Targeted treatment for acute stroke: development of prognostic models and decision support tools

Lead Research Organisation: University of Edinburgh
Department Name: Sch of Molecular. Genetics & Pop Health

Abstract

Stroke, the world‘s second biggest killer, is most often due to a blockage of a brain blood vessel by blood clot. Drugs that dissolve clots or prevent them from forming improve the chance of recovery after stroke, but they also increase the chance of bleeding; when bleeds occur into the brain they are particularly severe. Most stroke patients need to take drugs that affect blood clotting at some point in their illness, ranging from potent ‘clot busting‘ drugs to less risky drugs like aspirin.

If a doctor could reliably select which patients were helped rather than harmed by these drugs, this would be a big step forward. I hope to develop a method to predict which stroke patients are more likely to be harmed (by bleeding) than benefit (by avoiding forming blood clots) from medicines that affect clotting. I will use statistical methods to make predictions, and then explore the best way for doctors and patients to use them. This will lead to better decisions for each individual patient, and better treatment policies. This study will use the best information from existing methods as well as from newer technologies (e.g. blood tests and brain imaging) to ensure effective and personalised decisions for each stroke patient

Technical Summary

Background
Although thrombolytic, antithrombotic and antiplatelet drugs are used for the treatment of acute stroke, they can have severe side effects. Better targeting of these therapies could increase their net population health gain by reducing avoidable haemorrhagic and thrombotic events.

Aim
To develop decision support tools that provide clinically useful guidance and improve patient outcome by better application of existing treatments for stroke. These could be incorporated into the NHS electronic record should they show significant health benefits.

Objectives
1. Develop and validate statistical models to predict haemorrhagic and thrombotic arterial and venous events after stroke with data from a number of large cohorts.
2. Determine whether prediction of haemorrhagic events, based on existing clinical and imaging data, has a significant interaction with the treatment benefits of intravenous thrombolysis, heparin and aspirin in large randomised controlled trials.
3. Create a clinical decision tool, based on the prediction models for haemorrhage and arterial and venous thrombosis developed in parts 1-3
4. Pilot the application of the decision tool in stroke practice in NHS Lothian with a view to establishing a larger scale randomised multi-centre evaluation study.

Design/Methodology
I will develop and validate models for the prediction of haemorrhagic and thrombotic events after stroke in prospective hospital- and community-based cohort studies and randomised controlled trials, from (i) the Stroke Complications and Outcomes Prediction Engine collaboration based in Edinburgh (ii) the Kadoorie Study of Chronic Disease in China and (iii) the Virtual Internet Stroke Archive based in Glasgow
To examine the interaction between the results of models predicting haemorrhagic and thrombotic events after stroke and the effect of treatment I will use data from the MRC International Stroke Trial of aspirin and heparin, the Third International Stroke Trial of thrombolysis, and the Chinese Acute Stroke Trial of aspirin.
Using tested technology, in collaboration with a group experienced in health informatics, I will develop a tool to present the results of prognostic models as a clinical decision tool. I will evaluate its feasibility in practice, with a view to a larger study.

Medical and Scientific Opportunities
After stroke, the benefits of antithrombotic and thrombolytic drugs are offset to some extent by an increase in the risk of haemorrhage from the treatment. Better selection of patients for these commonly used treatments could - by focussing treatments on patients most likely to derive net benefit - improve outcome in individual stroke patients, with potentially great population health gains.

Publications

10 25 50

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Ali M (2013) More outcomes than trials: a call for consistent data collection across stroke rehabilitation trials. in International journal of stroke : official journal of the International Stroke Society

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Berge E (2016) Mortality after thrombolysis - Authors' reply. in The Lancet. Neurology

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Brady MC (2010) Reduce, reuse and recycle. in International journal of stroke : official journal of the International Stroke Society

 
Description Cited as evidence in MHRA planned review of medication
Geographic Reach National 
Policy Influence Type Implementation circular/rapid advice/letter to e.g. Ministry of Health
Impact The MHRA is reviewing their policy on the drug alteplase after multiple depositions by interested clinicians. Our systematic review will be a key piece of evidence to show that the drug is useful. The results of the review are not yet known (expected 2015)
URL http://www.mhra.gov.uk/NewsCentre/CON448382
 
Description Embolic Stroke of Uncertain Source Scientific Panel
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guidance committee
 
Description Chest Heart and Stroke Scotland Small Grants
Amount £4,500 (GBP)
Organisation Chest Heart & Stroke Scotland 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2011 
End 06/2013
 
Description Princess Margaret Research Development Fellowship
Amount £190,198 (GBP)
Funding ID TSA PMF 2013/03 
Organisation Stroke Association 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2013 
End 08/2016
 
Description Scottish Senior Clinical Fellowship
Amount £533,000 (GBP)
Funding ID SCAF/17/01 
Organisation Chief Scientist Office 
Sector Public
Country United Kingdom
Start 01/2018 
End 01/2023
 
Title Stroke Thrombolysis Trialists Collaboration 
Description A database held within the University of Oxford and the University of Alabama with all data from randomised controlled trials of alteplase 
Type Of Material Database/Collection of data 
Provided To Others? No  
Impact Lancet paper 
URL https://www.ctsu.ox.ac.uk/research/meta-trials/stt-1
 
Description ATTC 
Organisation University of Oxford
Department Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU)
Country United Kingdom 
Sector Academic/University 
PI Contribution Drafting proposals, contributing to meetings, joining an ongoing collaboration
Collaborator Contribution Data, analysis,
Impact None yet
Start Year 2014
 
Description Individual patient data meta analysis of heparins 
Organisation University of Edinburgh
Department School of Molecular and Clinical Medicine Edinburgh
Country United Kingdom 
Sector Academic/University 
PI Contribution Partners have shared data
Collaborator Contribution I have written analysis plan and analysed data
Impact Paper in Lancet Neurology
Start Year 2011
 
Description Individual patient data meta analysis of heparins 
Organisation University of Iowa
Department Department of Neurology
Country United States 
Sector Academic/University 
PI Contribution Partners have shared data
Collaborator Contribution I have written analysis plan and analysed data
Impact Paper in Lancet Neurology
Start Year 2011
 
Description Individual patient data meta analysis of heparins 
Organisation University of Nottingham
Department School of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution Partners have shared data
Collaborator Contribution I have written analysis plan and analysed data
Impact Paper in Lancet Neurology
Start Year 2011
 
Description Individual patient data meta analysis of heparins 
Organisation University of Oslo
Department Institute of Clinical Medicine
Country Norway 
Sector Academic/University 
PI Contribution Partners have shared data
Collaborator Contribution I have written analysis plan and analysed data
Impact Paper in Lancet Neurology
Start Year 2011
 
Description Natural language processing for brain imaging reports 
Organisation University of Edinburgh
Department School of Informatics Edinburgh
Country United Kingdom 
Sector Academic/University 
PI Contribution A collaboration to determine whether brain imaging features in radiology reports can be identified by natural language processing. I have identified a means of obtaining scans from routinely collected data, and built a case for their use with epidemiological datasets.
Collaborator Contribution Natural language processing
Impact None yet
Start Year 2014
 
Description Stroke Thrombolysis Trialists Collaboration 
Organisation Boehringer Ingelheim
Country Germany 
Sector Private 
PI Contribution Contributed to papers and editing of data
Collaborator Contribution Statistical analysis and hosting of dataset
Impact Study protocol published in International Journal of Stroke First manuscript in preparation
Start Year 2012
 
Description Stroke biomarkers University of London 
Organisation Imperial College London
Country United Kingdom 
Sector Academic/University 
PI Contribution I have contributed patient samples
Collaborator Contribution Partners are analysing the samples for blood biomarkers of stroke
Impact None
Start Year 2011
 
Title iPhone App for presentation of the results of predicted outcome of stroke patients to junior doctors 
Description We aim to present the results of predictions about the prognosis of stroke patients to junior doctors on a smartphone. We have developed a smartphone application that is in its final stages of development and will go to the iStore in early 2012. 
Type Diagnostic Tool - Non-Imaging
Current Stage Of Development Refinement. Non-clinical
Year Development Stage Completed 2011
Development Status Under active development/distribution
Impact As yet none, other than the experience gained by one of the programmers in the department. 
 
Title iPhone App for public education about the FAST test for the early identification of stroke 
Description An iPhone application to educate member of the public about the use of the FAST test. The programming aspects of this work have been supported b the CHSS (see the small grant section), in collaboration with NHS24 and the Scottish Ambulance Service. My time has been supported by my MRC Clinician Scientist Fellowship. 
Type Health and Social Care Services
Current Stage Of Development Refinement. Non-clinical
Year Development Stage Completed 2011
Development Status Under active development/distribution
Impact The development process has been important experience for one of the department's programmers in mobile computing. This work will be rolled out to the public in late 2011/early 2012 with possibility of further work with heart attack and other medical emergencies. 
 
Description ABN research day 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Talking to UK neurology registrars about the way into a career in research

Continued interest from neurology registrars in my research area. Excellent feedback.
Year(s) Of Engagement Activity 2014
 
Description Academy of Medical Sciences Developing a career in academic medicine 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Discussed working in large teams in a joint presentation with Prof. Phillpa Saunders

Interest from academic trainees in working in team based science, and publicising Academy's survey on team based science
Year(s) Of Engagement Activity 2014
URL http://www.acmedsci.ac.uk/more/events/developing-a-career-in-academic-medicine-edinburgh/
 
Description Autumn School, Edinburgh Neuroscience 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact Educating post-graduate researchers in careers and research methods. My involvement was to deliver a lecture, and planning a session

Continuing support to Neuroscience students in Edinburgh
Year(s) Of Engagement Activity 2011,2012
 
Description BMJ Masterclass 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact BMJ Stroke Masterclass. Invited to speak about work to 90 Stroke physicians in UK.

98% felt the talk was good or excellent.
Year(s) Of Engagement Activity 2014,2015
URL http://masterclasses.bmj.com/physician-courses/stroke
 
Description Development of a smartphone App for FAST test communication 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact We have developed an iPhone/Android telephone App with Chest Heart and Stroke Scotland to educate the public about the FAST test. The FAST test is a method for early identification of patients with stroke by members of the general public. It is due to be rolled out to the i Store and Google app store in early December 2011.

Rolled out, led to media coverage on Scottish TV and national newspapers, and featured in the MRC annual report. The app has been downloaded ~1,400 times.
Year(s) Of Engagement Activity 2011
URL https://play.google.com/store/apps/details?id=com.chss.fasttest&hl=en
 
Description Lecture on thrombolysis to Royal College of Physicians and Surgeons, Glasgow 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Education day in stroke and thrombolysis
Year(s) Of Engagement Activity 2016
 
Description School visit 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact 30 pupils talking about careers in research and medicine

Continuing interest from pupils and parents
Year(s) Of Engagement Activity 2014
 
Description World Stroke Day Public Lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact I lectured on access to medicines to prevent stroke as part of a WSO Stroke Day event, sponsored by Edinburgh Global Health Academy and Edinburgh Neuroscience

Education of Edinburgh public about the poor access to medicines. No specific metric.
Year(s) Of Engagement Activity 2015
URL https://www.eventbrite.co.uk/e/access-to-medicines-the-global-story-of-strokes-tickets-18848177406