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Meta-analysis and meta-regression analysis of outcomes of endovascular repair for
ruptured abdominal aortic aneurysm
Short title: Meta-regression analysis of EVAR for ruptured AAA
1Nikos Kontopodis MD, PhD, MSc, 2Nikos Galanakis MD, 3Stavros A. Antoniou MD, PhD, MPH,
FEBS, 2Dimitrios Tsetis MD, PhD, 1Christos V. Ioannou MD, PhD, 4,5Frank J. Veith MD, 6Janet T.
Powell MD, 7,8*George A. Antoniou MD, PhD, MSc, FEBVS
1Vascular Surgery Unit, Department of Cardiothoracic and Vascular Surgery, University
Hospital of Heraklion, University of Crete, Heraklion, Greece
2Department of Radiology, University Hospital of Heraklion, University of Crete, Heraklion,
Greece
3Department of Surgery, School of Medicine, European University Cyprus, Nicosia, Cyprus
4Department of Vascular Surgery, New York University Langone Medical Center, New York,
USA
5Department of Vascular Surgery, Cleveland Clinic, Cleveland, Ohio, USA.
6Vascular Surgery Research Group, Imperial College London, London, UK
7Department of Vascular and Endovascular Surgery, The Royal Oldham Hospital, Pennine
Acute Hospitals NHS Trust, Manchester, UK
8Division of Cardiovascular Sciences, School of Medical Sciences, University of Manchester,
Manchester, UK
Corresponding author:
Mr George A. Antoniou MD, PhD, MSc, FEBVS
Address: Surgical Offices, Phase 1, The Royal Oldham Hospital, Rochdale Road, Oldham OL1
2JH, UK, E-mail: [email protected], [email protected]
Word Count: 8434
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ABSTRACT
Background: The role and potential advantages of endovascular aneurysm repair (EVAR) in
the management of ruptured abdominal aortic aneurysm (AAA) is controversial. We aimed
to assess the perioperative mortality of EVAR versus open surgical repair for ruptured AAA
and investigate potential associations between time and institutional caseload and
outcomes.
Methods: We performed a systematic review that conformed to the Preferred Reporting
Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines using a registered
protocol (CRD42018106084). We selected studies reporting perioperative mortality data of
EVAR for ruptured AAA. We conducted a proportion meta-analysis of perioperative mortality
and obtained summary estimates of odds ratios (ORs) and 95% confidence intervals (CIs) for
EVAR versus open surgical repair using random-effects models. Mixed-effects regression
models were formed to investigate changes in outcomes over time and with institutional
caseload.
Results: We included 109 studies (4 randomized control trials) in quantitative synthesis
reporting a total of 183,956 patients (EVAR 33,146; open surgery 150,810). The pooled
perioperative mortality of EVAR and open surgical repair was 0.249 (95% CI 0.236 – 0.264)
and 0.391 (95% CI 0.377 – 0.404), respectively. EVAR was associated with reduced
perioperative mortality compared to open surgery (OR 0.54, 95% CI 0.51 – 0.57, P<0.0001).
Meta-regression analysis found decreasing perioperative mortality following EVAR
(P=0.0002) and open repair for ruptured AAA over time (P=0.0003), and a significant
association between the OR of EVAR versus open surgical repair for perioperative mortality
and the median study point, with the OR decreasing over time in favour of EVAR (P=0.0002).
Meta-regression also found a significant association between perioperative mortality and
institutional case load for open surgical repair (P=0.015) but not for EVAR (P=0.058).
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Conclusion: The outcomes of both EVAR and open surgical repair have improved, and the
difference in perioperative mortality in favour of EVAR has become more pronounced over
the years. There is a significant association between perioperative mortality and institutional
case load for open surgical repair of ruptured AAA but not for EVAR. If it can be done, EVAR
is a better treatment for ruptured AAA than open repair.
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INTRODUCTION
There is a sufficient body of evidence demonstrating an early survival advantage of elective
endovascular treatment for abdominal aortic aneurysm (AAA) over conventional surgical
repair.[1] However, the role and potential advantages of endovascular aneurysm repair
(EVAR) in the management of ruptured AAA remains controversial.[2] Even though
prospective and retrospective observational cohort studies and national/international
registries and administrative databases have demonstrated a reduced perioperative
mortality with EVAR for ruptured AAA compared to open surgery,[3,4] randomized clinical
trials have failed to show a similar benefit.[5,6] EVAR has the theoretical advantage of
avoiding aortic cross-clamping, ischaemia-reperfusion injury, hypothermia, large vessel
injury and increased blood loss which may add to the physiologic insult of rupture.
Moreover, EVAR can be performed under local anaesthesia, obviating the effects of
vasodilatation and reduced systemic resistance that are often seen with general anaesthesia.
However, patient- (e.g. age or comorbid burden) and/or aneurysm-related factors (e.g.
anatomy, intra or retroperitoneal rupture and haemodynamic status) may have an
additional or even more eminent prognostic role in cases of AAA rupture than the type of
surgery. Recent guidelines of the Society for Vascular Surgery recommend an EVAR-first
approach in patients with ruptured AAA, acknowledging a low quality of evidence for this
recommendation.[7]
Time trends can provide an insight into the optimal management strategy for
ruptured AAA. With the accumulated experience and improved skills with EVAR, the
development of specialized aortic centres, advances in endovascular techniques and
technology, and new generation aortic devices, outcomes of EVAR for ruptured AAA may be
expected to improve with time. Furthermore, advances in the care of the critically ill patient
and enhanced anaesthetic management may have resulted in improved outcomes of
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patients with ruptured AAA. Even though there is evidence to support improved survival
after elective treatment for AAA,[8] it remains unknown whether surgical treatment of AAA
in the emergency setting is associated with similar improvements over time. Anecdotal
evidence from recent observational studies suggests that periprocedural mortality of
ruptured AAA has not changed significantly over the years.[3,9,10]
High institutional case volume has also been shown to be related to improved
outcomes for elective cases of AAA treatment.[11-13] Models of service delivery have
undergone reconfiguration in several countries to accommodate optimum elective AAA
services. It is likely that centers with instituted protocols, reflecting advanced healthcare
delivery infrastructure, have superior outcomes with endovascular or open management of
ruptured AAA, but there is insufficient evidence to quantify a potential association between
institutional case load and outcomes in ruptured AAA.
OBJECTIVES
Our primary objective was to investigate the perioperative mortality after endovascular
repair of ruptured AAA. The secondary objectives were:
1. To examine whether the perioperative mortality for ruptured AAA has changed over
time.
2. To examine whether there is an association between centre volume and
perioperative mortality for ruptured AAA.
METHODS
Design
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The objectives and methodology of our review were prespecified in a protocol, which we
registered with the registration number CRD42018106084 at the International Prospective
Register of Systematic Reviews in Health and Social Care (PROSPERO).[14] We conducted
and reported our review in accordance with the Preferred Reporting Items for Systematic
Reviews and Meta-Analyses (PRISMA) guidelines.[15]
Criteria for considering studies
Types of studies
We considered single-arm or comparative observational cohort studies and randomized
control trials (RCTs) reporting outcomes of endovascular repair for ruptured AAA. We
excluded case studies of less than 5 patients treated for ruptured AAA. Studies reporting on
a specific subpopulation of patients with ruptured AAA (e.g. those using an age criterion or
examining only stable or unstable patients) were also not included.
Types of participants
Eligible participants were male or female patients of any age undergoing interventional
treatment for ruptured infrarenal AAA. We did not consider patients presenting with
symptoms related to the AAA but no confirmed rupture on diagnostic imaging investigations
or laparotomy. We also excluded patients with pararenal or suprarenal aortic aneurysms
requiring complex endovascular or open surgery (e.g. endovascular repair with the chimney
technique). Ruptured AAA following previous EVAR (secondary rupture) was not an
exclusion criterion.
Types of intervention
The intervention of interest was standard EVAR. Such treatment could be performed with
any commercially available bifurcated or aorto-uni-iliac device. EVAR could be performed
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with any type of anaesthesia (local, regional or general) using a percutaneous access to or
surgical exposure of the femoral arteries. For comparative studies, the comparator
intervention was open surgical repair with a transperitoneal or retroperitoneal exposure.
Types of outcome measures
Primary outcomes
The primary outcome measure was in-hospital mortality or mortality occurring within 30
days of EVAR, referred to as perioperative mortality throughout.
Secondary outcomes
Secondary outcome measures were the following:
1. Mortality trend over time for patients treated with endovascular and open surgery.
2. The association between primary outcome of interest and volume of procedures for
ruptured AAA in the participating centers.
Search methods for identification of studies
We conducted an electronic literature search using the National Library of Medicine’s
database (MEDLINE), the Cochrane Register of Studies (CRS) (CENTRAL) and OpenGray. We
applied a combination of controlled vocabulary (Expanded Medical Subject Headings
(MeSH)) and free text terms to identify relevant studies using Boolean operators as
appropriate. There were no language restrictions. The last search was run in June 2018. A
second level search consisted of manual interrogation of the reference list of selected
articles and relevant reviews to identify additional sources of data.
Selection of studies and data management
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Primary selection of relevant studies was based on title and abstract. We performed a
secondary selection according to the full text of publications. Assessment of eligibility was
performed by two review authors (NK, NG) independently. The outcomes of study selection
were then assessed for consistency. Discrepancies in results were discussed between the
review authors conducting the searches; a third review author (GA) arbitrated in case of
disagreement.
We specified data to be extracted in advance using an electronic data extraction
template. One review author (NK) extracted data from selected studies. The collected data
were then crosschecked by a second review author (NG). We tabulated the extracted data
using spreadsheets from Microsoft Excel. Data were retrieved from the main text, tables or
graphs of the selected articles. We considered published data only and made no attempt to
obtain missing data by contacting authors of the primary studies. We extracted the following
information:
1. Study-related data: 1st author, journal and year of publication, study period, study
design (observational study or RCT, prospective or retrospective study design, study
reporting administrative datasets or registries), single- or multicentre study, sample
size (number of patients with ruptured AAA undergoing EVAR or open surgical
repair).
2. Data pertaining to risk of bias assessment (see “Assessment of risk of bias of
included studies” section).
3. Outcome data, as outlined in the “Criteria for considering studies” section.
Assessment of risk of bias of included studies
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We used the risk of bias tool developed by the Cochrane Collaboration to assess the risk of
bias of selected RCTs.[16] The tool evaluates 6 main domains: random sequence generation
and allocation concealment (selection bias), blinding of participants and personnel
(performance bias), blinding of outcome assessment (detection bias), incomplete outcome
data (attrition bias), selective reporting (reporting bias), and other sources of bias.
The methodological quality of observational cohort studies was assessed with the
Newcastle-Ottawa scale (NOS).[17] Using the tool, each study was judged on eight items,
categorized into three groups: the selection of the study groups, the comparability of the
groups, and the ascertainment of outcome of interest. Stars awarded for each quality item
served as a quick visual assessment. Stars were awarded such that the highest quality
studies were awarded up to nine stars.
The risk of bias assessment was performed independently by two review authors
(NK, NG). A third review author (GA) acted as an adjudicator in the event of disagreement.
Data synthesis
Measures of treatment effect and data synthesis
We pooled the primary outcome endpoint (in-hospital or 30-day mortality) in the entire
review population by meta-analyzing data from individual studies. The pooled proportion
was calculated as the back transformation of the weighted mean of the transformed
proportions.
We also conducted a meta-analysis of comparative studies for perioperative
mortality of EVAR versus open surgical repair. Analysis was carried out using the odds ratio
(OR) as the summary statistic, and the precision of the effect was reported as 95%
confidence interval (CI). In view of the anticipated variability in intervention effect in
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different studies, mainly as a consequence of clinical or methodological diversity among the
selected studies, we calculated the summary estimates using the random-effects models of
DerSimonian and Laird.[18]
Furthermore, we conducted separate meta-analyses of risk-adjusted comparative
observational studies for in-hospital or 30-day mortality using the inverse-variance method
and reported the result as summary OR and associated 95% CI. Acceptable risk-adjustment
methods included propensity score analyses and multivariate logistic regression models.
Unit of analysis
The unit of analysis was the individual patient.
Assessment of heterogeneity
In-between study heterogeneity was examined with the Cochrane’s Q (χ2) test. We
quantified inconsistency by calculating I2 and interpreted it using the following guide: 0% to
40% might not be important; 30% to 60% may represent moderate heterogeneity; 50% to
90% may represent substantial heterogeneity; and 75% to 100% may represent considerable
heterogeneity.[19]
Reporting or publication bias
For each study, we plotted the effect by the inverse of its standard error. We assessed
publication bias both visually evaluating the symmetry of the funnel plot and mathematically
using the Egger’s regression intercept.
Sensitivity and subgroup analysis
We conducted a separate meta-analysis of observational cohort studies, multicentre
registries / administrative datasets and RCTs and tested for subgroup differences.
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Furthermore, we conducted separate meta-analyses of RCTs based on intention-to-treat and
treatment received. We also developed separate meta-analysis models for studies that
reported 30-day mortality data and for those reporting in-hospital mortality and tested for
subgroup differences.
We pre-specified additional analyses (sensitivity analyses) to assess the robustness
of our results. We explored the contribution of risk of bias or methodological quality by
removing studies that were judged to be high risk of bias in two or more domains using the
Cochrane Collaboration’s risk of bias tool, or of moderate or low quality as judged using the
NOS.
We had planned to perform subgroup analysis for primary versus secondary rupture
and for treatments in patients with friendly versus hostile aortic anatomy, if pertinent data
were available.
Meta-regression analysis
We formed meta-regression models to explore potential heterogeneity as a result of
changes in practice over time and centre volume. As moderators, we used the individual
mid-study point and the number of EVARs or open surgical repairs performed in single-
centre studies per year during the study period. The mid-time study point was considered to
be a more representative and relevant indicator of the period during which the results of
each report were obtained and was therefore preferred over year of publication for the
statistical analysis. We examined the impact of mid-study point and centre volume on the
primary outcome parameter (perioperative mortality) for EVAR, open surgical repair and the
difference in the outcome of interest between EVAR and open surgical repair. The slope
coefficient and the p-value were calculated for each covariate against the outcome of
interest. The p-value indicates significance of a possible association, while the slope
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determines strength of the association (i.e. the extent to which the outcome changes per
unit change of the covariate).
Statistical software
We used the following statistical software for data analysis: Review Manager (RevMan)
[Computer program]. Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane
Collaboration, 2014; and Comprehensive Meta-Analysis (CMA) software (Biostat,
Englewood, NJ, USA).
RESULTS
Results of the literature search
Search of the literature applying the defined strategy retrieved 1,021 reports. One-hundred-
and-nine studies fulfilled the inclusion criteria and were included in qualitative and
quantitative synthesis (Appendix 1). The study selection process is presented in a flow
diagram (Figure 1).
Description of studies
Ninety-two studies were comparative and the remaining 17 were single-arm observational
studies. The majority of the comparative studies had an observational design with only 4
being randomized clinical trials. We identified 25 reports of national / international registries
and / or administrative datasets. The remaining observational studies were conducted in a
single (69 studies) or multiple centres (11 studies). The selected studies were published
between 2002 and 2018, whereas the study recruitment period spanned from 1994 to 2016.
The total number of patients recruited in the 4 RCTs was 868, of whom 316 underwent
EVAR, 457 open surgical repair, and the rest had no interventional treatment or had other
discharge diagnosis. Administrative databases reported a total of 174,597 patients (29,300
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underwent EVAR and 145,297 open surgery), and the remaining observational studies
reported a total of 8,586 patients (3,530 underwent EVAR and 5,056 open surgery). The
study characteristics are summarized in Table 1.
Risk of bias in included studies
The risk of bias of the 4 RCTs was judged to below in most domains except the selection
domain, in which the random sequence generation and allocation concealment was
inadequate or unclear in ECAR and Hinchliffe trial. (Appendix 1, References 22, 38, 73, 76).
Even though blinding was not possible because of the nature of intervention, we considered
that lack of blinding was unlikely to have influenced results (low risk of performance and
detection bias). All trials provided sufficient details and reasoning about subjects that were
included or excluded from the analysis and reported all outcomes of interest and were
therefore judged to be of low risk of attrition and reporting bias (Figure 2a and 2b). Support
for judgment is provided in Appendix 2.
Using to the NOS assessment, the median value of stars allocated to each study was
6 (range,4 – 9]. In most reports, the comparability of cohorts on the basis of design and
analysis was inadequate. Some studies considered haemodynamic instability as a contra-
indication to computed tomography (CT) and a relative indication for open surgery, which
almost certainly influenced the results. Other studies reported outcomes in patient cohorts
after implementing an EVAR protocol for ruptured AAA and compared the results to those of
open surgical repair in historic controls. Representativeness of the exposed cohort and
selection of the non-exposed cohort was therefore judged to be inadequate. The quality
assessment of cohort studies is summarized in Table 2.
Effects of interventions
Primary outcomes
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The pooled perioperative mortality estimate for EVAR was 0.249 (95% CI 0.236 – 0.264). The
between-study statistical heterogeneity was significant (P<0.0001, I2=80%), and the
likelihood of publication bias was high (P=0.017). The pooled perioperative mortality
estimate for open surgical repair was 0.391 (95% CI 0.377 – 0.404). The statistical
heterogeneity was significant (P<0.001, I2=92%), but the likelihood of publication bias was
low (P=0.299).
Pooled overall analysis of comparative studies found that EVAR had a significantly
lower perioperative mortality than open surgical repair (OR 0.54, 95% CI 0.51 – 0.57,
P<0.0001), with similar findings for randomized trials and registry/administrative study
databases only. The statistical heterogeneity was moderate (P<0.0001, I2=47%), and the
publication bias was significant (P=0.007).The forest and funnel plots of comparison of EVAR
versus open surgical repair are presented in Figure 3a, b and c and Figure 4.
Meta-analysis of studies that reported adjusted ORs for perioperative mortality
using the inverse-variance method showed a significantly reduced mortality with EVAR
compared with open surgical repair (OR 0.52, 95% CI 0.46 – 0.59, P<0.0001). The statistical
heterogeneity was considerable (P<0.0001, I2=63%) (Supplementary Figure 1).
Secondary outcomes
Time trend
Meta-regression analysis found that the perioperative mortality following EVAR for ruptured
AAA has decreased over time, and the association between perioperative mortality and the
median study point was significant (slope P=0.0002, Q=13.66, df=1.0) (Figure 5a). Similarly,
meta-regression analysis showed that the perioperative mortality rate of open surgical
repair for ruptured AAA has decreased over time with a significant association between the
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primary outcome of interest and the median study point (slope P=0.0003, Q=12.97, df=1.0)
(Figure 5b).
Meta-regression analysis of comparative data found a significant association
between perioperative mortality and the median study point, with the OR of perioperative
mortality decreasing over time in favour of EVAR (slope P=0.0002, Q=13.94, df=1.0)
(Figure5c).
Institutional case load
Meta-regression analysis with centre volume per year as covariate found no significant
association between perioperative mortality and the number of EVAR cases per institution
(slope P=0.058, Q=3.568. df=1.0) (Figure 5a). Similar analysis found a significant association
between perioperative mortality and institutional case load of open surgical repair per year,
with a decreasing mortality in centres reporting a higher case load (slope P=0.015, Q=5.973,
df=1.0) (Figure 5b).
Meta-regression analysis found no significant association between the OR for
perioperative mortality of EVAR versus open surgery and institutional case volume per year
(slope P=0.088, Q=2.911, df=1.0) (Figure 5c).
Sensitivity and subgroup analysis
Meta-analysis of observational cohort studies found a significant difference in perioperative
mortality in favour of EVAR (OR 0.44, 95% CI 0.39 – 0.50, P<0.0001). Similarly, meta-analysis
of registries / administrative databases showed that EVAR was associated with reduced
perioperative mortality compared to open surgical repair (OR 0.57, 95% CI 0.54 – 0.61,
P<0.0001). Meta-analysis of RCTs considering the intervention that subjects actually received
revealed a perioperative survival advantage of EVAR over open surgical repair (OR 0.67, 95%
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CI 0.48 – 0.92, P=0.02). Intention-to-treat analysis of the RCTs indicated no difference in the
outcome of interest between EVAR and open surgical repair (OR 0.89, 95% CI 0.67 – 1.18,
P=0.41) (Supplementary Figure 2). Test for subgroup differences found significant
differences in pooled perioperative mortality analysis between single- / multicentre
observational studies, registries / administrative datasets and RCTs (P=0.0009).
The results of meta-analysis of studies reporting 30-day and those reporting in-
hospital mortality are presented in Supplementary Table 1. The pooled estimate of in-
hospital mortality was higher than that of 30-day mortality for both EVAR and open surgical
repair, and the subgroup differences was significant. Furthermore, the OR for in-hospital
mortality was higher than that for 30-day mortality, and the test for subgroup differences
was significant.
Sensitivity analysis excluding comparative observational studies that scored <7 stars
in the NOS scale did not affect the direction of the pooled estimate (OR 0.56, 95% CI 0.52 –
0.60, P<0.0001) (Supplementary Figure 3). Furthermore, sensitivity analysis excluding the
ECAR trial that was judged to be of high risk of bias in two domains did not affect the
direction of effect estimate (OR 0.66 95% CI 0.47-0.94, P=0.02) (Supplementary Figure 4).
DISCUSSION
We conducted a systematic review of the literature and collated outcome data from 105
observational studies and 4 RCTs reporting a total of 33,146 patients with ruptured AAA
treated with EVAR and another 150,810 patients with ruptured AAA treated with open
surgical repair. Our review attempted to reach conclusions despite very divergent results
from various centers with different variables. We found that EVAR was associated with a
significantly reduced perioperative mortality compared to open surgical repair, although this
may result, at least in part, from the morphological selection bias for EVAR. Thus, we should
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say “If one can treat a RAAA patient wih EVAR, it will yield better results than if one treats a
patient with open repair.” We also found that the perioperative mortality of both EVAR and
open surgical repair for ruptured AAA has decreased over time. Furthermore, meta-
regression found that a high institutional case load was associated with decreased
perioperative mortality for open surgical repair but not for EVAR. There was a significant
difference in intervention effect when subgroup analysis was conducted for observational
studies, registries / administrative databases and RCTs, with the former two demonstrating a
higher intervention effect than randomized clinical trials.
The difference in perioperative mortality in favour of EVAR was confirmed in a
separate meta-analysis of RCTs when the intervention received was considered but not
when intention-to-treat analysis was undertaken. The IMPROVE trial has been criticized for
assigning patients to a treatment strategy before suitability for EVAR was determined; for
the purposes of the analysis, patients stayed in the allocated treatment arm even if they
switched from one treatment modality to the other.[20] Of the 316 patients allocated to
EVAR, only 154 (49%) actually underwent EVAR with a mortality rate of 27%; another 112
patients were judged unsuitable for EVAR and underwent open surgery with a mortality rate
of 38%; 33 patients had other diagnosis, and 17 patients died before any intervention could
be undertaken. Of the 297 patients randomized to open surgical repair, 220 (74%)
underwent the allocated treatment with a mortality rate of 37%; another 36 patients
underwent EVAR with a mortality rate of 22%; 22 patients had other diagnosis, and 19
patients died shortly after admission and had no repair. Criticizers of the IMPROVE trial
support that intention-to-treat and intervention-received groups are not comparable, which
may confound conclusions. Another perspective of the issue is that the IMPROVE trial is a
pragmatic trial representing real-world practice, which evaluates current management of
ruptured AAA. On the contrary, in the ECAR and AJAX trials, randomization took place after
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initial investigation with CT to establish the diagnosis and assess suitability for EVAR. In the
AJAX trial, there were two cross-overs from EVAR to open surgical repair, but separate
information on these two patients is not provided. Hinchliffe et al employed a design similar
to that of the IMPROVE trial, where anatomic suitability for EVAR was determined after
randomization. Sensitivity analysis of RCTs excluding the IMPROVE and Hinchliffe et al trials
showed no significant difference in perioperative mortality between EVAR and open surgical
repair (OR 0.75, 95% CI 0.39 – 1.41, P=0.37). The ECAR and AJAX trials have been criticized
for excluding patients because of haemodynamic instability, who may be precisely the
patients who may derive a mortality benefit if they were treated by EVAR. Previous
systematic reviews and meta-analyses of the 4 RCTs based their analysis on intention-to-
treat data only and, similar to our results, found no survival benefit of EVAR over open
surgical repair at 30-days.[5,6] An individual patient data meta-analysis that was based on
intention-to-treat data, found an early (at 30 and 90 days) survival advantage of EVAR for
women only.[6]
Meta-analysis of observational studies found a significant perioperative survival
advantage of EVAR compared to open surgery for ruptured AAA. Despite their inherent
limitations, the most important being selection bias, observational studies represent real-
world practice reporting a large number of patients across different institutions. In an
attempt to minimize selection bias, we conducted a separate meta-analysis of risk-adjusted
outcomes and found a significantly reduced perioperative mortality of EVAR compared to
open surgery. The confounding factors for which adjustments were made mostly concerned
preoperative haemodynamic status, demographics (age, gender), comorbidities, aneurysm
morphometric characteristics, and year of the procedure.
It is well recognized that cases started with EVAR but then converted to open repair
carry very high mortality. It is a limitation of most observational studies that they do not
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report whether such cases are included in the EVAR or open repair patients. With the
increasing utilization of EVAR to treat AAA, secondary ruptures following endovascular
treatment are likely to be seen more often. It can be postulated that secondary rupture after
previous EVAR may have a higher associated perioperative mortality due to technical
challenges, but there are no data available to draw definite conclusions. Only three studies
included in our review explicitly reported that they included patients undergoing treatment
for secondary rupture but they provided no data suitable for subgroup analysis.[Appendix 1,
References 16,18,51]
Another critical issue that may confound our results is anatomic suitability for EVAR,
with open repair cases having more challenging and difficult anatomy.[21] Most studies
considered aneurysm morphology prior to assigning patients to treatment, offering EVAR in
patients with a more favorable aortic anatomy. None of the observational studies provide
separate information on patients with favourable aortic anatomy undergoing EVAR or open
surgery, thus subgroup analysis is not possible. Of the RCTs, the ECAR and AJAX trials
randomized only patients who were eligible for EVAR. They also excluded patients in shock.
Therefore, the equivalent results of EVAR and open repair (OR 0.75, 95% CI 0.39 – 1.41,
P=0.37) may have not reflected the improved mortality that could have been afforded these
higher risk patient groups.
A key finding of our analysis is the decreasing perioperative mortality of EVAR over
the years. Another interesting finding is that, even though a similar improvement in
perioperative mortality was noticed for open surgical repair of ruptured AAA, the difference
in perioperative mortality between EVAR and open surgery in favour of the former became
more pronounced over the years. This is not surprising considering the accumulated
experience and improved skills with endovascular techniques, the availability of new
generation aortic devices and the establishment of institutional treatment protocols that
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allow a rapid diagnosis, transportation and definite management of patients with ruptured
AAA. Even though a similar time trend has been reported for EVAR undertaken in the
elective setting,[8] previous meta-regression analyses failed to identify a significant
improvement in perioperative mortality of EVAR for ruptured AAA.[3,9,10] The significant
association found in our analysis may be explained by the relatively larger number of
patients and the broader time span of reported data extending from 1994 to 2016, allowing
the evaluation of the impact of 3rd generation aortic devices and new technologies on
perioperative outcomes of ruptured AAA. This is of particular importance in a constantly
evolving field where data accumulate rapidly rendering information outdated or irrelevant.
The decreasing perioperative mortality of open surgical repair for ruptured AAA
reflects improvements in diagnostics, transport, treatment protocols, better anaesthetic
management and perioperative care of the critically ill patient. A previous report published
more than 10 years ago failed to demonstrate such an association, indicating that advances
in the care of the ruptured AAA patient may have taken place in the past two decades.[22]
Differences in perioperative mortality between EVAR and open surgery have become more
pronounced in favour of EVAR over the years, which adds to the evidence base for applying
an EVAR-first policy in the management of ruptured AAA.
Our analysis found improved perioperative mortality in high volume centres for
open surgery but not for emergency EVAR. Such an association has previously been
demonstrated for elective treatment of AAA,[11,12] which may be extrapolated to the
emergency treatment for ruptured AAA, since the evidence demonstrating an association
between institutional case load and mortality in emergency settings is scarce.[13] With the
ever decreasing number of elective open AAA repair performed worldwide and rapidly
expanding use of EVAR, experience in open surgery has reduced dramatically resulting in
diminished skills of surgical and anaesthetic teams performing open repairs.[23,24]
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There was variability in the reported outcome among the studies, with some
reporting 30-day, others reporting in-hospital and some mixed mortality data. Subgroup
analysis showed that the OR for in-hospital mortality in favour of EVAR was higher than that
for 30-day mortality. Thirty-day mortality seems to be a more accurate outcome measure,
particularly taking into account that discharge policies may have changed with time.
The findings of our study should be interpreted in the context of its strengths and
limitations. We conducted a comprehensive review of the literature and analysis of the
largest to date cohort of patients with ruptured AAA undergoing treatment. The analysis is
limited by the observational design of most of the studies, many of which are retrospective,
with the inherent limitation of selection bias. Observational studies and registries /
administrative databases, however, represent real-world practices. Another limitation is the
inconsistency in reporting clinical parameters, such as haemodynamic instability, and the
possibility of different demographics and clinical characteristics of patients that underwent
EVAR or open surgery. We attempted to circumvent this issue by conducting a separate
analysis of RCTs and analysis of studies that performed adjustment for potential
confounding factors. Furthermore, we noted considerable between-study statistical
heterogeneity representing clinical and methodological diversity, such as different treatment
algorithms, levels of experience and expertise among institutions, and different study
designs. We found evidence of publication bias for studies reporting perioperative mortality
data for EVAR but not for open surgical repair, reflecting the possibility of selective reporting
of favorable results after endovascular treatment of ruptured AAAs.
CONCLUSIONS
Available data indicate that perioperative mortality after EVAR is lower than after open
surgery for ruptured AAA. The outcomes of both treatments have improved significantly
over the years as has the difference in perioperative mortality in favour of EVAR. There is a
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significant association between perioperative mortality and institutional case load for open
surgical repair of ruptured AAA, but not for EVAR. Our analysis supports the wider use of
EVAR for the treatment of ruptured AAA. Further research should focus on clinical and
anatomic factors that have a potential impact on outcomes of EVAR or open surgery for
ruptured AAA.
Funding: None
Conflicts of Interest: None to declare
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11. McPhee JT, Robinson WP 3rd, Eslami MH, Arous EJ, Messina LM, Schanzer A.
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Author Journal Year Study period Type of study Design
Outcome (type of mortality reported)
Secondary Ruptures
Briggs J Vasc Surg. 2018 2012-2016 Retrospective Comparative 30-day Not reported
Fujimura J Vasc Surg. 2018 2012-2016 Retrospective Single-arm 30-day Not reported
Wang Medicine (Baltimore) 2018 2005-2015 Retrospective Comparative 30-day Excluded
Butz-Lilly Eur J Vasc Endovasc Surg 2017 2010-2013 Registry Comparative 30-day OR in-
hospital Not reported
Chen J Vasc Surg. 2017 2011-2014 Registry Single-arm 30-day Not reported
Kansal Vascular 2017 1999-2015 Retrospective Single-arm 30-day Not reported
Kapma J Cardiovasc Surg 2017 Retrospective Comparative 30-day Not reported
Papazoglou J Cardiovasc Surg 2017 2010-2013 Retrospective Single-arm 30-day Not reported
Schechter Ann Vasc Surg. 2017 2000-2011 Retrospective Comparative 30-day Not reported
Adkar J Vasc Surg. 2016 2005-2013 Registry Single-arm 30-day Not reported
Aziz Ann Vasc Surg. 2016 2005-2010 Registry Comparative 30-day Not reported
Broos J Endovasc Ther 2016 1998-2012 Retrospective Single-arm 30-day Excluded
De Rango Eur J Vasc Endovasc Surg 2016 2006-2015 Prospective Comparative 30-day Not reported
Guo Ann Vasc Surg. 2016 2003-2014 Retrospective Comparative 30-day Not reported
Gurnason Eur J Vasc Endovasc Surg 2016 2008-2012 Registry Comparative 30-day Not reported
Healey Ann Vasc Surg. 2016 2006-2015 Registry Comparative 30-day Not reported
Hultgren World J Surg 2016 2009-2013 Retrospective Comparative 30-day Not reported
Martinez Chir Espan 2016 2002-2014 Retrospective Comparative 30-day Not reported
Robinson J Vasc Surg. 2016 2003-2013 Registry Comparative In-hospital Excluded
Soden J Vasc Surg. 2016 2011-2013 Registry Comparative 30-day Excluded
Spanos Ann Vasc Surg. 2016 2006-2011 Retrospective Comparative 30-day Not reported
Taylor NZMJ 2016 2010-2014 Registry Comparative In-hospital Not reported
Thompson J Vasc Surg. 2016 2005-2014 Retrospective Comparative Not reported Not reported
Tremont Vasc Endovasc Surg. 2016 2005-2009 Registry Comparative 30-day AND In-
hospital Not reported
Warner Ann Surg. 2016 2002-2015 Retrospective Comparative 30-day Not reported
Ali J Vasc Surg. 2015 2003-2013 Registry Comparative In-hospital Not reportedDesgranges
(ECAR)Eur J Vasc
Endovasc Surg 2015 2008-2013 RCT Comparative 30-day Not reported
Dunvjak D Med J 2015 2012-2013 Retrospective Comparative 30-day Not reported
Kucukay Eur J Radiol. 2015 2008-2014 Retrospective Single-arm 30-day Not reported
McHugh Surgeon 2015 2008-2012 Retrospective Comparative Not reported Not reported
Oyague Ann Vasc Surg. 2015 2009-2013 Retrospective Comparative 30-day Not reported
Spencer West J Emerg Med. 2015 2005-2010 Retrospective Comparative Not reported Not reported
Van Beek Eur J Vasc Endovasc Surg 2015 2004-2011 Retrospective Comparative In-hospital Not reported
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3
Edwards J Vasc Surg. 2014 2001-2008 Registry Comparative 30-day OR In-hospital Not reported
Gulu Chirurgia 2014 2004-2012 Retrospective Single-arm In-hospital Not reported
Gupta J Vasc Surg. 2014 2005-2010 Registry Comparative 30-day Not reported
Meijenfeldt Eur J Vasc Endovasc Surg 2014 2000-2013 Retrospective Comparative 30-day OR in-
hospital Excluded
Powel (Improve) BMJ 2014 2009-2013 RCT Comparative 30-day Excluded
Raupach Vasc Endovasc Surg 2014 2010-2013 Retrospective Comparative 30-day Not reported
Rollins BMJ 2014 2006-2012 Retrospective Comparative 30-day Not reported
Speicher Ann Vasc Surg. 2014 2005-2011 Registry Comparative 30-day Not reported
Ulus Vasc Endovasc Surg 2014 2006-2013 Retrospective Comparative 30-day Excluded
Antonopoulos Ann Vasc Surg. 2013 2006-2012 Retrospective Comparative In-hospital Not reported
Fosaceca Cardiovasc Interv Radiol 2013 2005-2012 Retrospective Single-arm 30-day Not reported
Mehta J Vasc Surg. 2013 2002-2011 Retrospective Comparative 30-day Not reported
Mohan Cardiovasc Interv Radiol 2013 2001-2010 Registry Comparative In-hospital Not reported
Park J Am Coll Surg 2013 2005-2009 Registry Comparative In-hospital Not reportedReimerick (AJAX) Ann Surg 2013 2004-2011 RCT Comparative 30-day Not reported
Wallace J Vasc Surg. 2013 2007-2012 Retrospective Comparative In-hospital Not reported
Wu Heart Vessels 2013 2005-2012 Retrospective Comparative 30-day Not reported
Guzzardi Vascular 2012 2005-2008 Retrospective Single-arm 30-day Not reported
Ioannidis Int Angiol 2012 2003-2008 Retrospective Comparative 30-day AND In-hospital Not reported
Mayer Ann Surg 2012 1998-2011 Retro Prospe data Comparative 30-day Not reported
Nedeau J Vasc Surg. 2012 2000-2010 Retrospective Comparative 30-day OR in-hospital Not reported
Noorani Eur J Vasc Endovasc Surg 2012 2006-2010 Retrospective Comparative In-hospital Not reported
Saqib J Vasc Surg. 2012 2001-2010 Retrospective Comparative 30-day OR in-hospital Not reported
Ten Bosch Vascular 2012 2002-2008 Retrospective Comparative 30-day Not reported
Conroy Persp Vasc Surg 2011 1994-2008 Retrospective Single-arm 30-day Not reported
Mani Eur J Vasc Endovasc Surg 2011 2005-2009 Registry Comparative 30-day OR In-
hospital Not reported
Sarac Ann Vasc Surg. 2011 1990-2008 Retrospective Comparative 30-day Excluded
Van Schaik J Cardiovasc Surg 2011 2006-2008 Retrospective Comparative 30-day Not reported
Chapgar Vasc Endovasc Surg 2010 2003-2008 Retrospective Comparative 30-day Not reported
Cho J Vasc Surg. 2010 2001-2008 Retrospective Comparative 30-day OR In-hospital Included
Davenpont J Vasc Surg. 2010 2005-2007 Registry Comparative 30-day Not reported
Holt BJS 2010 2003-2008 Registry Comparative In-hospital Not reported
Lyons Vascular 2010 2006-2007 Retrospective Comparative 30-day Included
Starnes J Vasc Surg. 2010 2007-2009 Prospective Comparative 30-day AND In-hospital Not reported
Coppi J Vasc Surg. 2009 1999-2007 Retrospective Comparative 30-day Included
Giles J Endovasc Ther 2009 2005-2007 Registry Comparative 30-day Not reported
Giles J Endovasc Ther 2009 2000-2005 Registry Comparative In-hospital Not reported
Holst Eur J Vasc Endovasc Surg 2009 2000-2007 Retrospective Single-arm 30-day Not reported
28
Makar J Vasc Surg. 2009 2004-2007 Prospective Comparative Not reported Not reported
McPhee J Vasc Surg. 2009 2001-2006 Registry Comparative In-hospital Not reported
Richards Eur J Vasc Endovasc Surg 2009 1994-2007 Retrospective Single-arm 30-day Not reported
Veith Ann Surg 2009 2001-2006 Retrospective Comparative 30-day Not reported
Verhoven Torino 2009 2002-2009 Retrospective Comparative Not reported Not reported
Visser J Vasc Surg. 2009 2004-2006 Prospective Comparative 30-day Not reported
Vogel Vasc Endovasc Surg 2009 2001-2005 Registry Comparative In-hospital Not reported
Vun Vascular 2009 2004-2008 Retrospective Comparative In-hospital Not reported
Lee Rich Ann Vasc Surg. 2008 2002-2006 Retropsective Comparative 30-day OR in-hospital Not reported
Lesperance J Vasc Surg. 2008 2003-2004 Registry Comparative In-hospital Not reported
Sadat Eur J Vasc Endovasc Surg 2008 2006-2007 Retrospective Comparative In-hospital Not reported
Acosta Eur J Vasc Endovasc Surg 2007 2000-2004 Retrospective Comparative In-hospital Not reported
Anain J Vasc Surg. 2007 2001-2006 Retrospective Comparative 30-day Not reportedHassen-Khodja J Cardiovasc Surg 2007 2004-2005 Retrospective Single-arm 30-day Not reported
Moore J Vasc Surg. 2007 2004-2006 Prospective Comparative 30-day Not reported
Najjar Arch Surg 2007 2000-2005 Retrospective Comparative 30-day Not reported
Ockert J Endovasc Ther 2007 2000-2005 Retrospective Comparative 30-day Not reported
Sharif J Endovasc Ther 2007 2001-2006 Retrospective Comparative 30-day OR in-hospital Not reported
Van der Viet Vascular 2007 2004-2006 Prospective Comparative 30-day Not reported
Van Marle S Afr J Surg 2007 2003 Retrospective Single-arm 30-day Not reported
Arya J Vasc Surg. 2006 2002-2004 Prospective Comparative In-hospital Not reported
Dalainas WJS 2006 1998-2005 Retrospective Comparative 30-day Not reported
Franks Eur J Vasc Endovasc Surg 2006 1996-2003 Retrospective Comparative 30-day Not reported
Greco J Vasc Surg. 2006 2000-2003 Registry Comparative In-hospital Not reported
Hinchliffe Eur J Vasc Endovasc Surg 2006 2002-2004 RCT Comparative 30-day Excluded
Peppelenbosch J Vasc Surg. 2006 2003-2004 Prospective Comparative 30-day OR in-
hospital Not reported
Alsac Eur J Vasc Endovasc Surg 2005 2001-2004 Retrospective Comparative 30-day Not reported
Brandt J Vasc Interv Radiol 2005 2003-2004 Retrospective Comparative 30-day OR in-
hospital Not reported
Castelli Abdominal Imaging 2005 2001-2004 Retrospective Comparative In-hospital Not reported
Hechelhammer J Vasc Surg. 2005 1997-2003 Retrospective Single-arm 30-day Not reported
Larzon J Endovasc Ther 2005 2001-2004 Retrospective Comparative 30-day OR In-hospital Not reported
Vaddineri Ann Vasc Surg. 2005 1999-2004 Retrospective Comparative 30-day Not reported
Lee W J Vasc Surg. 2004 2002-2004 Retrospective Comparative Not reported Not reportedPeppelenbo
schEur J Vasc
Endovasc Surg 2003 2001-2002 Retrospective Comparative 30-day Not reported
Reichart Eur J Vasc Endovasc Surg 2003 2000-2002 Retrospective Comparative Not reported Not reported
Resch J Endovasc Ther 2003 2001-2002 Retrospective Comparative 30-day Not reported
Lachat Eur J Vasc Endovasc Surg 2002 1998-2001 Prospective Single-arm In-hospital Not reported
Yilmaz J Endovasc Ther 2002 1999-2001 Prospective Comparative 30-day Not reported
29
Table 1: Overview of study characteristics
Study Definition adequate
Representativeness Selection Definition
of controls
Comparabi
lity
Ascertainment of exposure
Same method
non response rate
Total no of *
Briggs 2018 * * * ** * * * 8Wang 2018 * * * * ** * * * 9Butz-Lilly 2017 * * * ** * * * 8Kapma 2017 * * * * * * 6Schechter 2017 * * * * * * 6Aziz 2016 * * * ** * * * 8De Rango 2016 * * * ** * * * 8Guo 2016 * * * * * * * 7Gurnason 2016 * * * ** * * * 8Hultgren 2016 * * * * * * 6Healey 2016 * * * ** * * * 8Martinez 2016 * * * * 4Robinson 2016 * * * * * * * * 8Soden 2016 * * * * ** * * * 9Spanos 2016 * * * * * * * 7Taylor 2016 * * * * * * 6Thompson 2016 * * * * * * 6Tremont 2016 * * * ** * * * 8Warner 2016 * * * * * * 6Ali 2015 * * * ** * * * 8Dunvjak 2015 * * * * * * 6McHugh 2015 * * * * * * 6Oyague 2015 * * * * * 5Spencer 2015 * * * * * * 6Van Beek 2015 * * * * * * * 7Edwards 2014 * * * ** * * * 8Gupta 2014 * * * ** * * * 8Meijenfeldt 2014 * * * * ** * * * 9Raupach 2014 * * * * * * 6Rollins 2014 * * * * * * 6Speicher 2014 * * * ** * * * 8Ulus 2014 * * * * * * * 7Antonopoulos 2013 * * * * * 5
Mehta 2013 * * * ** * * * 8Mohan 2013 * * * * * * 6Park 2013 * * * ** * * * 8Wallace 2013 * * * ** * * * 6Wu 2013 * * * * * * 6Ioannidis 2012 * * * * * * 6Mayer 2012 * * * ** * * * 8Nedeau 2012 * * * * * * 6Noorani 2012 * * * * * * 6Saqib 2012 * * * ** * * * 8Ten Bosch 2012 * * * * * * * 7Mani 2011 * * * ** * * * 8Sarac 2011 * * * ** * * * 8
30
1
2
3
Van Schaik 2011 * * * * 4Chapgar 2010 * * * ** * * * 8Cho 2010 * * * * * * * 7Davenpont 2010 * * * ** * * * 8Holt 2010 * * * ** * * * 8Lyons 2010 * * * * * * * 7Starnes 2010 * * ** * * * 7Giles 2009 * * * ** * * * 8Giles 2009 * * * ** * * * 8Makar 2009 * * * * * * 6McPhee 2009 * * * ** * * * 8Veith 2009 * * * * 4Verhoven 2009 * * * * * * * 7Visser 2009 * * * * * 6Vogel 2009 * * * * * 5Vun 2009 * * * * * 5Coppi 2009 * * * * * * 6Lee Rich 2008 * * * * * * 6Lesperance 2008 * * * ** * * * 8Sadat 2008 * * * * * * 6Acosta 2007 * * * * * * * 7Anain 2007 * * * * * * 6Moore 2007 * * * * * 5Najjar 2007 * * * * * 5Ockert 2007 * * * * * * 6Sharif 2007 * * * * * 5Van der Viet 2007 * * * * * * 6Arya 2006 * * * * * * 6Dalainas 2006 * * * * * * 6Franks 2006 * * * * * * 6Greco 2006 * * * ** * * * 8Peppelenbosch 2006 * * * * 4
Alsac 2005 * * * * * * 6Brandt 2005 * * * * * * 6Castelli 2005 * * * * * * 6Larzon 2005 * * * ** * * * 8Vaddineri 2005 * * * * * * 6Lee W 2004 * * * * * 5Peppelenbosch 2003 * * * * * 5
Reichart 2003 * * * * * * 6Resch 2003 * * * * 5Yilmaz 2002 * * * * 4
Table 2: Methodological assessment of observational studies using the Newcastle - Ottawa scale
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4
5
6
Figure Legends
Figure 1: Flow chart of the literature search.
Figure 2a,b: Risk of bias graph (a) and summary (b) of randomized control trials (RCTs).
Figure 3a,b: Forest (a) and funnel plot (b)of comparison of perioperative mortality of EVAR
versus open surgical repair including observational studies and randomized control trials
(RCTs) (analysis based on treatment received).
Figure 4a-c: Scatter plots of the association between mid-study point and perioperative
mortality after endovascular aneurysm repair (EVAR) (a), open surgical repair (b), and the
odds ratio (OR) for perioperative mortality (random-effects meta-regression) (c).
Figure 5a-c: Scatter plots of the association between institutional case load and
perioperative mortality for endovascular aneurysm repair (EVAR) (a), open surgical repair
(b), and the odds ratio (OR) for perioperative mortality (random-effects meta-regression) (c).
Supplementary Figure 1: Forest plot of comparison of adjusted perioperative mortality of
endovascular aneurysm repair (EVAR) versus open surgical repair.
Supplementary Figure 2: Forest plot of RCTs taking into account intention-to-treat rather
than treatment-received as the dependant variable.
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Supplementary Figure 3: Forest plot of comparison of perioperative mortality of
endovascular aneurysm repair (EVAR) versus open surgical repair including observational
studies with ≥6 stars in the Newcastle-Ottawa scale (NOS).
Supplementary Figure 4: Forest plot of comparison of perioperative mortality of
endovascular aneurysm repair (EVAR) versus open surgical repair excluding the ECAR trial
which presented high risk of bias in 2 domains.
Figure 1 Flow chart of the literature search
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Figure 2 Risk of bias graph (A) and randomised studies (B)
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Figure 3 Forest plots (A–C) Forest plot of comparison of peri-operative mortality of endovascular
aneurysm repair (EVAR) vs. open surgical repair (OSR) including observational studies (A), randomised
control trials (RCTs) (analysis based on treatment received) (B) and registries/administrative databases
(C). The solid squares denote the odds ratios (ORs), the horizontal lines represent the 95% confidence
intervals (CIs), and the diamonds denote the pooled ORs. M−H = Mantel–Haenszel.
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Figure 4 Funnel plot of the comparison of peri-operative mortality of endovascular aneurysm
repair vs. open surgery. OR = odds ratio; RCTs = randomised control trials; SE = standard error.
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Figure 5 (A–C) Scatter plots of the association between mid-study point (x axis) and peri-operative
mortality (y axis) after endovascular aneurysm repair (A) and open surgical repair (B), and the odds ratio
for peri-operative mortality (y axis) (C) (random effects meta-regression). The x axis presents the mid-
study point and the y axis the log peri-operative mortality (A and B) or the log odds ratio for peri-
operative mortality (C).
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