Jesse Dawson

Detection of Atrial Fibrillation After Ischemic Stroke or Transient Ischemic Attack A Systematic Review and Meta-Analysis

Background and Purpose— Atrial fibrillation (AF) confers a high risk of recurrent stroke, although detection methods and definitions of paroxysmal AF during screening vary. We therefore undertook a systematic review and meta-analysis to determine the frequency of newly detected AF using noninvasive or invasive cardiac monitoring after ischemic stroke or transient ischemic attack. Methods— Prospective observational studies or randomized controlled trials of patients with ischemic stroke, transient ischemic attack, or both, who underwent any cardiac monitoring for a minimum of 12 hours, were included after electronic searches of multiple databases. The primary outcome was detection of any new AF during the monitoring period. We prespecified subgroup analysis of selected (prescreened or cryptogenic) versus unselected patients and according to duration of monitoring. Results— A total of 32 studies were analyzed. The overall detection rate of any AF was 11.5% (95% confidence interval, 8.9%–14.3%), although the timing, duration, method of monitoring, and reporting of diagnostic criteria used for paroxysmal AF varied. Detection rates were higher in selected (13.4%; 95% confidence interval, 9.0%–18.4%) than in unselected patients (6.2%; 95% confidence interval, 4.4%–8.3%). There was substantial heterogeneity even within specified subgroups. Conclusions— Detection of AF was highly variable, and the review was limited by small sample sizes and marked heterogeneity. Further studies are required to inform patient selection, optimal timing, methods, and duration of monitoring for detection of AF/paroxysmal AF.

Reliability of the Modified Rankin Scale A Systematic Review

Background and Purpose— A perceived weakness of the modified Rankin Scale is potential for interobserver variability. We undertook a systematic review of modified Rankin Scale reliability studies. Methods— Two researchers independently reviewed the literature. Crossdisciplinary electronic databases were interrogated using the following key words: Stroke*; Cerebrovasc*; Modified Rankin*; Rankin Scale*; Oxford Handicap*; Observer variation*. Data were extracted according to prespecified criteria with decisions on inclusion by consensus. Results— From 3461 titles, 10 studies (587 patients) were included. Reliability of modified Rankin Scale varied from weighted &kgr;=0.95 to &kgr;=0.25. Overall reliability of mRS was &kgr;=0.46; weighted &kgr;=0.90 (traditional modified Rankin Scale) and &kgr;=0.62; weighted &kgr;=0.87 (structured interview). Conclusion— There remains uncertainty regarding modified Rankin Scale reliability. Interobserver studies closest in design to large-scale clinical trials demonstrate potentially significant interobserver variability.

Functional outcome measures in contemporary stroke trials

Various instruments are used to describe poststroke functional outcome, with limited consensus as to optimal end-point for clinical trial use. Many of the popular assessment tools are administered with little formal guidance on best practice. Thus there is potential for substantial heterogeneity in functional outcome assessment poststroke, with consequent effects on trial quality. We examined functional assessment methodology in recent stroke trials. We reviewed six journals representing high-impact international publications in the fields of: stroke (Stroke); neurology (Neurology, Lancet Neurology) and internal medicine (Lancet, New England Journal Medicine; Journal of the American Medical Association). Journals were hand searched for all interventional studies in stroke patients between 2001 and 2006 inclusive. Chosen manuscripts were then analyzed for outcome assessment methodology. We identified 126 trials, comprising a mix of early hypothesis generating studies through to multicentre trials (phase I: four trials; phase II: 46 trials; phase III: 20 trials; noninvestigational medicinal product studies: 56 trials). The median number of patients assessed per trial was 100. Across the trials, 47 different outcome measures were used. One hundred trials had functional outcome assessment as the primary study end-point. The median number of outcome measures was two per trial (range 1–9). The modified Rankin scale was the most prevalent outcome assessment (64·3%); followed by Barthel index (40·5%). A minority of trials (33·3%) provided full details on outcome assessment methodology. Among these trials there was substantial heterogeneity in data collection procedures. There is heterogeneity in the use of functional outcome measures in stroke trials. This compromises comparison and meta-analysis. Trialists continue to use poorly validated approaches to outcome assessment. Given the potential effects on data quality, explicit description of methodology should be mandatory for all trials and rigour is desirable.

Detection of atrial fibrillation after ischemic stroke or TIA: a systematic review and meta-analysis.

Background and Purpose— Atrial fibrillation (AF) confers a high risk of recurrent stroke, although detection methods and definitions of paroxysmal AF during screening vary. We therefore undertook a systematic review and meta-analysis to determine the frequency of newly detected AF using noninvasive or invasive cardiac monitoring after ischemic stroke or transient ischemic attack. Methods— Prospective observational studies or randomized controlled trials of patients with ischemic stroke, transient ischemic attack, or both, who underwent any cardiac monitoring for a minimum of 12 hours, were included after electronic searches of multiple databases. The primary outcome was detection of any new AF during the monitoring period. We prespecified subgroup analysis of selected (prescreened or cryptogenic) versus unselected patients and according to duration of monitoring. Results— A total of 32 studies were analyzed. The overall detection rate of any AF was 11.5% (95% confidence interval, 8.9%–14.3%), although the timing, duration, method of monitoring, and reporting of diagnostic criteria used for paroxysmal AF varied. Detection rates were higher in selected (13.4%; 95% confidence interval, 9.0%–18.4%) than in unselected patients (6.2%; 95% confidence interval, 4.4%–8.3%). There was substantial heterogeneity even within specified subgroups. Conclusions— Detection of AF was highly variable, and the review was limited by small sample sizes and marked heterogeneity. Further studies are required to inform patient selection, optimal timing, methods, and duration of monitoring for detection of AF/paroxysmal AF.

Serum uric acid and the risk of cardiovascular and renal disease.

Substantial evidence suggests that chronic hyperuricemia is an independent risk factor for hypertension, metabolic syndrome, chronic kidney disease (CKD) and cardiovascular diseases. This highlights the need for greater attention to serum uric acid levels when profiling patients, and suggests that the threshold above which uricemia is considered abnormal is 6  mg/dl, in light of the available evidence. Another important question is whether lowering serum uric acid can improve cardiovascular and renal outcomes, and what therapeutic mechanism of action could provide more clinical benefits to patients; the available literature shows a trend toward improvement associated with administration of urate-lowering drugs, in particular for the xanthine oxidase inhibitors. The demonstrated efficacy of urate-lowering therapy on outcomes other than gout flares leads to the consideration that treatment may be beneficial even in the absence of overt gout when hyperuricemia accompanies other clinical conditions, such as urate deposition, advanced CKD or cardiovascular risk factors.

Diagnosis and Prediction of CKD Progression by Assessment of Urinary Peptides

Progressive CKD is generally detected at a late stage by a sustained decline in eGFR and/or the presence of significant albuminuria. With the aim of early and improved risk stratification of patients with CKD, we studied urinary peptides in a large cross-sectional multicenter cohort of 1990 individuals, including 522 with follow-up data, using proteome analysis. We validated that a previously established multipeptide urinary biomarker classifier performed significantly better in detecting and predicting progression of CKD than the current clinical standard, urinary albumin. The classifier was also more sensitive for identifying patients with rapidly progressing CKD. Compared with the combination of baseline eGFR and albuminuria (area under the curve [AUC]=0.758), the addition of the multipeptide biomarker classifier significantly improved CKD risk prediction (AUC=0.831) as assessed by the net reclassification index (0.303±-0.065; P<0.001) and integrated discrimination improvement (0.058±0.014; P<0.001). Correlation of individual urinary peptides with CKD stage and progression showed that the peptides that associated with CKD, irrespective of CKD stage or CKD progression, were either fragments of the major circulating proteins, suggesting failure of the glomerular filtration barrier sieving properties, or different collagen fragments, suggesting accumulation of intrarenal extracellular matrix. Furthermore, protein fragments associated with progression of CKD originated mostly from proteins related to inflammation and tissue repair. Results of this study suggest that urinary proteome analysis might significantly improve the current state of the art of CKD detection and outcome prediction and that identification of the urinary peptides allows insight into various ongoing pathophysiologic processes in CKD.

Xanthine oxidase inhibition for the treatment of cardiovascular disease: a systematic review and meta-analysis.

BACKGROUND Xanthine oxidase inhibition (XOI) reduces oxidative stress in the vasculature. Moreover it reduces uric acid levels, a risk factor for the development of cardiovascular disease. As such, XOI holds a potentially dual mechanism for the treatment of cardiovascular disease. AIMS Through systematic review, we sought to clarify the extent of available evidence that has evaluated the effect of XOI upon clinical or surrogate markers of cardiovascular disease and function in humans. METHODS A systematic search strategy was used to interrogate the Ovid Medline (1950-June Week 4 2010) and Embase (1980-2010 Week 25) databases, to identify relevant studies. Meta-analysis was planned for frequently studied endpoints. RESULTS Thirty-eight publications (reporting 40 studies) were identified. There was heterogeneity between studies in all aspects of study design, including the outcome measures of interest. Prospective assessment of surrogate markers predominated. Combined meta-analysis was feasible for three outcome parameters, with favorable modifications in each following xanthine oxidase inhibition: brachial artery flow mediated dilatation (five studies: XOI n = 75, control n = 69) increased by 2.50% (95% CI, 0.15-4.84); forearm blood flow responses to acetylcholine infusion (five studies: XOI n = 74, control n = 74) increased by 68.80 (95% CI, 18.70-118.90; percent change relative to noninfused control arm); circulating markers of oxidative stress (malondialdehyde, six studies: XOI n = 78, control n = 68) reduced by 0.56 nmol/mL (95% CI, 0.26-0.87). CONCLUSIONS XOI improves endothelial function and circulating markers of oxidative stress in patients with, or at risk of, cardiovascular disease. Large prospective studies examining definitive end points are lacking but now appear indicated.

Initial Experience of a Digital Training Resource for Modified Rankin Scale Assessment in Clinical Trials

Background and Purpose— The modified Rankin Scale (mRS) is the preferred measure of disability in cerebrovascular clinical trials, but its value is restricted by interobserver variability. Poor reliability reduces the statistical power of clinical trials and leads to underestimation of effect size. Strategies to improve mRS grading are required. Video training has previously improved application of the National Institutes of Health Stroke Scale in clinical research. We developed an mRS training resource in an attempt to minimize interobserver variability. Methods— We produced a complete training resource comprising an instructional DVD with accompanying written materials and assessment recordings of patient interviews. Formal assessment of training involved grading of real-life cases. Results of initial training and recertification were collected centrally and scored. Results— Data from 1564 assessments are presented. The majority of assessors were participating in 2 large prospective clinical stroke trials. Assessors represented a mixed group of disciplines and nationalities. After training, most trainees (90%) achieved certification in mRS assessment. The majority (85%) of investigators who did not reach an acceptable score on initial testing achieved certification after further exposure to the package. Conclusions— Mass training in mRS assessment for clinical trials is possible. We outline the development of a video-based training package, including technical issues, patient selection procedures, and methods of scoring and assessment. Certification results suggest that use of the resource can improve mRS grading. Acceptability of the training has been demonstrated by its successful use in 2 international acute stroke trials, SAINT 1 and CHANT.

Noninvasive Cardiac Event Monitoring to Detect Atrial Fibrillation After Ischemic Stroke A Randomized, Controlled Trial

Background and Purpose— Atrial fibrillation (AF) elevates risk of recurrent stroke but is incompletely identified by standard investigation after stroke, though detection rates correlate with monitoring duration. We hypothesized that 7 days of noninvasive cardiac-event monitoring early after stroke would accelerate detection of AF and thus uptake of effective therapy. Methods— We performed a pragmatic randomized trial with objective outcome assessment among patients presenting in sinus rhythm with no AF history, within 7 days of ischemic stroke symptom onset. Patients were randomized to standard practice investigations (SP) to detect AF, or SP plus additional monitoring (SP-AM). AM comprised 7 days of noninvasive cardiac-event monitoring reported by an accredited cardiac electrocardiology laboratory. Primary outcome was detection of AF at 14 days. Results— One-hundred patients were enrolled from 2 centers. Within 14 days of stroke, sustained paroxysms of AF were detected in 18% of patients undergoing SP-AM versus 2% undergoing SP (P<0.05). Paroxysms of any-duration were detected in 44% of patients undergoing SP-AM versus 4% undergoing SP (P<0.001). These differences persisted at 90 days. Anticoagulant therapy was commenced within 14 days in 16% of SP-AM patients versus none randomized to SP (P<0.01). This difference persisted to 90 days (22% versus 6%; P<0.05). Conclusions— Routine noninvasive cardiac-event monitoring after acute stroke enhances detection of paroxysmal AF and early anticoagulation. Extended monitoring should be offered to all eligible patients soon after acute stroke. Guidelines on investigation for AF in stroke patients could be strengthened. Clinical Trial Registration— URL: http://www.controlled-trials.com/isrctn/. Unique identifier: ISRCTN97412358.

Associations between meteorological variables and acute stroke hospital admissions in the west of Scotland

Background –  We combined a large clinical stroke registry with the UK Met Office database to assess the association between meteorological variables and specific clinical subtypes of acute stroke.