Peter Sandercock

• MA, DM, FRCPE, FMedSci
• Professor at University of Edinburgh

Background Vascular prevention trials typically use dichotomous event outcomes although this may be inefficient statistically and gives no indication of event severity. We assessed whether ordinal outcomes would be more efficient and how to best analyse them. Methods Chief investigators of vascular prevention randomised controlled trials that show...

Importance The Restart or Stop Antithrombotics Randomized Trial (RESTART) found that antiplatelet therapy appeared to be safe up to 5 years after intracerebral hemorrhage (ICH) that had occurred during antithrombotic (antiplatelet or anticoagulant) therapy. Objectives To monitor adherence, increase duration of follow-up, and improve precision of e...

Background Among asymptomatic patients with severe carotid artery stenosis but no recent stroke or transient cerebral ischaemia, either carotid artery stenting (CAS) or carotid endarterectomy (CEA) can restore patency and reduce long-term stroke risks. However, from recent national registry data, each option causes about 1% procedural risk of disab...

Background Obtaining informed consent in people with acute stroke is complex since many, as a direct result of their stroke, lose capacity to make important decisions. Furthermore, reperfusion interventions are time dependent necessitating rapid consent. We developed four different consent approaches to facilitate recruitment of a broad range of pa...

Purpose CT attenuation of ischemic brain reduces with time after stroke onset. We aimed to quantify this relationship and test the feasibility and accuracy of estimating stroke onset time using only CT attenuation of visible ischemic lesions, the CT-Clock Tool. Methods We selected CT scans with ischemic lesions representing a range of stroke-onset...

Background Inflammation contributes to unstable atherosclerotic plaque and stroke. In randomised trials in patients with coronary disease, canukinumab (an interleukin-1B antagonist) and colchicine (a tubulin inhibitor with pleiotropic anti-inflammatory effects) reduced recurrent vascular events. Hypothesis: Anti-inflammatory therapy with low-dose c...

Background The CRASH-3 trial hypothesised that timely tranexamic acid (TXA) treatment might reduce deaths from intracranial bleeding after traumatic brain injury (TBI). To explore the mechanism of action of TXA in TBI, we examined the timing of its effect on death. Methods The CRASH-3 trial randomised 9202 patients within 3 h of injury with a GCS...

Background Alteplase improves functional outcomes of patients with acute ischaemic stroke, but its effects on symptomatic infarct swelling, an adverse complication of stroke and the influence of CT hyperdense artery sign (HAS) are unclear. This substudy of the Third International Stroke Trial aimed to investigate the association between HAS and sym...

Background Our Cochrane review of selective serotonin inhibitors for stroke recovery indicated that fluoxetine may improve functional recovery, but the trials were small and most were at high risk of bias. Objectives The Fluoxetine Or Control Under Supervision (FOCUS) trial tested the hypothesis that fluoxetine improves recovery after stroke. Des...

Background: Artificial intelligence-based software may automatically detect ischaemic stroke lesions and provide an Alberta Stroke Program Early CT score (ASPECTS) on CT, and identify arterial occlusion and provide a collateral score on CTA. Large-scale independent testing will inform clinical use, but is lacking. We aim to test e-ASPECTS and e-CTA...

Background and Purpose— We aim to identify factors associated with imaging-confirmed lacunar strokes and improve their rapid clinical identification early after symptom onset using data from the IST-3 (Third International Stroke Trial). Methods— We selected patients likely to have lacunar infarcts as those presenting with: Oxfordshire Community St...

Background Tranexamic acid reduces surgical bleeding and decreases mortality in patients with traumatic extracranial bleeding. Intracranial bleeding is common after traumatic brain injury (TBI) and can cause brain herniation and death. We aimed to assess the effects of tranexamic acid in patients with TBI. Methods This randomised, placebo-controll...

Background and Purpose— The FOCUS trial (Fluoxetine or Control Under Supervision) showed that fluoxetine did not improve modified Rankin Scale scores (mRS) but increased the risk of fractures. We aimed to describe the fractures, their impact on mRS and factors associated with fracture risk. Methods— A United Kingdom, multicenter, parallel-group, r...

Background: Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greate...

Background For adults surviving stroke due to spontaneous (non-traumatic) intracerebral haemorrhage (ICH) who had taken an antithrombotic (i.e. anticoagulant or antiplatelet) drug for the prevention of vaso-occlusive disease before the ICH, it is unclear whether starting antiplatelet therapy modifies the risks of recurrent ICH, major haemorrhagic e...

Background The long-term risk of stroke or myocardial infarction (MI) in patients with minor neurological symptoms who are not clinically diagnosed with transient ischaemic attack (TIA) or minor stroke is uncertain. Methods We used data from a rapid access clinic for patients with suspected TIA or minor stroke and follow-up from four overlapping d...

Background: For adults surviving stroke due to spontaneous (non-traumatic) intracerebral haemorrhage (ICH) who had taken an antithrombotic (i.e. anticoagulant or antiplatelet) drug for the prevention of vaso-occlusive disease before the ICH, it is unclear whether starting antiplatelet drugs modifies the risks of recurrent ICH, haemorrhagic events,...

Background: High blood pressure is common in acute stroke and is a predictor of poor outcome; however, large trials of lowering blood pressure have given variable results, and the management of high blood pressure in ultra-acute stroke remains unclear. We investigated whether transdermal glyceryl trinitrate (GTN; also known as nitroglycerin), a ni...

Focal cerebral ischemia, caused by a sudden occlusion of a cerebral blood vessel or sometimes just by low blood flow, initiates a series of events which can lead to irreversible neuronal damage and death (i.e. infarction) in the part of the brain supplied or drained by that vessel. Several pathophysiological cascades run in sequence (and in paralle...

Background The long-term risk of stroke or MI in patients with minor neurological symptoms who are not clinically diagnosed with transient ischaemic attack (TIA) or minor stroke is uncertain. Methods We used data from a rapid access clinic for patients with suspected TIA or minor stroke and follow-up from four overlapping data sources for a diagnos...

Background: For adults surviving stroke due to spontaneous (non-traumatic) intracerebral haemorrhage (ICH) who had taken an antithrombotic (i.e. anticoagulant or antiplatelet) drug for the prevention of vaso-occlusive disease before the ICH, it is unclear whether starting antiplatelet drugs modifies the risks of recurrent ICH, haemorrhagic events,...

Background: Results of small trials indicate that fluoxetine might improve functional outcomes after stroke. The FOCUS trial aimed to provide a precise estimate of these effects. Methods: FOCUS was a pragmatic, multicentre, parallel group, double-blind, randomised, placebo-controlled trial done at 103 hospitals in the UK. Patients were eligible...

Objective: To determine whether alteplase alters the development of ischemic lesions on brain imaging after stroke. Methods: The Third International Stroke Trial (IST-3) was a randomized controlled trial of IV alteplase for ischemic stroke. We assessed CT or brain MRI at baseline (pretreatment) and 24 to 48 hours posttreatment for acute lesion v...

Background: For adults surviving stroke due to spontaneous (non-traumatic) intracerebral haemorrhage (ICH) who had taken an antithrombotic (i.e. anticoagulant or antiplatelet) drug for the prevention of vaso-occlusive disease before the ICH, it is unclear whether starting antiplatelet drugs results in an increase in the risk of recurrent ICH or a...

Goal: Magnetic resonance imaging (MRI) is the preferred modality for research on structural age-related brain changes. However, computed tomography (CT) is widely available and has practical and cost advantages over MRI for large-scale brain imaging research studies in acutely unwell patients. However, the relationships between MRI and CT measures...

This is the first paper in a series of five on how to do good quality clinical research. It sets the scene for the four papers that follow. The aims of the series are to: promote reliable clinical research to inform clinical practice; help people new to research to get started (at any stage of their career); create teaching resources for experience...

Background The recommended maximum age and time window for intravenous alteplase treatment of acute ischemic stroke differs between the Europe Union and United States. Aims We compared the effects of alteplase in cohorts defined by the current Europe Union or United States marketing approval labels, and by hypothetical revisions of the labels that...

Higher blood pressure, blood pressure variability, and leukoaraiosis are risk factors for early adverse events and poor functional outcome after ischemic stroke, but prior studies differed on whether leukoaraiosis was associated with blood pressure variability, including in ischemic stroke. In the Third International Stroke Trial, blood pressure wa...

Purpose of Review The purpose of the review is to examine recent evidence on the effects of intravenous thrombolysis and identify the remaining uncertainties. Recent Findings We review the results of two large trials (the third International Stroke Trial (IST-3) and The Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED)) an...

Estimating time of ischaemic stroke onset using only brain attenuation changes in CT. Presented at the European Stroke Organisation Conference in Prague May 2017.

Stroke is a major burden to patients and society, and resources spent on stroke research must be used efficiently and produce good value in terms of improvements in human health. However, many instances of poor value from stroke research funding have resulted from the way in which stroke research topics have been chosen and how studies have been de...

Background: Low-molecular-weight heparins (LMWHs) and heparinoids are anticoagulants that may have more powerful antithrombotic effects than standard unfractionated heparin (UFH) but a lower risk of bleeding complications. This is an update of the original Cochrane Review of these agents, first published in 2001 and last updated in 2008. Objectiv...

Background: Leukoaraiosis is associated with impaired cerebral perfusion, but the effect of individual and combined small-vessel disease (SVD) features on white matter perfusion is unclear. Methods: We studied patients recruited with perfusion imaging in the Third International Stroke Trial. We rated individual SVD features (leukoaraiosis, lacun...

A framework for building an infrastructure that semantically integrates, archives, and reuses data for various research purposes in human brain imaging remains critical. In particular, problems of aligning technical, clinical, and professional systems in order to facilitate data sharing are a recurring issue in brain imaging. However, large samples...

Background and purpose: Computed tomographic angiography and magnetic resonance angiography are used increasingly to assess arterial patency in patients with ischemic stroke. We determined which baseline angiography features predict response to intravenous thrombolytics in ischemic stroke using randomized controlled trial data. Methods: We analy...

Background and Purpose— In patients with acute ischemic stroke, whether involvement of the insular cortex influences outcome is controversial. Much of the apparent adverse outcome may relate to such strokes usually being severe. We examined the influence of right and left insular involvement on stroke outcomes among patients from the IST-3 study (T...

This Review is intended to help clinicians, patients, and the public make informed decisions about statin therapy for the prevention of heart attacks and strokes. It explains how the evidence that is available from randomised controlled trials yields reliable information about both the efficacy and safety of statin therapy. In addition, it discusse...

Background: Thrombolytic therapy with intravenous alteplase within 4.5 hours of ischemic stroke onset increases the overall likelihood of an excellent outcome (no, or nondisabling, symptoms). Any improvement in functional outcome distribution has value, and herein we provide an assessment of the effect of alteplase on the distribution of the funct...

Background: The effect of alteplase on patient survival after ischaemic stroke is the subject of debate. We report the effect of intravenous alteplase on long-term survival after ischaemic stroke of participants in the Third International Stroke Trial (IST-3). Methods: In IST-3, done at 156 hospitals in 12 countries (Australia, Europe, and the U...

Randomized controlled trials are the most unbiased way to evaluate many types of healthcare interventions. Pharmaceutical and medical technology industries play an important role in developing and testing new interventions that have commercial potential. However, many interventions for the prevention, treatment and rehabilitation of stroke are eith...

Introduction Perfusion imaging is used increasingly to assess ischaemic stroke. IST-3 was a large multicentre randomised-controlled trial testing intravenous rt-PA for ischaemic stroke; selected centres collected perfusion imaging. Methods All IST-3 patients with baseline CT/MR perfusion are included. We assessed perfusion defects on cerebral blood...

Background: The success of randomized-controlled stroke trials is dependent on the recruitment and retention of a sufficient number of patients, but fewer than half of all trials meet their target number of patients. Methods: We performed a search and review of the literature, and conducted a survey and workshop among 56 European stroke trialist...

Background: Venous thromboembolism (VTE) including deep vein thrombosis (DVT) and pulmonary embolism is a frequent complication in immobile patients with acute ischemic stroke. This guideline document presents the European Stroke Organisation guidelines for the prophylaxis of VTE in immobile patients with acute ischaemic stroke. Guidelines for hae...

The independent oversight of clinical trials, which is recommended by the Medical Research Council (MRC) Guidelines for Good Clinical Practice, is typically provided by an independent advisory Data Monitoring Committee (DMC) and an independent executive committee, to whom the DMC makes recommendations. The detailed roles and function of this execut...

Objective: To assess whether the x-ray attenuation of intra-arterial obstruction measured on non-contrast CT in ischemic stroke can predict response to thrombolysis and subsequent functional outcome. Methods: The Third International Stroke Trial (IST-3) was a multicenter randomized-controlled trial of intravenous thrombolysis (rt-PA) given withi...

Clinical characteristics of the full IST-3 trial population and the subgroup with measurable intra-arterial obstruction on angiography. (DOCX)

Objective: To investigate whether the location and extent of the CT hyperdense artery sign (HAS) at presentation affects response to IV alteplase in the randomized controlled Third International Stroke Trial (IST-3). Methods: All prerandomization and follow-up (24-48 hours) CT brain scans in IST-3 were assessed for HAS presence, location, and ex...

This is a report about the 7th RTC of EAN held in Khartoum, Sudan in the period from 15-17th October 2015. Hosted by the University of Khartoum. I was the chair of the local organizing committee. This reflects the potential in Sudan for contributing to top class training activities in the world. reported by: Professor Peter Sandercock, MA, DM, FRCP...

Background: The independent oversight of clinical trials, which is recommended by the Medical Research Council (MRC) Guidelines for Good Clinical Practice, is typically provided by an independent advisory Data Monitoring Committee (DMC) and an independent executive committee, to whom the DMC makes recommendations. The detailed roles and function of...

Background and purpose: In patients with acute ischemic stroke, a high blood pressure or a highly variable blood pressure is a common reason for withholding thrombolytic treatment, but guidelines recommend a conservative approach to active blood pressure lowering in this setting. We have performed exploratory analyses to study the clinical effects...

Figure S3. Predicted risk of thrombosis vs. predicted risk of hemorrhage.

Table S1. Defined common ordinal outcome.

Figure S2. Pooled estimates of absolute risk reduction (ARR) in poor outcome. Q1 to Q4 denote quarters of risk defined on IST data.

Table S2. Characteristics of included trials.

Table S4. Outcome events in participants recruited to large randomised controlled trials of aspirin by 2 weeks after randomisation.

Figure S1. Forest plots for each outcome event summarising the effect of aspirin across the three included trials.

Table S3. Baseline characteristics of patients randomised into controlled trials of aspirin.

Table S5. Calibration metrics for re‐calibrated predicted risks for each trial.

The idea that different patients will respond differently to the same treatment is not new. The recent advances in genomics and laboratory medicine have led to the hope that it will be possible to maximize the benefit and minimize the harms of each medical therapy by using an individuals' biomarker status to 'personalize' their treatment. The selec...

Venous thromboembolism (VTE) is a common cause of death and morbidity in stroke patients. There are few data concerning the effectiveness of intermittent pneumatic compression (IPC) in treating patients with stroke. Objectives To establish whether or not the application of IPC to the legs of immobile stroke patients reduced their risk of deep vein...

The CLOTS 3 trial showed that intermittent pneumatic compression (IPC) reduced the risk of DVT and improved survival after stroke. To provide additional information which may help clinicians target IPC on the most appropriate patients by exploring the variation in its effects on subgroups defined by predicted prognosis. A multicentre, parallel grou...

Patients with TIA have high risk of recurrent stroke and require rapid assessment and treatment. The ABCD2 clinical risk prediction score is recommended for patient triage by stroke risk, but its ability to stratify by known risk factors and effect on clinic workload are unknown. We performed a systematic review and meta-analysis of all studies pub...

Randomized trial evidence on the risk/benefit ratio of thrombolysis for mild stroke is limited. We sought to determine the efficacy of intravenous recombinant tissue-type plasminogen activator (IV r-tPA) in a subset of patients with mild deficit in the third International Stroke Trial (IST-3). IST-3 compared IV r-tPA with control within 6 hours of...

Randomised trials are at the heart of evidence-based healthcare, but the methods and infrastructure for conducting these sometimes complex studies are largely evidence free. Trial Forge (www.trialforge.org) is an initiative that aims to increase the evidence base for trial decision making and, in doing so, to improve trial efficiency. This paper su...

The socioeconomic and health effect of stroke and other noncommunicable disorders (NCDs) that share many of the same risk factors with stroke, such as heart attack, dementia, and diabetes mellitus, is huge and increasing.1–4 Collectively, NCDs account for 34.5 million deaths (66% of deaths from all causes)3 and 1344 million disability-adjusted life...

Aspirin is of moderate overall benefit for patients with acute disabling ischemic stroke. It is unclear whether functional outcome could be improved after stroke by targeting aspirin to patients with a high risk of recurrent thrombosis or a low risk of haemorrhage. We aimed to determine whether patients at higher risk of thrombotic events or poor f...

Background Randomised trials have shown that alteplase improves the odds of a good outcome when delivered within 4·5 h of acute ischaemic stroke. However, alteplase also increases the risk of intracerebral haemorrhage; we aimed to determine the proportional and absolute effects of alteplase on the risks of intracerebral haemorrhage, mortality, and...

Erratum in Lancet. 2015 Feb 14;385(9968):606. Abstract BACKGROUND: High blood pressure is associated with poor outcome after stroke. Whether blood pressure should be lowered early after stroke, and whether to continue or temporarily withdraw existing antihypertensive drugs, is not known. We assessed outcomes after stroke in patients given drugs to...

Our aim was to identify whether particular subgroups of patients had an unacceptably high risk of symptomatic intracranial hemorrhage or low chance of benefit when treated with alteplase (recombinant tissue-type plasminogen activator). Third International Stroke Trial was an international randomized trial of the intravenous (IV) recombinant plasmin...

In acute ischemic stroke, the hyperdense artery sign (HAS) on noncontrast computed tomography (CT) is thought to represent intraluminal thrombus and, therefore, is a surrogate of arterial obstruction. We sought to assess the accuracy of HAS as a marker of arterial obstruction by thrombus. The Third International Stroke Trial (IST-3) was a randomize...

updated bibliography IST 3 trial

Background and purpose: Prompt thrombolytic therapy with intravenous alteplase reduces disability after acute ischemic stroke. In an exploratory analysis, we examined whether long-term survival varied by baseline characteristics after alteplase. Methods: In this open-treatment, international, randomized, controlled trial, ischemic stroke patient...

INTRODUCTION: CT angiography (CTA) is often used for assessing patients with acute ischaemic stroke. Only limited observer reliability data exist. We tested inter- and intra-observer reliability for the assessment of CTA in acute ischaemic stroke. METHODS: We selected 15 cases from the Third International Stroke Trial (IST-3, ISRCTN25765518) with v...

Background In the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) factorial trial, the combination of perindopril and indapamide reduced mortality among patients with type 2 diabetes, but intensive glucose control, targeting a glycated hemoglobin level of less than 6.5%, did not. We n...