A Systematic Review of the Prognostic Value of Inflammatory Biomarkers in Outcomes After Endovascular Abdominal Aortic Aneurysm Repair

Abstract

The present review aimed to evaluate the prognostic value of inflammatory biomarkers in patients undergoing endovascular aortic aneurysm repair (EVAR). A systematic review of relevant studies was performed according to PRISMA guidelines. Articles assessing associations of inflammatory biomarkers with the post-EVAR outcomes were considered. After screening, 34 studies were included (7019 patients were reviewed; mean age: 73.6 years; 91.6% were men); 22 different inflammatory biomarkers were identified among the included studies. Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) were investigated in 11, 4, and 3 studies, respectively. Nine studies evaluated the post-implantation syndrome (PIS) and examined its role in post-EVAR outcomes. Increased preoperative NLR was associated with all-cause mortality and acute kidney injury after EVAR. NLR was also reported as an independent risk factor for aneurysm sac regression failure. High preoperative PLR and low preoperative LMR were correlated with acute kidney injury and overall mortality, respectively. PIS was associated with a lower type 2 endoleak rate but had no impact on mortality rates. NLR may be a useful predictor for mortality and poor prognosis in EVAR populations. This may have clinical implications in post-EVAR surveillance programs.

Keywords

inflammatory biomarker neutrophil-to-lymphocyte ratio (NLR)post-implantation syndrome (PIS)mortality post-EVAR surveillance

Introduction

Appropriate surveillance and lifelong patient monitoring following endovascular abdominal aortic aneurysm repair (EVAR) are necessary to minimize subsequent aneurysm-related morbidity and mortality. Early detection of postoperative endoleaks provides the rationale for thorough follow-up after the procedure.¹ A pro-inflammatory state along with vascular wall inflammatory activity might be associated with post-EVAR outcomes.² Thus, the identification of inflammatory biomarkers for the prognosis following EVAR remains an area of active investigation.

Recently, it has been shown that inflammatory biomarkers might have a predictive value in oncologic patients and in patients with ST-segment elevation myocardial infarction, especially those undergoing percutaneous coronary intervention.^3
-6 More specifically, an elevated neutrophil-to-lymphocyte ratio (NLR) was reported to increase mortality and rehospitalization after transcatheter or surgical aortic valve replacement for aortic stenosis.⁷ Post-implantation syndrome (PIS) is also a marker of systemic inflammatory response following EVAR that may lead to high rates of 30-day mortality and major adverse cardiovascular events (MACE).⁸ However, published data are scarce regarding the potentially prognostic role of various inflammatory markers in post-EVAR outcomes. This information is vital for the vascular surgeon and can help recognizing EVAR patients at highest risk of developing postoperative complications.

The present study aimed to perform a systematic review of the available literature to document the predictive value of the existing inflammatory biomarkers in patients undergoing elective EVAR.

Methods

Study Design, Eligibility Criteria, and Patient Inclusion

This systematic review was undertaken according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.⁹ Before the full-text screening, a predefined detailed protocol of our systematic review was prospectively registered in the International Prospective Register of Systematic Reviews (PROSPERO, registration number: CRD420261293893). No institutional review board (IRB) approval was required since the present review utilized published work.

Articles assessing the possible association of inflammatory biomarkers with clinical outcomes following endovascular repair of intact abdominal aortic aneurysms (AAA) in the elective setting, irrespective of study design, were examined for inclusion. Exclusion criteria were: (i) studies including <20 patients, (ii) studies reporting on ruptured AAAs, (iii) articles referring to thoracic endovascular aortic repair (TEVAR), (iv) studies including patients undergoing complex EVAR procedures (eg, fenestrated/branched EVAR), (v) studies describing open surgical repair (OSR) of AAAs, (vi) articles reporting on pararenal or juxtarenal AAAs, (vii) inflammatory biomarkers derived from the cerebrospinal fluid, (viii) studies including patients suffering from aortic dissection, (ix) experimental animal studies or virtual aneurysm models, (x) patients undergoing endovascular aneurysm sealing (EVAS), (xi) studies including patients with a known history of systemic inflammatory disease or with clinical or laboratory evidence of an active infection preoperatively or postoperatively, and (xii) meta-analyses, systematic reviews, editorials, letters to the editor, or comments. Studies with overlapping populations were excluded unless they investigated different biomarkers or reported on different outcomes.

Information Sources and Search Strategy

We searched the MEDLINE (PubMed), Scopus, and Cochrane Library databases (last search: January 27, 2026) applying the algorithm: ((“inflammat* biomarker*”) OR (“inflammat* index*”) OR (“inflammat* indicator*”) OR (“inflammat* marker*”) OR (“systemic inflammat*”) OR (“NLR”) OR (“PLR”) OR (“LMR”) OR (“inflammat* status”) OR (“post-implantation syndrome”)) AND ((“endovascular abdominal aortic aneurysm repair”) OR (“endovascular aneurysm repair”) OR (EVAR) OR (“endovascular aortic aneurysm repair”)). No time, gender, or geographic limitations were used. The study selection process involved 2 authors (G.K., O.L.), blind to each other, inspecting the titles and abstracts of the retrieved literature. Publications with titles and abstracts satisfying the inclusion criteria were collected in full-text and analyzed. The full-text screening was performed by the same 2 authors. When studies from the same institution were identified, the most recent or the most relevant one was examined for inclusion. Any disagreement was resolved through discussion with a third investigator. We also hand-searched all studies for potentially eligible articles applying the snowball methodology.¹⁰

Data Extraction, Processing, and Definitions

Two authors independently extracted the data into a spreadsheet. The extracted information included the study author(s), publication year, study period, study design, number of patients, type of inflammatory biomarker examined, patient demographics, aneurysm-related details, and main findings of each study. The primary outcome was the perioperative inflammatory biomarkers and their correlation with the post-EVAR outcomes, as reported in the included studies.

The inflammatory biomarkers were defined as those measured in the perioperative period and included the NLR, platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), red blood cell distribution width (RDW), RDW-to-albumin ratio (RAR), hemoglobin-to-RDW ratio (HRR), white blood cells (WBC), platelets (PLT), C-reactive protein (CRP), procalcitonin (PCT), interleukin-1 (IL-1), IL-2, IL-6, IL-8, intercellular adhesion molecule-1 (ICAM-1), monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor alpha (TNF-a), systemic immune inflammatory index (SIII), systemic inflammatory response index (SIRI), volume of newly formed thrombus after the deployment of the endograft (fresh thrombus), fibrinogen, and PIS. PIS was defined across the included studies as an early systemic inflammatory response following EVAR and was characterized by flu-like symptoms, changes in temperature, and laboratory findings of inflammation, in the absence of infection.¹¹ Notably, PIS was considered either as inflammatory marker or as post-EVAR outcome in this review. The volume of fresh thrombus was defined as the volume of contrast filling the aneurysmal sac in the preoperative computed tomography angiography (CTA) after subtracting the endograft volume following device deployment, and was observed in the first postoperative CTA. The remaining biomarkers were measured perioperatively in blood samples. A proposed calculation formula for these biomarkers is shown in Table 1.

Table 1.

Calculation Formulas for Inflammatory Biomarkers.

Biomarker	Computing method
NLR	Neutrophil count/lymphocyte count
PLR	Platelet count/lymphocyte count
LMR	Lymphocyte count/monocyte count
RAR	RDW/albumin
HRR	Hemoglobin/RDW
SIII	(Platelet count × neutrophil count)/lymphocyte count
SIRI	(Neutrophil count × monocyte count)/lymphocyte count
Fresh thrombus	Contrast volume filling the aneurysmal sac in preoperative CTA − endograft volume in first postoperative CTA

Abbreviations: NLR, neutrophil-to-lymphocyte ratio; PLR, platelet-to-lymphocyte ratio; LMR, lymphocyte-to-monocyte ratio; RDW, red blood cell distribution width; RAR, RDW-to-albumin ratio; HRR, hemoglobin-to-RDW ratio; SIII, systemic immune inflammatory index; SIRI, systemic inflammatory response index; CTA, computed tomography angiography.

The clinical outcomes following EVAR included all-cause mortality, perioperative mortality, endoleak, MACE, reintervention, AAA shrinkage/growth, acute kidney injury, and PIS rates. To increase data completeness, whenever necessary, an email was sent to the corresponding author of the study requesting the missing information.

Assessment of Study Quality and Risk of Bias

The risk of bias and study quality of the included studies was evaluated using the methodological index for non-randomized studies (MINORS) tool.¹² Scoring quality of non-comparative studies was defined as low (0-8), moderate (9-12), and high (13-16). Scoring quality for comparative studies was labeled as low (0-12), moderate (13-18), and high (19-24). The intraclass correlation coefficient (ICC) and the 2-way mixed model were applied to estimate inter-observer agreement.

Results

Study and Patient Characteristics

The literature search yielded 253 potentially eligible articles after duplicates were removed. Following full-text screening, 34 studies met our eligibility criteria, as summarized in the PRISMA flow diagram (Figure 1).^11,13
-45 These were 29 retrospective and 5 prospective cohort studies. A total of 7019 patients undergoing EVAR were identified. One study included 24 EVAR patients out of 75 patients scheduled to undergo non-cardiac vascular surgery procedures and underscored the predictive value of inflammatory status in outcomes following these procedures.¹³ The mean MINORS score for the non-comparative studies was 10.9 ± 0.7 (range: 10-12; moderate quality). The mean score for the comparative studies was 18.1 ± 1.8 (range: 14-20; moderate quality). Interobserver agreement in the assessment of study methodology was excellent (ICC: 0.97; 95% confidence interval: 0.95-0.98). The baseline characteristics of the included studies are outlined in Table 2. The mean age of the cohort was 73.6 ± 2.1 years (range: 70.3-78.5 years), and 5155 of the 5627 patients (91.6%) were men. Of those with available data (n = 4832), their mean AAA diameter was 56 ± 2.8 mm (range: 49.9-61 mm). Additionally, the patients shared the usual atherosclerotic risk factors of a population with AAA. The extracted data on patient demographics are presented in Table 3.

Figure 1.

PRISMA flowchart (last search: January 27, 2026).

Table 2.

Baseline Characteristics of the Included Studies. Studies Appear in Reverse Chronological Order (Publication Year).

Author	Year	Study period	Country	Design	No of EVAR patients
Ahmed et al	2025	NR	UK	P	24
Del Rio-Sola et al	2025	2018-2021	Spain	P	100
Ribeiro et al	2025	2011-2023	Portugal	R	434
Toncelli et al	2025	2015-2023	Italy	R	823
Wang et al	2025	2016-2024	China	R	174
Aytekin et al	2024	2021-2024	Turkey	R	171
Kikuchi et al	2024	2008-2021	Japan	R	146
Nishibe et al	2024	2012-2016	Japan	R	176
Seretis et al	2024	2011-2013	Greece	R	76
Zhao et al	2024	2016-2023	China	R	147
Ntalouka et al	2023	2016-2019	Greece	R	322
Pasqui et al	2023	2017-2020	Italy	R	184
Xie et al	2023	NR	China	R	200
Nana et al	2022	2017-2020	Greece	R	268
Nishibe et al	2022	2012-2016	Japan	R	178
Ferreira et al	2021	2004-2010	The Netherlands	R	149
Lecumberri et al	2021	2000-2019	Spain	R	284
Ntalouka et al	2021	2016-2019	Greece	R	230
Octeau et al	2021	2001-2017	USA	R	777
Oddi et al	2021	2014-2019	Italy	R	367
King et al	2020	2010-2018	USA	R	108
Martinelli et al	2020	2013-2018	Italy	R	111
Sousa et al	2020	2008-2017	Portugal	R	133
Jeong et al	2019	2008-2015	Korea	R	168
Lee et al	2018	2012-2017	Korea	R	34
Veraldi et al	2018	2016-2018	Italy	R	124
Kwon et al	2016	2008-2013	Korea	R	204
Arnaoutoglou et al	2015	2010-2013	Greece	P	214
Baek et al	2015	2008-2012	Korea	R	178
Lin et al	2015	NR	China	R	204
Kakisis et al	2014	2011	Greece	P	87
Nano et al	2014	2000-2013	Italy	R	118
Arnaoutoglou et al	2011	2007-2008	Greece	P	40
De La Motte et al	2011	2007	Denmark	R	66

Abbreviations: EVAR, endovascular abdominal aortic aneurysm repair; NR, not reported; P, prospective; R, retrospective.

Table 3.

Patient Demographics and Comorbidities.

Author	No of EVAR patients	Age	Males	Smoking	CAD	DM	PAD	HTN	COPD	DL	AAA diameter
Ahmed et al	24	NR	NR	NR	8	4	3	10	NR	7	NR
Del Rio-Sola et al	100	72.8	87	40	NR	7	NR	64	20	36	52
Ribeiro et al	434	74	416	297	NR	106	117	380	NR	NR	60
Toncelli et al	823	75.3	756	415	283	147	NR	662	281	500	56
Wang et al	174	72.5	154	86	NR	32	NR	127	13	59	55
Aytekin et al	171	70.3	159	102	91	35	9	91	67	69	NR
Kikuchi et al	146	77.2	123	92	NR	26	NR	103	NR	58	49.9
Nishibe et al	176	78.5	148	114	89	38	NR	137	48	79	52.4
Seretis et al	76	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR
Zhao et al	147	72.2	128	67	70	26	NR	107	11	43	55
Ntalouka et al	322	72.3	316	203	138	49	10	249	145	228	59.2
Pasqui et al	184	75.8	158	64	52	17	16	155	41	128	54
Xie et al	200	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR
Nana et al	268	72.1	268	186	123	43	NR	223	128	212	59.1
Nishibe et al	178	77.5	150	143	91	39	NR	139	49	80	52.9
Ferreira et al	149	72.6	131	46	66	24	NR	NR	24	44	60
Lecumberri et al	284	75.1	270	250	83	41	95	217	82	NR	55.6
Ntalouka et al	230	72.6	228	162	101	38	NR	193	118	183	58.6
Octeau et al	777	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR
Oddi et al	367	72.8	327	190	108	46	NR	301	NR	225	NR
King et al	108	75.5	78	87	52	27	25	88	37	73	55.5
Martinelli et al	111	74	NR	NR	NR	19	NR	76	NR	42	NR
Sousa et al	133	75.5	127	NR	52	29	NR	112	33	89	NR
Jeong et al	168	70.8	154	111	52	26	NR	117	NR	94	56.1
Lee et al	34	75.7	25	NR	6	5	NR	25	NR	NR	57.2
Veraldi et al	124	75	114	NR	42	14	NR	122	NR	NR	NR
Kwon et al	204	71	185	129	66	28	NR	144	84	NR	57
Arnaoutoglou et al	214	72.3	206	129	111	45	NR	187	100	168	58
Baek et al	178	71	159	NR	58	NR	NR	NR	NR	NR	56
Lin et al	204	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR
Kakisis et al	87	72.6	81	33	28	13	NR	48	17	24	54.6
Nano et al	118	72.7	110	61	62	58	NR	102	29	45	54
Arnaoutoglou et al	40	72.1	38	NR	NR	NR	NR	NR	NR	NR	55
De La Motte et al	66	73.5	59	30	32	12	13	49	26	NR	61

Continuous data are presented as mean and categorical data as number. Age (years), AAA diameter (mm).

Abbreviations: EVAR, endovascular abdominal aortic aneurysm repair; CAD, coronary artery disease; DM, diabetes mellitus; PAD, peripheral arterial disease; HTN, hypertension; COPD, chronic obstructive pulmonary disease; DL, dyslipidemia; AAA, abdominal aortic aneurysm; NR, not reported.

Inflammatory Biomarkers and Post-EVAR Outcomes

The associations of various inflammatory biomarkers with the clinical outcomes following EVAR are described in detail in Table 4. A total of 22 different inflammatory biomarkers were investigated in the 34 studies. NLR, PLR, and LMR were investigated in 11, 4, and 3 articles, respectively. Nine studies considered the PIS as a marker of inflammatory status in the immediate postoperative period and examined its role in post-EVAR outcomes. Increased preoperative NLR was found to be a significant predictor of all-cause mortality and acute kidney injury in EVAR patients.^{15,16,22,23,27} This predictive value remained even when NLR was measured postoperatively.^28,29 With regards to the impact of NLR on the reintervention rate, mixed results were found. Octeau et al indicated that high NLR values >3.6 were an independent predictor of reinterventions at 30 days, 1, and 5 years.³⁰ Nevertheless, a single-center, retrospective analysis of 108 patients undergoing elective EVAR failed to detect any association with reintervention rate or sac enlargement.³² NLR was reported as an independent risk factor for no shrinking AAA with no effect, though, on the endoleak rate.^19,24 Additionally, low preoperative LMR <3.21 was correlated with overall mortality, whereas, high postoperative PLR >22.8 was associated with acute kidney injury.^20,29 Mortality rates were similar between patients who experienced PIS and those who did not, while PIS was significantly associated with a lower type 2 endoleak rate.^11,18,34,38 There was also a considerable controversy among the included studies as to whether PIS could be predictive or not of the adverse events following EVAR.^{11,33,34,38,39,43}

Table 4.

Inflammatory Biomarkers and Their Association With Post-EVAR Outcomes.

Author	Inflammatory biomarkers	Timing of measurement	Main findings	Conclusions
Ahmed et al	CRP, IL-1, IL-6, ICAM-1, fibrinogen	Preoperatively and postoperatively	ICAM-1 showed significant difference between the MACE and non-MACE group on POD1 and POD2	Measuring inflammatory biomarkers in vascular surgery pts is a valuable aid to clinicians in potentially identifying pts at risk
Del Rio-Sola et al	IL-1, IL-2, IL-6, IL-8, MCP-1, TNF-a	Preoperatively and postoperatively	Preoperative IL-8, MCP-1 at 7 d post-EVAR, and IL-1 at 12 mo post-EVAR were significantly associated with endoleak	Inflammatory biomarkers such as IL-1, IL-8, MCP-1 may help identify pts at high risk of developing endoleaks
Ribeiro et al	NLR	Preoperatively	NLR >2.4 was associated with lower survival rates and lower freedom from aortic reinterventions	NLR is a prognostic marker that can predict major adverse events and mortality
Toncelli et al	NLR	Preoperatively	Preoperative NLR >5 showed significant lower survival rates	Preoperative NLR >5 is a risk factor for post-EVAR long-term mortality
Wang et al	RAR	Preoperatively	RAR mediated 23.8% of the relationship between frailty and all-cause mortality	RAR is an innovative inflammatory biomarker and can identify high-risk AAA pts
Aytekin et al	PIS	Postoperatively	PIS-experienced pts had significantly higher mural thrombus in the 1-y CTA and lower T2EL rate	Polyester endografts are associated with a higher incidence of PIS and thrombogenicity but a lower incidence of T2EL
Kikuchi et al	NLR	Preoperatively	The NLR was significantly lower in pts with persistent T2EL than in those without persistent T2EL	Preoperative low NLR can predict the presence of persistent T2EL
Nishibe et al	LMR	Preoperatively	Low preoperative LMR (<3.21) was an independent predictor for overall mortality	LMR may help in decision-making regarding the prediction of poor prognosis after EVAR
Seretis et al	PLT, fresh thrombus	Preoperatively and postoperatively	PLT absolute count and PLT drop post-EVAR were significantly associated with the occurrence of PIS. Fresh thrombus had no impact on PIS	PLT and their decrease after EVAR seem to be an important factor in developing PIS
Zhao et al	NLR, PLR, HRR, SIII, SIRI	Preoperatively	Preoperative NLR >2.77 was significantly associated with an elevated risk of death and HRR <10.64 was strongly related to a higher risk of death	Preoperative NLR and HRR can predict mortality risk after elective EVAR
Ntalouka et al	NLR	Preoperatively and postoperatively	Preoperative NLR was associated with acute kidney injury	Preoperative NLR may serve as a predictor for acute kidney injury following EVAR
Pasqui et al	NLR, PLR	Preoperatively	NLR was an independent risk factor for no-shrinking AAA but had no impact on endoleak rate	Inflammatory biomarkers, such as NLR and PLR, can be used as a preoperative index of AAA sac behavior post-EVAR
Xie et al	Fibrinogen, LMR	Preoperatively and postoperatively	Postoperative fibrinogen <284 mg/dL and LMR difference >−1.7 were independent risk factors for short-term endoleak	Postoperative fibrinogen and LMR can independently predict the occurrence of endoleak in short-term
Nana et al	WBC, CRP	Preoperatively	High CRP value was independently associated with postoperative fever	CRP is a reliable biomarker for post-EVAR fever
Nishibe et al	NLR	Preoperatively	High preoperative NLR (>3.19) was an independent predictor for overall mortality	NLR is a useful biomarker to stratify pts at risk for poor prognosis after EVAR
Ferreira et al	PIS	Postoperatively	PIS was non-predictive of cardiovascular events or mortality. There was a higher rate of T2EL for non-PIS patients. Sac dynamics were similar between PIS and non-PIS groups	PIS is not a predictor of cardiovascular events and has no impact on mortality. PIS pts have fewer T2ELs
Lecumberri et al	NLR, PLR, LMR, SIII	Preoperatively	There was an independent relationship between survival and NLR, PLR and SIII. NLR >3 was independently associated with lower survival rates at 2 and 5 y	NLR >3 may be used to identify pts with a low survival rate and help in decision-making
Ntalouka et al	NLR, PLR	Preoperatively and postoperatively	Postoperative NLR >9.9 and postoperative PLR >22.8 were highly associated with acute kidney injury	Postoperative NLR and PLR can predict the occurrence of acute kidney injury after EVAR
Octeau et al	NLR	Preoperatively	High NLR >3.6 was an independent predictor of death at 5 y and of reinterventions at 30 d, 1, and 5 y	NLR is an inflammatory biomarker predisposing pts to higher risk of death and reinterventions
Oddi et al	CRP	Preoperatively and postoperatively	Postoperative CRP >109.3 mg/L was significantly associated with the occurrence of PIS	Postoperative CRP was a significant marker to detect PIS
King et al	NLR	Preoperatively	NLR was not associated with perioperative mortality, reintervention rate or sac enlargement, but it was associated with overall mortality	Preoperative NLR may be used as a prognostic indicator for post-EVAR mortality
Martinelli et al	PIS	Postoperatively	Adverse outcomes rates did not significantly differ in pts with and without PIS	PIS does not have any significant prognostic implications in terms of early major adverse events
Sousa et al	PIS	Postoperatively	PIS was significantly associated with MACE but had no impact on mortality rates	PIS did not influence survival but was a predictor of MACE
Jeong et al	PIS	Postoperatively	Sac regression was more likely to occur in pts with PIS	PIS is a good predictor of aneurysm sac behavior
Lee et al	Fresh thrombus	Preoperatively and postoperatively	CTA findings did not show significant difference between the PIS and non-PIS groups	Volume of mural thrombus is an important risk factor for the elevation of WBC and CRP post-EVAR, but cannot predict the PIS
Veraldi et al	RDW	Preoperatively and postoperatively	Delta RDW >1 after EVAR was associated with over 3-fold enhanced risk of developing PIS	Delta RDW is a good diagnostic tool for predicting the development of PIS
Kwon et al	PIS	Postoperatively	PIS was associated with a decreased risk of T2EL and had no impact on long-term mortality and postoperative complications. Reintervention rate was significantly higher in non-PIS pts	PIS was beneficial in preventing T2ELs
Arnaoutoglou et al	PIS	Postoperatively	PIS was an independent predictor of MACE during the first 30 d, especially when CRP >125 mg/L	The intensity of inflammation post-EVAR correlates with the presence of a cardiovascular or any other adverse event during the first 30 postoperative days
Baek et al	WBC	Preoperatively and postoperatively	Preoperative WBC count was significantly associated with an increased risk of developing PIS	Preoperative WBC count serves as a predictor of PIS
Lin et al	PCT	Postoperatively	High PCT levels were significantly correlated with in-hospital mortality	PCT can predict short-term adverse prognosis post-EVAR
Kakisis et al	Fresh thrombus	Preoperatively and postoperatively	The volume of new-onset thrombus was significantly higher in patients with PIS	The volume of new-onset thrombus is associated with the development of PIS, whereas chronic mural thrombus appears to be an inert material
Nano et al	PIS	Postoperatively	PIS was not associated with post-EVAR long-term complications but it was correlated to the preoperative burden of thrombus of the aneurysmal sac	PIS is a benign complication following EVAR
Arnaoutoglou et al	WBC, PLT, fibrinogen, CRP, IL-1, IL-6, TNF-a	Preoperatively and postoperatively	PIS showed significant greater changes of CRP and IL-6 compared with the non-PIS group	PIS is associated with features of a systemic inflammatory response
De La Motte et al	PIS	Postoperatively	11 Pts (28%) in the PIS-group and 4 pts (15%) in the non-PIS group underwent reinterventions (P > .05)	30-D mortality and reintervention rate did not differ based on PIS status

Abbreviations: EVAR, endovascular abdominal aortic aneurysm repair; CRP, C-reactive protein; IL, interleukin; ICAM, intercellular adhesion molecule; MCP, monocyte chemoattractant protein; TNF, tumor necrosis factor; NLR, neutrophil-to-lymphocyte ratio; RAR, RDW-to-albumin ratio; RDW, red cell distribution width; PIS, post-implantation syndrome; LMR, lymphocyte-to-monocyte ratio; PLT, platelets; PLR, platelet-to-lymphocyte ratio; HRR, hemoglobin-to-RDW ratio; SIII, systemic immune inflammatory index; SIRI, systemic inflammatory response index; WBC, white blood cells; PCT, procalcitonin; MACE, major adverse cardiovascular events; POD, postoperative day; pts, patients; AAA, abdominal aortic aneurysm; CTA, computed tomography angiography; T2EL, type 2 endoleak.

Discussion

The present systematic review summarizes the evidence base reporting on the prognostic value of 22 inflammatory biomarkers in patients scheduled to undergo endovascular intervention for intact infrarenal AAA. The majority of studies investigating NLR demonstrated an association between increased NLR and low survival rates after EVAR. Furthermore, elevated NLR and PLR seemed promising for predicting acute kidney injury postoperatively, although these were only investigated by a few studies. The impact of LMR on post-EVAR outcomes is less well described, with fewer studies suggesting a decreased LMR be a predictor of poor prognosis following EVAR. Additionally, the presence of PIS was not predictive of mortality but was correlated with a decreased risk of type 2 endoleak.

The prognostic value of NLR in an EVAR population has been supported by several of the included studies. High preoperative NLR values have been independently associated with an elevated overall mortality risk and acute kidney injury after EVAR.^{15,16,22,23,27} Octeau et al evaluated 777 EVAR patients and showed that NLR levels were related to increased 5-year mortality, as well as higher reintervention rates at 30 days, 1, and 5 years.³⁰ Similar conclusions have been reached by other investigators supporting that NLR elevation might predict increased secondary aortic interventions.¹⁵ However, King et al showed that although NLR is a good prognostic marker for mortality, it cannot predict reinterventions or sac behavior.³² This discrepancy might be the result of low numbers of patients and events in the last study or differences in follow-up duration. A multicentric retrospective study of 823 EVAR patients validated the predictive value of NLR in post-EVAR long-term mortality and showed that only 9.5% of deaths were attributed to AAA-related causes.¹⁶ This possibly explains that elevated NLR mainly reflects the patient’s overall clinical frailty and systemic vulnerability. Thus, the adverse events and poor prognosis following EVAR, observed in the high-NLR cohort, are primarily due to the patients’ overall frail health status rather than to EVAR technical failure. Patient comorbidities, age, smoking status, and baseline frailty, often revealing an inflammatory background, may be potential confounding factors that obviously influence the values of inflammatory biomarkers and, thus, may affect the clinical course of EVAR patients.

The precise mechanism by which chronic systemic inflammation contributes to clinical outcomes following EVAR is poorly described. There is an established relationship between chronic inflammation and cardiovascular long-term mortality.^46,47 Chronic systemic inflammation also serves as a key etiological component of the development and progression of atherosclerotic disease.⁴⁸ AAA patients, as in our patient cohort, often present risk factors and systemic features of atherosclerosis. Therefore, it is reasonable to assume that chronic inflammatory response, expressed by inflammatory biomarkers, might predispose EVAR patients to increased mortality risk. However, it remains unclear whether systemic inflammation drives the progression of aneurysmal disease, or whether aneurysm-related factors drive the systemic inflammation.⁴⁹ Apparently, an increased NLR indicates an immune profile of chronic low-grade inflammatory state. Neutrophilia might be related to endothelial cellular injury, microvascular plugging, and hypercoagulability.⁵⁰ The other component, lymphopenia may be associated with adverse physiological stress, possibly leading to systemic susceptibility.⁵¹

Additionally, the optimal cutoff value of NLR with the strongest association with post-EVAR outcomes varies across the included studies and ranges from 2.4 to 5.0 preoperatively, whereas, it can reach up to 9.9 in cases of postoperative measurement.^15,16,29 This fluctuation could be partially justified by the differences in study design, patient selection, sample size, and timing of measurement. One of the highest-quality studies uncovered a cutoff point of 3.6 in a training set of 388 patients showing that patients with a preoperative NLR <3.6 had improved mortality rates.³⁰ Another recent study with high methodological quality suggested a 2.4 NLR cutoff as a fair discriminator for long-term mortality.¹⁵ The prospective UK Biobank cohort study of ~440 000 participants reported that in cancer-free controls the “normal” mean value of NLR was 2.35.⁵² Taking these data into consideration, we suggest that a cutoff point of 2.5 to 3 regarding preoperative NLR may be a good risk stratification tool to guide clinicians in perioperative decision-making.

Predicting aneurysm sac behavior following EVAR is of paramount importance if high clinical success rates are to be achieved. A large retrospective analysis of Vascular Quality Initiative (VQI) data underlined that sac behavior is associated with the development of new endoleaks, reintervention, and long-term mortality. Not only sac expansion but also sac regression failure is correlated with lower long-term survival, independent of reinterventions or endoleaks.⁵³ Notably, high preoperative PLR and NLR values have been linked to no-shrinking AAA post-EVAR. In particular, a PLR <104.8 and an NLR <3.81 were selected as the cutoff values for AAA shrinkage.²⁴ Another study showed that high PLR and NLR levels, measured in the immediate postoperative period, can predict the occurrence of acute kidney injury after EVAR,²⁹ establishing their role as biomarkers both preoperatively and postoperatively. Although PLR was found to be linear and independently related to long-term survival following EVAR, only NLR moderately enhanced the discriminative power of a survival predictive model.²⁸ The association of PLR with survival rates, however, could not be confirmed in a more recent study, probably reflecting differences in follow-up duration and number of enrolled patients.²² Regarding LMR, a low preoperative value might predict overall mortality and poor prognosis after EVAR. A higher number of monocytes compared to lymphocytes might be suggestive of impaired immune response and poor post-EVAR outcomes.²⁰

The precise effect of PIS on clinical outcomes following EVAR remains debatable. Several of the included studies have documented that PIS is a benign condition and does not appear to have a major prognostic value or impact on survival rates in an EVAR population.^11,43,45 Patients experiencing PIS, though, had a decreased risk of developing type 2 endoleaks.^18,38 One possible explanation for this finding could be that PIS, reflecting a systemic inflammatory response, may eradicate low pressure arteries which potentially can be responsible for type 2 endoleaks. Furthermore, Kakisis et al reported that the volume of new-onset thrombus is associated with the occurrence of PIS.⁴² Therefore, PIS patients have greater volume of new-onset thrombus and might experience more frequently total sac thrombosis, thereby minimizing type 2 endoleak rate. There is also inconsistency throughout the literature regarding the prognostic implications of PIS in terms of MACE.^33,34 Nevertheless, a recent systematic review evaluating 309 patients experiencing PIS demonstrated an association between 30-day mortality and MACE and PIS.⁸ Again, this discrepancy may be justified by the differences in follow-up duration and sample size.

According to the Society for Vascular Surgery (SVS) guidelines on the care of patients with AAA, biomarkers such as fibrinogen, D-dimer, and IL-6 have been consistently correlated with the presence of AAA in multiple studies.^1,54 However, these biomarkers have been used primarily aiming to detect the presence of an aortic aneurysm rather than predict clinical outcomes following EVAR. No relevant recommendation exists incorporating inflammatory indicators for post-EVAR surveillance. To address this gap, our systematic review presents reliable indexes that could be used to estimate the patient perioperative inflammatory status and correlate it with outcomes after EVAR. We suggest that inflammatory biomarkers, especially NLR, could serve as predictors of clinical sequelae following EVAR. It is a simple and inexpensive test derived from a complete blood count, that is, measured as part of the perioperative work-up. Incorporating such biomarkers in sophisticated EVAR follow-up algorithms may result in early detection of complications and improve post-EVAR surveillance programs. However, further well-designed studies with prospective data collection and low risk of bias are warranted to validate these findings, shed light on topics of debate, and determine the optimal cutoff values for the aforementioned inflammatory biomarkers, before these markers can be reliably incorporated into routine post-EVAR surveillance algorithms.

Study Limitations

The results of the present study should be interpreted in the context of several limitations. First, this review is limited by the retrospective design and non-blinded nature of the included studies. The predominance of retrospective studies and moderate methodological quality of included data might affect the strength of conclusions. The heterogeneity across studies in terms of biomarker cutoff values, timing of measurement, and outcome definitions may also limit the applicability of our results. Additionally, overlapping populations from the same centers might have been included occasionally but the relevant authors either investigated different biomarkers or reported on different clinical outcomes. The prognostic role of some biomarkers might have been discussed only by a few studies, thereby reducing the validity and preventing from drawing conclusions for these biomarkers. Given the large variety of inflammatory biomarkers and associated outcomes examined, no quantitative synthesis of results could be performed, further restricting the impact of our findings. Lastly, complex EVAR procedures possibly associated with more intense inflammatory response were excluded.

Conclusions

This study summarizes the available literature regarding the prognostic value of 22 inflammatory biomarkers in outcomes after elective EVAR. NLR seems to be a good predictor for mortality and adverse events following EVAR. Additionally, PIS was found to be associated with a lower type 2 endoleak rate. Current evidence is insufficient to substantially support the role of other biomarkers. Further studies are needed to validate these findings and refine post-EVAR surveillance policy.

Footnotes

ORCID iDs

George Koudounas

Konstantinos G. Moulakakis

Author Contributions

All authors contributed to: (1) substantial contributions to conception and design, or acquisition of data, or analysis and interpretation of data, (2) drafting the article or revising it critically for important intellectual content, and (3) final approval of the version to be published.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data Availability Statement

The data associated with the paper are available from the corresponding author on reasonable request.

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