Factors That Can Affect the External Validity of Randomised Controlled Trials

Citation: Rothwell, P. M. (2006). 'Factors that can affect the external validity of randomised controlled trials' PLoS Clinical Trials, 1(1): e9. [Available at http://clinicaltrials.ploshubs.org]. Copyright 2006 Peter M. Rothwell. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Prognostic significance of short-term blood pressure variability in acute stroke

Background and Purpose— Blood pressure variability (BPV) may be an important prognostic factor acutely after stroke. This review investigated the existing evidence for the effect of BPV on outcome after stroke, also considering BPV measurement techniques and definitions. Methods— A literature search was performed according to a prespecified study protocol. Two reviewers independently assessed study eligibility and quality. Where appropriate, meta-analyses were performed to assess the effect of BPV on poor functional outcome. Results— Eighteen studies from 1359 identified citations were included. Seven studies were included in a meta-analysis for the effect of BPV on functional outcome (death or disability). Systolic BPV was significantly associated with poor functional outcome: pooled odds ratio per 10-mm Hg increment, 1.2; confidence interval (1.1–1.3). A descriptive review of included studies also supports these findings, and in addition, it suggests that systolic BPV may be associated with increased risk of intracranial hemorrhage in those treated with thrombolytic therapy. Conclusions— This systematic review and meta-analysis suggest that greater systolic BPV, measured early from ischemic stroke or intracerebral hemorrhage onset, is associated with poor longer-term functional outcome. Future prospective studies should investigate how best to measure and define BPV in acute stroke, as well as to determine its prognostic significance. </jats:sec

GALA: an international multicentre randomised trial comparing general anaesthesia versus local anaesthesia for carotid surgery

Background: Patients who have severe narrowing at or near the origin of the internal carotid artery as a result of atherosclerosis have a high risk of ischaemic stroke ipsilateral to the arterial lesion. Previous trials have shown that carotid endarterectomy improves long-term outcomes, particularly when performed soon after a prior transient ischaemic attack or mild ischaemic stroke. However, complications may occur during or soon after surgery, the most serious of which is stroke, which can be fatal. It has been suggested that performing the operation under local anaesthesia, rather than general anaesthesia, may be safer. Therefore, a prospective, randomised trial of local versus general anaesthesia for carotid endarterectomy was proposed to determine whether type of anaesthesia influences peri-operative morbidity and mortality, quality of life and longer term outcome in terms of stroke-free survival. Methods/design: A two-arm, parallel group, multicentre randomised controlled trial with a recruitment target of 5000 patients. For entry into the study, in the opinion of the responsible clinician, the patient requiring an endarterectomy must be suitable for either local or general anaesthesia, and have no clear indication for either type. All patients with symptomatic or asymptomatic internal carotid stenosis for whom open surgery is advised are eligible. There is no upper age limit. Exclusion criteria are: no informed consent; definite preference for local or general anaesthetic by the clinician or patient; patient unlikely to be able to co-operate with awake testing during local anaesthesia; patient requiring simultaneous bilateral carotid endarterectomy; carotid endarterectomy combined with another operation such as coronary bypass surgery; and, the patient has been randomised into the trial previously. Patients are randomised to local or general anaesthesia by the central trial office. The primary outcome is the proportion of patients alive, stroke free ( including retinal infarction) and without myocardial infarction 30 days post-surgery. Secondary outcomes include the proportion of patients alive and stroke free at one year; health related quality of life at 30 days; surgical adverse events, re-operation and re-admission rates; the relative cost of the two methods of anaesthesia; length of stay and intensive and high dependency bed occupancy

Randomised controlled trial of a Calcium Channel or Angiotensin Converting Enzyme Inhibitor/Angiotensin Receptor Blocker Regime to Reduce Blood Pressure Variability following Ischaemic Stroke (CAARBS): a protocol for a feasibility study

Introduction Raised blood pressure (BP) is common after stroke and is associated with a poor prognosis, yet trials of BP lowering in the immediate poststroke period have not demonstrated a benefit. One possible explanation for this may be that BP variability (BPV) rather than absolute levels predicts outcome, as BPV is increased after stroke and is associated with poor outcomes. Furthermore, there is evidence of distinct antihypertensive class effects on BPV despite similar BP-lowering effects. However, whether BPV in the immediate poststroke period is a therapeutic target has not been prospectively investigated. The objectives of this trial are to assess the feasibility and safety of recruiting patients following an acute ischaemic stroke or transient ischaemic attack (TIA) to an interventional randomised controlled trial comparing the effects of two different antihypertensive drug classes on BPV. Secondary exploratory objectives are to assess if different therapeutic strategies have diverse effects on levels of BPV and if this has an impact on outcomes. Methods 150 adult patients with first-ever ischaemic stroke or TIA who require antihypertensive therapy for secondary prevention will be recruited within 7 days of the event from stroke services across three sites. After baseline assessments they will be randomly assigned to treatment with a calcium channel blocker or ACE inhibitor/angiotensin receptor blocker-based regimen and followed up for a period of three months. Ethics and dissemination Ethical and regulatory approvals have been granted. Dissemination is planned via publication in peer-reviewed medical journals and presentation at relevant conferences. Trial registration number ISRCTN10853487

A population based study of the prevalence of fatigue following transient ischaemic attack and minor stroke

BACKGROUND AND PURPOSE: Fatigue is common after stroke and can be attributable to the increased physical effort associated with severe neurological deficits; however, its presence in those with little motor deficit raises the possibility of confounding by other factors, such as comorbidity, anxiety, and medication. To control for such factors and determine the extent of stroke-specific fatigue, we compared patients with minor stroke who had little or no residual neurological deficit with patients with TIA; both groups had undergone similar investigations and treatment. METHODS: The prevalence of fatigue 6 months after TIA or minor stroke was assessed in consecutive patients using the Chalder fatigue scale in a population-based incidence study (Oxford Vascular Study). Patients were included if they were independent in self-care Barthel Index (>or=18/20) and without major cognitive impairment (Mini-Mental State Examination >or=24/30). Stroke severity at baseline was assessed with the National Institute of Health Stroke Scale (NIHSS). Other potential causes of fatigue were assessed including anxiety, depression, recent life events, medication, and abnormalities in biochemistry or hematologic tests. RESULTS: Seventy-six participants had minor stroke (mean age, 74.1 years; 42 men) and 73 had TIA (mean age, 72.5 years; 40 men). At 6-month follow-up, median Barthel Index score was 20 (interquartile range, 20-20) in both groups. However, fatigue was more common after stroke than TIA (56% vs 29%; OR, 3.14; 95% CI, 1.51-6.57; P=0.0008). This difference was present both in patients with modified Rankin score of 0 at 6 months (23.8% vs 10.3%) and patients with modified Rankin score >or=1 (69.2% vs 48.6%), and remained more frequent in stroke patients after adjustment for potential confounders. Within the group of patients with stroke, the prevalence of fatigue increased with initial stroke severity (87% NIHSS >or=4 vs 48% NIHSS <or=3; P=0.0087); however, stroke patients with initial NIHSS of 0 were still more fatigued than patients with TIA (57% vs 29%; P=0.015). CONCLUSIONS: The prevalence of fatigue after minor stroke is higher than after TIA, suggesting that it is not simply a consequence of the stress of a recent acute cerebral event, comorbidity, medication, or other potential confounders. The high levels of fatigue in stroke patients without neurological impairment suggest it has a central origin rather than being the result of increased physical effort required after stroke

Identification of Novel Associations and Localization of Signals in Idiopathic Inflammatory Myopathies Using Genome-Wide Imputation

Idiopathic inflammatory myopathies; GenomeMiopatías inflamatorias idiopáticas; GenomaMiopaties inflamatòries idiopàtiques; GenomaObjective The idiopathic inflammatory myopathies (IIMs) are heterogeneous diseases thought to be initiated by immune activation in genetically predisposed individuals. We imputed variants from the ImmunoChip array using a large reference panel to fine-map associations and identify novel associations in IIM. Methods We analyzed 2,565 Caucasian IIM patient samples collected through the Myositis Genetics Consortium (MYOGEN) and 10,260 ethnically matched control samples. We imputed 1,648,116 variants from the ImmunoChip array using the Haplotype Reference Consortium panel and conducted association analysis on IIM and clinical and serologic subgroups. Results The HLA locus was consistently the most significantly associated region. Four non-HLA regions reached genome-wide significance, SDK2 and LINC00924 (both novel) and STAT4 in the whole IIM cohort, with evidence of independent variants in STAT4, and NAB1 in the polymyositis (PM) subgroup. We also found suggestive evidence of association with loci previously associated with other autoimmune rheumatic diseases (TEC and LTBR). We identified more significant associations than those previously reported in IIM for STAT4 and DGKQ in the total cohort, for NAB1 and FAM167A-BLK loci in PM, and for CCR5 in inclusion body myositis. We found enrichment of variants among DNase I hypersensitivity sites and histone marks associated with active transcription within blood cells. Conclusion We found novel and strong associations in IIM and PM and localized signals to single genes and immune cell types.Supported by the Intramural Research Program, National Institute of Environmental Health Sciences, NIH. Dr. Lundberg's work was supported by grants from the Swedish Research Council and Stockholm Regional Council (ALF). Dr. Vencovsky's work was supported by the Czech Ministry of Health–Conceptual Development of Research Organization (award 00023728) (Institute of Rheumatology). Drs. Hanna and Machado's work were supported by the NIHR University College London Hospitals Biomedical Research Centre. Drs. De Bleecker and De Paepe's work were supported by the European Reference Network for Rare Neuromuscular Diseases (ERN EURO-NMD). Dr. Wedderburn's work was supported by Versus Arthritis (awards 21593 and 21552), the Wellcome trust (award 085860), Myositis UK, the Cure JM Foundation, the Remission Charity, and the NIHR Biomedical research Centre at GOSH. Dr. Chinoy's work was supported by the Medical Research Council UK (award MR/N003322/1), Myositis UK, and the NIHR Manchester Biomedical Research Centre Funding Scheme. Dr. Lamb's work was supported by the Medical Research Council UK (award MR/N003322/1) and Myositis UK

TRECVID 2004 experiments in Dublin City University

In this paper, we describe our experiments for TRECVID 2004 for the Search task. In the interactive search task, we developed two versions of a video search/browse system based on the Físchlár Digital Video System: one with text- and image-based searching (System A); the other with only image (System B). These two systems produced eight interactive runs. In addition we submitted ten fully automatic supplemental runs and two manual runs. A.1, Submitted Runs: • DCUTREC13a_{1,3,5,7} for System A, four interactive runs based on text and image evidence. • DCUTREC13b_{2,4,6,8} for System B, also four interactive runs based on image evidence alone. • DCUTV2004_9, a manual run based on filtering faces from an underlying text search engine for certain queries. • DCUTV2004_10, a manual run based on manually generated queries processed automatically. • DCU_AUTOLM{1,2,3,4,5,6,7}, seven fully automatic runs based on language models operating over ASR text transcripts and visual features. • DCUauto_{01,02,03}, three fully automatic runs based on exploring the benefits of multiple sources of text evidence and automatic query expansion. A.2, In the interactive experiment it was confirmed that text and image based retrieval outperforms an image-only system. In the fully automatic runs, DCUauto_{01,02,03}, it was found that integrating ASR, CC and OCR text into the text ranking outperforms using ASR text alone. Furthermore, applying automatic query expansion to the initial results of ASR, CC, OCR text further increases performance (MAP), though not at high rank positions. For the language model-based fully automatic runs, DCU_AUTOLM{1,2,3,4,5,6,7}, we found that interpolated language models perform marginally better than other tested language models and that combining image and textual (ASR) evidence was found to marginally increase performance (MAP) over textual models alone. For our two manual runs we found that employing a face filter disimproved MAP when compared to employing textual evidence alone and that manually generated textual queries improved MAP over fully automatic runs, though the improvement was marginal. A.3, Our conclusions from our fully automatic text based runs suggest that integrating ASR, CC and OCR text into the retrieval mechanism boost retrieval performance over ASR alone. In addition, a text-only Language Modelling approach such as DCU_AUTOLM1 will outperform our best conventional text search system. From our interactive runs we conclude that textual evidence is an important lever for locating relevant content quickly, but that image evidence, if used by experienced users can aid retrieval performance. A.4, We learned that incorporating multiple text sources improves over ASR alone and that an LM approach which integrates shot text, neighbouring shots and entire video contents provides even better retrieval performance. These findings will influence how we integrate textual evidence into future Video IR systems. It was also found that a system based on image evidence alone can perform reasonably and given good query images can aid retrieval performance

Early time course of major bleeding on antiplatelet therapy after TIA or ischemic stroke

Objective: To study the early time course of major bleeding and its subtypes in patients with cerebral ischemia on dual and single antiplatelet therapy. Methods: We performed a post hoc analysis on individual patient data from 6 randomized clinical trials (Clopidogrel Versus Aspirin in Patients at Risk of Ischaemic Events [CAPRIE], Second European Stroke Prevention Study [ESPS-2], Management of Atherothrombosis With Clopidogrel in High Risk Patients [MATCH], Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance [CHARISMA], European/Australasian Stroke Prevention in Reversible Ischaemia Trial [ESPRIT], and Prevention Regimen for Effectively Avoiding Second Strokes [PRoFESS]) including 45,195 patients with a TIA or noncardioembolic ischemic stroke. We studied incidence rates of bleeding per antiplatelet regimen stratified by time from randomization (≤30, 31–90, 91–180, 181–365, >365 days). We calculated incidence rates per trial and pooled estimates with random-effects meta-analysis. We performed Poisson regression to assess differences between time periods with adjustment for age and sex. Results: The incidence of major bleeding on aspirin plus clopidogrel and aspirin plus -dipyridamole was highest in the first 30 days, 5.8 and 4.9 per 100 person-years, respectively, and was significantly higher than at 31 to 90 days (rate ratio 1.98, 95% confidence interval 1.16–3.40 for aspirin plus clopidogrel; rate ratio 1.94, 95% confidence interval 1.24–3.03 for aspirin plus dipyridamole). Incidence rates on aspirin and clopidogrel monotherapy were 2.8 and 2.5 per 100 person-years, respectively, in the first 30 days, with no significant change over time. The time course was similar for gastrointestinal bleeds. There was no early excess of intracranial hemorrhage in patients on either dual or single antiplatelet therapy. Conclusion: Dual antiplatelet therapy is associated with high early risks of major and gastrointestinal bleeding that decline after the first month in trial cohorts