- Academic Editor
†These authors contributed equally.
Background: This systematic review and meta-analysis aims
to investigate whether antiplatelet agents are associated with the
reduction, expansion, and rupture of abdominal aortic aneurysm (AAA).
Methods: A thorough exploration was conducted on four prominent
databases, namely EMBASE, Ovid, PubMed, and Scopus, to identify studies that
reported the influence of antiplatelet agents on the sac development of AAA. The
assessment was carried out until March 2023. R software v.4.1 was used for
statistical analysis. Results: After reviewing 13 publications which
included a total of 5392 patients (1446 in the antiplatelet group and 2540 in the
control group), a meta-analysis was conducted. The results of the analysis
revealed that there was no significant difference in the annual growth rate of
AAA diameter between those who received antiplatelet agents and those who did not
(mean difference (MD) = –0.04, 95% CI = [–0.37, 0.30]; heterogeneity:
p
Abdominal aortic aneurysm (AAA) is a specific form of atherothrombotic disease, which is usually characterized by dilated abdominal aorta greater than 30 mm or exceeding 50% the normal aortic diameter [1]. Endovascular repair, open surgery, and various medications such as statins, aspirin, and warfarin were used to slow the expansion rate and even regress sac volume [2, 3, 4, 5]. However, the result of using the above methods for restricting the expansion rate on AAA was still uncertain. The most recent guideline from the European Society for Vascular Surgery (ESVS) recommends the use of antiplatelet agents for patients undergoing AAA surgery, however this is without any evidence for the potential impact of antiplatelet agents on sac volume [6]. To further clarify the role of antiplatelet agents in the treatment of AAA, we performed a systematic review and meta-analysis to investigate whether antiplatelet agents are associated with the reduction, expansion, and rupture of sac capsules.
We registered the analysis protocol under the registration number CRD42022326589, on the International Prospective Register of Systematic Reviews (PROSPERO). The analysis followed the guidelines provided in the Preferred Reporting of Systematic Reviews and Meta-Analysis (PRISMA) statement [7]. The primary objective of the analysis was to investigate the impact of antiplatelet treatment on sac volume in patients with AAA. To select relevant articles, the P.I.C.O. (patient: patients with AAA; intervention: antiplatelet treatment; comparison: antiplatelet medication vs. placebo or other medications; outcome: sac regression or expansion, and rupture, among others) model was utilized [8].
For this study, a search was conducted across four databases, EMBASE, Ovid, PubMed, and Scopus. The literature search strategy utilized the following keywords: (“aspirin” OR “clopidogrel” OR “antiplatelet”) AND (“abdominal aortic aneurysm” OR “aortic aneurysm repair” OR “aortic diameter” OR “growth rate”). The search was conducted up until March 2023. In addition, references for all included literature and for similar Meta-analyses were searched.
The inclusion criteria for this study were as follows: (1) reported results for cohorts of more than 10 patients receiving antiplatelet agents with at least one imaging data, and (2) compared the sac change of AAA patients receiving antiplatelet agents with that of patients receiving placebo or other agents without antiplatelet function. Studies that did not meet the following exclusion criteria were not considered: (1) case reports, meetings, and literature reviews, (2) studies that referred to biomarkers of AAA patients unless they included radiographic features of the sac volume, (3) articles with inadequate data (less than 25% of predefined variables extractable), and (4) studies reporting on the same population of patients. In the latter case, only the latest report was included unless the outcomes were mutually exclusive.
Duplicate citations were removed, and an independent reviewer was responsible for reviewing all titles and abstracts. Full-text versions of studies that met the inclusion criteria were obtained, and data extraction was performed by another independent reviewer. In cases where a consensus could not be reached between the two reviewers, a third reviewer was consulted to assist with the re-review of the full text of the article (Fig. 1). The extraction of data was performed by the first author and independently verified by the co-authors using a standardized data collection. Data collected included first author, publication year, study design, sample size, interventions, follow-up year, and outcome data (sac diameter reduction or expansion, and rupture).
Flow diagram adhering to the Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines to illustrate the search and selection process during the initial stages of our review.
The Cochrane Risk of Bias tool was used to assess the quality of included randomized controlled studies, including selection bias, performance bias, detection bias, attrition bias, reporting bias, and other biases [9]. Non-randomized controlled studies were assessed by the Newcastle-Ottawa scale (NOS) for selection bias in the antiplatelet drug and control groups, comparability bias in the two cohorts, and outcome assessment bias [10].
The continuous variables were compared between the two groups using
t-test and the categorical variables were compared using the
We reviewed a total of 1872 references published within the predefined time
frame of the analysis. Following a thorough examination of 22 articles, we
ultimately included 13 studies that reported on the effects of antiplatelet
agents on AAA progression in a total of 5392 patients (Table 1, Ref. [5, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22]).
Three of them were randomized controlled clinical studies, two were prospective
studies, and eight were retrospective studies. Eight studies reported on annual
growth rate of sac diameter after taking antiplatelet agents; four reported on
the number of cases of change in aneurysm diameter after taking antiplatelet
agents; and one reported on aneurysm rupture after taking antiplatelet agents in
patients. In terms of the following baseline characteristics: gender, smoking,
and basic disease (including hypertension, diabetes mellitus, chronic obstructive
pulmonary disease, and chronic renal insufficiency), there were no significant
differences between the antiplatelet drug group and the control group (p
Research | Type of research | Year of publication | Duration | Drugs | Number of patients | Outcome measurement | Ending | NOS score | |
Non-antiplatelet | Antiplatelet | ||||||||
Lindholt et al. (diameter |
Randomized controlled study | 2008 | 10 years | Low-dose aspirin | 17 | 14 | Aneurysm diameter growth rate (mean |
Unmedicated increase 2.92 |
NA. |
Lindholt et al. (diameter |
Randomized controlled study | 2008 | 10 years | Low-dose aspirin | 69 | 48 | Aneurysm diameter growth rate (mean |
Unmedicated increase 2.52 |
NA. |
Wanhainen et al. [12] | Randomized controlled study | 2020 | 1 year | Tegretol | 69 | 67 | Aneurysm diameter growth rate (mean |
The diameter of the sac increased by 1.8 |
NA. |
Karlsson et al. [13] | Randomized controlled study | 2009 | 18 months | Aspirin | 110 | 101 | Aneurysm diameter growth rate (mean |
Increase in sac diameter without medication 2.6 |
NA. |
Aoki et al. [14] | Retrospective study | 2011 | 6 months | Anti-platelet agents | 34 | 23 | Aneurysm diameter reduction rate (mean |
Decrease in sac diameter without medication 14.6 |
8 |
Thompson et al. [15] | Retrospective study | 2010 | 25 years | Anti-platelet agents | 757 | 443 | Aneurysm diameter growth rate (mean |
The diameter of the sac increased by 1.54 |
9 |
Ahmad et al. [16] | Retrospective study | 2017 | 20 years | Aspirin | 77 | 40 | Aneurysm diameter growth rate (mean |
Increase in sac diameter without medication 2.4 |
8 |
Sweeting et al. [17] | Forward-Looking Research | 2010 | 1.9 years | Anti-platelet agents | 1200 | 501 | Aneurysm diameter growth rate (mean |
The diameter of the sac increased by 2.76 |
7 |
Rasmussen et al. [18] | Forward-Looking Research | 2014 | 1.78 years | Aspirin | 207 | 209 | Aneurysm diameter growth rate (mean |
The diameter of the sac increased by 3.01 |
7 |
Chen et al. [5] | Retrospective study | 2013 | 4.01 years | Low-dose aspirin | 110 | 118 | Aneurysm rupture | Ruptured sac without medication 2; ruptured sac with medication 5 | 7 |
Morisaki et al. [19] | Retrospective study | 2022 | 1 year | Anti-platelet agents | 103 | 79 | Reduction in sac diameter | Decrease in sac diameter without medication 39; decrease in sac diameter with medication 16 | 8 |
Balceniuk et al. [20] | Retrospective study | 2018 | NA. | Aspirin | 43 | 223 | Reduction in sac diameter | Reduction in sac diameter by drug administration OR: 3.327, 95% CI (1.409–7.857), p = 0.006 | 8 |
Marcos et al. [21] | Retrospective study | 2017 | 41.5 months | Anti-platelet agents | 12 | 66 | Expansion in sac diameter | Increase in sac diameter without medication 4; increase in sac diameter with medication 21 | 8 |
Ferguson et al. [22] | Retrospective study | 2010 | 5 years | Aspirin | 289 | 363 | Expansion in sac diameter | Increase in sac diameter by drug administration OR: 1.10, 95% CI (0.78–1.56), p = 0.575 | 9 |
NOS, Newcastle-Ottawa scale; OR, odds ratio. NA means data is not available.
Control group (n/n) | Anti-platelet agents group (n/n) | p-value | ||
Male | 235/283 (0.83) | 223/266 (0.84) | 0.018 | 0.892 |
Smoking | 157/259 (0.61) | 117/210 (0.56) | 0.955 | 0.329 |
High blood pressure | 210/295 (0.71) | 256/332 (0.77) | 2.569 | 0.109 |
Diabetes | 35/283 (0.12) | 40/266 (0.15) | 0.618 | 0.432 |
Coronary heart disease | 45/122 (0.37) | 100/184 (0.54) | 8.286 | 0.004 |
Chronic obstructive pulmonary disease | 50/192 (0.26) | 66/253 (0.26) | 0 | 1 |
Renal insufficiency | 10/110 (0.09) | 15/118 (0.13) | 0.439 | 0.508 |
Risk assessment using the Cochrane Risk Assessment Tool for all included randomized controlled clinical studies showed a low overall risk for these three studies [11, 12, 13] (Fig. 2). The quality of the literature for non-randomized controlled studies was assessed using the NOS scale and was high in all cases (Table 1).
Risk of bias. The ROBINS-I checklist for randomized trials was used to assess the methodological quality and potential risk of bias. ROBINS-1, Risk of Bias In Non-Randomized Studies of Interventions.
Of the total studies, the AAA growth rate was reported in eight studies
(antiplatelet group: 1446, control group: 2540), including four with aspirin, one
with ticagrelor, and three with any antiplatelet agents [11, 12, 13, 14, 15, 16, 17, 18]. Of all the
literature, only one reported a reduction in AAA diameter with the use of
antiplatelet agents (control group: 14.6
Annual growth rate of AAA diameter (mm/year) in patients using antiplatelet agents vs. not using antiplatelet agents. SD, standard deviation; MD, mean difference; CI, confidence interval; AAA, abdominal aortic aneurysm.
Four studies (antiplatelet group: 731, control group: 447) reported on the
number of cases of aneurysm diameter change after the use of antiplatelet agents,
two with aspirin and two with any antiplatelet drug [19, 20, 21, 22]. Meta-analysis showed
no significant difference between AAA diameter growth with or without
antiplatelet agents (odds ratio (OR) = 0.96, 95% CI = [0.41, 2.25];
heterogeneity: p
Number of patients (n) who experienced aneurysm diameter expansion using antiplatelet agents vs. not using antiplatelet agents. CI, confidence interval; OR, odds ratio.
Only one study described aneurysm rupture after the use of antiplatelet agents with a multifactorial Cox regression analysis showing that the risk of AAA rupture was not significantly altered with or without low-dose aspirin (hazard ratio (HR) = 1.019, 95% CI = [0.993, 1.044], p = 0.951) [5].
The results of our meta-analysis suggest that antiplatelet agents do not affect AAA process, either in terms of sac expansion, reduction, or rupture. Although some of the findings hold opposite opinions, an increasing number of studies suggest that the effectiveness of antiplatelet agents in slowing the expansion of AAA may be due to the antiplatelet agents’ capacity to decrease platelet-derived cytokines expression and plasminogen activation, and to diminish the infiltration of platelets and macrophages within the vascular wall [11, 13, 22, 23]. Our findings may be different, as meta-analysis does not demonstrate any significant differences in growth rates in patients taking antiplatelet agents (MD = –0.04, 95% CI = [–0.37, 0.30]) (Fig. 3).
Unlike statins, which have been clearly demonstrated to slow AAA expansion and
prevent rupture through anti-inflammatory and antioxidant effects and by reducing
matrix metalloproteinase secretion [24, 25], the mechanism of antiplatelet agents
on AAA remains to be investigated. Hofmann et al. [26] analyzed the
effects of aspirin and therapeutic anticoagulants on mRNA and protein expression
of heme oxygenase-1 (HO-1) in AAA patients. They showed that aspirin and
therapeutic anticoagulants were not significantly associated with HO-1 expression
(p
Of note, a total of three included papers described a reduction in AAA aneurysms
in patients who underwent Endovascular aneurysm repair (EVAR) of abdominal aorta
with the use of antiplatelet agents. Aoki et al. [14] found that there
was no significant difference in AAA diameter reduction in patients with or
without antiplatelet agents after receiving EVAR (control group: 14.6
In summary, antiplatelet agents have no effect on the development of AAA, either in terms of AAA expansion, reduction or rupture, and there is no benefit to AAA patients taking antiplatelet agents for the purpose of slowing down the growth rates of sac diameter.
YJL, and ZYW designed the research study. YY, YPD and CL performed the data collection. YY, CL, ZYW and ZGC analyzed the data. YY, ZYW, YPD and YJL prepared the manuscript. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.
Not applicable.
Not applicable.
This study is supported by the National Key Research and Development Project of China (No.2020YFC2008003), the Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (CIFMS. 2021-I2M-1-050) and the National High Level Hospital Clinical Research Funding (No. BJ-2021-205).
The authors declare no conflict of interest.
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