Introduction
The incidence of TIA has been estimated as ranging from 20,000 to 90,000 in the
UK,9,173 and from 200,000 to 500,000 in the USA.169,170 The risk of recurrent stroke after TIA is high,
especially during the first week after the index event (see Chapters 1 and 3).121 The benefit of medical therapy to prevent
recurrent stroke after TIA is greatest if given as early as possible after
TIA.24,122,153 Likewise, the benefit of endarterectomy for symptomatic carotid
stenosis is highest when performed within 2 weeks after the index event and
falls rapidly with increasing delay.171 A deferred intervention would be futile, or at least of much
reduced benefit, as the high-risk period without medical or surgical
intervention will have passed.10
Consequently, patients with TIA need a rapid comprehensive assessment to reduce
the short- and long-term risks of recurrent stroke and other vascular
conditions.
However, delays between the onset of symptoms and specialist assessment and
treatment have previously been reported in the UK172,173 and are confirmed in a survey conducted for this report (see
Chapter 8). These
delays would decrease the proportion of patients started on appropriate
secondary prevention treatment soon after the index event and before disabling
stroke occurs. At this point, the use of a clinical score to predict the early
risk of recurrent stroke after TIA emerges as a reasonable strategy for
identifying patients with the highest stroke risk, in whom a more urgent
clinical approach is needed. Assuming that a clinical score correctly predicts
the early stroke recurrence after TIA, its use would allow efforts and resources
to be concentrated on those with a higher risk, reducing the incidence of stroke
in this population.
Numerous clinical risk prediction scores have been developed all aiming to do the
same thing – identify patients at high risk of stroke to prioritise
services. However, the ABCD2 and related scores have achieved particular
prominence such that the ABCD2 score is recommended for use in UK stroke
prevention services67 to triage
the speed at which patients pass through clinics and access services. Hence,
some detail is worthwhile here as to how it initially developed and has
evolved.
A northern California study8
demonstrated that simple clinical variables were associated with the risk of
stroke at 90 days in patients with a diagnosis of TIA who were initially
admitted to an ED. Age, presence of diabetes mellitus, duration of episode
> 10 minutes, weakness and speech impairment during episode were
independently associated with the risk of stroke after TIA; the estimated risk
of further stroke was 34% in patients presenting with all five predictors. In
addition, a population-based study127 conducted in Canada showed that age, and diabetes mellitus
together with hypertension, were associated with a higher risk of stroke 1 year
after TIA. Subsequently, the ABCD score was created to predict the stroke risk
during the first week after TIA using those clinical variables that have been
independent predictors of stroke.61 Derived from the OCSP population and validated in the OXVASC and
local TIA clinic populations, the score showed a fair accuracy in the prediction
of stroke risk at 7 days in these patients. A further validation of the ABCD and
California scores showed that both had a fair accuracy in the prediction of
early recurrent stroke at 2, 7 and 90 days.62 By combining the components of these two scores,
the authors generated a unified prediction tool, the ABCD2 score, in 2007
(Table
3).62
Details of the ABCD2 score (0–7)
The ABCD2 score includes age, blood pressure elevation on first assessment after
TIA, unilateral weakness, speech disturbance, duration of symptoms and diabetes
mellitus as clinical variables, and predicted the early risk of stroke in the
California and Oxford cohorts at 2, 7 and 90 days. The score classifies TIA or
minor stroke patients at low, moderate or high risk using cut-off points of
< 4, 4–5 and > 5. Recently, the ABCD2
risk prediction score has been adopted by many stroke prevention services in the
UK as part of NICE guidance67 to
prioritise patients who need urgent treatment. Stratification strategies to
effectively prioritise TIA patients have become essential because (1) it is very
challenging to assess every TIA/minor stroke patient within 24 hours of symptoms
onset and (2) approximately half of the patients referred to stroke prevention
services ultimately do not have a diagnosis of TIA or minor stroke (see
Chapters 7 and
8). For these
reasons, recent clinical guidelines have recommended the use of the ABCD2 score
as a tool to select patients for whom an urgent management is required.67 However, the ability of ABCD2
score to distinguish between TIA and non-TIA/mimics and to predict risk of
stroke early after TIA has been questioned. Some independent validation studies
of ABCD and ABCD2 scores have shown conflicting results in their discriminatory
ability to predict stroke,69,70,151,152 and, in particular, a number of studies have suggested that high
ABCD2 scores do not reliably identify patients with high stroke risk conditions,
such as the presence of severe carotid stenosis.132,170,174
The ABCD/ABCD2 scores have spawned numerous other variants (ABCD2-I, ABCD3,
ABCD3-I),147,150 which add either more clinical
or brain or carotid imaging variables, most of which have not been tested
independently. Numerous variations may be causing confusion. For example, there
is no consensus on the best ABCD2 cut-off for stratifying the risk of stroke and
select patients for whom an urgent assessment is needed. Clinical guidelines
issued by the AHA, for example, advocate admission to hospital and early
assessment/treatment for patients with an ABCD2 score of
≥ 3,17 whereas
national guidelines in the UK recommended a specialist assessment and
investigation within 24 hours of symptoms for patients with an ABCD2 score of
≥ 4 and within 1 week for those patients with an ABCD2 score of
< 4.67
The aim of this systematic review was to evaluate all existing evidence on the
performance of the ABCD2 prediction score to predict stroke recurrence in
patients at high risk (score ≥ 4) and low risk (score of
< 4) of stroke, i.e. at cut-off points used in current clinical
guidelines.67
Methods
Objectives
We followed the PRISMA guidelines for systematic reviews of observational
studies to conduct this review.175 We aimed to identify all published studies in which ABCD2
score was used to predict risk of stroke among patients with TIA and/or
minor stroke irrespective of the clinical setting or type of study design
and that reported on the actual rate of recurrent stroke.
Identification of studies
We searched indexed records which appeared in MEDLINE (Ovid) from January
2005 to November 2011. The choice of this time period reflected the
introduction of the ABCD prediction score into clinical practice (even
although the ABCD2 score was published for the first time in 2007, we
adopted an over-inclusive approach and searched the literature from 2005
when the ABCD clinical prediction score was originally developed). The
MEDLINE search strategy included both subject headings (MeSH terms) and text
words for the target condition (e.g. stroke, TIA, minor stroke) and the
prediction score under consideration (ABCD). We did not apply any language
restrictions. We adapted the MEDLINE search to search EMBASE. In particular,
we ‘translated’ the MEDLINE MeSH terms into the
corresponding terms available in the Emtree vocabulary. The searches were
initially run in November 2010, and updated in November 2011. Full details
of both the MEDLINE and the EMBASE search strategies are presented in
Appendix 1.
We imported all citations identified by the MEDLINE and EMBASE search
strategies into the Reference Manager bibliographic database. We
hand-searched all proceedings of the International Stroke Conference (2011)
and the European Stroke Conference (2011, 2012). We also contacted experts
in the field and perused the reference lists of all relevant articles to
identify further published studies for possible inclusion in the review.
Only full-text articles were deemed suitable for inclusion.
Inclusion/exclusion criteria
One review author (MB) examined the identified titles and abstracts, and
retrieved all potentially relevant citations in full. Full-text articles
were retained if they studied the application of the ABCD2 score in cohorts
of TIA and minor stroke patients and reported early risk of stroke assessed
at 7, 90 and > 90 days. Studies that did not consider the
incidence of further stroke in TIA/minor stroke patients; assess patients by
means of the ABCD2 score; classify patients at high and low risk according
to the cut-off score of 4; or report original data were excluded.
Quality assessment and data extraction
Two review authors (MB, HM) independently conducted data extraction and
review the methodological quality of selected studies. Disagreements were
resolved by discussion or referred to a third author (JMW) if necessary. We
recorded data on study methods (e.g. setting, study design) characteristics
of patients (first vs. recurrent TIA) and outcomes (stroke events at 7, 90
and > 90 days). We also collected information on the
following methodological aspects, which we considered more likely to
introduce potential biases: prospective compared with retrospective study
design, data source for cohort identification (e.g. registries, databases,
medical notes), patients’ selection criteria, spectrum of disease
severity, definition of TIA, timing of clinical assessment, evaluating
clinicians, and method of outcome ascertainment (active vs. passive).
Data synthesis
For each study we calculated the total number of patients with an ABCD2 score
of > 4 and < 4, and the proportion of
patients in each ABCD2 dichotomised category suffering a recurrent stroke at
7, 90 and > 90 days. The pooled risks of stroke for ABCD2
score of > 4 and < 4 at 7, 90 and
> 90 days were calculated by means of univariate
random-effects meta-analyses with within-study variance modelled as
binomial. The discriminative ability of the ABCD2 cut-off score of 4 for
stroke risk at 7, 90 and > 90 days was evaluated either by
bivariate ROC curve random-effects meta-analyses or by random-effects
univariate meta-analyses. We analysed all studies regardless of whether they
reported recurrent stroke at only 7 or 90 days, and also restricted the
analysis to just those studies that reported recurrent stroke at both 7 and
90 days, the latter to reduce the impact of some methodological differences
between studies. We calculated estimates of sensitivity, specificity,
positive and negative predictive values for a hypothetical cohort of 1000
TIA patients and expressed the proportion with recurrent stroke per 1000
patients assessed to improve the clinical relevance of the results. We used
the statistical software R version 2.14.2 for our analyses.
Results
Number of included/excluded studies
The electronic searches identified 3406 citations. Of these, we considered 59
reports to be potentially relevant and retrieved the full-text articles for
detailed assessment. Hand-searching of reference lists and of recent issues
of Stroke journal (not yet indexed in MEDLINE) resulted in
a further two reports to be included. We subsequently excluded 33 articles.
The most common reason for exclusion was that the study did not provide data
in sufficient detail to allow calculation of the ABCD2 score for above and
below 4. Twenty-six studies published in 28 reports fulfilled our inclusions
criteria ().
Thirteen were observational prospective cohort studies and 13 were
observational retrospective cohort studies. The included studies ranged in
size from 69 to 1679 patients, and the total number of TIA/minor stroke
patients assessed was 12,586.
Identification and selection of studies.
Characteristics of included studies
The methodological characteristics of the individual studies are shown in
Table
4.
Methodological characteristics of ABCD2 included studies
All studies used a time-based definition of TIA as opposed to the recently
new proposed tissue-based definition.176
Four studies assessed population-based cohorts,132,140,144,151 three studies
hospital-based cohorts,142,155,160 nine studies patients from
EDs,87,134,135,143,149,153,158,162,163 and 10
studies patients from specialist stroke or neurology units.62,137–139,145,146,150,152,164,177
In 15 studies the ABCD2 score was derived directly by patient assessment,
whereas in the remaining 11 studies it was retrospectively calculated from
medical notes.
Timing of patient assessment after symptom onset varied across studies. In
seven studies ,TIA patients were assessed within 24 hours of symptoms onset,
in four studies within 48 hours, in one study within 72 hours, and in two
studies within 7 days. Another three studies reported that ‘patients
were assessed as soon as possible after the event’ but did not give
a time, and another study stated that the median time from symptoms onset
was 15 days. Eight studies did not clearly provide this information (see
Table
4).
Most of the studies included only patients with a definite or confirmed TIA
by a neurologist/stroke physician and excluded TIA mimics. TIA diagnosis was
made by a neurologist in 14 studies, by an emergency medicine physician in
six studies, initially by an emergency medicine physician and subsequently
confirmed by a neurologist in two studies and by a stroke physician in
another two studies; The status of the diagnosing physician was not reported
in the remaining two studies.
Little information was available on patients with carotid stenosis or use of
endarterectomy. Similarly, information on how many TIA patients received
secondary prevention drugs was rarely reported in the included studies. Only
five studies stated that approximately 45–50% of TIA patients were
administered antithrombotic therapy,143,152,153,158,162 and another study that 15% of patients received
aspirin.149
Ascertainment of stroke events after TIA was carried out by face-to-face
patient assessment or telephone interviews in 17 studies, by medical records
in five studies, by mixed methods (i.e. both telephone interviews and
medical records) in three studies, and was not clearly reported in one study
(see Table 4).
Six cohorts reported only stroke events at 7 days,87,132,138,140,142,144 seven studies at 90 days,134,135,145,153,162,164,177 10
studies reported stroke events both at 7 and 90 days,62,137,139,143,149–152,158,163 and three
studies reported stroke events at > 90 days.146,155,160
Main findings
Considering all 16 studies that reported stroke events at 7 days, the total
number of TIA patients with an ABCD2 score of ≥ 4 was
4590/6920 (66%) and the total number of recurrent strokes at 7 days was 488.
In contrast, the total number of TIA patients with an ABCD2 score of
< 4 was 2330/6920 (34%) and the total number of recurrent
strokes at 7 days was 76.
In the 19 studies reporting stroke events at 90 days, the total number of TIA
patients with an ABCD2 score of ≥ 4 was 6294/9849 (64%), and
the total number of recurrent strokes at 90 days was 544 (Table 5). In contrast,
the total number of TIA patients with an ABCD2 score of < 4
was 3555/9849 (36%) and the total number of recurrent strokes at 90 days was
80.
Studies results according to the ABCD dichotomised score
(≥ 4 and < 4)
In the three studies146,155,160 reporting stroke events at
> 90 days, 736/1073 (69%) patients with an ABCD2 score of
≥ 4 experienced a total of 152 recurrent strokes. In
contrast, 337/1073 (31%) TIA patients with ABCD2 score of
< 4 had a total of 44 recurrent strokes.
The corresponding pooled risks of stroke for patients with ABCD2 score of
> 4 and < 4 at 7, 90 and
> 90 days are shown in Table 6.
Pooled stroke risks for ABCD2 dichotomised score at 7, 90 and
> 90 days for all included studies
The pooled risks of stroke for patients with an ABCD2 score of
> 4 and < 4 at 7, 90 and
> 90 days for all included studies are shown in
–.
ABCD2 score of ≥ 4 and risk prediction at 7 days: all
included studies.
ABCD2 score of ≥ 4 and risk prediction at
> 90 days: all included studies.
Many studies presented their results as accuracy of stroke risk prediction
expressed as the area under receiver operating characteristic curve (AUROC)
analyses. For completeness, we summarise the published area under the curve
(AUC) values and 95% CI for stroke risk at 7 and 90 days in Table 7. We list these
in order of publication year as it might be expected that patients would
have been assessed more rapidly after TIA/minor stroke in the more recent
studies (owing to greater awareness of the importance of seeking medical
attention rapidly, better organised clinics, faster services, fewer
recurrent strokes missed) and that this might have had some impact on the
early stroke recurrence rate (higher rates in more recent studies) and in
turn on the performance of risk prediction scores. However, there is no
obvious trend in either the 7- or 90-day stroke risk or in the performance
of the ABCD2 score in more recent years compared with earlier years, even
allowing for the republication of some earlier data sets among later
meta-analytic studies.
ABCD2 score and AUROCs for stroke prediction at 7 and 90 days
– show considerable
heterogeneity between studies and wide CIs, which may reflect variation in
study methods or different populations of patients contributing to estimates
of recurrence at different times, as outlined in the results above, rather
than true differences in stroke rates at 7 and 90 days or in times to
assessment. A previous meta-analysis found that the predictive value for
7-day stroke risk was higher in studies using in-person or clinical records
to calculate the score than in studies with retrospective calculations of
the ABCD2 score from hospital records.178
To reduce the impact of any between-study heterogeneity, we considered
separately the 10 studies that provided data on stroke risk at both 7 and 90
days.62,137,139,143,149–152,158,163 The study by Asimos and
colleagues was published in two reports.136,143 Even although the same cohort of patients was studied in
both publications, data on risk of stroke at 7 days were reported in the
2010 publication, whereas data on risk of stroke at 90 days were reported in
the 2009 publication. The number of recurrent events at 90 days was
strangely low compared with that at 7 days (see Table 5). Therefore,
we excluded this study from further analyses to avoid introducing
conflicting or mismatched estimates and examined the remaining nine studies
that considered risk of stroke at both 7 and 90 days in the exact same
cohorts of patients. These nine studies included a total of 4291 patients.
Five of the nine studies identified patients retrospectively from review of
medical records or equivalent. These five studies included 2019 patients,
47% of the total data from studies providing information at both 7 and 90
days. In these nine studies, the total number of TIA patients with an ABCD2
score of ≥ 4 was 2719/4291 (63%), and the total number of
recurrent strokes at 7 days and 90 days was 176 and 264, respectively. In
contrast, the total number of TIA patients with an ABCD2 score of
< 4 was 1572/4291 (37%), and the total number of recurrent
strokes at 7 and 90 days was 29 and 44, respectively. The pooled stroke risk
at 7 and 90 days for these nine studies is shown in Table 8 (these studies
did not provide data on stroke risk after 90 days).
Pooled stroke risks for ABCD2 dichotomised score for the nine studies
that reported data at both 7 days and 90 days
The pooled sensitivity and specificity estimates for the ABCD2 score of
≥ 4 for predicting risk of stroke at 7 and 90 days are shown
in Table 9.
Sensitivity and specificity estimates for ABCD2 score
≥ 4 for the nine studies that provided recurrent
stroke rates at 7 and 90 days after TIA/minor stroke
Forest plots for the proportion of TIA/minor stroke patients with recurrent
stroke at 7 days and ABCD2 score of > 4 and
< 4 are shown in and respectively, whereas forest plots
for the proportion of patients with recurrent stroke at 90 days and ABCD2
score of > 4 and < 4 are shown in
and ,
respectively. Results from the nine studies that provide stroke risk at both
7 and 90 days (see and : ABCD2 ≥ 4 and stroke
recurrences), show reduced heterogeneity compared with those from all
identified studies (see and ). This suggests that as yet undefined methods
differences between studies were the most likely sources of the considerable
heterogeneity between studies rather than true differences in rates of
recurrent stroke after TIA.
Proportion of patients with an ABCD2 score of > 4 who
have a stroke at 7 days from the subset of nine studies that
provided data at both 7 days and 90 days.
Proportion of patients with an ABCD2 score of < 4 who
have a stroke at 7 days from the subset of nine studies that
provided data at both 7 days and 90 days.
Proportion of patients with an ABCD2 score of
> 4 who have a stroke at 90 days from the subset of
nine studies that provided data at both 7 days and 90 days.
Proportion of patients with an ABCD2 score of < 4 who
have a stroke at 90 days from the subset of nine studies that
provided data at both 7 days and 90 days.
ABCD2 score of ≥ 4 and risk prediction at 90 days:
all included studies.
ABCD2 and proportions of patients with tight carotid stenosis
We examined all of the data on associations between the proportion of
patients with high or low ABCD2 scores and an ipsilateral tight carotid
stenosis, a key risk factor for recurrent stroke, to determine how many
patients with tight carotid stenosis might have their investigations delayed
and be at increased risk of stroke through having a low ABCD2 score. Four
studies provided some data on carotid stenosis by ABCD2 score.132,151,180,181
Ipsilateral carotid stenosis of > 50% was more frequent in
patients with ABCD2 score of ≥ 4 but was not negligible in
patients with ABCD2 score of < 4. In the SOS-TIA study (SOS
Transient Ischaemic Attack), which enrolled a total of 1176 TIAs, among 679
of patients with ABCD2 scores of < 4, 9%, 6% and 8% of patients,
respectively, had carotid stenosis of > 50%, AF or some
other high-risk factor requiring immediate attention, compared with 14%, 11%
and 10% of patients, respectively, among 497 with ABCD2 score of
≥ 4.180
Basically, one-fifth of patients with an ABCD2 score of < 4
had a serious risk factor and one-third of patients with an ABCD2 score of
≥ 4.180
In a further analysis of the SOS-TIA data, the 90-day stroke rate was 3.4%
in patients with ABCD2 score of ≥ 4, 3.9% in patients with
ABCD2 score of < 4 and carotid stenosis or other key risk
factors, and 0.4% in patients with ABCD2 score of < 4
without key risk factors.164
In another study assessing 220 TIAs, 11%, 22% and 22%, respectively, of 55
patients with ABCD2 scores of < 4 had carotid stenosis of
> 50%, AF or both, compared with 14%, 18% and 18%,
respectively, of 165 patients with an ABCD2 score of
≥ 4.132
In a cohort of 443 specialist-confirmed TIAs, 23% of 169 patients with ABCD2
scores of < 4 had carotid stenosis of > 50%,
compared with 25% of 274 patients with ABCD2 score of
≥ 4.151
Another study that assessed TIA patients with an ABCD2 score of
≥ 5, showed that the recurrent stroke rate at 90 days
increased with increasing degree of carotid stenosis.182 Similarly, in a cohort of 40 patients with
specialist-confirmed carotid territory TIA, 15% of 233 patients with ABCD2
scores of < 4 had carotid stenosis of > 50%,
compared with 13% of 507 patients with an ABCD2 score of
≥ 4.181
In short, the ABCD2 score does not predict carotid stenosis.
ABCD2 scores in transient ischaemic attack/minor stroke mimics
There was little information on ABCD and related scores in all patients
presenting to stroke clinics with suspected TIA or minor stroke (i.e.
including mimics), as most of the above studies specifically excluded
non-TIA/minor stroke patients by specialist neurological examination and did
not always differentiate TIA from minor stroke. In a retrospective cohort of
3646 patients presenting to an outpatient TIA service, of whom 1769 (48.5%)
did not have TIA, a positive association was found between low ABCD2 scores
and the diagnosis of non-CV events; after dichotomisation at 0–1 or
0–2 scores, the positive predictive values of ABCD2 score for a
non-CV diagnosis were 0.81 and 0.74, respectively.72 The analysis of the AUC for use of the score
in the diagnosis of non-CV patients suggested a reasonable accuracy [0.74
(95% CI 0.73 to 0.76)].72 In a
prospective cohort (north Dublin TIA study), the diagnostic usefulness of
ABCD2 score to distinguish TIA or minor stroke from non-CV events was also
assessed in 594 patients.183
Mean ABCD2 score decreased across diagnostic groups [4.9, standard deviation
(SD) 1.4 for minor ischaemic stroke; 3.9, SD 1.5 for TIA and 2.9, SD 1.5 for
non-CV, p < 0.00001], as well the
proportion of patients with ABCD2 scores of ≥ 4 and
≥ 6, respectively. An ABCD2 score of ≥ 4 increased
the likelihood of a final diagnosis of confirmed TIA [odds ratio (OR) 2.8;
95% CI 2.0 to 3.9] and minor stroke (OR 8.4; 95% CI 3.8 to 18.9) compared
with non-CV diagnosis. Scores of ≥ 4 had 60.3% sensitivity
and 64.6% specificity for discriminating TIA from non-CV diagnosis and 82.2%
sensitivity and 64.6% specificity for discriminating minor stroke from
non-CV diagnosis. However, significant proportions of patients with a CV
event (18% of minor stroke and 39% of TIA patients) had ABCD2 scores of
< 4, and 35% of those with non-CV diagnoses had an
intermediate or high ABCD2 score (≥ 4).183 In a retrospective review (medical records)
of 713 patients seen in 16 northern California EDs (from March 1997 to
February 1998) who received an initial diagnosis of TIA, 79 patients (10%)
had a final diagnosis of TIA mimic and 29 of them (41%) had an ABCD2 score
of ≥ 4.135
This indicates that, by placing over-reliance on the ABCD2 score, many true
TIAs or minor strokes (with lower scores) would be missed while a
substantial proportion of TIA mimics (35–41%) would be rapidly
investigated.
ABCD2 scores and prediction of number per 1000 with recurrent
stroke
Based on all available data for the ABCD2 score and predicted risk, we
calculated the number of recurrent strokes by low or high ABCD2 scores in a
hypothetical cohort of 1000 patients with probable or definite TIA attending
a stroke prevention clinic. This requires that all patients initially
referred to the TIA clinic as possible TIA/minor stroke have been filtered
out by clinical assessment, which would have to be performed by a stroke
physician or neurologist, as occurred in all published studies. We
restricted the analysis to data from the nine studies that provided data on
stroke at both 7 and 90 days. Among the 1000 selected probable or definite
TIA/minor stroke patients there would be 634 with an ABCD2 score of
≥ 4 and 366 with ABCD2 score of < 4, of whom
30 and 6, respectively would have a recurrent stroke within 7 days, and 52
and 10, respectively, would have a recurrent stroke by 90 days. These
numbers would shift substantially downwards if the starting population were
the actual unfiltered population of patients that are referred to stroke
prevention services with a suspected TIA/minor stroke,
including the large proportion (45%) of patients with a stroke mimic as
documented in the literature summarised in Chapter 7 and as found in the survey of UK
stroke prevention services summarised in Chapter 8. Even a theoretical analysis of
these data is substantially hampered by lack of information on the
distribution of ABCD2 scores in all patients presenting to stroke prevention
services. However, assuming that the neurologist was still filtering the
patients into those with mimics and those with probable or definite TIA,
then of the 1000 patients presenting to the TIA clinic, about 450, would
have a mimic, and 550 would have TIA or minor stroke. Among patients with
TIA/minor stroke, 349/550 would have ABCD2 score of ≥ 4 and
201/550 a core of < 4, of whom 16 and 5, respectively, would
have a recurrent stroke by 7 days, and 27 and 5 by 90 days. Among the 450
with a mimic, 35–41%135,183 (say 38%)
or 171 would have an ABCD2 score of ≥ 4 and 279 a score of
< 4, making a total of 520/1000 (52%) clinic attendees with
an ABCD2 score of ≥ 4, and 480/1000 48% with a score of
< 4.
Discussion
Our systematic review combined data from 26 cohorts including 12,586 patients
with TIA/minor stroke, representing all published studies to date on recurrent
stroke after TIA/minor stroke in patients dichotomised at the ABCD2 cut-off
point of ‘4’ as per UK National clinical guidelines. In terms of
applying the ABCD2 score in routine practice, the review highlights several
problems with the evidence that seems to have been overlooked previously and
mean that the performance of the score will not be the same in routine practice
as in these studies.
About half of the studies were retrospective, using patients identified
through case note review and/or an ABCD2 score calculated also
retrospectively from information derived from case notes or clinical
databases, including five of the nine studies (47% of patients) that
provided data on both 7- and 90-day recurrent stroke rate, rather than
prospective collection of new patients presenting to stroke prevention
services with the ABCD2 score assigned immediately in ‘real
time’ after clinical assessment. Retrospective studies are known
to be prone to numerous methodological biases that limit their
reliability.
Most studies focused on patients with a definite (neurologist-determined)
diagnosis of TIA/minor stroke, as opposed to patients with a possible
diagnosis of TIA/minor stroke or even the large number of non-TIA/minor
stroke patients who are referred to stroke prevention clinics. About 45%
of patients attending TIA/minor stroke clinics do not have a TIA/minor
stroke but have a mimic (see
Chapters 7 and
8). Two studies that provided relevant
data showed that about one-third of patients with non-CV diagnoses (35%
and 41%, respectively) had an ABCD2 score of ≥ 4. This
compares with one-fifth of minor stroke and 40% of true TIA patients who
have a ABCD2 score of < 4.
72,183 The immediate and obvious implication of these findings
is that the ABCD2 score should not be used in stroke prevention clinics
except after the patient has been confirmed as a definite TIA/minor
stroke by the examining stroke physician or neurologist, as it was not
derived in, nor has its performance been ascertained in, the patients in
whom it is being applied ‘at the front door’ by a
non-specialist before a diagnosis of definite TIA/minor stroke has been
made. It was not derived in patients with TIA/stroke mimics and
therefore should not be used in mimics or even possible TIA/minor stroke
patients. The equivalent for a drug would be testing the drug in an
randomised controlled trial (RCT) in a population of patients with the
disease that the drug was designed to treat (say thrombolysis for
ischaemic stroke) but then using the drug in a different population
(e.g. all stroke – including haemorrhagic and ischaemic stroke
– and stroke mimics) coming to a hospital/clinic, many of whom
did not actually have the disease that the drug was expected to treat
and therefore might not only be precluded from gaining any benefit but
could indeed be harmed by the intervention. This is an extreme example
but serves to make the point.
Even if it were not obvious that possible TIAs and TIA mimics had been
excluded from the studies, the high proportion of patients with ABCD2
scores of ≥ 4 (two-thirds or more across all studies and
time points) should immediately raise alarm bells. Predicting risk when
most of the patient population are regarded as high risk either
indicates a fundamental flaw in the score (or in the choice of the
cut-off point) or that the population is biased and not representative
of routine clinical practice. We suspect that all of these three
assumptions apply. These cohorts were highly filtered; the retrospective
case ascertainment and assigning of the ABCD2 score will have inflated
the number with risk points. Many people operating stroke prevention
clinics would not regard the majority of patients as being at such high
risk but rather most at low or moderate risk and only a few at high
risk. What is the rationale of a score developed to identify and triage
patients at high risk for rapid treatment if it suggests that most of
them are at high risk and thereby swamps the system, the exact opposite
of what it was supposed to achieve?
There is little evidence that the ABCD2 score picks out patients with
established markers of high risk, such as carotid stenosis,
164,181 supported by evidence that adding
carotid stenosis to the ABCD2 or any other clinical prediction score
(see
Chapter 5)
improves recurrent stroke prediction.
147,184 The high risk of early recurrent stroke after TIA or
minor stroke in patients with significant carotid stenosis is well
established.
66,128,182,185 Approximately 10–15% of patients with an ABCD2
score of < 4 have carotid stenosis of
> 50% or even > 70% (very similar to the
rate in patients with ABCD2 scores of ≥ 4) and should
therefore be referred for endarterectomy.
132,162,164,181 Notably, in a French
cohort, patients with TIA and ABCD2 score of < 4 had
similar 90-day risk of recurrent stroke (3.9%) as those with a score of
≥ 4 (3.4%) in the presence of internal carotid or
intracranial artery stenosis of ≥ 50% by North American
Symptomatic Carotid Endarterectomy Trial (NASCET) criteria or major
cardiac source of embolism. In this cohort, one TIA patient in five with
a ABCD2 score of < 4 had a major finding that required
immediate medical decision.
164 The presence of symptomatic carotid stenosis in patients
with low ABCD score has also been shown in other cohorts, ranging from
9% to 23%.
132,151,164,181 Under present NICE guidance,
67 patients with ABCD2 scores of
< 4 would not be triaged for rapid assessment and would
not reach endarterectomy in time for it to have maximum benefit. This
risks undermining one of the strongest pieces of evidence that we have
for stroke prevention, from the several 1000 patients in the carotid
endarterectomy trials, which demonstrate that endarterectomy reduces the
risk of ipsilateral ischaemic stroke in patients with a tight carotid
stenosis by ≥ 50%.
25Few studies indicated what secondary prevention measures were used in
their patients (endarterectomy, medical therapy) yet these have been
established in guidelines for at least 15 (endarterectomy) or more
(aspirin, statins, BP-lowering drugs) years. It is unlikely that
patients in these studies would have been denied such treatments and
presumably they were not, but the application of endarterectomy and
drugs may have reduced the risk of stroke that they were attempting to
observe.
Other limitations with the literature are that there was significant
heterogeneity between included studies, which could be explained by clinical and
methodological factors. Clinical setting, time of assessment from symptom onset,
diagnosis of TIAs, and evaluating clinicians varied considerably across studies.
Our crude assessment of variation in recurrent stroke rates after TIA with year
of study publication did not suggest that simple changes in referral rates would
explain the heterogeneity. Many studies did not differentiate recurrent
disabling stroke from any recurrent stroke and some studies may have counted a
recurrent TIA as a stroke recurrence. Furthermore, in some studies the authors
could not establish with certainty whether early strokes were due to progression
of initial symptoms or a new event.
Various attempts have been made to improve the yield of clinical prediction
scores in the stratification of stroke risk after TIA by including the use of
brain and carotid imaging findings,69,147 and resulted
in a confusing plethora of ABCD2 clones with limited validation or evidence of
truly improved performance. The effect of adding brain imaging to the ABCD2
score is summarised in Chapters
5 and 6.
A recent systematic review and meta-analysis of ABCD2 scores and stroke risk125 in 33 studies, 16,070 patients,
published shortly before submission of this report, is entirely consistent with
our results. Differences between their work and ours are that they did not
dichotomise on ABCD2 score of 4; they included information only published in
abstract; and they did not identify the issues regarding case ascertainment,
assignment of ABCD2 score, population distribution of scores, uncertainty over
risk factor identification or treatment of these, or filtering by experts that
we have highlighted. However, they did observe that many studies come from the
same few research groups and, like us, experienced difficulty in avoiding
double-counting of the same patient data appearing in multiple publications.
Their pooled sensitivity and specificity for stroke risk at 7 days were nearly
identical to ours. They concluded that ‘the ABCD2 score leads to only
small revisions of baseline stroke risk particularly in settings of very low
baseline risk and when used by non-specialists’, although most of the
data in their review came from specialists. A systematic review and pooled
analysis of validation studies of ABCD and ABCD2 scores showed pooled AUCs for
the prediction of stroke at 7 days of 0.72 (95% CI 0.67 to 0.77) and 0.72 (95%
CI 0.63 to 0.80) for studies using the ABCD and ABCD2 score, respectively; the
pooled AUCs for studies using both scores were 0.72 (95% CI 0.66 to 0.78) and
0.72 (95% CI 0.63 to 0.82) respectively, with significant heterogeneity for all
given estimates.178 The pooled
AUCs for the ABCD2 score assessed in the Oxford or California cohorts and
independent studies were 0.77 (95% CI 0.63 to 0.91) and 0.69 (95% CI 0.64 to
0.74) respectively; the predictive value for 7-day stroke risk was higher for
studies using in person or clinical records calculations of the score than
studies with retrospective calculations from ED records.
Since the publication of this systematic review, a number of further studies
evaluating the ABCD2 score have been published, with conflicting results.19,20,37,39,46,67 A more recent meta-analysis of 16 ABCD2 score
validation studies assessed the predictive value of the score in stroke risk at
7 and 90 days after TIA using three strata of risk: low, moderate and high
(0–3, 4–5 and 6–7 points, respectively). The score
correctly predicted the occurrence of stroke at 7 days after TIA in all strata
of risk but tended to overpredict the occurrence of stroke at 90 days.166 There is an indication that
ABCD scores work differently in stroke and TIA patients, with some publications
suggesting that ABCD scores may predict stroke recurrence with any accuracy only
within the first 7 days of TIA. In the OXVASC population cohort the risk of
recurrent stroke at 90 days in patients presenting with a first minor stroke was
11.7%; the ABCD2 score was poorly predictive of stroke recurrence within 7 and
90 days in this group of patients – AUCs 0.57 (95% CI 0.47 to 0.68) and
0.60 (95% CI 0.53 to 0.67), respectively.186 Other scores have been used to predict the long-term risk of
stroke. An external validation of several prediction models for long-term risk
of major vascular events after TIA or minor stroke showed that the
discrimination was poor for all prediction models for risk at 2 years. After
adjustment for baseline risk and prevalence of risk factors, clinical usefulness
may be best for the ABCD2 model, with a reasonable c-statistic
(0.64). Notably, patients with AF, significant symptomatic carotid stenosis,
mechanical heart valve and a proven dissection were excluded.187 Another prospective assessment
of prognostic scores in patients with TIA or non-disabling stroke [including
Essen Stroke Risk Score (ESRS), Stroke Prognosis Instrument II (SPI-II), Life
Long After Cerebral ischaemia (LiLAC) score and Hankey score, discussed in
Chapter 5] showed
that the discrimination for annual risk of stroke was similar across each score,
with a marginal superiority of SPI-II score (AUC 0.65; 95% CI 0.6 to 0.7).154
Current clinical guidelines67
recommend urgent treatment only for patients with high ABCD2 scores, whereas
patients with low scores should be triaged for further clinical assessment
within 1 week.67,97 This would risk missing patients
with carotid stenosis requiring endarterectomy. On the other hand, not everyone
may be using these scores in real life, as indicated in the survey of stroke
prevention services in the UK, which indicates that only 13% of the respondents
described the use of ABCD2 score to stratify the promptitude of assessment of
TIA patients (see Chapter
8).
