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

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

White Matter Imaging Correlates of Early Cognitive Impairment Detected by the Montreal Cognitive Assessment after Transient Ischemic Attack and Minor Stroke

BACKGROUND AND PURPOSE:&nbsp; Among screening tools for cognitive impairment in large cohorts, the Montreal Cognitive assessment (MoCA) appears to be more sensitive to early cognitive impairment than the Mini-Mental State Examination (MMSE), particularly after transient ischemic attack (TIA) or minor stroke. We reasoned that if MoCA-detected early cognitive impairment is pathologically significant, then it should be specifically associated with the presence of white matter hyperintensities (WMH) and reduced fractional anisotropy (FA) on MRI. METHODS:&nbsp;Consecutive eligible patients with TIA or minor stroke (Oxford Vascular Study) underwent MRI and cognitive assessment. We correlated MoCA and MMSE scores with WMH and FA, then specifically studied patients with low MoCA and normal MMSE. RESULTS: Among 400 patients, MoCA and MMSE scores were significantly correlated (all p&lt;0.001) with WMH volumes (rMoCA=-0.336, rMMSE=-0.297) and FA (rMoCA=0.409, rMMSE=0.369), and -on voxel-wise analyses- with WMH in frontal white matter and reduced FA in almost all white matter tracts. However, only the MoCA was independently correlated with WMH volumes (r=-0.183, p&lt;0.001), average FA values (r=0.218, p&lt;0.001), and voxel-wise reduced FA in anterior tracts after controlling for the MMSE. In addition, patients with low MoCA but normal MMSE (N=57) had higher WMH volumes (t=3.1,p=0.002), lower average FA (t=-4.0,p&lt;0.001), and lower voxel-wise FA in almost all white matter tracts than those with normal MoCA and MMSE (N=238). CONCLUSIONS:&nbsp;In patients with TIA or minor stroke, early cognitive impairment detected with the MoCA but not with the MMSE was independently associated with white matter damage on MRI, particularly reduced FA

Effects of aspirin on risks of vascular events and cancer according to bodyweight and dose:analysis of individual patient data from randomised trials

Background A one-dose-fits-all approach to use of aspirin has yielded only modest benefits in long-term prevention of cardiovascular events, possibly due to underdosing in patients of large body size and excess dosing in patients of small body size, which might also affect other outcomes. Methods Using individual patient data, we analysed the modifying effects of bodyweight (10 kg bands) and height (10 cm bands) on the effects of low doses (≤100 mg) and higher doses (300–325 mg or ≥500 mg) of aspirin in randomised trials of aspirin in primary prevention of cardiovascular events. We stratified the findings by age, sex, and vascular risk factors, and validated them in trials of aspirin in secondary prevention of stroke. Additionally, we assessed whether any weight or height dependence was evident for the effect of aspirin on 20-year risk of colorectal cancer or any in-trial cancer. Results Among ten eligible trials of aspirin in primary prevention (including 117 279 participants), bodyweight varied four-fold and trial median weight ranged from 60·0 kg to 81·2 kg (pand#60;0·0001). The ability of 75–100 mg aspirin to reduce cardiovascular events decreased with increasing weight (pinteraction=0·0072), with benefit seen in people weighing 50–69 kg (hazard ratio [HR] 0·75 [95% CI 0·65–0·85]) but not in those weighing 70 kg or more (0·95 [0·86–1·04]; 1·09 [0·93–1·29] for vascular death). Furthermore, the case fatality of a first cardiovascular event was increased by low-dose aspirin in people weighing 70 kg or more (odds ratio 1·33 [95% CI 1·08–1·64], p=0·0082). Higher doses of aspirin (≥325 mg) had the opposite interaction with bodyweight (difference pinteraction=0·0013), reducing cardiovascular events only at higher weight (pinteraction=0·017). Findings were similar in men and women, in people with diabetes, in trials of aspirin in secondary prevention, and in relation to height (pinteraction=0·0025 for cardiovascular events). Aspirin-mediated reductions in long-term risk of colorectal cancer were also weight dependent (pinteraction=0·038). Stratification by body size also revealed harms due to excess dosing: risk of sudden death was increased by aspirin in people at low weight for dose (pinteraction=0·0018) and risk of all-cause death was increased in people weighing less than 50 kg who were receiving 75–100 mg aspirin (HR 1·52 [95% CI 1·04–2·21], p=0·031). In participants aged 70 years or older, the 3-year risk of cancer was also increased by aspirin (1·20 [1·03–1·47], p=0·02), particularly in those weighing less than 70 kg (1·31 [1·07–1·61], p=0·009) and consequently in women (1·44 [1·11–1·87], p=0·0069). Interpretation Low doses of aspirin (75–100 mg) were only effective in preventing vascular events in patients weighing less than 70 kg, and had no benefit in the 80% of men and nearly 50% of all women weighing 70 kg or more. By contrast, higher doses of aspirin were only effective in patients weighing 70 kg or more. Given that aspirin's effects on other outcomes, including cancer, also showed interactions with body size, a one-dose-fits-all approach to aspirin is unlikely to be optimal, and a more tailored strategy is required