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Summary
Lancet 2007; 370: 1432–42 Background The risk of recurrent stroke is up to 10% in the week after a transient ischaemic attack (TIA) or minor
Published Online stroke. Modelling studies suggest that urgent use of existing preventive treatments could reduce the risk by 80–90%,
October 9, 2007 but in the absence of evidence many health-care systems make little provision. Our aim was to determine the effect of
DOI:10.1016/S0140-
6736(07)61448-2
more rapid treatment after TIA and minor stroke in patients who are not admitted direct to hospital.
See Comment page 1398
Methods We did a prospective before (phase 1: April 1, 2002, to Sept 30, 2004) versus after (phase 2: Oct 1, 2004, to
See Lancet Neurol 2007;
6: 953–60
March 31, 2007) study of the effect on process of care and outcome of more urgent assessment and immediate
Stroke Prevention Research
treatment in clinic, rather than subsequent initiation in primary care, in all patients with TIA or minor stroke not
Unit, University Department of admitted direct to hospital. The study was nested within a rigorous population-based incidence study of all TIA and
Clinical Neurology, Radcliffe stroke (Oxford Vascular Study; OXVASC), such that case ascertainment, investigation, and follow-up were complete
Infirmary, Oxford, UK and identical in both periods. The primary outcome was the risk of stroke within 90 days of first seeking medical
(Prof P M Rothwell FRCP,
M F Giles MRCP,
attention, with independent blinded (to study period) audit of all events.
A Chandratheva MRCP,
L Marquardt MD, Findings Of the 1278 patients in OXVASC who presented with TIA or stroke (634 in phase 1 and 644 in phase 2),
O Geraghty MRCP, 607 were referred or presented direct to hospital, 620 were referred for outpatient assessment, and 51 were not
J N E Redgrave MRCP,
C E Lovelock FRACP,
referred to secondary care. 95% (n=591) of all outpatient referrals were to the study clinic. Baseline characteristics and
L E Binney BMBCh, L M Bull RGN, delays in seeking medical attention were similar in both periods, but median delay to assessment in the study clinic
F C Cuthbertson MCSP, fell from 3 (IQR 2–5) days in phase 1 to less than 1 (0–3) day in phase 2 (p<0·0001), and median delay to first
S J V Welch RGN, S Bosch, prescription of treatment fell from 20 (8–53) days to 1 (0–3) day (p<0·0001). The 90-day risk of recurrent stroke in the
F Carasco-Alexander MSc,
L E Silver MSc,
patients referred to the study clinic was 10·3% (32/310 patients) in phase 1 and 2·1% (6/281 patients) in phase 2
S A Gutnikov DPhil, (adjusted hazard ratio 0·20, 95% CI 0·08–0·49; p=0·0001); there was no significant change in risk in patients treated
Z Mehta DPhil) elsewhere. The reduction in risk was independent of age and sex, and early treatment did not increase the risk of
Correspondence to: intracerebral haemorrhage or other bleeding.
Prof Peter M Rothwell, Stroke
Prevention Research Unit,
University Department of Clinical
Interpretation Early initiation of existing treatments after TIA or minor stroke was associated with an 80% reduction
Neurology, Radcliffe Infirmary, in the risk of early recurrent stroke. Further follow-up is required to determine long-term outcome, but these results
Woodstock Road, Oxford have immediate implications for service provision and public education about TIA and minor stroke.
OX2 6HA, UK
peter.rothwell@clneuro.
ox.ac.uk
Introduction including aspirin,13 other antiplatelet agents,14–16 blood-
The risk of recurrent stroke in the week after a transient pressure-lowering drugs,17 statins,18 anticoagulation for
ischaemic attack (TIA) or minor stroke is up to 10%.1–3 atrial fibrillation,19 and endarterectomy for 50% or greater
About 150 000 suspected TIAs and minor strokes are symptomatic carotid stenosis.20,21 Assuming that these
referred to secondary care for assessment and investigation effects are independent, use of all of these interventions in
in England alone each year,4 and rates are similar in the appropriate patients would be predicted to reduce the
USA.5 These warning events provide a short window of long-term group risk of recurrent stroke by 80–90%.22
opportunity for prevention,6 but there is considerable Moreover, evidence from trials of treatment in acute stroke
variation in service provision, ranging from emergency and acute coronary syndromes suggests that the relative
inpatient care to non-urgent outpatient clinic assessment,7,8 benefits of several of these interventions are, if anything,
with little consensus about the most cost-effective likely to be even greater in the acute phase.23–28 However,
strategy.9,10 In the UK, it is recommended that patients are there are no large randomised trials of these, or any other
seen in specialist outpatient clinics,11 but many hospitals interventions, in the acute phase after TIA and minor
offer only a weekly clinic and about half of all patients in ischaemic stroke; this lack of evidence has undoubtedly
the UK wait more than 14 days to be seen, and have even contributed to the variation in service provision.
longer delays to investigation, and treatment.12 In 2002, in light of increasing evidence of the high early
Several treatments are effective in preventing stroke in risk of stroke after TIA,1,29 and of high rates of stroke
the long term after a TIA or minor ischaemic stroke, before assessment in an audit of referrals to our weekly
TIA clinic,30 we aimed to determine the effect of more indicated) were arranged during the following week. A
rapid treatment after TIA and minor stroke in patients report of the initial clinical assessment, with treatment
who are not admitted direct to hospital. Given the recommendations, was faxed to the primary-care
predicted benefits of early treatment, and emerging physician after the clinic (usually within 24 h), but no
evidence of substantial benefits of early endarterectomy treatment was given in the study clinic and no
for symptomatic carotid stenosis,31 we considered prescription was issued. However, patients were
randomisation to early versus delayed assessment and instructed to contact their primary-care physician as
treatment to be unethical and unfeasible. We therefore soon as possible.
instigated a rigorous observational study of the phased The treatment protocol recommended to the
introduction of early assessment and treatment (Early primary-care physician was tailored to the individual
use of EXisting PREventive Strategies for Stroke; patient but generally included: aspirin in patients not
EXPRESS), nested within a population-based study of all already on antiplatelet therapy (75 mg daily), or clopidogrel
incident and recurrent TIA and stroke in Oxfordshire, if aspirin was contraindicated; simvastatin (40 mg daily);
UK (Oxford Vascular Study; OXVASC).32,33 blood pressure lowering unless systolic blood pressure
was below 130 mm Hg on repeated measurement (either
Methods by increases in existing medication, or by commencement
Patients of perindopril 4 mg daily with or without indapamide
The methods of OXVASC and details of the study 1·25 mg daily); and anticoagulation as required. In
population have been reported previously.32,33 Briefly, the patients seen within 48 h of their event, or those seen
study population consisted of all 91 000 individuals, within 7 days who were thought to be at particularly high
irrespective of age, registered with 63 primary-care early risk,1 clopidogrel (75 mg daily, to be stopped after
physicians in nine primary-care practices in Oxfordshire, 30 days) was recommended in addition to aspirin. Brain
UK. In the UK, almost all individuals register with a imaging was required before starting combination
primary-care practice, which holds a lifelong medical antiplatelet treatment or anticoagulation after a minor
record. OXVASC was approved by our local research stroke.
ethics committee and began on April 1, 2002, after a In phase 2 (Oct 1, 2004, to March 31, 2007), we moved
3-month pilot to ensure reliable case ascertainment. This to a clinic at which no appointments were necessary, and
report concerns all events identified in the study at which treatment was initiated immediately if the
population in the first 5 years, with follow-up to June 30, diagnosis was confirmed. Thus, the mode of access to
2007. the clinic and time of treatment initiation were changed,
but recommendations on who should be referred to the
Procedures clinic were not. Primary-care physicians were requested
At the start of the EXPRESS study (April 1, 2002), we to send all patients directly to the study clinic each
introduced a daily TIA and minor stroke clinic to which weekday afternoon immediately after they presented to
collaborating primary-care physicians were asked to refer medical attention (ie, no written referral or appointment
all patients with suspected TIA and minor stroke in the was necessary). Patients were assessed in the same way
study population. However, in keeping with usual UK as in phase 1, but all those who were considered to have
practice, the clinic was appointment-based, with inherent had a TIA or stroke were given aspirin 300 mg to take in
delays in receiving referrals and contacting patients, and the clinic, together with a prescription for a 4-week supply
did not initiate treatment, but made treatment of any other study medication (using the same treatment
recommendations to the referring primary-care protocol as in phase 1) to start on the same day. A loading
physician. The EXPRESS study intervention was a dose of clopidogrel (300 mg) was also prescribed in cases
reduction in delay to clinic assessment and initiation of in whom this drug was initiated. A CT brain scan was
treatment in the study clinic from Oct 1, 2004 onwards. obtained during the clinic for patients with incomplete
Between April 1, 2002, and Sept 30, 2004 (phase 1), resolution of symptoms at the time of assessment to
primary-care physicians referred, by fax, any patient exclude intracerebral haemorrhage before giving aspirin,
they suspected had had a TIA or stroke but whom they clopidogrel, or anticoagulants. A report of the assessment,
did not consider required immediate hospital admission, investigations, and treatment given was faxed to the
to our daily TIA and minor stroke clinic. The study team primary-care physician as soon as possible after the clinic
contacted the patient at home (usually by telephone) to (usually within 24 h).
arrange a clinic appointment as soon as possible. The In both study periods, patients were assessed by a study
patient was seen in a daily (weekdays only) hospital physician in a standardised manner.32,33 Detailed data
outpatient clinic (or at home if too frail to attend were gathered on the times and methods of first contact
hospital), and brain imaging (usually CT) and ECG were with medical attention after the presenting event.34
obtained on the same day or shortly thereafter. Carotid Severity of stroke was assessed with the National
ultrasound imaging (all patients) and trans-thoracic or Institutes of Health Stroke Scale (NIHSS).35 All cases
trans-oesophageal echocardiography (when clinically were reviewed with the study senior neurologist (PMR)
and classified as TIA, stroke, or other condition by use of Although our primary interest in this study was in the
standard definitions.32,33 However, because of the potential outcome of patients referred to the neurovascular clinic,
inaccuracy in clinical diagnosis of TIA and to avoid any all patients presenting to medical attention with TIA or
bias due to possible changes in diagnostic practice over stroke in the study population were ascertained and
time, any referral to the study clinic that was thought followed up, irrespective of mode of presentation or
after assessment not to be a definite TIA but that went on referral (ie, all patients presenting to the emergency
to have a recurrent stroke within 90 days of clinic department, or referred for direct admission to hospital,
assessment was included in the analysis of recurrence or managed at home by the primary-care physician).
within 90 days of first presentation (this occurred in two Ascertainment was achieved as part of the OXVASC
cases in phase 1 and in one case in phase 2). study by several overlapping methods of hot and cold
pursuit, including prospective daily searches for acute
Phase 1 Phase 2 Total events and retrospective searches of hospital and
Whole population 634 644 1278 primary-care administrative and diagnostic coding data.
Presented with TIA 233 252 485 Details of the methods of ascertainment have been
Presented with stroke 401 392 793
published previously,32,33 and direct assessment of
Outpatient care 323 297 620
ascertainment has shown it to be complete.33,36
Referred to EXPRESS clinic 310 281 591
All patients in OXVASC were followed up by a research
Referred to other clinics 13 16 29
nurse or clinical research fellow after 1, 6, 12, and
24 months and asked about any new neurological
Presented with TIA 165 172 337
symptoms and any bleeding that had required medical
Presented with stroke 158 125 283
attention. Severity of bleeding events was classified as in
Hospital-based care 285 322 607
the CURE trial.26 Current medication was recorded and
Discharged from A&E department 33 54 87
resting blood pressure was measured twice, with
Inpatient care 252 268 520
measurements 5 min apart. In patients referred to the
Presented with TIA 56 67 123
study neurovascular clinic, data about the date of
Presented with stroke 229 255 484
prescription of all medications after the presenting TIA
Not referred to secondary care 26 25 51
or stroke were obtained from the collaborating
Presented with TIA 12 13 25
primary-care practices.
Presented with stroke 14 12 26
If a recurrent vascular event was suspected at a
Table 1: Number of patients seeking medical attention after a first event, follow-up visit, the patient was reassessed and investigated
stratified by place of initial referral, or by type of presenting event by a study neurologist. Details of all potential recurrent
strokes within 90 days of seeking medical attention,
All patients in study population Patients referred to EXPRESS clinic whether or not they had been seen in the neurovascular
clinic initially, were reviewed at the end of the study by an
Phase 1 (n=634) Phase 2 (n=644) Phase 1 (n=310) Phase 2 (n=281)
independent neurologist who was blinded to the phase of
Age (years) the study. The definition of recurrent stroke used in
<80 383 (60%) 376 (58%) 207 (67%) 189 (67%) OXVASC has been reported previously,2,37 and required a
≥80 251 (40%) 268 (42%) 103 (33%) 92 (33%) sudden new symptomatic neurological deterioration on a
Male sex 301 (47%) 299 (46%) 141 (45%) 132 (47%) background of stability or improvement after the
TIA 233 (37%) 252 (39%) 156 (50%) 160 (57%) presenting event. Gradual or stuttering progression after
Hypertension 365 (58%) 378 (59%)† 167 (54%) 164 (59%)¶ an initial event was not coded as a recurrent stroke.
Diabetes 74 (12%) 78 (12%)‡ 36 (12%) 37 (13%)¶ Strokes that occurred within 24 h of an initial TIA or
Previous myocardial 83 (13%) 74 (12%)‡ 36 (12%) 29 (10%)¶ minor stroke were included. If recurrence occurred
infarction before complete symptomatic resolution of the initial
Previous angina 114 (18%) 94 (15%)‡ 57 (18%) 42 (15%)¶ event, the initial event was coded as a stroke. The blinded
Previous PVD 59 (9%) 51 (8%)‡ 18 (6%) 20 (7%)¶ independent neurologist classified all potential recurrent
Prior antiplatelet 292 (46%)* 283 (44%)‡ 139 (45%) 109 (39%)¶ strokes as definite, probable, or not stroke. Probable
Prior statin 126 (20%)* 176 (28%)† 63 (20%) 89 (32%)¶ recurrent strokes were mainly sudden deteriorations
Smoking after a major acute stroke for which a clinical diagnosis
Current smoker 73 (12%)* 83 (13%)§ 42 (14%) 41 (15%)¶ of recurrent stroke had been made by the patient’s
Ex-smoker 267 (42%)* 268 (43%)§ 125 (40%) 120 (43%)¶ physicians but for which imaging evidence was equivocal
Never 293 (46%)* 277 (44%)§ 143 (46%) 118 (42%)¶ or imaging was unavailable.
Data are n (%). Data missing for *one case, †six cases, ‡three cases, §16 cases, ¶two cases. TIA=transient ischaemic
attack. PVD=peripheral vascular disease. Statistical analysis
The study denominator and rate of recurrence were
Table 2: Baseline clinical characteristics of all patients in the study population with first presentations with
defined from the point at which patients with TIA or
TIA or stroke during each study period, and of all patients who were referred to EXPRESS study clinic
stroke first sought medical attention (eg, contact with their
12
A
100
Phase 1 Phase 1
Phase 2 90
Phase 2
8 60
50
6 40
30
4 p=0·0001 20
10
2 0
0 B
100
0 10 20 30 40 50 60 70 80 90 90
Time (days)
D
Results 100
Table 1 shows the number of patients seeking medical 90
Cumulative proportion (%)
of first medical attention (table 3); 80 events were On aspirin and 30-day course of clopidogrel 26 (10%) 137 (49%) <0·0001
classified as definite and ten as probable (seven after On a statin 196 (65%) 233 (84%) <0·0001
major disabling strokes and three after TIA or minor On one or more blood-pressure-lowering drugs 187 (62%) 231 (83%) <0·0001
stroke). An analysis based on definite events alone is On two or more blood-pressure-lowering drugs 103 (34%) 168 (60%) <0·0001
shown in the webtable. The results of this analysis were Systolic blood pressure (mm Hg) 142 (20) 136 (21) 0·0019
qualitatively identical to our analyses with all 90 cases of Diastolic blood pressure (mm Hg) 80 (10) 75 (10) <0·0001
recurrent stroke; thus all analyses reported here are Time to carotid surgery n=17 n=15
based on all 90 probable or definite recurrent strokes. <7 days 0 (0%) 6 (40%) 0·006
There were also no qualitative differences between <30 days 2 (12%) 10 (67%) 0·001
analyses of 90-day rates of recurrence in patients Data are n (%), n/N (%), or mean (SD). *Analysis excludes patients who died before 30-day follow-up and seven
presenting with incident events versus that in all patients patients with incomplete data (five in phase 1 and two in phase 2).
(data not shown); the results presented here thus refer to
Table 5: Measures of process of care, assessed at 1-month follow-up, in all patients with TIA or stroke
all events.
who were referred to the study clinic
The risk of recurrent stroke within 90 days of first
presentation with TIA or stroke in the whole population
was significantly higher in phase 1 than it was in phase 2 There was no difference in the delay from the
(p<0·0001; figure 1 and table 3). Likewise, the 90-day presenting event to seeking medical attention in patients
risk of stroke in all patients in the study population subsequently referred to the study clinic between the
presenting with TIA was significantly higher in phase 1 two study periods (table 4). However, the median delay
than in phase 2 (p=0·0015; figure 1 and table 3). from seeking medical attention in primary care to
607 patients presented direct to emergency services assessment in clinic was 3 (IQR 2–5) days in phase 1,
(either via the emergency department or emergency compared with less than 1 (0–3) day in phase 2
ambulance, with or without first contacting primary (p<0·0001); the proportion seen within 6 hours was
care), or were already in hospital at the time of stroke significantly greater in phase 2 than it was in phase 1
(table 1). There were no differences in the baseline (p<0·0001, table 4). There were therefore fewer recurrent
clinical characteristics of these cases between the two strokes after presentation to primary care but before
study periods (data not shown) and the number of assessment in clinic in phase 2 (3/281) than there were
intracerebral haemorrhages was similar (32 in phase 1 in phase 1 (11/310; p=0·048).
and 34 in phase 2). There was no significant difference Of the 341 patients referred to the study clinic who
in the 90-day risk of recurrent stroke between phase 1 were not already taking antiplatelet treatment at
and phase 2 (table 3 and webtable). presentation, the primary-care physician initiated See Online for webtable
Of the 620 patients with TIA or stroke who were treatment before the clinic in 71 (45 in phase 1 and 26 in
referred to outpatient services during the study period, phase 2). Median time from seeking medical attention to
591 (95%) were referred direct to the study clinic (table 1). first prescription of one of the other treatments
The 29 cases referred to other clinics had mainly had recommended in the faxed letter from the study clinic to
ocular ischaemic events. The 591 referrals to the study primary care in phase 1 was 20 (IQR 8–53) days,
clinic with probable or definite TIA or stroke made up compared with a delay of 1 (0–3) day in phase 2
58% of the 1024 referrals of suspected events to the study (p<0·0001). The cumulative proportions of patients
clinic, and consisted of 316 TIAs and 275 minor strokes prescribed medication since first seeking medical
(including six patients with intracerebral haemorrhage; attention are shown in figure 3.
three in each study period). The median NIHSS score for The reduction in the 90-day risk of recurrent stroke in
minor strokes at the time of assessment in the study referrals to the study clinic was present for patients
clinic was 1 (IQR 0–3) in both study periods; 236 (86%) presenting with TIA and for those with stroke (TIA:
patients had a score of 3 or less, while 264 (96%) had a 16/156 in phase 1 vs 1/160 in phase 2; stroke: 16/154 vs
score of 5 or less. 5/121), for both sexes (men: 16/141 vs 2/132; women:
In patients referred to the study clinic, the risk of stroke 16/169 vs 4/149), and for patients of all ages (<70 years:
during the 90 days after presentation was significantly 11/100 vs 3/116; 70–79 years: 13/107 vs 1/73; ≥80 years:
lower in phase 2 than it was in phase 1 (2·1% vs 10·3%, 8/103 vs 2/92). Of the 17 patients in either phase who
p=0·0001; figure 2 and table 3). During the same period, were referred to the study clinic after presenting with a
there were three acute myocardial infarctions in phase 1 TIA and who had a stroke within 90 days of their
and one in phase 2, and seven deaths in phase 1 and four presenting event, 15 had an ABCD² score of 5 or more.
in phase 2. The overall risk of non-fatal stroke, myocardial Rather than decreasing gradually over the 5-year study
infarction, or death at 90 days was 11·9% (37/310) in period, the risk of recurrent stroke in patients referred
phase 1 and 3·6% (10/281) in phase 2 (p=0·0002). to the study clinic dropped substantially after the first
50
event, 210 (43·4%, data missing in one case) delayed
40
doing so for more than 24 hours. There was little
30 variation in occurence of TIA or minor stroke by day of
the week (data not shown), but patients were substantially
20 less likely to seek medical attention at the weekend
(figure 4, p<0·0001).
10
0 Discussion
Mon Tue Wed Thu Fri Sat Sun Our data indicate that urgent assessment and early
Day of the week initiation of a combination of existing preventive
treatments can reduce the risk of early recurrent stroke
Figure 4: Day of presentation for all patients with TIA or minor stroke in the study population who first after TIA or minor stroke by about 80%, and reduce the
sought medical attention via their primary-care physician total number of all early recurrent strokes in the whole
population by over half. Extrapolated across the UK
30 months of the study (9·3% [14/151] in months 1–15; population, this equates to the prevention of nearly
11·3% [18/159] in months 16–30; 2·5% [3/121] in 10 000 strokes per year.
months 31–45; and 1·9% [3/160] in months 46–60). Our study was not a randomised comparison, but it has
Early treatment did not increase the 30-day risk of produced a reliable estimate of the effect of urgent
bleeding events requiring medical attention in referrals to treatment of TIA and stroke, and should not be confused
the study clinic in phase 2. No symptomatic intracerebral with an historical controlled study. Historical control
or other intracranial haemorrhages were identified in studies use control groups that are assembled
either phase of the study, and there was no symptomatic retrospectively, with potential for both incomplete
haemorrhagic transformation of infarction. There were ascertainment of cases and selection bias. Such studies
three episodes of gastrointestinal bleeding in phase 1 (one can sometimes produce unreliable estimates of the
major and two minor by CURE trial criteria26) and four effects of interventions.38–40 By contrast, the control group
episodes in phase 2 (one major and three minor). There in our study (phase 1) was accrued prospectively, and
was one other episode of bleeding (menorrhagia) in included all patients presenting to medical attention in
phase 2 that necessitated medical attention. the whole study population, thus minimising any
Process of care in patients referred to the study clinic, potential for selection bias. Indeed, phase 1 of the study
assessed at 1-month follow-up, showed that those referred was itself a pre-planned prospectively assessed
in phase 2 were more likely to be taking a statin, to have improvement (ie, daily clinic) on usual secondary care in
been treated with aspirin and clopidogrel, and to be on the UK (ie, weekly clinic).
blood-pressure-lowering medication than those referred Because this study was nested in a rigorous and well
to the study clinic in phase 1 (table 5). Mean systolic and established population-based study of all incident and
diastolic blood pressures at 1 month were lower in recurrent TIA and stroke, with identical methods of case
phase 2 than in phase 1 (table 5). Similar numbers of ascertainment, diagnosis, investigation, and follow-up
patients had carotid endarterectomy for recently in both phases, we could reasonably reliably determine
symptomatic stenosis during the two periods, but surgery any clinically significant effect on outcome of the more
was done earlier in phase 2 than in phase 1 (table 5). rapid assessment and treatment in phase 2. Of particular
The number of outcome events was too small to allow importance, we could identify any temporal changes in
adjustment for all baseline characteristics, but adjustment referral patterns, patient characteristics, or other
for differences in premorbid use of statin and antiplatelet potential sources of bias, and assess the effect of the
drugs did not affect the results. Unadjusted hazard ratios clinic on the rate of recurrent stroke in the whole
for the rate of recurrence at 90 days in phase 2 versus in population, thereby minimising any potential selection
phase 1 were 0·20 (95% CI 0·08–0·48) for those or referral bias.
individuals referred to the study clinic and 0·40 There was little evidence of such bias. There was no
(0·26–0·63) for the whole population. The corresponding significant change in rates of referral to the clinic over
adjusted hazard ratios were 0·20 (0·08–0·49) for those the course of the study (table 1 and table 2), nor was there
referred to the study clinic and 0·41 (0·26–0·65) for the any change in the delay to seeking medical attention after
whole population. a TIA or minor stroke, or in the number of patients
to that seen between 1981 and 1986 in a population-based 1981–86 Phase 1 Phase 2
OCSP EXPRESS (2002–07)
study in the same primary-care practices as studied here
(figure 5)41—ie, the risk of early recurrent stroke without Figure 5: Risk of recurrent stroke during the 90 days after first seeking
urgent treatment had been stable before the study for at medical attention after an incident TIA or stroke in patients referred to the
least 20 years. Second, the rate of recurrence changed in study clinic in the Oxford Community Stroke Project (OCSP) compared with
that in patients with incident events referred to the study clinic in phase 1
October, 2004, immediately after the new clinic was and phase 2 of the EXPRESS study
introduced, rather than slowly over the 5 years of the Error bars are 95% CI.
study. Third, there was no evidence of any substantial
change in the characteristics of patients presenting with status, and severity of disease,52 as well as in their
TIA or stroke between the two periods, other than a small willingness to be randomised. By nesting our study in a
increase in the proportion that received premorbid statin rigorous population-based study of all TIA and stroke we
treatment, which was due mainly to re-presentation of avoided such selective recruitment. For example, a third
patients treated in phase 1. There was no significant of the patients treated in the study clinic were aged over
difference in premorbid statin use if the analysis was 80 years (and about 10% were over 90); most of these
confined to first presentations in the study period (data individuals would have been excluded from many trial
not shown). Moreover, the rate of recurrent stroke was protocols used in vascular disease.52 The data on the effect
unrelated to premorbid statin use, and a 10% absolute of the intervention on the whole population also facilitate
increase in use could account for only a small fraction of much more complete assessments of the effects of the
the 80% reduction in stroke risk observed.18 intervention on health economics and on public health.
Importantly, the observed reduction in risk of recurrent Our study does, however, have some shortcomings. In
stroke is also consistent with that predicted to result from particular, we do not know what the relative effect of each
use of the combination of treatments given.22 The low of the different treatments used was on the risk of
risk of stroke in phase 2 in patients with TIA who were recurrent stroke. One or more of the treatments could
referred to the study clinic is also entirely consistent with have been ineffective, but it is unlikely that any of the
data now emerging from other studies in which patients treatments were harmful, in view of the very low risk of
with TIA are treated urgently and intensively,42–44 whereas recurrent stroke and major bleeding in phase 2. Although
the high rate in phase 1 is consistent with similar studies more evidence from randomised trials is required for
in which patients were not treated urgently.41,45–48 some individual classes of drug, in view of the substantial
The large predicted effect size and our rigorous benefit of the combined treatment regime in phase 2 of
population-based sequential comparison approach made the EXPRESS study, it would probably be unethical to
randomisation less necessary than usual.49–51 Moreover, omit more than one element of the combination at a time
we did not consider randomisation of individuals to be in any future randomised comparison.
feasible—who would consent to possible randomisation Simply giving aspirin (with a loading dose of 300 mg)
to delayed treatment? Furthermore, we had insufficient more quickly after the presenting event probably
study primary-care practices to allow cluster accounted for a proportion of the benefit. The relative
randomisation, even if ethical approval could have been reduction in the 14-day risk of recurrent ischaemic
obtained. However, in certain respects our approach has stroke with aspirin in inpatient acute ischaemic stroke
produced results that are more useful than those that is about 30%,24,25 and could well be larger in patients
would be expected from a randomised controlled trial, with TIA or minor stroke. In patients with unstable
especially in relation to external validity.52 Most angina or non-Q wave myocardial infarction, initiation
randomised trials recruit only a small proportion of of treatment with a statin within 24–96 hours reduced
patients in the population with the disease of interest, the early risk of ischaemic stroke by about 50% compared
sometimes less than 1% and usually less than 10%,52 and with placebo,23 but benefit after TIA and minor stroke is
those recruited often differ from those not recruited in uncertain. The reduction in delays to carotid
relation to age, sex, ethnic origin, social class, educational endarterectomy in phase 2 will have substantially
improved the effectiveness of the procedure,21 but the of treatment in primary care. Even at 1-month follow-up
small proportion of patients operated on means that many patients had not yet received a prescription for a
this cannot have accounted for more than three or four statin or blood-pressure-lowering drug. Further research is
additional strokes prevented. required into the causes of this delay (eg, patient-related,
The greater use of clopidogrel in phase 2 was due to system-related, physician-related), but a policy of initiation
the higher proportion of patients seen within the first of treatment in secondary care, if not already given in
48 hours after TIA or minor stroke than in phase 1, when primary care, is clearly sensible in TIA and minor stroke.
patients are at very high risk of recurrence, and also Similar shortcomings in the speed of initiation of treatment
because we prescribed medication in the clinic rather and in the proportion of patients appropriately treated after
than simply making a recommendation to the primary TIA and stroke have been reported in North America and
care physician—ie, it was a direct consequence of the two elsewhere in Europe.8,10,46,56,57 Third, our results suggest that
changes to the study clinic that made up the study in patients with a recent TIA or minor stroke, a combination
intervention, rather than a confounding factor. There are of preventive treatments should be initiated as soon as they
some data from randomised trials to suggest that the seek medical attention, either in primary care or in the
combination of clopidogrel and aspirin might be more emergency department, with the exception of dual
effective in the acute phase after TIA and stroke than antiplatelet treatment before brain imaging. Any
either drug alone,28,53,54 but more evidence is required. inappropriate treatment of patients with non-vascular
More evidence is also needed on the effects of the conditions could be stopped after subsequent specialist
combination of aspirin and dipyridamole in the acute assessment.
phase after TIA and stroke, given the clear benefit over Finally, our results further highlight the need for
aspirin alone in the long term.15,16 More data from public education about the symptoms of TIA and minor
randomised trials on the risks and benefits of blood stroke and the need to seek medical attention urgently,
pressure lowering in the acute phase after TIA and minor which has been highlighted previously.34,58 A nationwide
stroke could also be required, depending on the results telephone survey of adults in the USA revealed
of ongoing randomised trials in the acute phase after that 3·2% recalled symptoms typical of TIA that were
major stroke. not brought to medical attention and, of those who
Another shortcoming is that we do not yet have reported a physician-diagnosed TIA, 36% did not recall
complete data on the management of all patients referred seeing a physician in the first 24 hours.58 A study of
directly to hospital. The high rate of early recurrent stroke 377 consecutive patients attending specialist TIA and
in these cases does not necessarily indicate a lack of early stroke clinics in Oxfordshire showed that 40% of those
or intensive treatment, especially in patients with major with minor stroke and 50% of those with TIA delayed
ischaemic stroke, recurrence after which might be less seeking medical attention for more than 24 hours.34
amenable to prevention. The proportion of patients with Only 45% of patients thought that the event was a
intracerebral haemorrhage was also higher in cases of medical emergency. This lack of a sense of urgency is
stroke that were referred to hospital than in outpatients. perhaps best illustrated by the dramatic fall-off in
The high rate of recurrence in hospital-referred patients patients seeking medical attention after TIA or minor
with TIA, who mainly self-referred to the A&E stroke at the weekend seen here (presumably not
department, is in part a result of the tendency for patients wishing to bother the on-call primary-care service).
with high-risk events (eg, motor weakness and long Having noted this occurrence during phase 1,34 we
duration) to present in this way.34 However, further study decided not to run the study clinic at weekends in
of process of care in this group is required. phase 2. Part of the problem with public education
Our results have several implications for the future about TIA and minor stroke has been the difficulty in
provision of clinical services for TIA and minor stroke. conveying a succinct message about how to recognise
First, proof that urgent assessment and treatment are an event because of the wide variety of potential clinical
highly effective in reducing the recurrence of stroke after manifestations. However, recent studies of the relation
TIA and minor stroke means that long delays to assessment between the nature of the clinical event and the early
in TIA clinics are no longer acceptable. Many health-care risk of stroke should allow public education to be simple
systems still provide care via weekly TIA clinics, audits of and more effectively focused.3,45
which usually identify long delays to assessment and high In conclusion, this rigorous population-based
rates of recurrent stroke before the clinic appointment.12,30,55,56 sequential comparison of all patients, irrespective of
Second, our results highlight the long delays to initiation age, presenting with TIA or minor stroke has shown
of treatment in primary care that can occur if treatment is that early initiation of existing treatments can prevent
not started in secondary care. The high rate of recurrence about 80% of early recurrent strokes. Further follow-up
in patients referred to the study clinic in phase 1 was clearly is required to determine long-term outcome, but these
a reflection of the fact that, even if patients sought medical results have immediate implications for service
attention immediately and were seen quickly in the clinic, provision and public education about TIA and minor
there were substantial delays to the subsequent prescription stroke.
37 Coull A, Rothwell PM. Under-estimation of the early risk of 49 Vandenbroucke JP. When are observational studies as credible as
recurrence after first stroke by the use of restricted definitions. randomized trials? Lancet 2004; 363: 1728–31.
Stroke 2004; 35: 1925–29. 50 Glasziou P, Chalmers I, Rawlins M, McCulloch P. When are
38 Sacks H, Chalmers TC, Smith H Jr. Randomized versus historical randomized trials unnecessary? Picking signal from noise. BMJ
controls for clinical trials. Am J Med 1982; 72: 233–40. 2007; 344: 349–51.
39 McKee M, Britton A, Black N, McPherson K, Sanderson C, Bain C. 51 Potts M, Prata N, Walsh J, Grossman A. Parachute approach to
Methods in health service research. Interpreting the evidence: evidence based medicine. BMJ 2006; 333: 701–03.
choosing between randomised and non-randomised studies. BMJ 52 Rothwell PM. External validity of randomised controlled trials: to
1999; 319: 312–15. whom do the results of this trial apply? Lancet 2005; 365: 82–93.
40 Concato J, Shah N, Horwitz RI. Randomised, controlled trials, 53 Diener H-C, Bogousslavsky J, Brass LM, et al, on behalf of the
observational studies, and the hierarchy of research designs. MATCH investigators. Aspirin and clopidogrel compared with
N Engl J Med 2000; 342: 1887–92. clopidogrel alone after recent ischaemic stroke or transient
41 Lovett J, Dennis M, Sandercock PA, Bamford J, Warlow CP, ischaemic attack in high-risk patients (MATCH): randomised,
Rothwell PM. The very early risk of stroke following a TIA. Stroke double-blind, placebo-controlled trial. Lancet 2004; 364: 331–37.
2003; 34: e138–40. 54 Kennedy J, Hill MD, Ryckborst KJ, et al. Fast assessment of stroke
42 Lavallée PC, Meseguer E, Abboud H, et al. A transient ischaemic and transient ischaemic attack to prevent early recurrence
attack clinic with round-the-clock access (SOS-TIA): feasibility and (FASTER): a randomised controlled trial. Lancet Neurol 2007;
effects. Lancet Neurol 2007; published online October 9. published online October 10. DOI:10.1016/S1474-4422(07)70250-8.
DOI:10.1016/S1474-4422(07)70248-X. 55 Widjaja E, Salam SN, Griffiths PD, Kamara C, Doyle C,
43 Cucchiara BL, Messe SR, Taylor RA, et al. Is the ABCD score useful Venables GS. Is the rapid assessment stroke clinic rapid enough in
for risk stratification of patients with acute transient ischemic assessing transient ischaemic attack and minor stroke?
attack? Stroke 2006; 37: 1710–14. J Neurol Neurosurg Psychiatry 2005; 76: 145–46.
44 Lavallée PC, Meseguer E, Cabrejo L, et al. TIA clinic: description 56 Scholte op Reimer WJ, Dippel DW, Franke CL, et al. Quality of
and first year experience. Cerebrovasc Dis 2007; 23 (suppl 2): 16. hospital and outpatient care after stroke or transient ischemic
45 Rothwell PM, Giles MF, Flossmann E, et al. A simple score (ABCD) attack: insights from a stroke survey in the Netherlands. Stroke
to identify individuals at high early risk of stroke after a transient 2006; 37: 1844–49.
ischaemic attack. Lancet 2005; 366: 29–36. 57 Mouradian MS, Majumdar SR, Senthilselvan A, Khan K, Shuaib A.
46 Gladstone DJ, Kapral MK, Fang J, Laupacis A, Tu JV. Management How well are hypertension, hyperlipidemia, diabetes, and smoking
and outcomes of transient ischaemic attacks in Ontario. CMAJ managed after a stroke or transient ischemic attack? Stroke 2002; 33:
2004; 1707: 1099–104. 1656–59.
47 Correia M, Silva MR, Magalhaes R, Guimaraes L, Silva MC. 58 Johnston SC, Fayad PB, Gorelick PB, et al. Prevalence and
Transient ischemic attacks in rural and urban northern Portugal: knowledge of transient ischemic attack among US adults. Neurology
incidence and short-term prognosis. Stroke 2006; 37: 50–55. 2003; 60: 1429–34.
48 Tsivgoulis G, Spengos K, Manta P, et al. Validation of the ABCD
score in identifying individuals at high early risk of stroke after a
transient ischemic attack: a hospital-based case series study. Stroke
2006; 37: 2892–97.