UOA04-11: Reduction of Stroke Risk by Risk Stratification and Urgent Intervention after a Transient Ischaemic Attack (TIA) or Minor Stroke
Submitting InstitutionUniversity of Oxford
Unit of AssessmentPsychology, Psychiatry and Neuroscience
Summary Impact TypeHealth
Research Subject Area(s)
Medical and Health Sciences: Clinical Sciences, Neurosciences, Public Health and Health Services
Summary of the impact
Research in Oxford by Rothwell and colleagues since 2000 has radically
changed how minor strokes and transient ischaemic attacks (TIAs) are
managed. First, the risk of a major stroke in days after a minor
stroke/TIA was found to be much higher than thought. In consequence, these
`warning' events were rebranded as a medical emergency in clinical
guidelines. Second, Rothwell showed that a delay in treating individuals
at high risk of major stroke substantially reduced the benefits. Third,
the Rothwell group developed a simple risk score (`ABCD system') to triage
high-risk individuals, showing that more urgent treatment reduced the
90-day risk of major stroke by 80%. This strategy has been implemented in
the National Stroke Strategy and NICE and international guidelines. In the
UK it is estimated to prevent 10,000 strokes per year, and to save the NHS
£200 million in acute care costs alone.
TIA and minor stroke comprise over 70% of all cerebrovascular events
(with major, disabling stroke accounting for the remainder). About 90% of
major strokes occur in patients who previously had a TIA or minor stroke.
The standard treatments aimed at preventing stroke include surgery to the
carotid artery (`carotid endarterectomy') and medical treatments with
drugs. Rothwell's research in Oxford since 2000 has focused on TIAs and
minor strokes, revealing their significance as precursors to major
strokes, and ways to identify and then decrease the risks of these
occurring by showing the benefits of earlier intervention.
Minor strokes/TIAs may herald an impending major stroke
Rothwell and colleagues showed that the risk of a major stroke soon after
a TIA or minor stroke had been greatly underestimated. They studied the
natural history of TIA and minor stroke in Rothwell's Oxford Vascular
Study and demonstrated that the 7-day risk of major stroke was about 10%
(Coull et al., 2004, cited in Section 3, and several other papers).
Identifying the patients at highest risk of early major stroke
Given this finding, it was important to identify who, amongst the 100,000
referrals with TIA per year, are at highest risk of an early major stroke.
Rothwell's group therefore developed the `ABCD system', a simple clinical
tool to identify the high-risk people and to prioritise them for treatment
(Rothwell et al., 2005). It was subsequently refined and validated (e.g.
Johnston et al., 2007).
Reducing delays in treatment after TIA reduces the risk of major
The above research revealed that there is a significant risk of a major
stroke soon after a TIA, and also provided a tool to identify those at
highest risk. In addition, Rothwell has shown that success in preventing
major strokes in people with TIAs is related to the delay to treatment:
First, the group demonstrated the need for greater urgency in
investigation and treatment of TIA and minor stroke in work on the risks
and benefits of carotid endarterectomy. Rothwell coordinated a pooled
analysis of individual patient data from the European Carotid Surgery
Trial and two other large randomised trials of carotid endarterectomy
versus medical treatment for symptomatic carotid stenosis (narrowing of
the artery). This demonstrated, for the first time, several important
interactions between clinical subgroups and treatment effects, notably
that the extent to which benefit from surgery falls with delay to
intervention (e.g. Rothwell et al., 2004).
Then, to determine the risks and benefits of more urgent treatment of TIA
and minor stroke, Rothwell and colleagues performed the EXPRESS Study
(Rothwell et al., 2007; See Section 4) — a population-based sequential
comparison study of the impact of acute assessment and treatment. As
predicted by their previous work, EXPRESS showed that urgent investigation
and treatment reduced the 90-day risk of major recurrent stroke by about
80%. By nesting a prospective "before versus after" study within a
rigorous population-based disease incidence study (Oxford Vascular Study),
with complete ascertainment and follow-up of all patients with TIA and
minor stroke in both phases, a reliable estimate of this effect was
obtained, and with good external validity.
Urgent interventions to prevent stroke are cost-effective
Subsequent health-economic analyses by Rothwell and colleagues
(Luengo-Fernandez et al., 2009) showed that urgent intervention reduced
the risk of disabling stroke and risk of hospitalisation, reducing overall
hospital bed-days by over two thirds, generating savings of £624 per
patient treated. Rolling the service out across the UK was estimated to
prevent about 10,000 strokes per year, saving the NHS up to £200 million
annually in acute care costs alone.
References to the research
Coull A, Lovett JK, Rothwell PM, on behalf of the Oxford Vascular Study.
Population based study of early risk of stroke after a transient ischaemic
attack or minor stroke: implications for public education and organisation
of services. BMJ 2004;328:326-328.
DOI:10.1136/bmj.37991.635266.44. 279 citations.
One of a series of papers by Rothwell and colleagues from 2000-2007
demonstrating the very high early risk of major stroke after TIA and
Rothwell PM, Giles MF, Flossmann E, Lovelock CE, Redgrave JNE, Warlow CP,
Mehta Z. A simple score (ABCD) to identify individuals at high early risk
of stroke after a transient ischaemic attack. Lancet 2005; 366:
29-36. DOI: 10.1016/S0140-6736(05). 259 citations.
Derivation and validation of the first ever risk score to identify
patients with TIA who are at high early risk of stroke.
Johnston SC, Rothwell PM, Nguyen-Huynh MN, Giles MF, Elkins JS, Bernstein
AL, Sidney S. Validation and refinement of scores to predict very early
stroke risk after transient ischaemic attack. Lancet
2007;369:283-92. DOI: 10.1016/S0140-6736(07)60150-0. 350 citations.
Independent validations of the clinical utility of the ABCD risk score.
Rothwell PM, Eliasziw M, Gutnikov S, Warlow C for the Carotid
Endarterectomy Trialists Collaboration. Effect of endarterectomy for
symptomatic carotid stenosis in relation to clinical subgroups and to the
timing of surgery. Lancet 2004;363:915-24. DOI:
10.1016/S0140-6736(03)12228-3. 555 citations.
Pooled analysis of data from three large randomised trials of carotid
endarterectomy versus medical treatment for symptomatic carotid
stenosis, demonstrating reliably that benefit from surgery was related
to the degree of carotid stenosis and hence the thresholds for
intervention. The study also revealed, for the first time, that benefit
from surgery falls with delay to intervention.
Rothwell PM, Giles MF, Chandratheva A, Marquardt L, Geraghty O, Redgrave
JNE, Lovelock CE, Binney LE, Bull LM, Cuthbertson FC, Welch SJV, Bosch S,
Carasco-Alexander F, Silver LE, Gutnikov SA, Mehta Z, on behalf of the
Early use of Existing Preventive Strategies for Stroke (EXPRESS) Study.
Effect of urgent treatment of transient ischaemic attack and minor stroke
on early recurrent stroke (EXPRESS study): a prospective population-based
sequential comparison. Lancet 2007; 370: 1432-42. DOI:
10.1016/S0140-6736(07)61448-2. 325 citations.
The first demonstration that urgent assessment and treatment of
patients with TIA or minor stroke substantially reduces the risk of
early recurrent stroke, with an 80% reduction in the 90-day risk.
Luengo-Fernandez R, Gray AM, Rothwell PM. Effect of urgent treatment for
transient ischaemic attack and minor stroke on disability and hospital
costs (EXPRESS study): a prospective population-based sequential
comparison. Lancet Neurol 2009;8:235-43.
DOI:10.1016/S1474-4422(09)70019-5. 41 citations.
Shows that urgent assessment and treatment of patients with TIA or
minor stroke using existing treatments is cost-saving, and assesses the
likely health-economic impact across the UK.
P. Rothwell (PI) "Development of simple prognostic tools to improve the
effectiveness of stoke prevention" MRC 01/03/06 - 01/03/09 £546K.
P. Rothwell (PI) "Oxford Vascular Study" . Dunhill Medical Trust 2006-12
P. Rothwell (PI) "Oxford Vascular Study: Phase 2" NIHR 2006-2011
P. Rothwell (PI) NIHR Senior Investigator Award (NIHR 2009 - 2014)
Rothwell was funded as an MRC Senior Clinical Fellow from 2000-5 and
HEFC-funded thereafter. Oxford colleagues include: Drs Coull,
Giles, Schulz, Flossmann, Lovelock, Chandratheva, Geraghty and Marquardt
were all Clinical Research Fellows. Dr Luengo-Fernandez is Senior
Researcher at Oxford University's Health Economics Research Centre. Dr
Silver is Study Coordinator of the Oxford Vascular Study, and Dr Mehta is
the Database Manager and Statistician.
Details of the impact
This underpinning research, mostly published since 2004, has rapidly and
profoundly affected how patients with TIA are viewed, investigated, and
treated, both in the UK and internationally.
More urgent assessment and investigation of TIAs
Prior to Rothwell's research, most guidelines suggested that patients
should be assessed and treated within four weeks of a TIA. After
publication of his research showing that the early risk of stroke after a
TIA had been substantially underestimated, guidelines rapidly changed,
markedly increasing the urgency with which investigation and treatment was
recommended. This was first highlighted in the 2007 Department of Health
National Stroke Strategy, which endorsed the "medical emergency" status of
TIA and minor stroke (Section 5, Source 1). It was then adopted in the
2008 NICE guidelines for stroke, which remain in force, and also in the
latest guideline from the Royal College of Physicians (2012). All now
recommend assessment of high-risk patients as an emergency, with
completion of initial investigations within 24 hours (Sources 2-5).
More effective identification of high-risk patients
Use of the ABCD system, developed and validated by Rothwell and
colleagues to triage and identify patients at highest risk of major stroke
after a TIA or minor stroke, is now recommended in all UK guidelines
(Sources 2-5). Indeed, the ABCD score is used to define the risk: `People
who have had a suspected TIA who are at high risk of stroke (that is,
with an ABCD score of 4 or above)...'. (NICE stroke guideline CG68,
p8; Source 2).
More urgent surgical treatment of TIAs
Rothwell's related work, notably from the EXPRESS study, showing benefits
of early intervention in prevention of stroke also rapidly changed
clinical guidelines, being included in the National Stroke Strategy and
the 2008 NICE guidelines (Sources 1 and 2). The guidelines also stipulate
that carotid endarterectomy should be performed within 48 hours or 14 days
of the presenting TIA or stroke (depending on its severity). To see
whether these recommendations are being met, Rothwell and colleagues set
up the UK National Carotid Endarterectomy Audit — an ongoing national
audit in collaboration with the Royal College of Physicians and the
Vascular Surgical Society. Repeated audits have shown that delays to
endarterectomy have been substantially reduced across the UK; for example,
in the early 2000s the average delay was over 3 months; by 2009-10 it was
21 days; by 2010-11 it had fallen to 15 days (Royal College of Physicians,
2012 [Source 5]; Mayor, 2012 [Source 6]).
The UK impacts affecting clinical guidelines for triage, investigation
and treatment are mirrored by similar recommendations from major
international guidelines, including the US National Stroke Association
(2006, 2011) and the European Stroke Association (2008), both of which
remain in force. Both cite Rothwell's work as evidence leading to their
guidance (Sources 7-9).
Overall, implementation of the guidelines that have resulted from the
work of Rothwell and his team has benefitted groups along the entire
healthcare supply chain, resulting in changes to GPs' practice and
hospital services through adoption of the NICE guidelines, reducing burden
on the NHS for acute care of major recurrent stroke. The findings have
also had a similar impact on clinical guidelines in Europe, USA and many
Sources to corroborate the impact
Impacts on how TIAs/minor strokes are investigated and managed in the
Department of Health. National Stroke Strategy 2007.
This influential Strategy cites Rothwell's research in several areas:
regarding the risks of stroke after a TIA (p22); the reduction in stroke
risk which early intervention produces (p23, 25), and the value of
identifying high-risk groups (p24). The work forms the Rationale for the
quality markers as to how TIAs should be assessed (QM5) and treated
(QM6) by the NHS. [The document is no longer on an active website; it
has been archived and is available on request].
National Institute for Health and Clinical Excellence: Stroke:
Diagnosis and initial management of acute stroke and transient
ischaemic attack (TIA). NICE clinical guidance 68.
The full version of the guidelines show that Rothwell's work was drawn
on heavily (e.g. in showing risks of early stroke, and the value of the
ABCD system), and rated as high-quality evidence, in coming to their
recommendations about rapid recognition and treatment of TIAs.
Royal College of Physicians Intercollegiate Stroke Working Party.
National clinical guideline for stroke, Fourth edition, 2012.
These detailed guidelines cite Rothwell group papers as the basis for
their recommendations about initial diagnosis of acute TIA (pp39-40),
for management of TIA (pp42-43), for identifying risk factors for
subsequent stroke (pp61-62), and for the role of carotid endarterectomy
in treatment of TIA (pp72-73).
NHS choices: www.nhs.uk/NHSEngland/NSF/Pages/Nationalstrokestrategy.aspx
Public webpage which summarises NICE guidance, noting: `a TIA is a
sign that you may be at risk of a more serious stroke...seek medical
help by calling 999 immediately.'
Royal College of Physicians Clinical Standards Department. UK
Carotid Endarterectomy Round 4 Public Report, 2012.
Latest of several recent audits, showing that the average delay to
carotid endarterectomy is falling in the UK year-on-year, reflecting the
recommendations of the National Stroke Survey, and NICE guidelines. It
also recommends consideration of closing units with excessive delays.
- Mayor S. Services with excessive delays in delivering carotid
endarterectomy should close, recommends audit. British Medical Journal
2012; 345:e5641. doi: 10.1136/bmj.e5641. Brings the above audit and its
recommendations to a general medical audience.
- Johnston SC, Nguyen-Huynh MN, Schwarz ME, et al. National Stroke
Association guidelines for the management of transient ischemic
attacks. Annals of Neurology 2006;60:301-313. These leading (and
current) American guidelines cite Rothwell's studies as being the major
or key data underpinning their recommendations in two areas: that TIAs
should undergo rapid assessment and investigation, and regarding the use
of carotid endarterectomy.
- Johnston SC, Albers GW, Goerlick PB, et al. National Stroke
Association recommendations for systems of care for transient ischemic
attack. Annals of Neurology 2011; 69: 872-877. Linked to the above
guideline, these systems-of-care guidelines cite Rothwell's work as
underpinning their guidance for the use and organisation of out-patient
services for management of TIAs.
European Stroke Organisation. Guidelines for management of
ischaemic stroke and transient ischaemic attack 2008.
Cerebrovascular Diseases 2008;25:457-507. These guidelines cite
references by Rothwell's group as `important' in their recommendations
regarding emergency management of TIAs, and the role of carotid