave odds ratio for improved modified Rankin score distribution of 1·13, 95% confidence interval 0·87-1·47, Cochran-Mantel-Haenszel P = 0·89. More patients achieved modified Rankin score 0-1 (odds ratio 1·44, 1·02-2·05, P = 0·04) but mortality and parenchymal hemorrhage type 2 bleeds were increased: odds ratio 1·56, 1·01-2·40, P = 0·04; odds ratio 15·6, 3·7-65·8, P = 0·0002, respectively. CONCLUSION: Selection of patients between 4·5 and 6 h based on simple clinical measures failed to deliver a population in whom the alteplase effect would be safe and effective.

The effect of time to treatment on outcome in very elderly thrombolysed stroke patients.

BACKGROUND: Intravenous thrombolysis is beneficial in, even very elderly, acute ischemic stroke patients. However, while the relation between treatment benefit and treatment delay (onset time to treatment) in patients younger than 80 years is well known, it is uncertain in the very elderly. AIMS: This analysis aims at examining this relationship in the elderly, and to provide a comparison with the derived relationship in younger patients as a check of validity. METHODS: We assessed the interaction between age, onset time to treatment, and thrombolysis exposure by analyzing the modified Rankin scale score distribution or mortality rate at 90 days, among patients registered in a trials archive. We established whether the effect of alteplase changes with onset time to treatment, by treating onset time to treatment as a continuum in a multivariate logistic regression model. RESULTS: Data were available for 3063 patients, of whom 2341 were thrombolysed. Five hundred ninety-seven patients were aged >80, of whom 352 were thrombolysed. Among patients aged >80, no significant interaction of outcome with onset time to treatment was observed (P = 0·4650), but the estimated slope of the decay in benefit with onset time to treatment was comparable with that established for younger patients. Analyzing the entire dataset, there was an interaction between onset time to treatment and alteplase treatment (P = 0·0159), but neither between age and onset time to treatment (P = 0·7098) nor between age and alteplase treatment (P = 0·0755). CONCLUSIONS: In this nonrandomized comparison, the relationship of benefit and safety with thrombolysis across onset time to treatment in very elderly stroke patients was comparable with that in their younger counterparts. Across the investigated time span of 3·5 h, we can safely treat with the same time window as we use for younger patients.

Impact of benzodiazepines on functional outcome and occurrence of pneumonia in stroke: evidence from VISTA.

BACKGROUND: Benzodiazepines have been proposed both as a neuroprotectant and risk factor for pneumonia in acute stroke. AIMS: We assessed the impact of benzodiazepine exposure on the modified Rankin scale score distribution at 90 days as well as pneumonia rates among patients registered in a trials archive. METHOD: We used an age, baseline National Institutes of Health Stroke Score, and thrombolysis-rate adjusted Cochran-Mantel-Haenszel test to test significance (P) followed by proportional odds logistic regression analysis to estimate the odds ratios for improved modified Rankin scale score, and binary logistic regression to estimate the odds ratio for developing pneumonia. RESULTS: Data were available for 5938 patients, of whom 1800 received benzodiazepines. No association of benzodiazepine use and overall stroke outcome could be found (odds ratio 0·90, 95% confidence interval 0·82-1·00, P=0·121). Pneumonia occurred in 12·8% of patients treated with benzodiazepines and in 13·6% of the controls (odds ratio 0·99, 95% confidence interval 0·83-1·18, P=0·904). CONCLUSION: In this nonrandomized comparison, treatment with benzodiazepines as a concomitant medication had no independent impact on stroke outcome.