Incidence of stroke following thoracic endovascular aortic repair for descending

aortic aneurysm: A Systematic Review of the Literature with Meta-analysis

Regula S von Allmen1*, Brigitta Gahl2, Janet T Powell3

1 Clinic for vascular surgery, Kantonsspital St. Gallen, Rorschacherstrasse, St. Gallen,

Switzerland

2 Clinic for cardiovascular surgery, University Hospital Bern and University of Bern,

Switzerland

3 Vascular Surgery Research Group, Imperial College London, Charing Cross Campus,

London, UK

* Address for correspondence: Regula S von Allmen; regula.vonallmen@kssg.ch; clinic for

vascular surgery, Kantonsspital St. Gallen, Rorschacherstrasse, St. Gallen, Switzerland

Original article

Systematic review and Meta-analysis

Running head: Meta-analysis on stroke risk following TEVAR

This work has been presented as a poster at the annual conference of the European Society

of Vascular Surgery in Porto, Portugal 2015

Word count: 3609

Abstract: 282

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Keywords

stroke; cerebrovascular event; TEVAR; endovascular; thoracic aortic aneurysms; systematic

review; meta-analysis

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What this study adds

This is a comprehensive review including a meta-analysis looking specifically at the stroke

risk of patients undergoing thoracic endovascular aortic repair (TEVAR) for descending

thoracic aortic aneurysm, thus eliminating heterogeneity regarding patient selection as

effectively as possible. There is an indication that stroke risk is increased if the left

subclavian artery (LSA) is covered during the procedure without revascularisation. Such data

are important for informing patients of procedure risks and to increase research efforts

towards stroke prevention.

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Abstract

Objectives: Stroke is an increasingly recognised complication following thoracic

endovascular aortic repair (TEVAR).The aim of this study was to synthesise systematically

the published data on perioperative stroke incidence during TEVAR for patients with

descending thoracic aneurysmal disease and assess the impact of left subclavian artery

(LSA) coverage on stroke incidence.

Data sources: A systematic review of English and German articles using MEDLINE and

EMBASE (2005–2015).

Review methods: A systematic review of studies looking at perioperative (in-hospital or

30day) stroke incidence following TEVAR for descending aortic aneurysm was performed,

including studies with ≥50 cases, published after January 2005. Pooled prevalence rate of

perioperative stroke and 95 per cent confidence interval (95% CI) was estimated using

random effect analyses. Heterogeneity was examined using I2 statistic.

Results: Of 215 studies identified, ten were considered suitable for inclusion. The included

studies enrolled a total of 2594 persons (61% were male) during 1997-2014 with a mean

weighted age of 71.8 (95% CI 71.1 to 73.6) years. The pooled prevalence rate for stroke was

4.1% (95% CI 2.9 to 5.5) with moderate heterogeneity between studies (I2=49.8%, P=0.04).

Five studies reported stroke incidences stratified by the management of the LSA; i.e.

uncovered versus covered and revascularised versus covered and not-revascularised. In

cases where the LSA remained uncovered, the pooled stroke incidence was 3.2% (95% CI

1.0 to 6.5). There was however, an indication that stroke incidence increased following LSA

coverage, to 5.3% (95% CI 2.6 to 8.6) in those with a revascularisation and 8.0% (95% CI

4.1 to 12.9) in those without revascularisation.

Conclusion: Stroke incidence is an important morbidity after TEVAR, and probably increases

if the LSA is covered during the procedure, particularly in those without revascularisation.

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Introduction

Thoracic endovascular aortic repair (TEVAR) is regarded as a lower-risk treatment for a

variety of thoracic aortic conditions and thus, is the preferred treatment approach over open

repair in many cases.1, 2 Due to its minimal invasiveness compared to open repair, TEVAR

has gained widespread adoption and has also been propagated in official guidelines to be

applied at an even lower diameter aneurysm threshold than open repair.3 The endovascular

aortic repair technique likely meets the wish of patients for a rapid recovery. Associated

neurologic complications, however, interfere considerably with this wish; first, neurologic

events may be fatal in up to 33%4 and second, the consequences of neurologic events, i.e.

long-term disability and handicap are highly correlated with impaired physical health related

quality of life.5 The most dreaded neurologic complications are paraplegia and stroke. The

incidence of spinal cord ischaemia following TEVAR varies considerably across studies

between 0 to more than 10%6-11 and a considerable body of research has led to a reduction

in paraplegia rate.12 So far, the reduction of stroke during endovascular aortic interventions

has attracted less interest, apart from differential revascularisation strategies when left

subclavian artery (LSA) coverage is needed. The risk of stroke during TEVAR is not

surprising; atherosclerotic disease of the aortic arch is not only a recognised risk factor for

unprovoked stroke13, but also for neurologic events after open heart surgery or during carotid

artery stenting.14 A recent study looking at midterm outcomes after TEVAR in relation to

aortic pathology reported a more than two-fold higher early-term stroke incidence among

thoracic aortic aneurysm patients compared to those with an aortic dissection.15 This may be

a reflection of more advanced atherosclerotic disease among the aneurysm patients.

Therefore, new therapies might focus on plaque-stabilisation, e.g. utilisation of high dose

statins, to prevent stroke and on the evolvement of technical adjuncts (i.e. further

development of fusion imaging techniques), which would allow to reduce the time the

endograft dangles within the aortic arch causing plaque dislocation. However, before

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designing any such studies, it is essential to know the exact magnitude of the problem, i.e.

stroke incidence.

Therefore, the aim of this study was to synthesise the published data on stroke incidence

following TEVAR for descending thoracic aortic aneurysm in a systematic review.

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Methods

Systematic review and protocol

The systematic review followed quality reporting guidelines set by the PRISMA (Preferred

Reporting Items for Systematic reviews and Meta-Analysis) group (http://www.prisma-

statement.org/).16 A review protocol including every step of the systematic review was

developed and approved by all authors.

Search strategy

Medline and EMBASE were initially searched up until the 16th February 2015, and

subsequently updated until 30th June 2016 using the following search terms in different

combinations; "Aorta, Thoracic/surgery"[Mesh], "Aorta, Thoracic/therapy"[Mesh], “stroke”,

“neurologic deficit”. Filters were used to restrict studies to human studies only and to articles

in English and German published 2005 onwards in order to focus on procedures with

technologically more advanced devices. In addition, reference lists of reviews were also

searched for further studies to be included.

Eligibility criteria, study selection

Potential studies were reviewed according to a set of eligibility criteria. The study participants

(minimum n=50, men or women) must have undergone TEVAR with indications being

separable between descending thoracic aortic aneurysms, traumatic aortic lesions and aortic

dissections. Studies were not excluded if penetrating aortic ulcers were not separable from

aneurysms. Studies on patients with connective tissue disease were excluded as well as

studies involving ascending aortic aneurysms. In addition, the following were also excluded:

review articles, studies where patient data were duplicated (in which case the most recent or

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comprehensive study was used), editorials, letters and case reports. Study authors were

contacted in cases where outcome data could not easily be separated according to

underlying aortic pathology.

Data collection process

A data extraction form to identify variables in the eligible studies was designed. The following

were extracted: the study design (prospective, retrospective, case series, observational

studies with or without comparison group, registries, multicentre or single-centre), author

affiliation, date of publication, and country (where study was undertaken), year of publication,

recruitment period, inclusion and exclusion study criteria, baseline data including age, sex

and other cardiovascular risk factors (e.g. blood pressure, history of smoking, drugs (i.e.

statins), ischaemic heart disease, diabetes), type of endograft, information on coverage of

the LSA and on revascularisation strategies, outcomes (stroke incidence in hospital or within

30 days of intervention, mortality rate in hospital or within 30 days of intervention). Two

authors (RSvA, JTP) independently extracted data of the potentially eligible primary studies

and crosschecked their results. Any disagreements between the two reviewers were

discussed and finally settled by agreement.

For studies that failed to provide baseline variables (age separable by aortic pathology,

stroke incidence according to coverage of LSA) study authors were contacted for completion

and if these variables were not available the studies were excluded for these specific

analyses.

Estimation of perioperative stroke incidence

The reported overall mean stroke incidence either within 30 days or in-hospital (if 30-day

outcome was not reported) was extracted from each study. In studies that reported on LSA

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coverage, stroke incidences were extracted according to revascularisation strategy of the

LSA (uncovered versus covered and revascularised versus covered and non-

revascularised).

Study quality

The Newcastle-Ottawa Scale was used to assess the quality of the included studies using a

'star system' based on three broad perspectives: the selection of the study groups; the

comparability of the groups; and the ascertainment of either the exposure or outcome of

interest for cohort studies. The different items were adapted to the study question of interest

(supplemental material). None of the studies could score for representativeness of the

exposed cohort, however a star was given for selection of the non-exposed cohort if

information on previous stroke had been reported. Each study was given two points; one for

ascertainment of exposure because all information relied on surgical records and for

demonstration that the outcome of interests was not present at the start of the study.

Consequently, in the selection category, all studies were given 2-3 points. Regarding

comparability category, studies yielded 0-2 points. They were given one point if key factors

were controlled for, i.e. coverage of the LSA and another point if separable details were

given for thoracic aortic aneurysm patients relating to age and sex ratio. In the final category

‘Outcome’ all studies yielded 1-3 points: Assessment of follow up was scored with one point

if a good quality assessment for stroke was applied (i.e. by imaging, diagnosed by

specialised neurologist). All the studies were given one point for the item ‘was follow-up long

enough for outcomes to occur’ because the outcome of interest was a postoperative event

and was an inclusion criterion. Studies with no patients lost to follow up for the early

postoperative primary outcome were given one point for ‘adequacy of follow up of cohorts’.

Taken together, all studies could receive a score of minimum 3 to maximum 8 points. The

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quality of reporting was independently analysed by two authors (RSvA and JTP);

disagreement were solved by consensus.

Statistical analysis

All analyses were conducted using STATA 12 (StataCorp, College Station, Texas, USA).

Meta-analysis estimates such as weighted summary proportions were generated in random

effects meta-analyses model17 and heterogeneity was assessed using the I2 test.18 We follow

Higgins et al. in quantifying heterogeneity by I2 into low (25%), moderate (50%), and high

(75%).18 The pooled estimates were calculated using the Freeman-Tukey double arcsine

transformation 19 and standard continuity correction (0.5) for zero events was used to

stabilise variances. The confidence intervals were based on the Wilson score method using

asymptotic variance.20

If means for age were not reported (one out of ten studies), the mean was approximated

using the median.21 If the range was quoted in place of standard deviation, it was converted

to standard deviation according to the recommendations of Hozo et al.21 In studies that

reported interquartile ranges, this was first converted to standard deviations (sd) using the

formula sd=IQR/1.35.21 The same was applied to the estimation of maximum aneurysm

diameter.

Three studies (Clough et al.22, Maldonado et al.23 and Patterson et al.15) reported separate

stroke incidences for the three different management strategies of the LSA, e.g. uncovered,

covered plus revascularisation and covered without revascularisation. Two further studies

reported separate stroke incidences for the two treatments, where LSA has been covered,

e.g. with and without revascularisation (Makaroun et al.24 and Fossaceca et al.25). For a

comparison of the stroke incidences following these strategies, we calculated risk ratios

using all available data, thus including the three or the five studies, respectively.

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An alternative funnel plot was constructed using study size instead of the inverse of standard

error on the y-axis due to the acknowledged risk of potentially misleading funnel plots for

non-comparative meta-analyses when traditionally constructed, which may be particularly

true for low or high proportional outcomes.25 In such circumstances, plot asymmetry could be

mistakenly interpreted as presence of a publication bias, whereas it has been proven that it

may have been caused by scale artefact due to correlations between outcome measures

and measure of precision.25

A sensitivity analysis for study size (≤ 150 versus >150 patients) was performed, with respect

to the primary endpoint to further investigate the possibility of a publication bias.

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Results

Identification of relevant studies

A total of 215 study titles were identified by the initial search strategy after removing

duplicate entries and of these 139 titles were excluded after title screening (Figure 1). A total

of 76 potential papers were selected. In the next stage, full records were reviewed. Of the

eligible publications, 66 were excluded for one or more of the following reasons: too few

patients (n=12); no original data or case reports (n=21); Studies with duplicated data/patients

(n=8); data not separable for descending thoracic aneurysms (n=22); reporting on occlusive

cerebrovascular disease (n=1); reporting on open repair only (n=1); stroke not being an

outcome (n=1). Ten studies were identified as potentially eligible for inclusion in the

systematic review and meta-analysis.15, 22-24, 26-30 Included studies are summarised in Table 1.

Data extraction: study characteristics

The publication dates of the ten potentially eligible studies for the meta-analysis ranged from

2005 to 2015 with patient recruitment from 1997 to 2014. Of these, six were prospective

studies (no randomised trials) and four were retrospective. Additional data from the study

authors were obtained for 2 studies.

Post-operative stroke was an outcome measure in all studies, defined as an event within 30

days for all except for the study from Clough et al.22, which reported in-hospital events only.

The diagnosis of stroke, stroke severity and fatality were reported inconsistently in the ten

included studies.

The included studies reported on 2594 persons with study sizes ranging from 53 to 823

patients. Sex ratio and age were extracted in all but two studies (Buth et al.27, Illig et al.31),

but in those that did, the proportion of men ranged from 58 to 85% of the study population.

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Mean or median age was extractable from all studies apart from the studies of Buth et al.27

and Illig et al.31, in which age was not separable for descending aortic aneurysm. The mean

study age ranged from 70-75 years resulting in a mean weighted age of 71.8 (95% CI 71.1

to 73.6).

All but two studies (Makaroun et al.24 and Illig et al.31) also included patients with

symptomatic thoracic aortic aneurysms, but the proportion with symptomatic lesions varied

considerably across studies from 6% (Patterson et al.15) to 43% (Andrassy et al.26)

Other patient characteristics, such as history of smoking, prevalence of diabetes, arterial

hypertension, proportion of participants with ischaemic heart disease and use of statins as

well as maximum aneurysm diameter were reported inconsistently across the ten studies

(Table 2). Information on thoracic aneurysm diameter and use of statin therefore were not

included.

Study quality according to the modified Newcastle-Ottawa Scale

Total quality score across all ten studies ranged from 4 to 8 (Table 1). A retrospective study

with the lowest sample size (Fossaceca et al.29) yielded the lowest quality score, while a

prospective phase 2 multi-centre study (Makaroun et al.24) achieved the highest quality

score. The majority (nine out of ten) scored a minimum five points indicating that most

studies were of at least moderate quality.

Prevalence rate of stroke

The pooled prevalence rate for stroke was 4.1% (95% CI 2.9 to 5.5) with moderate

heterogeneity between studies (I2=49.8%, P=0.04). The point prevalence of stroke within the

ten studies ranged between 0 to 7.2%. The largest study (Maldonado et al23) published the

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highest mean stroke incidence of 7.2% (95% CI 5.6 to 9.1). The corresponding forest plot is

shown in Figure 2, in which studies are sorted by study size.

The funnel plot, Figure 3, showed some evidence of bias: it was asymmetrical with respect

to a vertical line in the middle of the plot, and the points closer to the horizontal line were

shifted to the left, indicating that smaller studies reported lower stroke incidences. In a

sensitivity analysis stratifying studies by size, smaller studies with ≤ 150 patients had a

stroke incidence of 2.03% (95% CI 1.0 to 4.1) with low heterogeneity (I2 = 0.0%), whereas

larger studies reported a pooled stroke incidence of 5.4% (95% CI 3.0 to 6.9) with moderate

heterogeneity (I2 = 45.7%). Overall there was a small overlap of the confidence intervals

and significant heterogeneity between the groups (P = 0.021) with moderate overall

heterogeneity (I2 = 49.8%).

Stroke incidenceassociated with the management of the left subclavian artery during TEVAR

The three studies, that reported strokes stratified by the management of the LSA (Clough et

al.22, Maldonado et al.23 and Patterson et al.15); i.e. uncovered versus covered and

revascularised versus covered and not-revascularised, provided data on 1686 patients. In

these patients, the overall stroke incidence was 6.3% (95% CI 5.2 to 7.5). Two further

studies (Makaroun et al24 and Fossaceca et al.29) reported strokes separately for the two

treatments; i.e. revascularised versus covered and not-revascularised, providing data on 195

patients with five strokes. Overall stroke incidence across all the five studies was 4.9% (95%

CI 3.2 to 7.0).

In cases where the LSA remained uncovered, the pooled stroke incidence was 3.2% (95%

CI 1.0 to 6.1). There was, however, an indication for an increased pooled stroke incidence

following LSA coverage, with 5.3% (95% CI 2.6 to 8.6) for those with a revascularisation

versus 8.0% (95% CI 4.1 to 12.4) in those without revascularisation. The pairwise

comparison of the stroke incidence per treatment, using all available, information showed a

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risk ratio (RR) of covered and revascularised versus uncovered of 1.4 (95% CI 0.8 to 2.2), I2

= 37.4%. The RR of the two covered strategies without versus with revascularisation was

0.77 (95% CI 0.39 to 1.5), I2 = 38.9%. For those without revascularisation, the RR of covered

cases versus uncovered was 1.7 (95% CI 1.0 to 2.6), I2 = 79.9% showing a lower risk for

patients without LSA coverage. The corresponding forest plots are shown in supplemental

material.

Mortality rate

30-day mortality was available from nine studies and yielded a pooled mortality rate of 4.3%

(95% CI 1.9 to 7.5), but with high heterogeneity between the studies (I2=89.4%, P < 0.001).

Buth et al.27 did not report mortality. The corresponding forest plot is shown in Figure 4.

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Discussion

This systematic review, with meta-analysis, focused on post-operative stroke

incidencefollowing TEVAR for descending aortic aneurysms and has shown that stroke

affects at least one in every 25th patient, with an increased risk after coverage of the LSA

without revascularisation. Overall stroke incidenceoccurred in 4.1% of patients with a slightly

lower rate in cases where the LSA remained uncovered (3.2%), with an indication for an

increased stroke incidence following LSA coverage, with stroke in 5.3% patients after LSA

revascularisation rising to 8% in patients where the LSA was covered without

revascularisation. The larger studies reported higher stroke incidences.

A recent narrative review from Waterford et al.32 of stroke incidence following TEVAR

for various aortic pathologies focused on how stroke incidence varied with management of

the LSAstroke incidence. Their heterogeneous patient selection, together with inclusion of

duplicate patient data make generalisation of their findings difficult. In contrast, we restricted

our study to TEVAR for descending thoracic aortic aneurysms only. stroke incidenceWe

included fewer studies and less patients, partly because we restricted the aortic pathology

and excluded (according to protocol) small studies and those with duplicate patients. For

stroke incidence we still observed moderate heterogeneity with an I2 of 49.8% with smaller

studies reporting a lower stroke incidence, with lower heterogeneity. In a subgroup analysis

Waterford et al. reported pooled stroke incidence following TEVAR for all thoracic

aneurysms and found an overall increased stroke risk of 4.3% compared to TEVAR for

dissections (3.2%, P=0.043). Our review found a similar stroke risk of 4.1%, even though we

focused only on descending thoracic aneurysms and included two studies (Clough et al.22

and Maldonado et al.23) with 1016 patients, which had higher stroke incidences of 7.2 and

6.2%, respectively.

Waterford et al. stroke incidenceacknowledged that there are different approaches to

revascularise the LSA, some of which were associated with more extensive stentgraft

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coverage of the aortic arch, thus covering other supraaortic vessel branches. There is

evidence that stroke risk increases with the involvement of the aortic arch,33 probably due to

an increased risk of embolisation from a diseased arch. By including only descending

thoracic aortic aneurysms, we minimised this problem. Waterford et al.32 reported a stroke

incidence of 7.4% with LSA coverage compared to 4% in patients with devices deployed

distally to the LSA. In their review LSA coverage without revascularisation was associated

with a stroke incidence of 5.6%, while stroke incidence was 3.1% in those with LSA

revascularisation, but this difference did not reach statistical significance. In our review, we

observed a similar trend with a stroke incidence of 3.2% in uncovered situations compared

to an increased stroke incidence of 5.3% in those with covered and revascularised LSA and

8.0% in non-revascularised cases, a trend confirmed by another recent meta-analysis

looking specifically at revascularisation strategies in LSA coverage.34 Since we have

provided some evidence of publication bias, with the smaller studies reporting lower stroke

incidence, our inclusion of two larger studies (not included by Waterford), is likely to be an

important contributor to the higher stroke risks, which we report. On a real life population

basis, the stroke incidence may be even higher. The need for LSA coverage is an obvious

indicator for a more extensive procedure being associated with a higher adverse event rate.

A recent Cochrane database review also concluded that optimal management of LSA

coverage in TEVAR is still unknown.34

It has been suggested that strokes following LSA coverage were mainly due to

haemodynamic problems as a result of a compromised vertebral circulation. Ullery et al.35

looked specifically at stroke distribution in a series of 530 patients undergoing TEVAR for a

variety of aortic conditions. The risk of stroke in the posterior circulation was 6 times higher

in cases with LSA coverage (OR 6.11, 95% CI 1.15; 32.3) associated with increased

mortality (33% versus 0%) and a lower complete recovery rate (75% versus 17%) compared

to patients with a stroke in the anterior circulation.35 Revascularisation of the LSA seems a

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logical procedure to prevent particularly stroke in the posterior circulation. The present data

however cannot confirm that the stroke risk is significantly reduced by LSA revascularisation.

Other preventive measures towards mitigation of perioperative procedure-related

cerebral events, apart from LSA revascularisation, have not been investigated. The main

cause of cerebral lesions seems from embolisation of aortic debris from intravascular

manipulations, which is intrinsic to the procedure. The overall risk of embolisation is

significant, with a neuroimaging study identifying new cerebral lesions in almost two third of

patients following TEVAR.36 This risk is well known for many endovascular interventions that

are associated with navigation of the aortic arch with guidewires, catheters and even

delivery-systems and new mainly clinically undetected cerebral lesions have been reported

in up to 50% after carotid artery stenting37 and in more than 80% of cases following

transfemoral aortic valve implantation.38 This could be a particularly important research topic

for the future as this is a common feature for all endovascular treatment modalities with

aortic arch navigation and since long-term sequelae of such silent brain lesions are still

unknown.

Certain limitations of this review need to be acknowledged. First, some of the included

studies were not of very good quality. Second, reporting of stroke was heterogeneous not

formally requiring a radiological or specialised neurological assessment in all studies. Thus,

clinically less apparent strokes could have been underreported. Third, only insufficient data

relating to study subgroups, i.e. sex, were available, so that such relevant confounders might

have remained unrecognised. Fourth, we also may have included few patients with a

penetrating aortic ulcer (PAU), as this pathology was not always clearly separable from

aneurysms in the earlier publications. Whilst this might have introduced a certain bias as

patients with aortic ulcers show heavy atherosclerotic burden and are probably more prone

to dislodgment of embolic material, in the Illig study31 all the strokes occurred in the

aneurysm patients and none in the excluded PAU patients. Finally, although this study

strived to reduce heterogeneity by including descending aortic aneurysms only, moderate

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heterogeneity was found. This may be due to case-mix problems with smaller studies

including only easy cases whilst more complex cases were included in the larger and

multicentre studies.

In conclusion, stroke incidence is an important morbidity after TEVAR and more research is

needed to reduce the risk in the future, particularly where the LSA is to be covered.

Importantly, information on the actual stroke risk needs to be incorporated into patient

information sheets.

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Conflicts of interests:

None

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Figure Legend

Figure 1 PRISMA flow diagram

PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flow

diagram showing an overview of the study selection process

Figure 2 The effect size for the overall risk of stroke (within 30 days or in-hospital)

after thoracic endovascular aortic repair of descending artic aneurysms including the

95% confidence intervals.

Author, date, risk of stroke as a weighted summary proportion (95% CI) are shown. Studies

are listed by study size.

Figure 3 Funnel plot asymmetry used to determine publication bias

In this alternative Funnel plot, study size was used on the y-axis due to the acknowledged

risk of potentially misleading funnel plots for non-comparative meta-analyses when

traditionally constructed. The plot shows some evidence of bias with smaller studies

reporting a lower rate of strokes.

Figure 4

The effect size for the overall mortality (within 30 days or in-hospital) after thoracic

endovascular aortic repair of descending aortic aneurysms including the 95%

confidence intervals.

Author, date, risk of mortality as weighted summary proportion (95% CI) are shown.

26

Studies are listed by study size.

27

Figure 1

28

Studies included in qualitative and

quantitative synthesis (n= 10)

Full-text articles excluded (n=66) - Low number size, n=12

- No unique results*, n=21- Same patient population,

n=8- No separable data for

dTAA, n=22- Occlusive disease, n=1

Full-text articles assessed for eligibility

(n=76)

Records excluded (n =139)

Records screened (n=215)

Records after duplicates removed (n=215)

Additional records identified through other sources

(n=1)

Identificatio

Eligibility

Included

Screening

Records identified through database searching

(n=293)

Author replies (n=3)

466

29

467

Figure 2

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468

Figure 3

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Figure 4

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