Peter Higgins

Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE collaboration): a meta-analysis of genome-wide association studies.

Summary Background Various genome-wide association studies (GWAS) have been done in ischaemic stroke, identifying a few loci associated with the disease, but sample sizes have been 3500 cases or less. We established the METASTROKE collaboration with the aim of validating associations from previous GWAS and identifying novel genetic associations through meta-analysis of GWAS datasets for ischaemic stroke and its subtypes. Methods We meta-analysed data from 15 ischaemic stroke cohorts with a total of 12 389 individuals with ischaemic stroke and 62 004 controls, all of European ancestry. For the associations reaching genome-wide significance in METASTROKE, we did a further analysis, conditioning on the lead single nucleotide polymorphism in every associated region. Replication of novel suggestive signals was done in 13 347 cases and 29 083 controls. Findings We verified previous associations for cardioembolic stroke near PITX2 (p=2·8×10−16) and ZFHX3 (p=2·28×10−8), and for large-vessel stroke at a 9p21 locus (p=3·32×10−5) and HDAC9 (p=2·03×10−12). Additionally, we verified that all associations were subtype specific. Conditional analysis in the three regions for which the associations reached genome-wide significance (PITX2, ZFHX3, and HDAC9) indicated that all the signal in each region could be attributed to one risk haplotype. We also identified 12 potentially novel loci at p<5×10−6. However, we were unable to replicate any of these novel associations in the replication cohort. Interpretation Our results show that, although genetic variants can be detected in patients with ischaemic stroke when compared with controls, all associations we were able to confirm are specific to a stroke subtype. This finding has two implications. First, to maximise success of genetic studies in ischaemic stroke, detailed stroke subtyping is required. Second, different genetic pathophysiological mechanisms seem to be associated with different stroke subtypes. Funding Wellcome Trust, UK Medical Research Council (MRC), Australian National and Medical Health Research Council, National Institutes of Health (NIH) including National Heart, Lung and Blood Institute (NHLBI), the National Institute on Aging (NIA), the National Human Genome Research Institute (NHGRI), and the National Institute of Neurological Disorders and Stroke (NINDS).

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.

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.

The Modified Graeb Score: An Enhanced Tool for Intraventricular Hemorrhage Measurement and Prediction of Functional Outcome

Background and Purpose— Simple and rapid measures of intraventricular hemorrhage (IVH) volume are lacking. We developed and validated a modification of the original Graeb scale to facilitate rapid assessment of IVH over time. Methods— We explored the relationship between the modified Graeb scale (mGS), original Graeb scale, measured IVH volume, and outcome using data from the Clot Lysis: Evaluating Accelerated Resolution of Hemorrhage with rtPA B (CLEAR B) study. We also explored its reliability. We then evaluated the relationship between mGS and outcome in a large sample of participants with IVH using data contained within the Virtual International Stroke Trials Archive (VISTA). We defined outcome using the modified Rankin scale (>3 signifying poor outcome). Results— The CLEAR B study included 360 scans from 36 subjects. The mGS score and IVH volume were highly correlated (R = 0.80, P<0.0001, R2 0.65). Baseline mGS was predictive of poor outcome (area under receiving operating characteristic curve 0.74, 95% confidence interval, 0.57–0.91), whereas the original Graeb scale was not. The VISTA study included 399 participants. Each unit increase in the mGS led to a 12% increase in the odds of a poor outcome (odds ratio, 1.12; 95% confidence interval, 1.05–1.19). Measures of reliability (intra- and inter- reader) were good in both studies. Conclusions— The mGS, a semiquantitative scale for IVH volume measurement, is a reliable measure with prognostic validity suitable for rapid use in clinical practice and in research.

Allopurinol and Cardiovascular Outcomes in Adults With Hypertension

Allopurinol lowers blood pressure in adolescents and has other vasoprotective effects. Whether similar benefits occur in older individuals remains unclear. We hypothesized that allopurinol is associated with improved cardiovascular outcomes in older adults with hypertension. Data from the United Kingdom Clinical Research Practice Datalink were used. Multivariate Cox-proportional hazard models were applied to estimate hazard ratios for stroke and cardiac events (defined as myocardial infarction or acute coronary syndrome) associated with allopurinol use over a 10-year period in adults aged >65 years with hypertension. A propensity-matched design was used to reduce potential for confounding. Allopurinol exposure was a time-dependent variable and was defined as any exposure and then as high (≥300 mg daily) or low-dose exposure. A total of 2032 allopurinol-exposed patients and 2032 matched nonexposed patients were studied. Allopurinol use was associated with a significantly lower risk of both stroke (hazard ratio, 0.50; 95% confidence interval, 0.32–0.80) and cardiac events (hazard ratio, 0.61; 95% confidence interval, 0.43–0.87) than nonexposed control patients. In exposed patients, high-dose treatment with allopurinol (n=1052) was associated with a significantly lower risk of both stroke (hazard ratio, 0.58; 95% confidence interval, 0.36–0.94) and cardiac events (hazard ratio, 0.65; 95% confidence interval, 0.46–0.93) than low-dose treatment (n=980). Allopurinol use is associated with lower rates of stroke and cardiac events in older adults with hypertension, particularly at higher doses. Prospective clinical trials are needed to evaluate whether allopurinol improves cardiovascular outcomes in adults with hypertension.

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.

Socioeconomic Status and Transient Ischaemic Attack/Stroke: A Prospective Observational Study

Background: Lower socioeconomic status (SES) is associated with an increased risk of stroke but the mechanisms are unclear. We aimed to determine whether low-SES stroke/transient ischaemic attack (TIA) patients have a greater burden of vascular risk factors/co-morbidity and reduced health care access. Methods: We prospectively studied 467 consecutive stroke and TIA patients from 3 Scottish hospitals (outpatients and inpatients) during 2007/2008. We recorded vascular risk factors, stroke severity, co-morbidity measures, investigations and health service utilisation. SES was derived from postcodes using Scottish Neighbourhood Statistics and analysed in quartiles. Results: TIA/stroke patients in the lowest SES quartile were younger (64 years, SD 14.1) than those in the highest quartile (72 years, SD 12.9; p < 0.0001). They were more likely to be current smokers (42 vs. 22%; p = 0.001) but there was no association with other vascular risk factors/co-morbidity. There was a trend for those with lower SES to have a more severe stroke [modified National Institutes of Health Stroke Scale score and interquartile range: 4 (2–6) vs. 3 (1–5); multivariate p = 0.05]. Lower SES groups were less likely to have neuro-imaging (82 vs. 90%; p = 0.036) or an electrocardiogram (72 vs. 87%; p = 0.003), but differences were no longer significant on multivariate analysis. However, there was equal access to stroke unit care. Conclusions: Low-SES TIA and stroke patients are younger and have a more severe deficit; an increased prevalence of smoking is likely to be a major contributor. We found equal access to stroke unit care for low-SES patients.

The Potential for Xanthine Oxidase Inhibition in the Prevention and Treatment of Cardiovascular and Cerebrovascular Disease

There is a now a wealth of epidemiological, animal, and clinical data to suggest the benefits of uric acid reduction and hxanthine oxidase inhibition in prevention of vascular disease. This review discusses the available epidemiological, preclinical, and clinical data and considers arguments for and against a role for serum uric acid in common cardiovascular disorders. It concludes that large scale trials with clinical endpoints are justified to address this important question and to define whether use of drugs such as allopurinol should be a routine part of preventative strategies.

Allopurinol Initiation and Change in Blood Pressure in Older Adults With Hypertension

Hypertension is a key risk factor for cardiovascular disease, and new treatments are needed. Uric acid reduction lowers blood pressure (BP) in adolescents, suggesting a direct pathophysiological role in the development of hypertension. Whether the same relationship is present in older adults is unknown. We explored change in BP after allopurinol initiation using data from the UK Clinical Practice Research Datalink. Data were extracted for patients with hypertension aged >65 years who were prescribed allopurinol with pretreatment and during treatment BP readings. Data from comparable controls were extracted. The change in BP in patients with stable BP medication was the primary outcome and was compared between groups. Regression analysis was used to adjust for potential confounding factors, and a propensity-matched sample was generated. Three hundred sixty-five patients who received allopurinol and 6678 controls were included. BP fell in the allopurinol group compared with controls (between-group difference in systolic and diastolic BP: 2.1 mm Hg; 95% confidence interval, −0.6 to 4.8; and 1.7 mm Hg; 95% confidence interval, 0.4–3.1, respectively). Allopurinol use was independently associated with a fall in both systolic and diastolic BP on regression analysis (P<0.001). Results were consistent in the propensity-matched sample. There was a trend toward greater fall in BP in the high-dose allopurinol group, but change in BP was not related to baseline uric acid level. Allopurinol use is associated with a small fall in BP in adults. Further studies of the effect of high-dose allopurinol in adults with hypertension are needed.

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 …