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Research

Barts and The London Brain Attack Centre

Research

Barts and The London Brain Attack Centre is part of the Thames Stroke Research Network. We take part in national multi-centred trials and our patients have the opportunity to be involved in trials for new therapies for preventing or treating stroke.

These are some of the trials we have been involved in:

  • CLOTS (Clots in Legs Or Stockings after Stroke) trial looking at the effectiveness of graduated compression stockings to prevent deep vein thrombosis (DVT) after suffering a stroke.  
  • Rehabilitation trial involving patients with problems with arm function after stroke.
  • Annexin-1 trial investigating this protein which may have a protective effect against cell damage during stroke.
  • TRACS trial looking at the training of carers after stroke to improve outcomes for patients. 
  • ISRAS – Improving Stroke Recognition by Ambulance Services.  A single centre run trial – implementing the Rosier Assesment Tool.
  • Tomas – A rehabilitation study looking at people getting out of the house after stroke.
  • Whitehall – Looking at the role of depression in stroke.
  • IST-3 is an independent, investigator-led trial.

Trial hypothesis

That intravenous recombinant tissue plasminogen activator (rt-PA) in a dose of 0.9mg/kg (maximum 90mg) administered to patients with acute ischaemic stroke, within six hours of symptom onset, increases the proportion of people alive and independent at six months.

Background - Acute ischaemic stroke is a major public health problem

Stroke is a common cause of death and serious disability. It has been estimated that stroke causes over four million deaths in the world each year, three million of these in developing countries, and thus is the second most common single cause of death (after ischaemic heart disease).(1) In Europe alone, a quarter of a million people will become disabled after their first stroke each year. Although deaths from cerebrovascular diseases are declining in some parts of the world, rates are increasing in others (e.g. Eastern European countries).(2) Even if age specific stroke incidence remains stable or falls slightly, as more people live into old age, the numbers of new cases of acute stroke per year may still rise.

The recruiting phase is due to end on 30 June 2011.

These are the clinical trials we currently are recruiting to:

  • Brains - British Repository of DNA in stroke

Project aim

A non randomised controlled trial (RCT) to establish a DNA repository of all haemorrhagic and ischaemic stroke patients of any age.

Bakground

There are currently few treatments for acute stroke, comprising mainly of aspirin (which needs to be prescribed to ~80 patients to benefit one individual and clot-busting drugs; which have poor availability and are limited by the speed needed to administer. A clear need therefore exists to identify new drug targets. Recent advances in molecular biology enable us to use genetics to identify such new drug targets. While the environmental effects on stroke aetiology are likely to increase with age, identifying those genetically at risk early on can help target health campaigns more effectively, understand the pathophysiology of atherosclerotic disease and lead to novel therapeutic targets.

  • CADISS -Cervical Artery Dissection in Stroke Study (CADISS)

Aim

To determine the feasibility of a clinical trial comparing antiplatelet therapy with anticoagulation in the acute treatment of patients with cervical artery dissection. Specifically to address whether:

  1. There are sufficient clinical endpoints to provide the power to determine treatment effect
  2. Adequate numbers of patients can be recruited.

This study will lead on to a fully powered definitive treatment trial assuming the results of this feasibility phase indicate this is realistic, and particularly that sufficient end-points occur and adequate recruitment can be achieved. 

Background

Dissection of the carotid and vertebral arteries is a major cause of stroke in persons <50 years of age, mainly due to embolism from clot sealing the tear. At present physicians treat these patients with anticoagulants or antiplatelet drugs to prevent further stroke, but neither therapy is evidence-based. Anticoagulants may be powerful anti-embolic agents but are also more hazardous than aspirin, and potentially could encourage further dissection. Most published studies are flawed by retrospective data, with no reference to the number of patients in the original study cohort and do not include the critical principles of randomisation and ‘blinding’ of outcomes.

The only prospective data available(1) suggests that anticoagulants are more effective than antiplatelet agents in reducing further TIA and stroke after dissection, but the numbers were small and lack reliable statistical confirmation. This study was not a randomised controlled trial and therefore may be open to bias in selection of treatment. In addition, it found that most recurrent events occur within the first month and thereafter the number tails off. A total of about 1800 patients would be required for a two armed trial comparing antiplatelet agents with anticoagulants calculated on these data.

Authors of a previous Cochrane review (2) reviewing available published literature calculated that a total of about 2800 patients (1400 in each treatment arm) are needed for a blinded randomised trial of anticoagulants vs antiplatelet agents. This would need a major, probably international, study involving over 100 centres, and would be an expensive undertaking. Prior to starting such a study it is important to determine whether this would be feasible. This is particularly important for carotid and vertebral dissection which is a diagnosis frequently missed, at least during the acute phase. Limited natural history outcome data suggests the risk of recurrent stroke and TIA following carotid and vertebral dissection is only markedly raised during the first week to month (1, 3) and therefore early identification and recruitment of patients is essential if any treatment effect is to be demonstrated.

For these reasons a feasibility study is essential before any large scale clinical trial. Specifically two things need to be determined; firstly, whether sufficient patients can be recruited sufficiently early from participating centres, and secondly, in view of the limited data on the rate of recurrent TIA and stroke in patients with recent dissection, we need more data to obtain a robust estimate of early risk to inform power calculations for a large scale study.

A preliminary informal survey conducted by Clinical Neurosciences, St George’s University of London, in association with the Association of British Neurologists, has indicated that at least 27 neurologists/stroke physicians throughout the UK would be interested in collaborating and enrolling consecutive consenting patients into such a study comparing anticoagulation or antiplatelet therapy.

  • DNA lacunar - A DNA resource for lacunar (small vessel disease) stroke

Project aim

To establish a DNA resource of carefully phenotyped patients of lacunar stroke, aged <= 70 years.

Background

Much evidence suggests genetic factors are important in stroke. Several single gene disorders are associated with stroke including diseases such as CADASIL. However, the vast majority of cases of stroke have a multi-factorial pathogenesis and genetic contributions to this are likely to be polygenic. Nevertheless genetic factors also appear to be important in this population, as supported by a number of lines of evidence. Firstly, twin studies show greater concordance rates in monozygotic compared with dizygotic twins. Secondly, most family history studies have found that a family history of stroke is a risk factor for stroke in case control studies. Thirdly, animal studies suggest that specific genes influence the risk of cerebral ischaemia. Fourthly, recently a linkage based approach on extended pedigrees in Iceland has reported an independent stroke risk gene (STKR1), and further studies have identified the underlying gene as phosphodiesterase 4D.

Therefore a large body of evidence suggests genetic factors are important in stroke risk but the genes responsible remain to be determined.

  • ENOS - The Efficacy of Nitric Oxide in Stroke (ENOS) Trial

Project aim

A prospective, collaborative, international, multicentre, randomised, parallel-group, single and outcome blinded, controlled, factorial trial to investigate the safety and

efficacy of treatment with transdermal glyceryl trinitrate, a nitric oxide donor, and of continuing or stopping temporarily pre-stroke antihypertensive therapy, in patients with acute stroke

Summary

Nitric oxide is a multimodal candidate treatment for acute stroke having a number of properties which may be beneficial in acute stroke, including lowering blood pressure, causing cerebral vasodilatation, and improving central and systemic haemodynamics. Nitric oxide donors are effective in experimental stroke, and pilot studies in patients with acute stroke suggest that glyceryl trinitrate can be delivered easily in a transdermal preparation.

Around half of all patients admitted with acute stroke are taking antihypertensive therapy immediately prior to their stroke. No data exist as to whether it is beneficial or safe to continue or temporarily stop this treatment during the acute phase.

ENOS is a prospective, collaborative, international, multicentre, randomised, parallel-group, single and outcome blinded, controlled, factorial trial designed to test two questions related to the management of blood pressure immediately post-stroke:

1. The safety and efficacy of nitric oxide, given as transdermal glyceryl trinitrate.

2. The safety and efficacy of continuing versus stopping temporarily pre-stroke antihypertensive medication.

Previously independent adult patients who are conscious and have residual limb weakness are eligible for enrolment. Patients will be randomised, centrally via the internet to daily glyceryl trinitrate patch or no patch; a gauze dressing will be placed over the patch or a similar area of skin to maintain patient blinding to the patch. Additionally, patients taking antihypertensive medication immediately prior to their stroke will be randomised to continue or temporarily stop this. Treatment must be initiated within 48 hours of stroke onset and is given for 7 days. A CT scan is required before enrolment or within 7 days of randomisation. Early follow-up is performed at the local

centre over the 7 days of treatment, including recording of blood pressure, early stroke events, and serious adverse events. Central telephone follow-up by the National Co-ordinating Centre will be performed at 90 days. The primary outcome is combined death or dependency (modified Rankin Score >2).

  • Stroke INF

Summary

Nearly 40% of acute stroke patients have dysphagia, of whom up to 20% will develop aspiration pneumonia. This is associated with increased probablity of death, institutionalisation, poor participation in rehabilitation, increased duration of hospitalisation and increased costs of care. Although current guidelines have recommendations on the assessment, positioning and feeding of stroke patients to prevent chest infections, there are no guidelines for antibiotic use in these patients. Only 3 trials on antibiotic prophylaxis are available and show safety but not effectiveness, possibly because they include non-dysphagic patients, use mortality rather than infections as the end point and ignore duration of hospitalisation, participation in rehabilitation and costs as important outcomes. The aim of this cluster randomised trial is to evaluate the effectiveness and safety of prophylactic use of antibiotics (an "act first" approach) compared with monitoring for infection and treatment if necessary (a "wait and watch" approach) in reducing aspiration pneumonia and mortality whilst improving participation in rehabilitation and functional outcomes in acute stroke patients with dysphagia on clinical bedside swallowing assessment. Whether this approach results in reduced duration of hospitalisation and costs will also be assessed. A novel approach of using clinical and costs indicators as co-primary outcome measures will be adopted, to reflect the equal importance of clinical and economic endpoints in assessing the effectiveness of health interventions. We will study 1200 stroke patients with dysphagia admitted to 40 acute stroke units. We will use cluster randomization techniques to allocate units to either giving British Thoracic Society recommended antibiotic treatment for aspiration pneumonia as prophylaxis or to give antibiotic treatment only if signs of pneumonia develop. The clinical primary outcome measure will be the incidence of chest infections in the first 14 days after stroke onset or prior to discharge home if sooner than 14 days. The primary cost outcome measure will be the hospital cost for the presenting stroke. We will also monitor mortality, antibiotic related side effects, participation in rehabilitation, days spent in hospital, level of function and costs associated with care up to 3 months. An intention to treat analysis will be undertaken masked to allocation.

Studies planned to open soon

  • Clots 3 - A Randomised Trial to Establish the Effectiveness of Intermittent Pneumatic Compression to Prevent Post Stroke Deep Vein Thrombosis (DVT).

Aim of study

People who suffer a stroke are often drowsy and have weakness or

numbness of the limbs on one side of their body. It may cause loss of speech or part of the vision. Patients are often bed-bound for several days or weeks after the stroke although if they survive, most will make some recovery. In stroke patients who are unable to walk, and who may be paralysed on one side, the blood flows only slowly through the veins of their legs. This encourages clots to form in the legs - so called deep venous thrombosis or DVT. Pieces of this clot may break off and are carried by the bloodstream to the lungs. These, so called pulmonary emboli, can stop the heart and can cause patients with stroke to die suddenly. This may occur without warning because often the clots in the legs do not cause any leg swelling or pain - DVTs are often clinically silent. Blood thinning drugs can help reduce the risk of DVT and PE but in stroke patients they are not used routinely in the UK because they increase the risk of bleeding into the brain. Therefore, it is important to find alternative methods of reducing the risk of DVT. The CLOTS trials 1 & 2 tested whether graduated compression stockings - which are like long "flight socks" - reduce the risk of DVT after stroke. The results of these trials showed that routine use of graduated compression stockings in immobile stroke patients is not associated with a worthwhile reduction in risk of DVT. Another treatment which is used successfully to reduce the risk of DVT after surgery, but not currently in stroke units, is intermittent pneumatic compression (IPC). Sleeves which contain inflatable air sacs are wrapped around both legs and attached to a special air pump. The sleeves are

then inflated around one leg at a time. The sleeves around the lower leg inflate before the ones around the thigh - this squeezes blood up the veins in the legs, increases the flow, reducing stagnation and the likelihood of clots forming - at least that is the theory! The sleeves inflate and deflate at regular intervals. Although this sounds uncomfortable, most people actually quite like the sensation!

The CLOTS - 3 trial will include patients who have had a stroke and who have been admitted to a stroke unit. Patients who cannot walk independently, and who are at greatest risk of DVT will be invited to join the study. If they agree they will be randomly allocated to having routine care plus IPC or just routine care. Patients in both groups will have routine ultrasound scans on their legs to detect DVTs about one and four weeks after the stroke. They will also be followed up at six months by telephone or postal questionnaire to find out how well they have recovered and to detect any clots which have occurred after leaving hospital. The trial aims to enrol at least 2000 patients which will provide a precise estimate of the effect of IPC on the risk of DVT.

  • GOSH

A case-control study of genetic polymorphisms in aneurysmal subarachnoid haemorrhage

Short title - Genetics of Subarachnoid haemorrhage (GOSH)

Reason for the study

Aneurysmal subarachnoid haemorrhage causes death or dependence in approximately 70% of patients. There is substantial evidence of a genetic contribution to intracranial aneurysms. Methodological limitations of previous work include considering unruptured and ruptured aneurysms together, and failing to take account of aneurysm location.

Aims

This study will investigate whether specific susceptibility loci are associated with ruptured intracranial aneurysms, and the interaction between genetic factors and aneurysm location.

  • Stroke Oxygen Study

A multi-centre, prospective, randomised, open, blinded-endpoint study to assess whether routine oxygen treatment in the first 72 hours after a stroke improves long-term outcome

Trial summary

Mild hypoxia is common in stroke patients and may have significant adverse effects on the ischaemic brain after stroke. The use of oxygen treatment is rapidly increasing in European stroke units. A questionnaire survey of UK stroke physicians showed that almost 50% of respondents would start oxygen supplementation after stroke at a level of oxygen saturation of 95% or above, which is well within the normal physiological range. Oxygen treatment is

not without side effects. It impedes early mobilisation, could pose an infection risk, and may encourage the formation of toxic free radicals leading to further damage to the ischaemic brain. A small study of routine oxygen supplementation has shown no benefit in unselected patients, and potential harm in patients with mild strokes. Oxygen saturation is lower at night than during the day, and episodes of oxygen desaturation are common during sleep.

Nocturnal oxygen supplementation is likely to reduce the burden of hypoxia without interfering with daytime mobilisation and rehabilitation.

Before wider use of oxygen supplementation becomes established it is important to obtain better evidence on which patients benefit from such treatment. SOS is a large 'real life' trial which aims to produce reliable evidence on the balance of benefits and risks for different patient groups by randomising a large number of patients to routine oxygen supplementation or no routine oxygen treatment. The information on a few thousand patients randomised in SOS will help to guide the treatment of many thousands of future patients.

To make recruitment of a large, heterogeneous group of patients practicable procedures are kept simple, and eligibility is based on 'uncertainty'. Patients admitted to hospital with an acute stroke for whom there is substantial uncertainty whether or not they should receive oxygen or not are randomised to continuous oxygen treatment, nocturnal oxygen treatment or standard therapy (no routine oxygen) for 72 hours. Oxygen will be given at a rate of 2 or 3 litres/minute depending on baseline oxygen saturation. In this trial the extra work for collaborators is absolutely minimal. In addition to the randomisation form there is a one page baseline assessment and a brief clinical review at one week. Outcome data at 3, 6 and 12 months will be by a questionnaire sent to the patient by the trial centre.

There are other studies also being considered for this site, they will be added accordingly.

For details of our academic papers, please click here.