A systematic review and meta-analysis of stroke risk after transient ischaemic attack

Joanna Wardlaw; Miriam Brazzelli; Hector Miranda; Francesca Chappell; Paul McNamee; Graham Scotland; Zahid Quayyum; Duncan Martin; Kirsten Shuler; Peter Sandercock; Martin Dennis

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Wardlaw J, Brazzelli M, Miranda H, et al. An assessment of the cost-effectiveness of magnetic resonance, including diffusion-weighted imaging, in patients with transient ischaemic attack and minor stroke: a systematic review, meta-analysis and economic evaluation. Southampton (UK): NIHR Journals Library; 2014 Apr. (Health Technology Assessment, No. 18.27.)

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An assessment of the cost-effectiveness of magnetic resonance, including diffusion-weighted imaging, in patients with transient ischaemic attack and minor stroke: a systematic review, meta-analysis and economic evaluation.

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Chapter 3A systematic review and meta-analysis of stroke risk after transient ischaemic attack

Introduction

The early risk of recurrent stroke after TIA has been underestimated for many years. Approximately 15–20% of ischaemic strokes are preceded by a TIA¹¹⁷ and the appropriate detection and urgent diagnostic work-up for patients with TIA can avoid a further disabling stroke if the correct treatment is indicated. A retrospective study of consecutive patients attending emergency departments (EDs) within 24 hours after TIA demonstrated that the stroke risk after the index event was higher than previously thought; the stroke rate was 10.5% at 90 days, with half of the events (5.3%) occurring within 2 days of symptoms onset.⁸ A further analysis of a population-based TIA incidence study [Oxfordshire Community Stroke Project (OCSP)] also reported a high stroke rate after index TIA, with risks of 8.6% at 7 days and 12.0% at 30 days.²¹ Several studies have been published after these publications. With respect to stroke immediately after TIA, in a prospective population-based incidence study of TIA and stroke (OXVASC), in 488 patients with a first TIA the risks of stroke at 6, 12 and 24 hours were 1.2% (95% CI 0.2% to 2.2%), 2.1% (0.8% to 3.2%) and 5.1% (3.1% to 7.1%), respectively. Furthermore, 42% of all stroke during the 30 days after a first TIA occurred within the first 24 hours.¹¹⁸ Different studies have reported conflicting stroke rates after TIA, and cohorts from Oxford, UK and northern Portugal have published very high risks of stroke at 7 days (11% to 13%) and 90 days (17% to 21%), respectively.⁹^,¹¹⁹ A systematic review and meta-analysis of 11 observational studies reporting the early risk of stroke after TIA (total n = 7238), showed that risks of stroke ranged from 1.4–9.9% at 2 days, 3.2–17.7% at 30 days, and 3.9–17.3% at 90 days, with significant heterogeneity for all periods considered. Using a random-effects model, the pooled estimate of risk was 3.5% (95% CI 2.1% to 5.0%) at 2 days, 8.0% (5.7% to 10.2%) at 30 days, and 9.2% (6.8% to 11.5%) at 90 days; the risk was higher when the methodology of the studies involved active ascertainment of stroke outcome (9.9%, 13.4% and 17.3%, respectively).¹²⁰ Another systematic review and meta-analysis of studies reporting the risk of stroke exclusively within 7 days of TIA (total 18 cohorts, n = 10,126 patients) showed pooled risk of stroke of 3.1% (95% CI 2.0% to 4.1%) at 2 days and 5.2% (3.9% to 6.5%) at 7 days, with a substantial heterogeneity across studies for both pooled risk estimates. The risks of stroke after TIA observed in patients treated urgently by specialist stroke services were 0.6% (95% CI 0.0% to 1.6%) at 2 days, and 0.9% (95% CI 0.0% to 1.9%) at 7 days compared with 3.6% (95% CI 2.4% to 4.7%) at 2 days and 6.0% (95% CI 4.7% to 7.3%) at 7 days from other cohorts.¹²¹

Recent studies²⁴^,¹²² included in the systematic review by Giles and Rothwell¹²¹ have reported very low risks of recurrent stroke for patients in whom a secondary prevention treatment [mainly antiplatelet drugs and blood pressure (BP)-lowering drugs] was started immediately after confirmed diagnosis of TIA or minor stroke. An early detection of medical conditions with a high risk of early stroke recurrence, such as severe carotid stenosis or a cardiac source of embolism requiring specific treatments (i.e. carotid endarterectomy or anticoagulant therapy) can also explain the significant reductions in stroke rates in those cohorts.

Methods

Objectives

For the purpose of this HTA project we have conducted a systematic review considering all primary studies reporting the overall rate of stroke in TIA patients. Recent published systematic reviews on stroke risk after TIA (e.g. Wu and colleagues¹²⁰ and Giles and Rothwell¹²¹) were used only as a source of relevant references. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for systematic reviews of studies that evaluate health-care interventions to conduct this review.¹²³ We aimed to identify all published studies reporting the risk of recurrent stroke among patients with TIA and/or minor stroke irrespective of the clinical setting or type of study design.

Identification of studies

We searched indexed records that appeared in MEDLINE (Ovid) from January 1995 to November 2011. It is worth noting that for the purpose of this systematic review we combined the comprehensive literature searches we developed for Chapter 6 (DWI in patients with TIA and minor stroke) and for Chapter 4 (clinical prediction score and risk of stroke after TIA and minor stroke) of this assessment. The MEDLINE search strategy included both subject headings [medical subject headings (MeSH) terms] and text words for the target condition (e.g. stroke, TIA, minor stroke). 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. We did not apply any language restrictions. The searches were initially run in November 2010 and updated in November 2011. Full details of 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 version 11 (ISI Research Software, San Francisco, CA, USA). 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.¹²⁴

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 assessed by two reviewer authors (MB, HM) and retained if they reported the number and proportion of patients with stroke recurrence at 7 days, 90 days, and/or > 90 days after index TIA. We analysed all studies regardless of whether they reported recurrent stroke at 7 days, 90 days or > 90 days. We excluded non-English articles for which a full-text translation was not available.

Quality assessment and data extraction

Two review authors (MB, HM) independently conducted data extraction and review the methodological quality of selected studies using the primary papers. 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, definition of TIA and recurrent event, 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 stroke recurrence after index event (first or recurrent TIA). The pooled proportion of TIA patients with stroke recurrence was calculated by means of a univariate random-effects meta-analysis with within-study variance modelled as binomial. Heterogeneity between studies was assessed visually by inspection of the forest plots and by calculating I²-statistics.¹⁰⁹ Data were analysed in R version 2.14.2 (The R Foundation for Statistical Computing, Vienna, Austria) (cran.r-project.org).

Results

Number of included/excluded studies

The literature searches identified 11,389 citations. After initial screening of titles and abstracts we selected 248 citations for full-text retrieval. Two additional studies published in 2005 were included after hand-searching of reference lists of relevant studies, yielding a total of 250 studies. After full-text examination, 197 studies were excluded, leaving 53 studies that fulfilled the inclusion criteria. The main reason for exclusion was that the number of recurrent events was not clearly reported (Figure 5). We translated one report published in Spanish; all other included reports were originally published in English. We observed, as have others,¹²⁵ that some studies come from the same TIA cohorts (i.e. Oxford, north Dublin, California, Massachusetts, Lleida and Paris cohorts) and we experienced difficulty in avoiding double counting of the same patient data appearing in multiple publications. Many studies were published from the same research groups and the same cohorts of patients were described in multiple reports – with some reports assessing more than one patient cohort (i.e. Oxford, north Dublin, California, Massachusetts, Lleida and Paris cohorts). Even although we attempted to exclude multiple publications we found it challenging to identify which cohort was assessed in which study, as precise information were somehow lacking. When a single study included separate cohorts (e.g. community-based TIA patients and patients from specialist unit) for the purpose of the analyses we considered the separate cohorts as coming from separate studies.

FIGURE 5

Identification and selection of studies.

Characteristics of included studies

The methodological characteristics of selected studies are shown in Table 1.

TABLE 1

Methodological characteristics of included studies

The 53 studies varied in their primary objectives. Eleven were population-based studies including cohorts from the UK (Oxford), Ireland (Dublin), USA (Texas and Minnesota), Canada (Alberta) and northern Portugal.⁹^,²¹^,⁶¹^,¹¹⁹^,¹²⁶^,¹²⁷^,¹³²^,¹⁴⁰^,¹⁴⁴^,¹⁴⁷^,¹⁵¹ Seventeen were ED-based studies,²³^,⁶⁹^,⁸⁷^,¹²⁹^,¹³¹^,¹³⁴^–¹³⁶^,¹⁴³^,¹⁴⁹^,¹⁵³^,¹⁵⁶^–¹⁵⁹^,¹⁶¹^,¹⁶³ three were focused on TIA clinics (one included OXVASC participants),²⁴^,¹³⁰^,¹⁴⁵ 10 were hospital-based studies (the authors of which did not describe characteristics of the hospital unit),⁶⁵^,⁸¹^,¹²⁰^,¹³³^,¹⁴²^,¹⁴⁸^,¹⁵²^,¹⁵⁵^,¹⁶⁰^,¹⁶² 10 recruited patients admitted to a specialist unit [including stroke unit, neurological ward or highly-specialised neurovascular (NV) clinics],¹²²^,¹³⁷^–¹³⁹^,¹⁴¹^,¹⁴⁶^,¹⁵⁰^,¹⁵⁴^,¹⁶⁴^,¹⁶⁵ one focused on patients attending ED and TIA clinics (including OXVASC participants)⁶² and one¹²⁸ recruited patients as part of a hospital-based clinical trial. The 53 studies included a total of 30,558 participants. The risk of recurrent stroke at 7 days was reported in 28 studies (30 cohorts) of 12,332 participants, 34 studies (35 cohorts) of 19,769 participants reported the stroke risk at 90 days and nine studies of 8699 participants reported the stroke risk > 90 days. For studies reporting the stroke risk > 90 days, the length of follow-up ranged from 6 months to 14 years.

The study design was prospective in 33 studies⁹^,²¹^,²⁴^,⁶¹^,⁶⁵^,⁶⁹^,⁸¹^,¹¹⁹^,¹²²^,¹²⁶^,¹²⁸^,¹²⁹^,¹³²^–¹³⁴^,¹³⁶^,¹³⁸^,¹³⁹^,¹⁴¹^–¹⁴⁴^,¹⁴⁸^,¹⁵⁰^–¹⁵⁴^,¹⁵⁶^,¹⁶⁰^,¹⁶¹^,¹⁶⁴^,¹⁶⁵ and retrospective in 19;²³^,⁸⁷^,¹²⁰^,¹²⁷^,¹³⁰^,¹³⁵^,¹³⁷^,¹⁴⁰^,¹⁴⁵^–¹⁴⁷^,¹⁴⁹^,¹⁵⁵^,¹⁵⁷^–¹⁵⁹^,¹⁶²^,¹⁶³ one study⁶² included two cohorts recruited prospectively and retrospectively. Participants were included consecutively in 45 studies. The diagnosis of TIA was made by a neurologist or stroke physician in 36 studies,⁹^,²¹^,²⁴^,⁶¹^,⁶⁵^,⁶⁹^,⁸¹^,⁸⁷^,¹¹⁹^,¹²²^,¹²⁶^,¹²⁸^,¹³⁰^,¹³²^–¹³⁴^,¹³⁷^,¹³⁹^–¹⁴²^,¹⁴⁴^–¹⁴⁸^,¹⁵⁰^–¹⁵²^,¹⁵⁴^,¹⁵⁶^,¹⁵⁷^,¹⁶⁰^,¹⁶¹^,¹⁶⁴^,¹⁶⁵ by an emergency medicine physician in 10 studies,²³^,¹²⁷^,¹²⁹^,¹³¹^,¹³⁵^,¹³⁶^,¹⁴³^,¹⁴⁹^,¹⁵³^,¹⁵⁹ and by both in four;⁶²^,¹⁵⁸^,¹⁶²^,¹⁶³ in three studies¹²⁰^,¹³⁸^,¹⁵⁵ this information was not reported.

With respect to the timing of patient assessment after the index event, in 10 studies TIA patients were assessed within 24 hours of symptoms onset,⁶²^,⁶⁹^,⁸⁷^,¹³⁴^–¹³⁶^,¹³⁸^,¹⁴³^,¹⁵⁵^,¹⁶¹ in six studies within 48 hours,¹³⁷^,¹³⁹^,¹⁴¹^,¹⁴²^,¹⁵⁰^,¹⁶⁵ in one study¹⁴⁰ within 72 hours and in one study¹⁶⁰ within 7 days. Another four studies⁹^,⁶¹^,¹³²^,¹⁴⁴ reported that ‘patients were assessed as soon as possible after the event’ but did not give a time. One study⁶² (including two cohorts) assessed patients within 24 hours and ‘as soon as possible after the event’, another study¹²⁰ assessed patients ‘immediately’ after the event, and in three studies⁶⁵^,¹²⁸^,¹⁴⁵ the timing of assessment was beyond 7 days. The remaining 27 studies did not clearly provide this information (see Table 1). Four studies included patients with first-ever TIA, 34 included either first-ever or recurrent TIA, and in 15 studies the authors did not report this information.

The majority of studies (n = 46) used a time-based definition of TIA (see Table 1), one study¹⁴⁵ recruited patients retrospectively from clinical records using the International Classification of Diseases (ICD), Ninth Edition, definition of TIA, one study¹⁵⁷ included just patients with transient symptoms and DWI visible lesion, in five studies the information was not reported. One study¹²⁸ included a highly selected sample of patients with TIA and carotid stenosis, and three studies⁶⁵^,¹⁴¹^,¹⁵⁵ excluded patients with specific conditions [i.e. cardioembolic events or blood coagulation disorders, AF and posterior circulation TIAs, respectively].

The ascertainment of stroke events after TIA was carried out by face-to-face patient assessment or telephone interviews in 25 studies,⁹^,²¹^,²⁴^,⁶¹^,⁶⁹^,⁸¹^,¹¹⁹^,¹²²^,¹²⁸^,¹³²^–¹³⁴^,¹³⁷^–¹³⁹^,¹⁴⁴^,¹⁴⁹^–¹⁵²^,¹⁵⁵^,¹⁵⁶^,¹⁶¹^,¹⁶⁴^,¹⁶⁵ by medical records in 15 studies,²³^,⁶²^,⁸⁷^,¹²⁰^,¹²⁶^,¹²⁷^,¹²⁹^,¹³⁰^,¹³⁰^,¹³⁵^,¹³⁶^,¹⁴⁰^,¹⁴³^,¹⁴⁵^,¹⁵⁷^,¹⁵⁹ by mixed methods involving face-to-face assessment plus another method (i.e. telephone interviews, medical records, letters) in 11 studies,⁶⁵^,¹³¹^,¹⁴⁶^–¹⁴⁸^,¹⁵³^,¹⁵⁴^,¹⁵⁸^,¹⁶⁰^,¹⁶²^,¹⁶³ and was not reported in two studies.¹⁴¹^,¹⁴²

Main findings

Table 2 shows the proportion of patients with stroke recurrence reported in all studies at different time points. The number of events was 974 out of 12,332 patients for studies reporting stroke risk at 7 days, 1567 out of 19,803 patients for risk at 90 days, and 927 out of 8699 patients for risk > 90 days. The risk of stroke reported across studies ranged from 0.0% to 22.4% at 7 days, 0.6% to 23.7% at 90 days, and 4.7% to 27% at > 90 days. There was evidence of significant heterogeneity between studies; the I²-statistics were 96.4%, 96.3%, and 97.8% for stroke risk at 7, 90 and > 90 days, respectively. Using random-effects meta-analysis, the pooled risk of stroke was 5.2% (95% CI 3.9% to 5.9%) at 7 days, and 6.7% (95% CI 5.2% to 8.7%) at 90 days. For stroke risk at > 90 days the pooled estimate was 11.3% (95% CI 7.5% to 16.6%). Figures 6–8 show the forest plots for studies reporting the proportion of patients with stroke recurrence at 7, 90 and > 90 days after index TIA.

TABLE 2

Stroke risk after TIA at 7, 90 and > 90 days

FIGURE 6

Forest plot for studies reporting stroke recurrence at 7 days after index TIA. The Johnston paper reports results for two cohorts: (a) the California clinic and (b) the Oxford clinic. The Rothwell paper also reports results for two cohorts: (a) the OXVASC (more...)

FIGURE 8

Forest plot for studies reporting stroke recurrence beyond 90 days after index TIA.

FIGURE 7

Forest plot for studies reporting stroke recurrence at 90 days after index TIA. The Johnston paper reports results for two cohorts: (a) the California clinic and (b) the Oxford clinic.

Discussion

We identified 53 studies with a total of 30,558 participants, published between 2003 and 2011, providing data on stroke risk at 7 days, 90 days or > 90 days after TIA. The rate of recurrent stroke at all time points assessed varied widely from 0% to 22.4% at 7 days, 0.6% to 23.7% at 90 days, and 4.7% to 27.0% at > 90 days. The random-effects meta-analysis showed the pooled risk of recurrent stroke at 7 days to be 5.2% (95% CI 3.9% to 5.9%), at 90 days to be 6.7% (95% CI 5.2% to 8.7%) and at > 90 days to be 11.3% (95% CI 7.5% to 16.6%). The heterogeneity between studies was huge. In some individual studies the rate was up to three times higher than the median rate and up to 4–4.5 times higher than the pooled risk rate. However, this summary of all available data indicates that the pooled risk of stroke after TIA is one-quarter of that stated in the current NICE guidance, which states in the Guide to Implementing the National Stroke Strategy Guide, Imaging for TIA, p. 8, that ‘Approximately 20% of TIAs will be followed by a stroke within four weeks’.⁹⁷ The upper 95% CI of our pooled risk barely passes one-quarter of that value. The few individual studies that reported such high rates were all very small.

Two systematic reviews of the risk of stroke after TIA¹²⁰^,¹²¹ and one systematic review of the risk of recurrent stroke after first-ever stroke¹⁶⁹ have been published in 2007 and 2011, respectively. The review by Giles and Rothwell¹²¹ focused on stroke risk within 7 days of TIA and included 18 independent cohorts with 10,126 patients. The pooled stroke risk was 5.2% (95% CI 3.9% to 6.5%) at 7 days, ranging from 0.0% to 12.8%, and with substantial between study heterogeneity. The heterogeneity was largely explained by setting, with the lowest rates in emergency settings with urgent treatment and highest in population-based studies without urgent treatment. In the same year, Wu and colleagues¹²⁰ published a systematic review focusing on stroke risk at 2, 30 and 90 days, and included 11 studies with 7238 patients. The pooled risk for all studies was 3.5%, 8.0% and 9.2% at 2, 30 and 90 days, respectively. The pooled risk for studies with active prospective case ascertainment was 9.9%, 13.4% and 17.3% at 2, 30 and 90 days, respectively. Despite both addressing the same topic, 11/18 studies included in Giles and Rothwell¹²¹ were not included in Wu and colleagues,¹²⁰ and 5/11 studies in Wu and colleagues¹²⁰ were not included in the Giles and Rothwell study,¹²¹ some because stroke rates were not reported at the precisely required time, but this did not account for all omissions. Mohan and colleagues¹⁶⁹ published a review of 13 studies of 9115 patients published between 1961 and 2006 focusing on stroke recurrence after first-ever stroke (not TIA) showing a pooled risk of 3.1% (95% CI 1.7% to 4.4%) at 30 days and 11.1% (95% CI 9.0% to 13.3%) at 1 year, also with substantial heterogeneity between studies.

There has been considerable interest in the rate of stroke after TIA since the mid-2000s but this alone cannot account for the large difference between these earlier reviews of stroke risk after TIA and our study in the number of included studies or patients, our review including nearly treble the number of studies (53) and patients (30,558). Twenty-eight studies alone reported stroke risk at 7 days in 12,332 patients. We may inadvertently have included some of the same patients more than once as many of these studies come from the same few research groups and it was difficult to disentangle some of these studies. Substantial proportions of these studies were based in EDs (17, 32%) and, although details were a bit short in some studies, many of the rest could be considered to be recruiting in a rapid-access fast-response environment, and 33/53 were prospective, and 45/53 studies included consecutive patients. Our pooled risk rate is similar to that of Giles and Rothwell¹²¹ and midway between the estimates provided by Wu and colleagues.¹²⁰ Differences in the speed of assessment may account for differences in risk rates between studies, but many other factors are possible. For example, few studies reported on how patients were treated and how those with tight symptomatic carotid stenosis were managed. Presumably they were offered early endarterectomy, removing much of their stroke risk. Presumably many patients were offered immediate medical treatment, in many cases started by their family doctor prior to arriving at the specialist clinic or hospital ED. This practice might have increased since the publication of the Early use of eXisting PREventive Strategies for Stroke (EXPRESS) study in 2006²⁴ and might explain why some newer studies had lower stroke rates. With a few exceptions, these points are largely not mentioned. Regardless of that, lower rates were also observed in many older studies and therefore the real differences between studies are likely to be more complex than simply variation in rapidity of referral or early treatment.

Given the large variation in stroke risk between studies, and not having any good reasons to choose one group of studies over another, and, as the calculated pooled risk at each time point had pretty tight CIs indicating some reliability even if there is substantial heterogeneity, we will use the pooled risk rates at 7 days (28 studies, 12,332 patients), 90 days (34 studies; 19,769 patients) and > 90 days (nine studies; 8669 patients) as the most reliable base estimates of stroke risk in the present work.

Weaknesses of the review

Overall, our findings are limited by the great variation between included studies, especially in terms of study design, time of assessment from symptoms onset, type of TIA considered, and evaluating clinicians. As there is no a validated instrument for the quality assessment of observational studies on stroke risk, we pre-defined the methodological aspects that we considered more likely to represent potential sources of bias. The results of the quality assessment were used in only a descriptive way and not to inform further statistical analyses (e.g. meta-regression).

With regard to our literature searches, we focused mainly on two major electronic databases (MEDLINE and EMBASE). We did not search additional electronic databases, such as the Bioscience Information Service (BIOSIS), the Latin American and Caribbean Health Sciences Literature (LILACS) or the Science Citation Index (SCI), first because the number and relevance of indexed journals in these databases is limited compared with those indexed in MEDLINE and EMBASE, and, second, we are confident we have enhanced the overall sensitivity of our literature searches by hand-searching all recent conference proceedings of two major international stroke conferences, contacting experts in the field and perusing the reference lists of all relevant selected studies. Owing to time and resources constraints, we avoid searching grey literature sources, which are known to be time consuming and not particularly well developed.

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