Peter M Rothwell

Oxford University Hospitals NHS Trust, Oxford, England, United Kingdom

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Publications (490)4998.42 Total impact

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    ABSTRACT: Carotid angioplasty and stenting (CAS) is associated with higher risk of periprocedural stroke and death when compared with carotid endarterectomy (CEA). By contrast, the risk of myocardial infarction (MI) was higher after CEA than after CAS in randomized trials. However, numbers were small, and risk factors are unknown. We performed a systematic review and a meta-analysis of studies published from January 1980 to June 2014 and collected unpublished data. We extracted data on 9 predefined risk factors (age, contralateral carotid occlusion, coronary artery disease, diabetes mellitus, sex, hypertension, peripheral artery disease, type stenosis, and clinical presentation). We selected studies with data available on MI in at least 1 subgroup, calculated absolute and relative risks, and identified differential effects on risks of MI. The 30-day absolute risk of MI was 0.87% (95% confidence interval, 0.69-1.07) after CEA and 0.70% (95% confidence interval, 0.54-0.88) after CAS (Pint=0.38). After CAS, patients with symptomatic stenosis and restenosis were at higher risk of MI, whereas men were at lower risk. After CEA, age, history of coronary artery disease, peripheral artery disease, and restenosis increased the risk of MI. Only the effect of sex differed between CAS and CEA with men being at lower risk of MI than women after CAS, whereas there was no difference between after CEA (Pint=0.01). The risk of MI after CEA and CAS did not significantly differ. Risk factors for MI are overall similar in both techniques except that men are at lower risk of MI after CAS but not after CEA. © 2015 American Heart Association, Inc.
    Stroke 08/2015; DOI:10.1161/STROKEAHA.115.010052 · 6.02 Impact Factor
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    ABSTRACT: A third of transient ischaemic attacks (TIAs) and ischaemic strokes are of undetermined cause (ie, cryptogenic), potentially undermining secondary prevention. If these events are due to occult atheroma, the risk-factor profile and coronary prognosis should resemble that of overt large artery events. If they have a cardioembolic cause, the risk of future cardioembolic events should be increased. We aimed to assess the burden, outcome, risk factors, and long-term prognosis of cryptogenic TIA and stroke. In a population-based study in Oxfordshire, UK, among patients with a first TIA or ischaemic stroke from April 1, 2002, to March 31, 2014, we compared cryptogenic events versus other causative subtypes according to the TOAST classification. We compared markers of atherosclerosis (ie, risk factors, coronary and peripheral arterial disease, asymptomatic carotid stenosis, and 10-year risk of acute coronary events) and of cardioembolism (ie, risk of cardioembolic stroke, systemic emboli, and new atrial fibrillation [AF] during follow-up, and minor-risk echocardiographic abnormalities and subclinical paroxysmal AF at baseline in patients with index events between 2010 and 2014). Among 2555 patients, 812 (32%) had cryptogenic events (incidence of cryptogenic stroke 0·36 per 1000 population per year, 95% CI 0·23-0·49). Death or dependency at 6 months was similar after cryptogenic stroke compared with non-cardioembolic stroke (23% vs 27% for large artery and small vessel subtypes combined; p=0·26) as was the 10-year risk of recurrence (32% vs 27%; p=0·91). However, the cryptogenic group had fewer atherosclerotic risk factors than the large artery disease (p<0·0001), small vessel disease (p=0·001), and cardioembolic (p=0·008) groups. Compared with patients with large artery events, those with cryptogenic events had less hypertension (adjusted odds ratio [OR] 0·41, 95% CI 0·30-0·56; p<0·0001), diabetes (0·62, 0·43-0·90; p=0·01), peripheral vascular disease (0·27, 0·17-0·45; p<0·0001), hypercholesterolaemia (0·53, 0·40-0·70; p<0·0001), and history of smoking (0·68, 0·51-0·92; p=0·01), and compared with small vessel and cardioembolic subtypes, they had no excess risk of asymptomatic carotid disease (adjusted OR 0·64, 95% CI 0·37-1·11; p=0·11) or acute coronary events (adjusted hazard ratio [HR] 0·76, 95% CI 0·49-1·18; p=0·22) during follow-up. Compared with large artery and small vessel subtypes combined, patients with cryptogenic events also had no excess of minor-risk echocardiographic abnormalities (cryptogenic 37% vs 45%; p=0·18) or paroxysmal AF (6% vs 10%; p=0·17) at baseline or of new AF (adjusted HR 1·23, 0·78-1·95; p=0·37) or presumed cardioembolic events (1·16, 0·62-2·17; p=0·64) during follow-up. The clinical burden of cryptogenic TIA and stroke is substantial. Although stroke recurrence rates are comparable with other subtypes, cryptogenic events have the fewest atherosclerotic markers and no excess of cardioembolic markers. Wellcome Trust, Wolfson Foundation, UK Stroke Association, British Heart Foundation, Dunhill Medical Trust, National Institute for Health Research, Medical Research Council, and the NIHR Oxford Biomedical Research Centre. Copyright © 2015 Li et al. Open Access article distributed under the terms of CC BY-NC-ND. Published by Elsevier Ltd.. All rights reserved.
    The Lancet Neurology 07/2015; DOI:10.1016/S1474-4422(15)00132-5 · 21.82 Impact Factor
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    ABSTRACT: Abnormal coagulation has been implicated in the pathogenesis of ischemic stroke, but how this association is mediated and whether it differs between ischemic stroke subtypes is unknown. We determined the shared genetic risk between 14 coagulation factors and ischemic stroke and its subtypes. Using genome-wide association study results for 14 coagulation factors from the population-based TwinsUK sample (N≈2000 for each factor), meta-analysis results from the METASTROKE consortium ischemic stroke genome-wide association study (12 389 cases, 62 004 controls), and genotype data for 9520 individuals from the WTCCC2 ischemic stroke study (3548 cases, 5972 controls-the largest METASTROKE subsample), we explored shared genetic risk for coagulation and stroke. We performed three analyses: (1) a test for excess concordance (or discordance) in single nucleotide polymorphism effect direction across coagulation and stroke, (2) an estimation of the joint effect of multiple coagulation-associated single nucleotide polymorphisms in stroke, and (3) an evaluation of common genetic risk between coagulation and stroke. One coagulation factor, factor XIII subunit B (FXIIIB), showed consistent effects in the concordance analysis, the estimation of polygenic risk, and the validation with genotype data, with associations specific to the cardioembolic stroke subtype. Effect directions for FXIIIB-associated single nucleotide polymorphisms were significantly discordant with cardioembolic disease (smallest P=5.7×10(-04)); the joint effect of FXIIIB-associated single nucleotide polymorphisms was significantly predictive of ischemic stroke (smallest P=1.8×10(-04)) and the cardioembolic subtype (smallest P=1.7×10(-04)). We found substantial negative genetic covariation between FXIIIB and ischemic stroke (rG=-0.71, P=0.01) and the cardioembolic subtype (rG=-0.80, P=0.03). Genetic markers associated with low FXIIIB levels increase risk of ischemic stroke cardioembolic subtype. © 2015 The Authors.
    Stroke 07/2015; DOI:10.1161/STROKEAHA.115.009387 · 6.02 Impact Factor
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    ABSTRACT: Incidence and prevalence studies of neurologic disorders play an important role in assessing the burden of disease and planning services. However, the assessment of disease estimates is hindered by problems in reporting for such studies. Despite a growth in published reports, existing guidelines relate to analytical rather than descriptive epidemiologic studies. There are also no user-friendly tools (e.g., checklists) available for authors, editors, and peer reviewers to facilitate best practice in reporting of descriptive epidemiologic studies for most neurologic disorders. The Standards of Reporting of Neurological Disorders (STROND) is a guideline that consists of recommendations and a checklist to facilitate better reporting of published incidence and prevalence studies of neurologic disorders. A review of previously developed guidance was used to produce a list of items required for incidence and prevalence studies in neurology. A 3-round Delphi technique was used to identify the "basic minimum items" important for reporting, as well as some additional "ideal reporting items." An e-consultation process was then used in order to gauge opinion by external neuroepidemiologic experts on the appropriateness of the items included in the checklist. Of 38 candidate items, 15 items and accompanying recommendations were developed along with a user-friendly checklist. The introduction and use of the STROND checklist should lead to more consistent, transparent, and contextualized reporting of descriptive neuroepidemiologic studies resulting in more applicable and comparable findings and ultimately support better health care decisions. © 2015 American Academy of Neurology.
    European Journal of Epidemiology 06/2015; DOI:10.1007/s10654-015-0034-5 · 5.15 Impact Factor
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    ABSTRACT: Family history of stroke is an established risk factor for stroke. We evaluated whether family history of stroke predisposed to certain stroke subtypes and whether it differed by sex in young patients with stroke. We used data from the Stroke in Fabry Patients study, a large prospective, hospital-based, screening study for Fabry disease in young patients (aged <55 years) with stroke in whom cardiovascular risk factors and family history of stroke were obtained and detailed stroke subtyping was performed. A family history of stroke was present in 1578 of 4232 transient ischemic attack and ischemic stroke patients (37.3%). Female patients more often had a history of stroke in the maternal lineage (P=0.027) than in the paternal lineage. There was no association with stroke subtype according to Trial of Org 10172 in Acute Stroke Treatment nor with the presence of white matter disease on brain imaging. Patients with dissection less frequently reported a family history of stroke (30.4% versus 36.3%; P=0.018). Patients with a parental history of stroke more commonly had siblings with stroke (3.6% versus 2.6%; P=0.047). Although present in about a third of patients, a family history of stroke is not specifically related to stroke pathogenic subtypes in patients with young stroke. Young women with stroke more often report stroke in the maternal lineage. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00414583. © 2015 American Heart Association, Inc.
    Stroke 06/2015; DOI:10.1161/STROKEAHA.115.009341 · 6.02 Impact Factor
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    Peter M Rothwell
    The Lancet 05/2015; 342. DOI:10.1016/S0140-6736(15)60906-0 · 45.22 Impact Factor
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    ABSTRACT: The most common monogenic cause of cerebral small-vessel disease is cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, caused by NOTCH3 gene mutations. It has been hypothesized that more common variants in NOTCH3 may also contribute to the risk of sporadic small-vessel disease. Previously, 4 common variants (rs10404382, rs1043994, rs10423702, and rs1043997) were found to be associated with the presence of white matter hyperintensity in hypertensive community-dwelling elderly. We investigated the association of common single nucleotide polymorphisms (SNPs) in NOTCH3 in 1350 patients with MRI-confirmed lacunar stroke and 7397 controls, by meta-analysis of genome-wide association study data sets. In addition, we investigated the association of common SNPs in NOTCH3 with MRI white matter hyperintensity volumes in 3670 white patients with ischemic stroke. In each analysis, we considered all SNPs within the NOTCH3 gene, and within 50-kb upstream and downstream of the coding region. A total of 381 SNPs from the 1000 genome population with a mean allele frequency >0.01 were included in the analysis. A significance level of P<0.0015 was used, adjusted for the effective number of independent SNPs in the region using the Galwey method. We found no association of any common variants in NOTCH3 (including rs10404382, rs1043994, rs10423702, and rs1043997) with lacunar stroke or white matter hyperintensity volume. We repeated our analysis stratified for hypertension but again found no association. Our study does not support a role for common NOTCH3 variation in the risk of sporadic small-vessel disease. © 2015 The Authors.
    Stroke 05/2015; 46(6). DOI:10.1161/STROKEAHA.114.008540 · 6.02 Impact Factor
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    ABSTRACT: Cognitive outcomes in cohorts and trials are often based only on face-to-face clinic assessment. However, cognitive impairment is strongly associated with increased morbidity and mortality, leading to substantial loss to clinic follow-up. In the absence of previous population-based data, we determined the effect of such attrition on measured risk of dementia after transient ischemic attack and stroke. Patients with transient ischemic attack or stroke prospectively recruited (2002-2007) into the Oxford Vascular (OXVASC) study had baseline clinical/cognitive assessment and follow-up to 2014. Dementia was diagnosed through face-to-face clinic interview, supplemented by home visits and telephone assessment in patients unable to attend clinic and by hand-searching of primary care records in uncontactable patients. Of 1236 patients (mean age/SD, 75.2/12.1 years; 582 men), 527 (43%) died by 5-year follow-up. Follow-up assessment rates (study clinic, home visit, or telephone) of survivors were 947 in 1026 (92%), 857 in 958 (89%), 792 in 915 (87%), and 567 in 673 (84%) at 1, 6, 12 months and 5 years. Dementia developed in 260 patients, of whom 110 (42%; n=50 primary care records, n=49 home visit, and n=11 telephone follow-up) had not been available for face-to-face clinic follow-up at the time of diagnosis. The 5-year cumulative incidence of postevent dementia was 29% (26%-32%) overall but was only 17% (14% to 19%) in clinic assessed versus 45% (39%-51%) in nonclinic-assessed patients (P difference<0.001). Exclusion of patients unavailable for clinic follow-up reduces the measured risk of postevent dementia. Use of multiple follow-up methods, including home visits, telephone assessments, and consent, to access primary care records substantially increases ascertainment of longer-term dementia outcomes. © 2015 American Heart Association, Inc.
    Stroke 05/2015; 46(6). DOI:10.1161/STROKEAHA.115.009065 · 6.02 Impact Factor
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    D P J Howard · A Banerjee · J F Fairhead · A Handa · L E Silver · P M Rothwell
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    ABSTRACT: Contemporary population-based data on age-specific incidence and outcome from acute abdominal aortic aneurysm (AAA) events are needed to understand the impact of risk factor modification and demographic change, and to inform AAA screening policy. In a prospective population-based study (Oxfordshire, UK, 2002-2014), event rates, incidence, early case fatality and long-term outcome from all acute AAA events were determined, both overall and in relation to the four main risk factors: smoking, hypertension, male sex and age. Over the 12-year interval, 103 incident acute AAA events occurred in the study population of 92 728 (men 72·8 per cent; 59·2 per cent 30-day case fatality rate). The incidence per 100 000 population per year was 55 in men aged 65-74 years, but increased to 112 at age 75-84 years and to 298 at age 85 years or above. Some 66·0 per cent of all events occurred in those aged 75 years or more. The incidence at 65-74 years was highest in male smokers (274 per 100 000 population per year); 27 (96 per cent) of 28 events in men aged less than 75 years occurred in ever-smokers. Mean(s.d.) age at event was lowest in current smokers (72·2(7·2) years), compared with that in ex-smokers (81·2(7·0) years) and never-smokers (83·3(7·9) years) (P < 0·001). Hypertension was the predominant risk factor in women (diagnosed in 93 per cent), with 20 (71 per cent) of all 28 events in women occurring in those aged 75 years or above with hypertension. The 30-day case fatality rate increased from 40 per cent at age below 75 years to 69 per cent at age 75 years or more (P = 0·008). Two-thirds of acute AAA events occurred at age 75 years or above, and more than 25 per cent of events were in women. Taken with the strong associations with smoking and hypertension, these findings could have implications for AAA screening. © 2015 The Authors. BJS published by JohnWiley & Sons Ltd on behalf of BJS Society Ltd..
    British Journal of Surgery 05/2015; 102(8). DOI:10.1002/bjs.9838 · 5.21 Impact Factor
  • Neurology 05/2015; DOI:10.1212/WNL.0000000000001606 · 8.30 Impact Factor
  • European Stroke Organisation Conference, Glasgow; 04/2015
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    Stroke 04/2015; DOI:10.1161/STROKEAHA.115.008222 · 6.02 Impact Factor
  • Frank J Wolters · Nicola L M Paul · Linxin Li · Peter M Rothwell
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    ABSTRACT: Urgent assessment is essential after stroke. Several countries have had public education campaigns, based on the FAST (Face-Arm-Speech-Time) test to reduce delays in seeking attention. However, the impact of these campaigns on patient behavior is uncertain. We prospectively determined patient behavior after incident major stroke (NIHSS > 3) in a UK population based study (Oxford Vascular Study) before (2002-2008) and after (2009-2013) introduction of the FAST TV-campaign and assessed any sustained impact of campaign continuation. Among 668 consecutive patients with major stroke, medical attention was sought by a bystander in 553 (89·6%). Patients were more likely to present directly to emergency services (OR = 2·18, 95%CI:1·54-3·09, P < 0·0001) after the campaign and to arrive at hospital within 3 h (OR = 2·18, 1·55-3·06, P < 0·0001). Median [IQR] time to seeking attention fell from 53 [15-265] to 31 [7-120] minutes (P = 0·005) and median time to hospital arrival from 185 [88-885] to 119 [78-256] minutes (P < 0·0001). On time-series analysis improvements in hospital arrival within 3 h and use of emergency medical services were significantly associated to initiation of the campaign (aOR = 3·11, 1·53-6·29, P = 0·002; and 2·22, 1·05-4·67, P = 0·036, respectively), independent of trend, age, sex, ethnicity, educational level, social class, prior stroke and stroke severity, and have been sustained to 2013. Delays to seeking and receiving medical attention after major stroke in the UK. fell strikingly in 2009, coinciding with the start of the FAST TV campaign. That medical attention was sought by a bystander in nearly 90% of cases illustrates the importance of mass-media public education rather than focused programs in high-risk groups for major stroke. © 2015 The Authors. International Journal of Stroke published by John Wiley & Sons Ltd on behalf of World Stroke Organization.
    International Journal of Stroke 04/2015; DOI:10.1111/ijs.12484 · 4.03 Impact Factor
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    ABSTRACT: We aimed to assess the risk of recurrent ischemic events during hospitalization for stroke or transient ischemic attack (TIA) with optimal current management and to identify associated risk factors. We performed a retrospective analysis of all patients treated for acute ischemic stroke or TIA in 3 stroke units between 2010 and 2013. Recurrent stroke was defined as new persisting (≥24 hours) neurological deficit occurring >24 hours after the index event and not attributable to other causes of neurological deterioration. Cox proportional hazard regression identified risk factors associated with recurrent stroke. The study included 5106 patients. During a median length of stay of 5 days (interquartile range, 4-8), stroke recurrence (or stroke after TIA) occurred in 40 patients (0.8%) and was independently associated with history of TIA, symptomatic carotid stenosis (≥70%), or other determined etiology. Patients with recurrent stroke and other determined etiology had cervical arterial dissection (n=2), primary angiitis of the central nervous system (n=1), giant cell arteritis (n=1), and lung cancer with nonbacterial thrombotic endocarditis (n=1). In patients with initial TIA or minor stroke (National Institutes of Health Stroke Scale ≤5) recurrence was associated additionally with pneumonia after the inciting ischemic event but before stroke recurrence. Patients with initial stroke and aphasia had a lower stroke recurrence rate and there were no recurrences in patients with lacunar stroke. Recurrence was associated with significantly higher in-hospital mortality (17.5% versus 3.1%; P<0.001). In-hospital stroke recurrence was low with optimal current management. Patients with a history of TIA, severe symptomatic carotid stenosis, or uncommon causes of stroke were at higher risk. Pneumonia was associated with a higher risk of stroke recurrence in patients with initial TIA or minor stroke but not in the overall population studied. Aphasia may bias the detection rate by concealing new neurological symptoms. © 2015 American Heart Association, Inc.
    Stroke 03/2015; 46(4). DOI:10.1161/STROKEAHA.114.006886 · 6.02 Impact Factor
  • Stroke 02/2015; Suppl1(46). · 6.02 Impact Factor
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    ABSTRACT: Many previous studies on dementia in stroke have restrictive inclusion criteria, which may result in underestimation of dementia rates. We undertook a large prospective population-based study of all transient ischemic attack and stroke to determine the impact of study entry criteria on measured rates of pre- and postevent dementia. All patients with acute transient ischemic attack or stroke from a defined population of 92 728 are referred from primary care or at hospital admission to the Oxford Vascular Study (2002-2007) and have baseline clinical and cognitive assessment and follow-up. We examined the impact of early death, other nonavailability, and commonly used selection criteria, on measured rates of dementia. Among 1236 patients (mean age/SD 75.2/12.1 years, 582 men, 403 transient ischemic attack), 139 died or were otherwise unavailable for baseline assessment, 319 had prior dependency, 425 had comorbidity, 512 were aged ≥80 years, 85 were dysphasic, and 502 were hospitalized. Pre-event dementia was 3-fold higher in patients dying preascertainment (10/47, 21%) and twice as high in other nonassessed (14/92, 15%) versus assessed patients (69/1097, 6%; P=0.0006 and P=0.002) and was several-fold higher in those with prior functional impairment (24% versus 3%; P<0.0001), age >80 years (13% versus 3%; P<0.0001), dysphasia (11% versus 7%; P<0.0001), and comorbidity (10% versus 6%; P=0.04). Findings for postevent dementia were similar: prior functional impairment (40% versus 13%; P<0.0001), age >80 years (28% versus 10%; P<0.0001), dysphasia (39% versus 15%; P<0.0001), and comorbidity (20% versus 15%; P=0.04). Exclusion of patients unavailable for assessment, and other widely used selection criteria, results in underestimation of the measured rate of dementia associated with transient ischemic attack and stroke. © 2015 American Heart Association, Inc.
    Stroke 02/2015; 46(3). DOI:10.1161/STROKEAHA.114.008043 · 6.02 Impact Factor
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    ABSTRACT: We hypothesized that common variants in the collagen genes COL4A1/COL4A2 are associated with sporadic forms of cerebral small vessel disease. We conducted meta-analyses of existing genotype data among individuals of European ancestry to determine associations of 1,070 common single nucleotide polymorphisms (SNPs) in the COL4A1/COL4A2 genomic region with the following: intracerebral hemorrhage and its subtypes (deep, lobar) (1,545 cases, 1,485 controls); ischemic stroke and its subtypes (cardioembolic, large vessel disease, lacunar) (12,389 cases, 62,004 controls); and white matter hyperintensities (2,733 individuals with ischemic stroke and 9,361 from population-based cohorts with brain MRI data). We calculated a statistical significance threshold that accounted for multiple testing and linkage disequilibrium between SNPs (p < 0.000084). Three intronic SNPs in COL4A2 were significantly associated with deep intracerebral hemorrhage (lead SNP odds ratio [OR] 1.29, 95% confidence interval [CI] 1.14-1.46, p = 0.00003; r(2) > 0.9 between SNPs). Although SNPs associated with deep intracerebral hemorrhage did not reach our significance threshold for association with lacunar ischemic stroke (lead SNP OR 1.10, 95% CI 1.03-1.18, p = 0.0073), and with white matter hyperintensity volume in symptomatic ischemic stroke patients (lead SNP OR 1.07, 95% CI 1.01-1.13, p = 0.016), the direction of association was the same. There was no convincing evidence of association with white matter hyperintensities in population-based studies or with non-small vessel disease cerebrovascular phenotypes. Our results indicate an association between common variation in the COL4A2 gene and symptomatic small vessel disease, particularly deep intracerebral hemorrhage. These findings merit replication studies, including in ethnic groups of non-European ancestry. © 2015 American Academy of Neurology.
    Neurology 02/2015; 84(9). DOI:10.1212/WNL.0000000000001309 · 8.30 Impact Factor
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    ABSTRACT: Premature death after transient ischemic attack or stroke is more often because of heart disease or cancer than stroke. Previous studies found blood biomarkers not usefully predictive of nonfatal stroke but possibly of all-cause death. This association might be explained by potentially treatable occult cardiac disease or cancer. We therefore aimed to validate the association of a panel of biomarkers with all-cause death, particularly cardiac death and cancer death, despite the absence of associations with risk of nonfatal vascular events. Fifteen biomarkers were measured in 929 consecutive patients in a population-based study (Oxford Vascular Study), recruited from 2002 and followed up to 2013. Associations were determined by Cox regression. Model discrimination was assessed by c-statistic and the integrated discrimination improvement. During 5560 patient-years of follow-up, none of the biomarkers predicted risk of nonfatal vascular events. However, soluble tumor necrosis factor α receptor-1, von Willebrand factor, heart-type fatty-acid-binding protein, and N-terminal pro-B-type natriuretic peptide were independently predictive of all-cause death (n=361; adjusted hazard ratio per SD, 95% confidence interval: heart-type fatty-acid-binding protein: 1.31, 1.12-1.56, P=0.002; N-terminal pro-B-type natriuretic peptide: 1.34, 1.11-1.62, P=0.002; soluble tumor necrosis factor α receptor-1: 1.45, 1.26-1.66, P=0.02; von Willebrand factor: 1.19, 1.04-1.36, P=0.01). The independent contribution of the four biomarkers taken together added prognostic information and improved model discrimination (integrated discrimination improvement=0.028, P=0.0001). N-terminal pro-B-type natriuretic peptide was most predictive of vascular death (adjusted hazard ratio=1.80, 95% confidence interval, 1.34-2.41, P<0.0001), whereas heart-type fatty-acid-binding protein predicted cancer deaths (1.64, 1.26-2.12, P=0.0002). Associations were strongest in patients without known prior cardiac disease or cancer. Several biomarkers predicted death of any cause after transient ischemic attack and minor stroke. N-terminal pro-B-type natriuretic peptide and heart-type fatty-acid-binding protein might improve patient selection for additional screening for occult cardiac disease or cancer, respectively. However, our results require validation in future studies. © 2015 American Heart Association, Inc.
    Stroke 02/2015; 46(3). DOI:10.1161/STROKEAHA.114.007624 · 6.02 Impact Factor
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    ABSTRACT: Despite moderate heritability, the phenotypic heterogeneity of ischemic stroke has hampered gene discovery, motivating analyses of diagnostic subtypes with reduced sample sizes. We assessed evidence for a shared genetic basis among the 3 major subtypes: large artery atherosclerosis (LAA), cardioembolism, and small vessel disease (SVD), to inform potential cross-subtype analyses. Analyses used genome-wide summary data for 12 389 ischemic stroke cases (including 2167 LAA, 2405 cardioembolism, and 1854 SVD) and 62 004 controls from the Metastroke consortium. For 4561 cases and 7094 controls, individual-level genotype data were also available. Genetic correlations between subtypes were estimated using linear mixed models and polygenic profile scores. Meta-analysis of a combined LAA-SVD phenotype (4021 cases and 51 976 controls) was performed to identify shared risk alleles. High genetic correlation was identified between LAA and SVD using linear mixed models (rg=0.96, SE=0.47, P=9×10(-4)) and profile scores (rg=0.72; 95% confidence interval, 0.52-0.93). Between LAA and cardioembolism and SVD and cardioembolism, correlation was moderate using linear mixed models but not significantly different from zero for profile scoring. Joint meta-analysis of LAA and SVD identified strong association (P=1×10(-7)) for single nucleotide polymorphisms near the opioid receptor μ1 (OPRM1) gene. Our results suggest that LAA and SVD, which have been hitherto treated as genetically distinct, may share a substantial genetic component. Combined analyses of LAA and SVD may increase power to identify small-effect alleles influencing shared pathophysiological processes. © 2015 American Heart Association, Inc.
    Stroke 01/2015; 46(3). DOI:10.1161/STROKEAHA.114.007930 · 6.02 Impact Factor
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    ABSTRACT: Current abdominal aortic aneurysm (AAA) screening in men age 65 might have limited impact on overall AAA death rates if incidence is moving to older ages. Up-to-date population-based studies of age-specific incidence, risk factors, and outcome of acute AAA are needed to inform screening policy. In a prospective, population-based study (Oxfordshire, UK, 2002-2014), the incidence and outcome of acute AAA events were determined. Based on population projections and current incidence trends, the impact of screening strategies in the UK was estimated. Over the 12-year period, 103 incident acute AAA events occurred in the study population of 92 728. Incidence/100 000/year was 55 in men ages 65 to 74 years, but increased to 112 at 75 to 85 and 298 at ≥85, with 66.0% of all events occurring at age ≥75 years. Incidence at ages 65 to 74 was highest in male smokers (274), with 96.4% of events in men <75 years occurring in ever-smokers. Extrapolating rates to the UK population, using trial evidence of screening efficacy, the current UK screening program would prevent 5.6% of aneurysm-related deaths (315 200 scans/year: 1426/death prevented, 121/year-of-life saved). Screening only male smokers age 65 and then all men at age 75 would prevent 21.1% of deaths (247 900 scans/year; 297/death prevented, 34/year-of-life saved). By 2030, 91.0% of deaths will occur at age ≥75, 61.6% at ≥85, and 28.6% in women. Given that two thirds of acute AAA occurred at ≥75 years of age, screening older age groups should be considered. Screening nonsmokers at age 65 is likely to have very little impact on AAA event rates. © 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.
    Journal of the American Heart Association 01/2015; 4(8). DOI:10.1161/JAHA.115.001926 · 2.88 Impact Factor

Publication Stats

22k Citations
4,998.42 Total Impact Points

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Institutions

  • 2008–2015
    • Oxford University Hospitals NHS Trust
      • Department of Clinical Neurology
      Oxford, England, United Kingdom
    • Universitätsklinikum Tübingen
      Tübingen, Baden-Württemberg, Germany
  • 1999–2015
    • University of Oxford
      • Nuffield Department of Clinical Neurosciences
      Oxford, England, United Kingdom
  • 2013
    • NIHR Oxford Biomedical Research
      Oxford, England, United Kingdom
    • University of Cambridge
      • Department of Clinical Neurosciences
      Cambridge, England, United Kingdom
  • 2012
    • St George's, University of London
      • Stroke and Dementia Research Centre
      Londinium, England, United Kingdom
  • 2011
    • The Newcastle upon Tyne Hospitals NHS Foundation Trust
      Newcastle-on-Tyne, England, United Kingdom
  • 1994–2009
    • Western General Hospital
      Edinburgh, Scotland, United Kingdom
  • 2007
    • The University of Calgary
      Calgary, Alberta, Canada
    • Yale-New Haven Hospital
      New Haven, Connecticut, United States
    • Duke University
      Durham, North Carolina, United States
  • 1994–2007
    • The University of Edinburgh
      • Division of Clinical Neurosciences
      Edinburgh, Scotland, United Kingdom
  • 2006
    • Utrecht University
      Utrecht, Utrecht, Netherlands
    • University Medical Center Utrecht
      • Julius Center for Health Sciences and Primary Care
      Utrecht, Provincie Utrecht, Netherlands
  • 2005
    • University of Toronto
      • Department of Medical Imaging
      Toronto, Ontario, Canada
  • 1997
    • Erasmus Universiteit Rotterdam
      Rotterdam, South Holland, Netherlands
  • 1996
    • University of Santiago, Chile
      CiudadSantiago, Santiago Metropolitan, Chile