Kate McArthur

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.

Robotic Measurement of Arm Movements After Stroke Establishes Biomarkers of Motor Recovery

Background and Purpose— Because robotic devices record the kinematics and kinetics of human movements with high resolution, we hypothesized that robotic measures collected longitudinally in patients after stroke would bear a significant relationship to standard clinical outcome measures and, therefore, might provide superior biomarkers. Methods— In patients with moderate-to-severe acute ischemic stroke, we used clinical scales and robotic devices to measure arm movement 7, 14, 21, 30, and 90 days after the event at 2 clinical sites. The robots are interactive devices that measure speed, position, and force so that calculated kinematic and kinetic parameters could be compared with clinical assessments. Results— Among 208 patients, robotic measures predicted well the clinical measures (cross-validated R2 of modified Rankin scale=0.60; National Institutes of Health Stroke Scale=0.63; Fugl-Meyer=0.73; Motor Power=0.75). When suitably scaled and combined by an artificial neural network, the robotic measures demonstrated greater sensitivity in measuring the recovery of patients from day 7 to day 90 (increased standardized effect=1.47). Conclusions— These results demonstrate that robotic measures of motor performance will more than adequately capture outcome, and the altered effect size will reduce the required sample size. Reducing sample size will likely improve study efficiency.

What is it with the weather and stroke

An influence of climate upon cerebrovascular risk is both biologically plausible and supported by epidemiological evidence. These relationships are important as they could yield public health strategies to help protect the vulnerable from the increased death rates arising during extreme cold and heat waves. Change in temperature impacts on many cerebrovascular risk factors, including serum lipid and fibrinogen concentration and blood pressure. The relationship between stroke and meteorological variables is complex because of the number of potentially relevant meteorological variables, differences in study design and climate between geographical areas and potential for confounding. Behavioral factors are also influenced by the weather, which may in turn affect stroke risk. Some studies suggest that lower temperature increases stroke risk and others suggest the converse, while changes in atmospheric pressure may link with increased intracranial hemorrhage risk. To date, data are confusing and conflicting and well-conducted prospective studies are required to help clarify these potentially important relationships.

Allopurinol reduces brachial and central blood pressure, and carotid intima-media thickness progression after ischaemic stroke and transient ischaemic attack: a randomised controlled trial

Objective Central blood pressure (CBP) and carotid intima-media thickness (CIMT) are surrogate measures of cardiovascular risk. Allopurinol reduces serum uric acid and oxidative stress and improves endothelial function and may therefore reduce CBP and CIMT progression. This study sought to ascertain whether allopurinol reduces CBP, arterial stiffness and CIMT progression in patients with ischaemic stroke or transient ischaemic attack (TIA). Methods We performed a randomised, double-blind, placebo-controlled study, examining the effect of 1-year treatment with allopurinol (300 mg daily), on change in CBP, arterial stiffness and CIMT progression at 1 year and change in endothelial function and circulating inflammatory markers at 6 months. Patients aged over 18 years with recent ischaemic stroke or TIA were eligible. Results Eighty participants were recruited, mean age 67.8 years (SD 9.4). Systolic CBP [−6.6 mm Hg (95% CI −13.0 to −0.3), p=0.042] and augmentation index [−4.4% (95% CI −7.9 to −1.0), p=0.013] were each lower following allopurinol treatment compared with placebo at 12 months. Progression in mean common CIMT at 1 year was less in allopurinol-treated patients compared with placebo [between-group difference [−0.097 mm (95% CI −0.175 to −0.019), p=0.015]. No difference was observed for measures of endothelial function. Conclusions Allopurinol lowered CBP and reduced CIMT progression at 1 year compared with placebo in patients with recent ischaemic stroke and TIA. This extends the evidence of sustained beneficial effects of allopurinol to these prognostically significant outcomes and to the stroke population, highlighting the potential for reduction in cardiovascular events with this treatment strategy. Trial registration number ISRCTN11970568.

Functional assessment in older people

#### Summary points Older people often present to healthcare services with acute and chronic problems that act together to adversely affect function. A common pathway comprises functional decline, followed by loss of independence and need for institutional care. However, this process is not necessarily inevitable or irreversible. Timely recognition of functional difficulties can lead to interventions that may prevent or arrest the decline. This article focuses on the functional assessment of older adults by generalist clinicians (see box 1 for terminology used in this broad field). In this video, filmed in Australia, Dr Kurrle performs a functional assessment of an older adult in the home. We show some of the basic components of functional assessment that it is important for a doctor to know, some of which may be used in other settings, such as the GP surgery or on a hospital ward. In many settings an occupational therapist would provide a detailed assessment of the patients home and their activities of daily living. #### Sources and selection criteria This review is based on the authors’ clinical and research experience and is informed by a search of published literature. We searched electronic databases (Medline and Embase) from inception to December 2010 inclusive, using truncated keywords based on National Library of Medicine, medical subject headings: “aged” OR “aged, 80 or over”, “rehabilitation”, and “geriatric assessment”. In addition, key reference works and national and international guidelines were searched for relevant papers. Particular attention was given to systematic reviews and meta-analyses. For this manuscript the intention was not to …

Prestroke Modified Rankin Stroke Scale Has Moderate Interobserver Reliability and Validity in an Acute Stroke Setting

Background and Purpose— The modified Rankin Scale (mRS) is the recommended functional outcome assessment in stroke trials. Utility of mRS may be limited by interobserver variability. prestroke function, described using mRS, is often used as trial entry criterion. We assessed the reliability and validity of prestroke mRS in acute stroke. Methods— We present two complementary analyses of the properties of prestroke mRS: (1) Paired interviewers (trained in mRS) performed independently a blinded assessment of mRS and prestroke mRS. Interobserver variability was described using percentage agreement and weighted (kw) &kgr; statistics with 95% confidence interval (95% CI). Validity was assessed by comparing prestroke mRS with other markers of function (comorbidity; medication count; need for carers). (2) We further assessed validity using a larger retrospective dataset. We compared prestroke mRS with Charlson comorbidity index (CCI) and the Rockwood frailty index. Rank correlation coefficient or Fisher exact test were used as appropriate. Results— Paired interviewers assessed 74 stroke survivors. Median standard mRS was 4 (interquartile range [IQR], 2–4), median prestroke mRS was 1 (IQR, 0–3; range, 0–4). Reliability for standard mRS interview was 56% agreement, kw=0.55 (95% CI, 0.39–0.71). Reliability for prestroke mRS was 70%, kw=0.70 (95% CI, 0.53–0.87). The retrospective dataset described 231 subjects. In this data set, Spearman Rho for prestroke mRS and frailty index was J. 0.82 (95% CI, 0.78–0.86); CCI 0.50 (95% CI, 0.40–0.59); patient age 0.45 (95% CI, 0.34–0.54); medication count 0.28 (95% CI, 0.15–0.40). There was no association between need for carers and prestroke mRS (p=0.10). Conclusions— Interobserver reliability of prestroke mRS is limited but comparable with standard mRS. Poor correlation of prestroke mRS with certain markers of function suggests limited validity. Our data would suggest that relying on mRS alone may be a suboptimal measure of prestroke function and could potentially bias trial samples.

Post-acute care and secondary prevention after ischaemic stroke

#### Summary points In the first part of this two part review ( BMJ 2011;342:d1938) we discussed acute diagnosis and management of cerebrovascular events. Much of the focus of recent research, public health initiatives, and health policy has been around acute and hyperacute management of stroke. However, important goals of stroke care are to maximise functional recovery and prevent recurrent events. Here we draw on evidence from randomised trials and meta-analyses to discuss models of care, rehabilitation, and secondary prevention in stroke. An important aspect of post-acute stroke care is rehabilitation. Rehabilitation research remains a “young” science, although an evidence base is emerging. As we make progress in this field, we need a common language to describe this important intervention. In the box we offer our own definition of stroke rehabilitation, although others may offer differing suggestions. Many questions remain unanswered regarding timing, optimal components, and frequency and intensity of rehabilitation. Further discussion of rehabilitation as a concept or rehabilitation theory specific to stroke is beyond the scope of this article, but recent high quality publications on the subject are available.w1 …

Reliability of Structured Modified Rankin Scale Assessment

To the Editor: The modified Rankin Scale (mRS) is the most prevalent stroke outcome assessment in clinical trials, yet literature describing the properties of the scale remains limited,1 so we were pleased to see 2 papers describing clinometric assessment of mRS in the May issue of the Journal . Saver and colleagues describe a Rankin Focused Assessment Tool (RFAT),2 whereas Bruno’s group describes a simplified mRS questionnaire.3 The proposed use of structured assessment is in saving interviewers’ time and decreasing interobserver variability; both of these points are worthy of further discussion. The issue of time spent conducting mRS assessment is interesting. Based on collected data from 100 video-recorded, paired mRS interviews, we performed multivariate analysis to …

Advances in Emerging Therapies 2006

Stroke has multiple etiologies and presents in many forms. Therefore, it will continue to pose challenges in prevention, diagnosis, and treatment. 2009 has brought modest advances in terms of new acute stroke therapies but has provided encouraging preliminary reports of possible developments to come. The main progress of 2009 has been in the area of primary and secondary prevention, providing exciting new therapies that are likely to alter our practice significantly in the future. Prevention is better than cure. Statins have a role alongside antithrombotic and antihypertensive agents for secondary prevention of stroke.1 The JUPITER investigators recently demonstrated the efficacy of a statin for primary prevention.2 JUPITER was a randomized, double-blind, placebo-controlled trial of high-dose rosuvastatin (20 mg per day). The study population consisted of 17 802 apparently healthy men (>50 years of age) and women (>60 years of age) who, at screening, had low levels of low-density lipoprotein cholesterol (<3.4 mmol/L) and increased levels of high-sensitivity C-reactive protein (<2.0 mg/L). Nearly 90 000 patients had to be screened to attain this enrollment. The trial was stopped early after median follow-up of only 1.9 years of the planned 4 because of a striking reduction in the primary end point of first major cardiovascular event: 0.77 versus 1.36 events per 100 person years of follow-up, respectively (hazard ratio for rosuvastatin, 0.56; 95% CI, 0.46 to 0.69; P <0.00001). Of these major cardiovascular events, there were 33 strokes in the rosuvastatin group (n=8901) and 64 strokes in the placebo group (n=8901). This 48% reduction in stroke risk was found to be driven by a reduction in ischemic cerebrovascular events. There were similar numbers of hemorrhagic stroke in both groups. Subgroup analysis suggested that the patients who gained most benefit from rosuvastatin therapy were those with increased traditional risk factors, such …

Predictive Value of Newly Detected Atrial Fibrillation Paroxysms in Patients With Acute Ischemic Stroke, for Atrial Fibrillation After 90 Days

Background and Purpose— Extended cardiac monitoring immediately after acute ischemic stroke (AIS) increases paroxysmal atrial fibrillation (PAF) detection, but its reliability for detection or exclusion of longer term paroxysmal PAF is unknown. We evaluated the positive and negative predictive value (PPV and NPV) of AF detection early after AIS, for PAF confirmation 90 days later. Methods— We investigated 49 patients within 7 days of AIS for PAF according to current guidelines; 23 patients received 7 days of additional noninvasive cardiac event monitoring with an R-test device early after their stroke (ISRCTN 97412358). Ninety days after AIS, everyone underwent 7 days of cardiac event monitoring. We calculated the PPV and NPV of immediate PAF detection through extended cardiac event monitoring and through any investigative modality, for the presence of PAF on the 90-day event monitor. Results— PAF detected by a 7-day event monitor within 2 weeks of AIS had a PPV of 100% (95% confidence interval, 72%–100%) for PAF confirmation after 90 days. NPV after 7 days of event monitoring was 64% (95% confidence interval, 35%–87%). PAF detected early through any modality had a PPV of 100% (95% confidence interval, 76%–100%). However, the NPV in the absence of R-test monitoring was only 42% (95% confidence interval, 28%–58%). Conclusions— AF detection through any means immediately after stroke holds strong PPV for confirmation after 90 days, justifying treatment decisions on early monitoring alone. However, failure to identify AF through early monitoring has only modest NPV even after 7 days of monitoring; repeated investigation is desirable.