Systematic review and meta-analysis of the association between intraluminal thrombus volume and abdominal aortic aneurysm rupture

Systematic review and meta-analysis of the association between intraluminal thrombus volume and abdominal aortic aneurysm rupture Tejas P. Singh, MBBS, MPH,a,b Shannon A. Wong,a Joseph V. Moxon, PhD,a,c T. Christian Gasser, PhD,d and Jonathan Golledge, MChir, FRACS,a,b,c Townsville, Queensland, Australia; and Stockholm, Sweden

ABSTRACT Background: Intraluminal thrombus (ILT) is present in most abdominal aortic aneurysms (AAAs), although its role in AAA progression is controversial. Methods: A literature search was performed to identify studies that investigated the association between ILT volume and AAA rupture. A study assessment tool was developed to assess the methodologic quality of included studies. A metaanalysis was conducted using an inverse variance-weighted random-effects model to compare the ILT volume in ruptured and asymptomatic intact AAAs. Leave-one-out sensitivity analyses were conducted to assess the robustness of the findings. A subanalysis was performed including studies in which patients with asymptomatic intact and ruptured AAAs were matched for aortic diameter. Interstudy heterogeneity was assessed using the I2 statistic. Results: Eight studies involving 672 patients were included in this systematic review. Meta-analysis of all studies found a greater ILT volume in patients with ruptured AAAs than in patients with asymptomatic intact AAAs (standardized mean difference, 0.56; 95% confidence interval, 0.17-0.96; P ¼ .005; I2 ¼ 79.8%). Sensitivity analyses suggested that the findings were robust; however, aortic diameter was significantly larger in ruptured than in asymptomatic intact AAAs (mean 6 standard deviation, 78 6 18 and 64 6 15 mm, respectively; P < .001). In the subanalysis of studies that matched for diameter, no significant difference in ILT volume between groups was found (standardized mean difference, 0.03; 95% confidence interval, 0.27 to 0.33; P ¼ .824; I2 ¼ 0%). Conclusions: This meta-analysis suggests that ILT volume is greater in patients with ruptured AAAs than in patients with asymptomatic intact AAAs, although this is most likely due to the larger diameter of ruptured AAAs. (J Vasc Surg 2019;-:1-9.) Keywords: Abdominal aortic aneurysm; Rupture; Thrombus; Prognosis

In current clinical practice, maximum abdominal aortic aneurysm (AAA) diameter is used to guide decisionmaking regarding when to perform AAA repair because it is the best known measure of AAA rupture risk.1-3 Based on previous randomized controlled trials, current guidelines recommend elective repair of asymptomatic AAAs when they reach 55 mm in men and 50 mm in women.2 Some smaller AAAs do rupture, however (1%-2%/y based on data from the UK Small Aneurysm Trial),1 and some large AAAs remain stable throughout a patient’s lifetime,4 suggesting that diameter alone is an imperfect measure to identify patients who require surgical intervention. Intraluminal thrombus (ILT) is present in most

AAAs, and the amount of ILT can be readily measured by modern imaging methods, such as computed tomography (CT), enabling it to be added to risk algorithms for AAA rupture.5 The role of ILT in AAA progression is controversial. Previous studies have reported that ILT decreases AAA peak wall stress and therefore may be protective against AAA rupture.6-8 In contrast, observational studies have suggested that ILT may promote AAA growth and rupture, possibly by the high concentrations of proinflammatory proteins and proteinases contained within it.9 Furthermore, an association between large ILT volume and higher risk of cardiovascular events has also been reported.10 Assessment of ILT volume

From the Queensland Research Centre for Peripheral Vascular Disease, College

Clinical trial registration: CRD42018117395 (www.crd.york.ac.uk).

of Medicine and Dentistry,a and Australian Institute of Tropical Health and

Author conflict of interest: none.

Medicine,c James Cook University, and the Department of Vascular and

Additional material for this article may be found online at www.jvascsurg.org.

Endovascular Surgery, Townsville Hospital,b Townsville; and the Department

Correspondence: Jonathan Golledge, MChir, FRACS, Queensland Research

of Solid Mechanics, School of Engineering Sciences, Royal Institute of Tech-

Centre for Peripheral Vascular Disease, College of Medicine and Dentistry,

nology, Stockholm.d

James Cook University, Townsville, Queensland, Australia 4811 (e-mail:

The Townsville Hospital and Health Services Study, Education and Research

[email protected]).

Trust Fund, and Queensland Government supported this work. J.G. holds a

The editors and reviewers of this article have no relevant financial relationships to

Practitioner Fellowship from the National Health and Medical Research

disclose per the JVS policy that requires reviewers to decline review of any

Council (1117061) and a Senior Clinical Research Fellowship from the Queensland Government, Australia. J.V.M. holds an Advance Queensland Mid-Career

manuscript for which they may have a conflict of interest. 0741-5214

fellowship from the Queensland Government. T.P.S. holds a Junior Doctor

Copyright Ó 2019 by the Society for Vascular Surgery. Published by Elsevier Inc.

Research Fellowship from the Queensland Government.

https://doi.org/10.1016/j.jvs.2019.03.057

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could potentially assist in identifying AAAs that are at higher risk of rupture.11 The aim of this systematic review and meta-analysis was to investigate the association between ILT volume and AAA rupture.

METHODS Literature search. This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement.12 A protocol was developed before commencing the review and published in the International Prospective Register of Systematic Reviews.13 The Medline (through OvidSP, 1966), PubMed, Web of Science (through ISI Web of Knowledge, 1965), and Cochrane Library databases were searched to identify studies investigating the association between ILT volume and AAA rupture. The following search terms were used across all fields: “abdominal aortic aneurysm” AND “thrombus” AND “volume” AND “rupture.” The search was performed in September 2018 without any language or study design restrictions by two authors (T.S. and J.G.). Reference lists of studies identified in the primary search were reviewed to increase the yield of relevant studies. Titles and abstracts were screened to identify studies of potential relevance to this systematic review. If the suitability of an article was uncertain, the full text was reviewed. To be eligible, studies needed to compare ILT volume in patients with ruptured or asymptomatic intact AAAs. The authors needed to report both the ILT volume and maximum AAA diameter. Furthermore, patients were required to have a CT scan of the intact or ruptured AAA before endovascular or open surgical repair. Studies including patients with symptomatic but not ruptured AAAs were excluded unless ILT volume was reported separately for patients with asymptomatic intact and ruptured AAAs. In this case, the patients with symptomatic AAAs, rather than the study, were excluded. Studies were evaluated against the inclusion criteria independently by two authors (T.S. and J.G.), with any disagreements resolved in a consensus meeting. Data extraction and assessment of strengths and weaknesses of included studies. Data from the included studies were extracted by three authors independently (T.S., S.W., and J.G.) in predefined tables. Data on the following variables were collected: study design, sample sizes for patients with ruptured and intact AAAs, maximum AAA diameter, ILT volume, age, sex, smoking, diabetes, hypertension, coronary artery disease, and aspirin and statin prescription. Where data were not available in the publication, the corresponding author was contacted for this information. A study assessment tool was created using components of two previously reported quality assessment tools: Standard Quality Assessment Criteria for Evaluating Primary Research Papers14 and the Newcastle-Ottawa Scale.15 Additional

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criteria that were of relevance to this study were also included. This included assessing whether the method of ILT volume estimation was documented, previously validated, and reproducible. The time points at which CT scans were performed were also noted (eg, after rupture, before rupture, or both). Importantly, we also assessed whether ruptured and intact AAAs were matched for aortic diameter or other variables that are established risk factors for AAA rupture (eg, age, sex, smoking, and hypertension).16 Further details regarding the quality assessment tool can be found in Supplementary Table I (online only). Statistical analysis. A meta-analysis was performed comparing ILT volume between patients with asymptomatic intact AAAs and patients with ruptured AAAs. Corresponding authors were contacted to obtain data in terms of mean 6 standard deviation (SD) where required. In cases in which data could not be obtained from the corresponding authors, appropriate formulas were used to convert data to mean 6 SD.17 In studies in which asymptomatic intact AAAs were separated into further groups (eg, small intact AAAs and large AAAs), data were combined using the relevant formulas reported in Cochrane Handbook for Systematic Reviews of Interventions18 (Supplementary Table II, online only). Patients with symptomatic AAAs were excluded from the meta-analysis. The process by which all conversions were conducted is documented in Supplementary Table II (online only). Results were combined using an inverse variance-weighted random-effects model as previously described19 and reported as standardized mean difference (SMD) and 95% confidence intervals (CIs). A random-effects model was used to account for expected heterogeneity in the methods to analyze ILT volume and patient characteristics. Heterogeneity was assessed using the I2 statistic; I2 values corresponding to 25%, 50%, and 75% were considered low, moderate, and high heterogeneity, respectively.20 Leave-one-out sensitivity analyses were conducted to assess the influence of each study on the pooled estimate by omitting one study at a time and recalculating the combined estimates for the remaining studies.21 Summated sample-weighted mean 6 SD of aortic diameter was calculated separately for ruptured and intact AAA groups18 and statistically compared using independent samples t-test. An additional subanalysis was performed that included only studies in which asymptomatic intact and ruptured AAAs were matched for aortic diameter. Publication bias was assessed by funnel plots comparing the summary estimate of each study with its precision (1/standard error).21 Analyses were conducted using Stata version 13.0 software (StataCorp LP, College Station, Tex). All statistical tests were two sided, and a P value of <.05 was considered significant.

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Fig 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses diagram illustrating the identification and selection of the included studies. *Ten studies did not include patients with ruptured abdominal aortic aneurysms (AAAs); five studies did not estimate the volume of intraluminal thrombus (ILT); one study was identified by hand searching of reference lists.

RESULTS Study identification. The initial database searches yielded 102 studies after removal of duplicates. After title and abstract screening, the full texts of 23 studies were evaluated against the inclusion criteria. Fifteen studies were removed after evaluation of the full text (reasons for exclusion are listed in Supplementary Table III, online only). Finally, eight studies were included in this systematic review (Fig 1).11,22-28 Study characteristics. A total of 672 patients with asymptomatic intact (n ¼ 469) or ruptured (n ¼ 203) AAAs were investigated in the eight included studies (Table).11,22-28 All studies were case-control in design. Two studies included a group of symptomatic AAAs (n ¼ 26) that were excluded.24,27 The included studies were published between 2005 and 2018, with sample

sizes ranging between 34 and 220 (Table).11,22-28 Two studies were conducted in the United States,11,22 Germany,24,25 and Sweden.23,28 The remaining studies were conducted in Australia26 and The Netherlands.27 The inclusion criteria for the individual studies varied. For example, in three studies, patients were included only if the CT scans performed for AAA patients met specific imaging criteria.11,24,27 In one study, ILT needed to be clearly distinguishable from the lumen on CT and the aorta needed to be visible from the level of the renal arteries to the iliac bifurcation.27 Erhart et al24 excluded patients if the CT scans performed had evidence of features known to limit finite element analysis (eg, vessel wall angulation and contrast material extravasation). In two studies, patients with infrarenal AAAs of inflammatory etiology were excluded.11,27 Further details of the inclusion criteria can be found in

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Table. Characteristics of included studies Study Hans et al, 2005

Country 22

Study design

Sample sizea

Inclusion criteria

United States

Casecontrol

98 67 iAAAs 31 rAAAs

AAA and underwent elective repair or emergent repair for rupture; CT scan of abdominal aorta in all elective patients and only hemodynamically stable rAAA patients before surgical repair

Gasser et al,23 2010

Sweden

Casecontrol

50 30 iAAAs 20 rAAAs

AAA and available CT scan before emergency or elective surgical repair; sufficiently high resolution of image data and good identification of exterior surface of AAA

Erhart et al,24 2015

Germany

Casecontrol

45 30 iAAAs 15 rAAAs

AAA with available CT scan before repair; no imaging features precluding finite element analysis; elective repair of AAA with maximum diameter >5.0 cm without symptoms or signs of rupture on preoperative CT in the iAAA group and extravasation of contrast medium or retroperitoneal hematoma on CT for the rAAA group

Erhart et al,25 2016

Germany

Casecontrol

34 23 iAAAs 11 rAAAsb

AAA with CT available before and after rupture event; no surgical repair of AAA before rupture

Golledge et al,26 2014

Australia

Casecontrol

84 56 iAAAs 28 rAAAs

Ruptured AAA diagnosed by vascular specialist and available CT after rupture but before repair; intact AAA with available CT scan before repair; patient with iAAA able to be matched for maximum aortic diameter to a patient with a ruptured AAA

Haller et al,11 2018

United States

Casecontrol

51 15 large iAAAs 14 large rAAAs 13 small iAAAs 9 small rAAAs

AAA not of mycotic, thoracic, nature; no isolated iliac aneurysm; preoperative CT scan available

Leemans et al,27 2018

The Netherlands

Casecontrol

220 175 iAAAs 45 rAAAs

Noninflammatory infrarenal AAA (including extension to common iliac arteries); suitable preoperative CT images (aorta was visible from the renal arteries to the iliac bifurcation and the lumen was distinguishable from intraluminal thrombus)

Siika et al,28 2018

Sweden

Casecontrol

90 60 iAAAs 30 rAAAs

rAAAs and iAAAs with selection based on the availability of good-quality CT scans

AAA, Abdominal aortic aneurysm; CT, computed tomography; iAAA, asymptomatic intact AAA; ILT, intraluminal thrombus; N/A, not applicable; rAAA, ruptured AAA. a Excludes patients with symptomatic AAAs (n ¼ 26). b CT scans were available before and during the rupture event (median time from pre-rupture to rupture CT investigation was 308 days (range, 22009 days).

the Table. In all studies, ILT volume was estimated from CT scans; however, the methods by which this was estimated varied. To estimate ILT volume, five studies used the A4research (VASCOPS GmbH, Graz, Austria) workstation23-25,27,28; one study used the MxView Visualization Workstation (Philips Healthcare, Andover, Mass)26; one study used the AutoCAD 2000 workstation (Autodesk, San Rafael, Calif)22; and another study used the Mimics Research 18.0 (Materialise NV, Leuven, Belgium) or an in-house MATLAB program (MathWorks, Natick, Mass).11 Participants’ characteristics. Participants’ characteristics were variably reported. In one study, the clinical characteristics of intact and asymptomatic ruptured AAA patients were presented in terms of small and large AAAs,11 whereas the remaining studies did not stratify patients’ characteristics by AAA size (Supplementary

Table IV, online only).22-28 The average age of patients ranged between 68 and 81 years, and the proportion of patients who were male ranged between 62% and 100%. In one study, the proportion of male patients was significantly higher among patients with intact AAAs than among patients with ruptured AAAs.26 The proportion of participants who were current or previous smokers ranged from 47% to 100%, although two studies did not report smoking history.22,23 In one study, there were significant differences in the proportion of patients with diabetes and hypertension in ruptured and asymptomatic intact cases,22 although three studies did not report hypertension23,27,28 and diabetes history.23,24,28 In the two studies that reported prescription of statins11,26 and the one study that reported aspirin prescription,26 there were no significant differences between patients with ruptured AAAs and patients with asymptomatic intact AAAs.

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Table. Continued. Imaging modality

Thrombus characteristics reported

Method of estimating thrombus volume

CT

ILT volume (cm3); ILT morphology (anterior-eccentric, posterior-eccentric or eccentric-equal, concentric)

The following calculations were undertaken: Area of ellipse ¼ p  (minor diameter)  (major diameter)/4 Volume ¼ area  length of segment or disk (each segment or disk recorded at 10-mm intervals) Volume of thrombus per segment or disk ¼ volume of outer disk e volume of inner disk Total ILT volume ¼ sum of volume of each disk Workstation used: AutoCAD 2000

CT

ILT volume (cm3)

AAA reconstruction was conducted with an analytical imaging software, and a semiautomated image segmentation approach was used to create four finite element models, of which two included ILT volume Workstation used: A4research

CT

ILT volume (cm3)

AAA reconstruction with a semiautomatic analyzing analytical software; analysis based on segmentation and calculation of morphologic parameters (including ILT); ILT was divided into voxels for subsequent biomechanical calculation Workstation used: A4research

CT

ILT volume (cm3)

AAA reconstruction with a semiautomatic analyzing analytical software; analysis based on segmentation and calculation of morphologic parameters (including ILT) Workstation used: A4research

CT

ILT volume (cm3); thrombus percentage

Images from the origin of the lowest renal artery (excluding accessory arteries) to the aortic bifurcation were analyzed; volume-of-interest tool was used to define a region of interest; selected images were reloaded in three-dimensional mode and ILT volume was computed Workstation used: Philips MxView Visualization Workstation

CT

ILT volume (mL); ILT size (thickness)

Geometric analysis used to analyze the amount and distribution of ILT within the AAA; ILT and lumen volume estimated by aortic wall creation, by intraluminal mesh creation, and by calculating the total aneurysm volume occupied by ILT Workstation used: Mimics Research 18.0 (or an in-house MATLAB program)

CT

ILT volume (cm3)

AAA geometry was reconstructed by semiautomatic segmentation of the vessel lumen, ILT, and vessel wall using deformable snake and balloon models; a mesh was generated, and the finite element analysis was executed Workstation used: A4research

CT

ILT volume (cm3); ILT area Finite element analysis performed by semiautomatic segmentation to create a three-dimensional (mm2) model of the AAA and its ILT Workstations used: A4research and Sectra PACS IDS7

Strengths and weaknesses of included studies. The strengths and weaknesses of the included studies are reported in Supplementary Table V (online only). All studies were of retrospective design. The selection criteria were described in all studies.11,22-28 In four studies, the method of ILT volume estimation was well described and the authors reported information about the reproducibility of the method used to measure ILT volume.24-26,28 All four of these studies referred to reproducibility assessments in other publications24-26,28; however Golledge et al26 also assessed the reproducibility of their method as a part of study design (mean coefficient of variation for intraobserver and interobserver reproducibility of ILT volume was <5% for both assessments). The finite element analysis method used in the other three studies had good intraobserver and interobserver reproducibility (mean percentage difference 6SD of w7% 6 6% for both assessments) that

was reported in an earlier publication.29 In the remaining four studies, the method of ILT volume estimated was described but not previously validated or reported to be reproducible.11,22,23,27 Only one study provided an objective and detailed definition of AAA rupture that included objective evidence of blood within the retroperitoneum or peritoneum identified on a CT scan and diagnosis by a qualified vascular surgeon.26 The sample size of included studies ranged between 50 and 100 participants for six studies11,22-24,26,28 and <50 participants25 and >200 participants27 for two studies. Only one study employed a sample size estimation.26 In only one study, participants with AAAs underwent a CT scan before rupture as well as after rupture (median time from pre-rupture to rupture was 308 days [range, 2-2009 days]),25 whereas in the other seven studies, CT scans were performed after AAA rupture only (Supplementary Table V, online only).11,22-24,26-28 Importantly, four studies matched

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ruptured and asymptomatic intact AAAs for maximum aortic diameter.23,26-28 The remaining four studies did not match intact and ruptured AAA cases for diameter,11,22,24,25 although two studies matched for other variables that are also established predictors of AAA rupture, such as age,22 sex,22 and blood pressure16,23 (Supplementary Table V, online only). Association between ILT volume and AAA rupture. ILT volume was reported to be significantly greater in ruptured AAAs compared with asymptomatic intact AAAs in only three studies22,27,28 but not in the remaining five studies (Supplementary Table IV, online only).11,23-26 In these three studies, the mean 6 SD ILT volume in the ruptured groups ranged from 149 6 90 cm3 to 186 6 135 cm3, whereas the ILT volume in asymptomatic intact groups ranged from 83 6 61 cm3 to 102 6 79 cm3. Importantly, the mean 6 SD AAA diameter was significantly greater in the ruptured cases than in asymptomatic intact cases in all three of these studies (Supplementary Table IV, online only).22,27,28 In addition, the proportion of patients with a history of hypertension was significantly greater in the patients with ruptured AAAs than in the patients with asymptomatic intact AAAs (97% vs 82%; P < .05) in one of these studies,22 although the other two studies did not report information on this variable.27,28 Three studies conducted smaller subanalyses including patients with ruptured and asymptomatic intact AAAs matched for diameter.23,27,28 Only two of these studies assessed ILT volume in the subanalysis,23,27 of which one study reported higher ILT volume in the ruptured group compared with the asymptomatic intact group, although this difference was not significant (158 6 117 cm3 vs 129 6 91 cm3, respectively; P ¼ .34).27 Only one study matched patients with asymptomatic intact and ruptured AAAs by design.26 In that study, the ILT volume was lower in the ruptured group than in the asymptomatic intact group, although the difference was not significant (P ¼ .41). Data synthesis. In the meta-analysis, ILT volume was greater in ruptured than in asymptomatic intact AAAs (SMD, 0.56; 95% CI, 0.17; 0.96; P ¼ .005; Fig 2). High interstudy heterogeneity was observed (I2 ¼ 79.8%). The summated maximum aortic diameter was significantly greater in ruptured than in asymptomatic intact AAAs (78 6 18 mm and 64 6 15 mm, respectively; P < .001). Leave-one-out sensitivity analyses demonstrated that the results of the meta-analysis were not dependent on the inclusion of any one study (Supplementary Fig 1, online only). The funnel plot had an asymmetric distribution, suggesting the presence of publication bias (Supplementary Fig 2, online only). The subanalysis of asymptomatic intact and ruptured AAAs matched for aortic diameter included three studies of 77 patients with ruptured AAAs and 104

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patients with asymptomatic intact AAAs. In this analysis, ILT volume was similar in ruptured and asymptomatic intact AAAs (SMD, 0.03; 95% CI, 0.27 to 0.33; P ¼ .824; Fig 3). Interstudy heterogeneity in the subanalysis was low (I2 ¼ 0%).

DISCUSSION The main results from this meta-analysis suggest that ILT volume is greater in ruptured than in asymptomatic intact AAAs. This finding was robust in the leave-oneout sensitivity analyses. However, in a subanalysis including only studies matched for maximum aortic diameter, ILT volume was similar in ruptured and asymptomatic intact AAAs. The importance of maximum aortic diameter in estimating AAA progression and rupture risk has been established in numerous studies,1,30 and this measure is currently the best predictor of rupture risk. There are, however, a number of limitations of this method, including significant intraobserver and interobserver variability in measuring diameter on ultrasound and CT. An error margin of 2 to 3 mm has been reported,31 which is larger than the annual growth of some small AAAs.32 There is considerable interest in identifying additional predictors of rupture that may assist in risk stratification of AAA patients. ILT contains proteolytic enzymes and inflammatory cytokines that are implicated in AAA progression,5 and targeted inhibition of ILT with an antiplatelet drug is the focus of a current clinical trial.33 ILT volume has previously been positively correlated with AAA diameter,10 and the differences in ILT volume observed in ruptured and asymptomatic intact AAAs in this study are likely to be related to the significantly larger aortic diameters of ruptured compared with intact AAAs. Collectively, the evidence from this meta-analysis suggests that the reported larger ILT volume in patients with ruptured AAAs most plausibly relates to the greater maximum AAA diameter in these patients. This finding supports the theory that ILT is an incidental phenomenon associated with AAA rather than a contributing cause in progression, although this remains controversial. Other characteristics of ILT related to its structure may be of greater relevance to rupture risk.22,34-36 For example, in a previous case-control study, curvilinear zones of higher attenuation (the crescent sign) on CT were more frequently observed in ruptured than in asymptomatic intact AAAs of similar diameter (38% vs 14%, respectively; P ¼ .02).37 Similarly, results from a prospective observational study reported that small AAAs with unorganized loose thrombus, characterized by high signal intensity on magnetic resonance imaging (MRI), are more likely to have higher aneurysm growth rates than AAAs with low signal intensity of thrombus.38 Such characteristics of ILT may influence the stress transmitted through the thrombus to the aortic wall and provide important prognostic information for AAAs;

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Fig 2. Association between intraluminal thrombus (ILT) volume and abdominal aortic aneurysm (AAA) rupture. The standardized mean difference (SMD) is the mean difference in ILT volume between patients with ruptured AAAs and patients with asymptomatic intact AAAs, standardized to 1 standard deviation (SD) difference. The summary SMD was estimated from inverse variance-weighted meta-analysis. The box areas are inversely proportional to the variance of the SMD, and the horizontal lines illustrate 95% confidence intervals (CIs).

Fig 3. Association between intraluminal thrombus (ILT) volume and abdominal aortic aneurysm (AAA) rupture in studies in which ruptured and asymptomatic intact AAAs were matched for aortic diameter. The standardized mean difference (SMD) is the mean difference in ILT volume between patients with ruptured AAAs and patients with asymptomatic intact AAAs, standardized to 1 standard deviation (SD) difference. The summary SMD was estimated from inverse variance-weighted meta-analysis. The box areas are inversely proportional to the variance of the SMD, and the horizontal lines illustrate 95% confidence intervals (CIs).

however, they are unlikely to be well defined by CT.34 Alternative imaging modalities such as MRI have superior soft tissue discrimination compared with CT and may be able to better characterize ILT structure,34 although the clinical practicality of conducting MRI scans for this purpose is unclear. Importantly, volume measurements of ILT do not provide information on thrombus biochemistry. Previous studies have suggested that ILT contains increased concentrations of matrix-

degrading enzymes and cytokines, which have been suggested to play a role in AAA progression and rupture risk.33 None of the included studies reported information on these other characteristics of ILT. There are several limitations of this meta-analysis, including the limited number of studies and substantial interstudy heterogeneity. One of the main limitations of the included studies is that seven11,22-24,26-28 of the eight studies measured ILT volume only from CT scans carried

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out after AAA rupture, and it is not possible to be certain whether these images were reflective of the situation before rupture. One study also conducted CT scans before rupture, although the ILT volume in that group did not significantly differ from that in patients with asymptomatic intact AAAs.25 This study also reported that the volume of ILT did not significantly differ when measured from CT scans performed before or after AAA rupture.25 This finding provides some support that the time point at which CT scans were performed was unlikely to adversely influence the comparisons reported in this review. However, it is not known what the consistency of ILT volume is over time and how ILT remodeling affects the proinflammatory and proteolytic activity of the ILT.33,34 Furthermore, because most studies measured ILT volume after aortic rupture, these measurements may have been confounded by the presence of retroperitoneal hematoma and the difficulty in identifying the AAA wall.25 Importantly, only three studies could be included in the subanalysis matched for aortic diameter. Statistical comparison of the summated aortic diameter in ruptured and asymptomatic intact groups assumed a normal distribution of data, which could not be accurately determined as individual study data sets were not available. Patients with ruptured AAAs included in this study all had CT scans before surgical repair, which suggests that these patients may belong to a more medically stable group, and therefore selection bias in the included studies is likely. Last, the relevance of the findings of this meta-analysis to patients with small AAAs is limited as seven22-28 of the eight studies included only patients with large AAAs (mean 6 SD aortic diameter ranged between 63 6 15 mm and 84 6 14 mm within included patient groups). Only one study, conducted by Haller et al,11 evaluated ILT thickness and volume in a group of patients with small AAAs. In that study, both a larger ILT thickness and a larger ILT volume were independently associated with AAA rupture in small aneurysms with low wall stress but not in large aneurysms.11 The findings also suggested that greater ILT volume may potentially be a feature of high-risk small AAAs, although larger prospective studies are required to further investigate this theory.

CONCLUSIONS The results of this study do not suggest an independent association between ILT volume and AAA rupture, although findings are limited by small numbers and substantial interstudy variability, particularly with respect to aortic diameter. Ideally, a large prospective noninterventional study of small AAA patients under surveillance is needed to assess the clinical usefulness of measuring ILT volume. Biomechanical and biochemical properties of ILT may be of relevance to AAA progression and should be investigated in future studies.

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Professor Jonathan Golledge, Professor Christian Gasser, and Dr Philip Erhart provided unpublished data to facilitate the meta-analysis.

AUTHOR CONTRIBUTIONS Conception and design: TS, JM, JG Analysis and interpretation: TS, SW, JM, TG, JG Data collection: TS, SW, JG Writing the article: TS, JG Critical revision of the article: TS, SW, JM, TG, JG Final approval of the article: TS, SW, JM, TG, JG Statistical analysis: TS, JG Obtained funding: TS, JM, TG, JG Overall responsibility: TS

REFERENCES 1. Greenhalgh R, Brady A, Brown L, Forbes J, Fowkes F. Mortality results for randomised controlled trial of early elective surgery or ultrasonographic surveillance for small abdominal aortic aneurysms. The UK Small Aneurysm Trial Participants. Lancet 1998;352:1649-55. 2. Moll FL, Powell JT, Fraedrich G, Verzini F, Haulon S, Waltham M, et al. Management of abdominal aortic aneurysms clinical practice guidelines of the European Society for Vascular Surgery. Eur J Vasc Endovascular Surg 2011;41: S1-58. 3. Thompson A, Cooper J, Ashton H, Hafez H. Growth rates of small abdominal aortic aneurysms correlate with clinical events. Br J Surg 2010;97:37-44. 4. Cao P, De Rango P, Verzini F, Parlani G, Romano L, Cieri E, et al. Comparison of surveillance versus aortic endografting for small aneurysm repair (CAESAR): results from a randomised trial. Eur J Vasc Endovascular Surg 2011;41:13-25. 5. Piechota-Polanczyk A, Jozkowicz A, Nowak W, Eilenberg W, Neumayer C, Malinski T, et al. The abdominal aortic aneurysm and intraluminal thrombus: current concepts of development and treatment. Front Cardiovasc Med 2015;2: 19. 6. Wang DH, Makaroun MS, Webster MW, Vorp DA. Effect of intraluminal thrombus on wall stress in patient-specific models of abdominal aortic aneurysm. J Vasc Surg 2002;36:598-604. 7. Thubrikar M, Robicsek F, Labrosse M, Chervenkoff V, Fowler B. Effect of thrombus on abdominal aortic aneurysm wall dilation and stress. J Cardiovasc Surg (Torino) 2003;44: 67-77. 8. Georgakarakos E, Ioannou C, Volanis S, Papaharilaou Y, Ekaterinaris I, Katsamouris A. The influence of intraluminal thrombus on abdominal aortic aneurysm wall stress. Int Angiol 2009;28:325-33. 9. Behr-Rasmussen C, Grøndal N, Bramsen M, Thomsen M, Lindholt JS. Mural thrombus and the progression of abdominal aortic aneurysms: a large population-based prospective cohort study. Eur J Vasc Endovascular Surg 2014;48:301-7. 10. Parr A, McCann M, Bradshaw B, Shahzad A, Buttner P, Golledge J. Thrombus volume is associated with cardiovascular events and aneurysm growth in patients who have abdominal aortic aneurysms. J Vasc Surg 2011;53:28-35. 11. Haller SJ, Crawford JD, Courchaine KM, Bohannan CJ, Landry GJ, Moneta GL, et al. Intraluminal thrombus is

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associated with early rupture of abdominal aortic aneurysm. J Vasc Surg 2018;67:1051-8.e1. Moher D, Shamseer L, Clarke M, Ghersi D, Liberati A, Petticrew M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev 2015;4:1. Singh T, Wong S, Moxon J, Golledge J. Systematic review and meta-analysis of the association between intra-luminal thrombus volume and abdominal aortic aneurysm rupture. PROSPERO 2018 CRD42018117395. Available at: http://www.crd.york.ac.uk/PROSPERO/display_record.php? ID¼CRD42018117395. Accessed December 12, 2018. Kmet LM, Cook LS, Lee RC. Standard quality assessment criteria for evaluating primary research papers from a variety of fields. Edmonton: Alberta Heritage Foundation for Medical Research; 2004. Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 2010;25:603-5. Sweeting M, Thompson S, Brown L, Powell J; RESCAN collaborators. Meta-analysis of individual patient data to examine factors affecting growth and rupture of small abdominal aortic aneurysms. Br J Surg 2012;99:655-65. Hozo SP, Djulbegovic B, Hozo I. Estimating the mean and variance from the median, range, and the size of a sample. BMC Med Res Methodol 2005;5:13. Higgins J. Green S (editors). Cochrane handbook for systematic reviews of interventions version 5.1. 0. The Cochrane Collaboration, 2011. Available at: http://handbook.cochrane. org. Accessed December 12, 2018. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 1959;22:719-48. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002;21:1539-58. Sterne JA, Gavaghan D, Egger M. Publication and related bias in meta-analysis: power of statistical tests and prevalence in the literature. J Clin Epidemiol 2000;53:1119-29. Hans SS, Jareunpoon O, Balasubramaniam M, Zelenock GB. Size and location of thrombus in intact and ruptured abdominal aortic aneurysms. J Vasc Surg 2005;41:584-8. Gasser TC, Auer M, Labruto F, Swedenborg J, Roy J. Biomechanical rupture risk assessment of abdominal aortic aneurysms: model complexity versus predictability of finite element simulations. Eur J Vasc Endovascular Surg 2010;40:176-85. Erhart P, Hyhlik-Dürr A, Geisbüsch P, Kotelis D, MüllerEschner M, Gasser TC, et al. Finite element analysis in asymptomatic, symptomatic, and ruptured abdominal aortic aneurysms: in search of new rupture risk predictors. Eur J Vasc Endovascular Surg 2015;49:239-45. Erhart P, Roy J, de Vries JP, Liljeqvist ML, Grond-Ginsbach C, Hyhlik-Dürr A, et al. Prediction of rupture sites in abdominal aortic aneurysms after finite element analysis. J Endovasc Ther 2016;23:115-20. Golledge J, Iyer V, Jenkins J, Bradshaw B, Cronin O, Walker PJ. Thrombus volume is similar in patients with

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

ruptured and intact abdominal aortic aneurysms. J Vasc Surg 2014;59:315-20. Leemans EL, Willems TP, Slump CH, van der Laan MJ, Zeebregts CJ. Additional value of biomechanical indices based on CTa for rupture risk assessment of abdominal aortic aneurysms. PLoS One 2018;13:e0202672. Siika A, Lindquist Liljeqvist M, Hultgren R, Gasser TC, Roy J. Aortic lumen area is increased in ruptured abdominal aortic aneurysms and correlates to biomechanical rupture risk. J Endovasc Ther 2018;25:750-6. Teutelink A, Cancrinus E, van de Heuvel D, Moll F, de Vries JP. Preliminary intraobserver and interobserver variability in wall stress and rupture risk assessment of abdominal aortic aneurysms using a semiautomatic finite element model. J Vasc Surg 2012;55:326-30. Brady AR, Thompson SG, Fowkes FG, Greenhalgh RM, Powell JT. Abdominal aortic aneurysm expansion: risk factors and time intervals for surveillance. Circulation 2004;110: 16-21. Lederle FA, Wilson SE, Johnson GR, Reinke DB, Littooy FN, Acher CW, et al. Variability in measurement of abdominal aortic aneurysms. J Vasc Surg 1995;21:945-52. Golledge J, Muller J, Daugherty A, Norman P. Abdominal aortic aneurysms: pathophysiological mechanisms and clinical implications. Arterioscler Thromb Vasc Biol 2006;26: 2605-13. Golledge J, Norman PE, Murphy MP, Dalman RL. Challenges and opportunities in limiting abdominal aortic aneurysm growth. J Vasc Surg 2017;65:225-33. Doyle BJ, Miller K, Newby DE, Hoskins PR. Commentary: computational biomechanics-based rupture prediction of abdominal aortic aneurysms. J Endovasc Ther 2016;23:121-4. Riveros F, Martufi G, Gasser TC, Rodriguez-Matas JF. On the impact of intraluminal thrombus mechanical behavior in AAA passive mechanics. Ann Biomed Eng 2015;43:2253-64. Polzer S, Gasser TC, Swedenborg J, Bursa J. The impact of intraluminal thrombus failure on the mechanical stress in the wall of abdominal aortic aneurysms. Eur J Vasc Endovascular Surg 2011;41:467-73. Roy J, Labruto F, Beckman MO, Danielson J, Johansson G, Swedenborg J. Bleeding into the intraluminal thrombus in abdominal aortic aneurysms is associated with rupture. J Vasc Surg 2008;48:1108-13. Nguyen V, Leiner T, Hellenthal F, Backes W, Wishaupt M, van der Geest R, et al. Abdominal aortic aneurysms with high thrombus signal intensity on magnetic resonance imaging are associated with high growth rate. Eur J Vasc Endovascular Surg 2014;48:676-84.

Submitted Dec 28, 2018; accepted Mar 19, 2019.

Additional material for this article may be found online at www.jvascsurg.org.

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Supplementary Table I (online only). Criteria used to perform the methodologic quality assessment Response Category Clearly defined objective?

Criteria

Yes

Clear hypothesis stated and tested Objective easily identified in introductory section (or first paragraph of methods section) d Specifies all the following: purpose, participants/target population, and the specific association(s)/descriptive parameter(s) under the investigation d Study setting defined (eg, hospital based; single/multicenter)



Partial



Vaguely/incompletely reported (eg, “describe the effect of” or “examine the role of”) or substantial information must be collected from parts of the paper other than introduction/background/ objective section



Question or objective is not reported or is incomprehensible Prospective study design?

Hypothesis designed before enrollment and observation period of participants d

d

Selection criteria well described?

 

Hypothesis and selection criteria designed after the occurrence of respective end points (eg, AAA rupture) Data collection conducted retrospectively after participants experienced outcomes of interest

Described and appropriate Selection strategy designed to obtain an unbiased sample of the relevant target population d Methods for selection/recruitment/sampling detailed in the study d Definition of AAA adequately described (eg, appropriate investigations used, including ultrasound, angiography, or clinical assessment by a vascular specialist; scheduled surgical intervention for AAA) d At least three of the specified exclusion criteria described (listed next)





Selection methods (and inclusion/exclusion criteria) are not completely described, but no obvious inappropriateness; or selection methods described elsewhere d Included patients who have either an intact or ruptured AAA and no previous endovascular or open surgical repair d Available CT scan of nonruptured AAA or d Available CT scan of ruptured AAA at the time of rupture before any surgical intervention d Excluded patients for whom poor quality of CT scans or technical factors (eg, vessel wall angulation; contrast material extravasation) precluded ILT assessment



No information provided; or obviously inappropriate selection procedures Was an objective definition of AAA rupture used?

Appropriate definition of AAA rupture used, including both of the following criteria: d Diagnosis of a ruptured AAA by a consultant vascular physician/ surgeon d AAA associated with objective evidence of blood within the peritoneum identified on a CT scan or alternative imaging modality Limited definition of ruptured AAA described: Definition restricted to diagnosis by consultant vascular physician/ surgeon or d Definition restricted to diagnosis on imaging, but no description of radiologic findings to support diagnosis of ruptured AAA

No





d

No definition of ruptured AAA described



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Supplementary Table I (online only). Continued. Response Category Assessment of outcomedWas an appropriate method of estimating ILT volume used?

Criteria Method of estimating ILT well described and Previously validated or d Reproducibility evaluated and reported within paper and d Reproducibility determined to be moderate-high

Yes

Partial



d



Method of estimating ILT well described: d But not previously validated or d No assessment of reproducibility reported or d Reproducibility determined to be low



Method of estimating ILT not described or limited description provided and no assessment of reproducibility made Sample size calculation/ estimation reported in methodology?

Details of sample size calculation/estimation reported in methodology





Required sample size reported, but no details on how this was calculated/estimated



No sample size calculation/estimation conducted What was the sample size?

<50 or 50-100 or >100

N/A

N/A

N/A

Not reported

N/A

N/A

N/A

Did participants with AAA rupture undergo a CT scan before rupture and after rupture?

For all patients, CT data were present both before and during the rupture event

Were participant characteristics adequately described?

Sufficient relevant baseline information clearly characterizing the participants is provided (or reference to previously published baseline data is provided) Includes at least five of the following: d Age, sex, AAA diameter (mm), smoking, hypertension, diabetes, coronary artery disease, statin prescription, aspirin prescription Poorly defined criteria or incomplete relevant baseline/demographic information (eg, information on likely confounders not reported) d Includes fewer than five of the characteristics reported above

Were participants in the ruptured and intact AAA groups matched for diameter?

No







No baseline/demographic information provided



To provide an objective comparison of ruptured and intact AAAs, both groups were matched for maximum diameter



(Continued on next page)

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Supplementary Table I (online only). Continued. Response Category Were participants matched for other confounding factors for AAA rupture?

Criteria Adjustments are made for at least two of the following variables: d Age, sex, hypertension, smoking, and diabetes

Did not meet the criteria above or did not specify which variables were adjusted for No adjustment made for confounding factors other than maximum diameter AAA, Abdominal aortic aneurysm; CT, computed tomography; ILT, intraluminal thrombus.

Yes

Partial

No



 

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Supplementary Table II (online only). Extraction and calculation of missing data from studies included in this review Study Erhart et al,24 2015

Missing data

Authors contacted

Data obtained

Approach to estimating data required for meta-analysis if not provided by corresponding author

Yes

Yes (twice)

No

Mean 6 SD of age, ILT volume (cm3), and AAA diameter (mm): Variables were reported in the paper as median values 6SD (lowest-highest values). This was converted into mean 6 SD using formulas previously published by Hozo et al17 and subsequently combined using formulas documented in the Cochrane Handbook for Systematic Reviews of Interventions (2011), Part 2: 7.7.3 Data extraction for continuous outcomes, Table 7.7.a: Formulae for combining groups. Conversion of AAA diameter (iAAA) to mean 6 SD:

Conversion of AAA diameter (rAAA) to mean 6 SD:

iAAA: mean= 59

rAAA mean=

66+(2.84)+134 4 =92

iAAA and rAAA mean AAA diameter 6SD combined:

Mean 6 SD¼70 6 21 Conversion of age (iAAA) to mean 6 SD:

Conversion of age (rAAA) to mean 6 SD:

iAAA: mean=71

Conversion of ILT volume (iAAA) to mean 6 SD: iAAA: mean=67

Conversion of ILT volume (rAAA) to mean 6 SD:

rAAA mean=

6+(2.134)+401 4 =168.75

(Continued on next page)

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Supplementary Table II (online only). Continued. Study Erhart et al,25 2016

Missing data Yes

Authors contacted Yes (twice)

Data obtained No

Approach to estimating data required for meta-analysis if not provided by corresponding author Mean 6 SD of age, ILT volume (cm3), and AAA diameter (mm) were reported in the paper as mean (lowest-highest values). The SD was estimated using formulas previously published by Hozo et al.17 Estimation of SD for iAAAs (n ¼ 23) using method of Hozo et al17:

Golledge et al,26 2014

Yes

Haller et al,11 2018

Yes

Yes

Yes (thrice)

Estimation of SD for rAAAs (n ¼ 11) using method of Hozo et al17:

Age SD: (86-59)/4¼ 6.75

Age SD: (81-58)/4 ¼ 5.75

AAA diameter SD: (89-61)/4¼ 7

AAA diameter SD: (106-64)/4¼10.5

ILT volume SD: (327-26)/4¼ 75.25

ILT volume SD: (310-51)/4¼64.75

Yes

N/A; corresponding author provided original data set from which this was calculated.

No

Combined mean 6 SD age: mean 6 SD age was reported separately for each group. Combined mean 6 SD age was combined using formulas documented in the Cochrane Handbook for Systematic Reviews of Interventions (2011), Part 2: 7.7.3 Data extraction for continuous outcomes, Table 7.7.a: Formulae for combining groups. Combined iAAA mean 6 SD age:

Combined rAAA mean 6 SD age:

Mean 6 SD ILT volume: This was estimated from Fig 3, D of the publication and combined using formulas documented in the Cochrane Handbook for Systematic Reviews of Interventions (2011), Part 2: 7.7.3 Data extraction for continuous outcomes, Table 7.7.a: Formulae for combining groups. Combined iAAA mean 6 SD ILT volume:

Combined rAAA mean 6 SD ILT volume:

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Supplementary Table II (online only). Continued. Study

Missing data

Authors contacted

Data obtained

Approach to estimating data required for meta-analysis if not provided by corresponding author Mean 6 SD AAA diameter: This was reported in the paper as mean 6 SD across four groups. The combined mean 6 SD was obtained by using formulas documented in the Cochrane Handbook for Systematic Reviews of Interventions (2011), Part 2: 7.7.3 Data extraction for continuous outcomes, Table 7.7.a: Formulae for combining groups. Combined iAAA mean 6 SD AAA diameter:

Leemans et al,27 2018

Yes

No (not required; converted)

N/A

Combined rAAA mean 6 SD AAA diameter:

Combined mean 6 SD age: mean 6 SD age was reported separately for each group. Combined mean 6 SD age was combined using formulas documented in the Cochrane Handbook for Systematic Reviews of Interventions (2011), Part 2: 7.7.3 Data extraction for continuous outcomes, Table 7.7.a: Formulae for combining groups. iAAA and rAAA mean AAA diameter (mm) 6 SD combined:

Mean 6 SD ¼ 63 6 15 AAA, Abdominal aortic aneurysm; iAAA, asymptomatic intact AAA; ILT, intraluminal thrombus; N/A, not applicable; rAAA, ruptured AAA; SD, standard deviation. Hozo SP, Djulbegovic B, Hozo I. Estimating the mean and variance from the median, range, and the size of a sample. BMC Med Res Methodol 2005;5:13.

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Supplementary Table III (online only). Details of studies excluded after full-text evaluation Study

Reason for exclusion

Barret et al (2018)

ILT volume assessed in patients with intact AAAs only

Conlisk et al (2016)

ILT volume assessed in patients with intact AAAs only

Gasser et al (2010)

Volume of ILT not assessed

Georgakarakos et al (2010)

ILT volume assessed in patients with intact AAAs only

Georgakarakos et al (2011)

ILT volume assessed in patients with intact AAAs only.

Georgakarakos et al (2009)

ILT volume assessed in patients with intact AAAs only

Golledge et al (2008)

ILT volume assessed in patients with intact AAAs only

Khosla et al (2014)

Systematic review; ILT not examined

Kontopod et al (2013)

ILT volume assessed in patients with intact AAA only

Kontopod et al (2014)

ILT volume assessed in patients with intact AAAs only

Nikolova et al (2016)

Not a case-control study; included patients with intact AAAs only

Parr et al (2011)

ILT volume assessed in patients with intact AAAs only

Speelman et al (2010)

ILT volume assessed in patients with intact AAAs only

Stevens et al (2017)

ILT volume assessed in patients with intact AAAs only

Wang et al (2002)

ILT volume assessed in patients with intact AAAs only

AAA, Abdominal aortic aneurysm; ILT, intraluminal thrombus.

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Supplementary Table IV (online only). Clinical characteristics of participants with ruptured and asymptomatic intact abdominal aortic aneurysms (AAAs)

Study Hans et al,22 2005

Gasser et al,23 2010 Erhart et al,24 2015a Erhart et al,25 2016b

Sample size

Age, years

Male, %

AAA diameter, mm

67 iAAAs

72 6 6

70

60 6 12e

92 6 76e (65)f

NR

82e

19e

49

NR

NR

31 rAAAs

74 6 9

74

73 6 17e

149 6 90e (28)f

NR

97e

0e

55

NR

NR

30 iAAAs

76 6 8

87

70 6 23

116 6 159

NR

NR

NR

NR

NR

NR

NR

77 6 11

80

81 6 20

107 6 76

NR

NR

NR

NR

NR

30 iAAAs

71 (50-86)

100

59 6 10

67 6 72

67

97

NR

40

NR

NR

15 rAAAs

73 (60-88)

93

84 618

134 6 96

53

80

NR

40

NR

NR

23 iAAAs

71 (59-86)

100

65 (61-89)

112 (26-327)

57

96

13

39

NR

NR

11 rAAAs

74 (58-81)g

62

65 (56-91)g

99 (38-238)g

62

100

23

15

NR

NR

96

64

35

52

68

52

h

76 (58-81) (11)f

Haller et al,11 2018d

Leemans et al,27 2018 Siika et al,28 2018

Aspirin, (%)

20 rAAAs

h

Golledge et al,26 2014c

ILT volume, Smoking, HTN, Diabetes, CAD, Statins, % % % % % cm3

f

81 (64-106) (11)

134 (51-310)h (11)f

84 6 14

207 6 143

56 iAAAs

71 6 7

96e

28 rAAAs

74 6 7

75e

85 6 15

185 6 136

84

81

15

42

50

50

15 large iAAAs

71 6 10

87

686 12

163 6 79

100

67

13

20

60

NR

14 large rAAAs

81 6 10

64

78 6 13

213 6 150

71

57

14

43

50

NR

13 small iAAAs

72 6 8

77

55 6 3

83 6 54

77

77

8

31

62

NR

9 small rAAAs

68 6 6

67

52 6 8

92 6 31

100

89

22

33

22

NR

175 iAAAs

72 6 9

89

60 6 11e

83 6 61e

49

NR

13

61

NR

NR

45 rAAAs

74 6 9

87

77 6 19e

186 6 135e

47

NR

15

51

NR

NR

60 iAAAs

76 6 8

77

62 6 13

102 6 79

e

65

NR

NR

NR

NR

NR

30 rAAAs

77 6 10

77

77 6 15e

180 6 111e

77

NR

NR

NR

NR

NR

e

CAD, Coronary artery disease; HTN, hypertension; iAAA, asymptomatic intact AAA; N/A, not applicable; NR, not reported; rAAA, ruptured AAA. Data are reported as mean 6 standard deviation unless indicated otherwise. a Continuous variables reported as median values 6standard deviation or (lowest-highest values) for age, AAA diameter, and ILT volume. b Continuous data are reported as means (range). c Mean 6 standard deviation values for age, AAA diameter, and ILT volume were provided by the corresponding author. d ILT volume was estimated from Fig 3, A of the publication. e Significant difference between iAAA and rAAA (P < .05). f The number of participants for whom data were available. g Characteristics before rupture. h Characteristics during rupture; data have been converted to the nearest whole number.

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Supplementary Table V (online only). Strengths and weaknesses of studies included in this systematic review

Study

Inclusion of CT scan Matching Selection Objective before Participants’ Matching for other Sample Clearly Prospective criteria definition Appropriate size Sample and after characteristics for AAA confounding defined study well of AAA measure of a rupture described diameter variables size objective design described rupture ILT volume calculation

Hans et al,22 2005

Yes

No

Partial

No

Partial

No

50-100

No

Yes

No

Yes

Gasser et al,23 2010

Yes

No

Yes

No

Partial

No

50-100

No

Partial

Yes

Partial

Erhart et al,24 2015

Yes

No

Yes

Partial

Yesb

No

50-100

No

Yes

No

No

Erhart et al,25 2016

Yes

No

Yes

No

Yesb

No

<50

Yes

Yes

Noc

No

Golledge et al,26 2014

Yes

No

Yes

Yes

Yesb,d

Yes

50-100

No

Yes

Yes

No

Haller et al,11 2018

Yes

No

Yes

No

Partial

No

50-100

No

Yes

No

No

Leemans et al,27 2018

Yes

No

Yes

Partial

Partial

No

>200

No

Yes

Yes

No

Siika et al,28 2018

Yes

No

Partial

No

Yesb

No

50-100

No

Partial

Yese

No

AAA, Abdominal aortic aneurysm; CT, computed tomography; ILT, intraluminal thrombus. a Method was well described, was previously validated, or had moderate-high reproducibility (Supplementary Table I). b Reproducibility assessments of method to estimate ILT volume were reported in other publications. c Matching for aortic diameter was conducted only for asymptomatic intact AAA patients and ruptured AAA patients who had a CT scan before rupture. d This study also performed an intraobserver reproducibility assessment of the method used to estimate ILT volume as a part of study design and reported the results of this within the publication. e In this study, diameter was matched in a subanalysis in which ILT volume was not reported.

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Standard Error .3 .2 .1

0

Funnel plot with pseudo 95% confidence limits

-.5

0 Erhart et al. (2015) Gasser et al. (2010) Haller et al. (2018) Leemans et al. (2018) L owe r C I Pooled

Supplementary Fig 1 (online only). Leave-one-out sensitivity analysis for the association between intraluminal thrombus (ILT) volume and abdominal aortic aneurysm (AAA) rupture. CI, Confidence interval.

.5 SMD

1

1.5

Erhart et al. (2016) Golledge et al. (2014) Hans et al. (2005) Siika et al. (2018) U ppe r C I

Supplementary Fig 2 (online only). Funnel plot with pseudo-95% confidence intervals (CIs) of the association between intraluminal thrombus (ILT) volume and abdominal aortic aneurysm (AAA) rupture. SMD, Standardized mean difference.2