Post Implantation Syndrome and Administration on NSAIDs in Patients Undergoing EVAR for AAA
Post Implantation Syndrome and Administration on NSAIDs in Patients Undergoing EVAR for AAA
INTRODUCTION Post-implantation syndrome is the clinical and biochemical expression of an
 inflammatory response following endovascular repair of an aortic aneurysm. PIS is mainly a
 clinical condition associated with the implantation of an endograft and is diagnosed by the
 presence of fever accompanied by elevated WBC count above normal without any evidence of an
 infection.

 The correlation between the type of the endograft placed and the development of PIS may
 indicate that the inflammatory reaction is due to the material of the endograft itself (
 polyester or PTFE ). Based on the results of different studies the type of endograft's
 material seems to play an important role in PIS development and may have a predictive role
 for a significant number of patients undergoing endovascular repair of abdominal aortic
 aneurysm (EVAR).

 In most studies PIS is considered a benign condition, although it may lead to a more
 demanding postoperative care characterized by prolonged hospitalization. In an other
 prospective study patients with PIS were more likely to suffer from an adverse event during
 the 30 days after the procedure. The occurrence of PIS was the only independent predictor of
 a MACE ( major cardiovascular events ) or an adverse event during the follow-up period.

 Current available literature data certainly raise the question of altering current approach
 and treat patients with PIS by focusing on the reduction of the inflammatory response by
 administration of steroid or non-steroidal drugs.

 The aim of the present randomized placebo-controlled study is to evaluate whether the
 perioperative administration of Naproxen (NPR) an anti-inflammatory drug with a beneficial
 cardiovascular safety profile in patients with an abdominal aortic aneurysm undergoing
 endovascular repair could have any effect on the inflammatory response and patients outcome
 during the first year of follow-up after the surgery.

 METHOD PIS will be considered as the presence of fever (persisting body temperature > 38 ° C
 lasting more than 1 day during hospitalization) and leukocytosis ( white blood cell count >
 12,000 / mL ) with negative blood and urine culture. All patients with AAA that will be
 subjected to EVAR in our department since February 2018 and who will receive an endograft
 made from polyester will be included in this study.

 All patients after being informed pre-operatively about the way and the purpose of the
 clinical study, the patients will be randomly selected to receive either naproxen ( NPR ) 500
 mg x 2 or placebo, starting the previous day before the procedure and for 3 days
 postoperatively. The NPR was selected due to the expected significant anti-inflammatory
 activity and favorable cardiovascular safety profile.

 All patients presenting with fever during the post-operative period, whether or not
 fulfilling the PIS criteria, will undergo a thorough work up for possible infection. If any
 of these tests reveal evidence of an early pulmonary, urinary tract or any other kind of
 infection, the patient will not be considered to suffer from PIS. Patients will be discharged
 in the absence of any complications, with a body temperature < 38oC for at least 24 hours and
 a WBC < 12.000/mL.

 Besides the traditional inflammatory markers (WBC, hs-CRP, and fibrinogen ) the investigators
 will also measure interleukin 6 (IL-6) because it was the only marker significantly altered
 in PIS patients in a previous study.

 The follow-up will be performed at 1, and 12 months after surgery. Patient quality of life
 will also be studied by completing the SF36 questionnaire preoperatively and in the first
 year post-operative follow-up.
INTRODUCTION Post-implantation syndrome is the clinical and biochemical expression of an
 inflammatory response following endovascular repair of an aortic aneurysm.1 PIS is mainly a
 clinical condition associated with the implantation of an endograft and is diagnosed by the
 presence of fever accompanied by elevated WBC count above normal without any evidence of an
 infection. The reported incidence of PIS in the literature has been varying widely from 14 to
 60%.2-5 The correlation between the type of the endograft placed and the development of PIS
 may indicate that the inflammatory reaction is due to the material of the endograft itself
 (polyester or PTFE). Gerasimidis et al. in a relatively underpowered study concluded for the
 first time in 2005 that fever was more common in a group of patients receiving an endograft
 made from polyester in contrast to those receiving a PTFE graft. Interleukin 8 (IL-8) was
 higher in the first group, indicating a stronger host reaction in the specific material.
 Voute et al. in a later study showed that the implantation of stent grafts based on polyester
 was independently associated with a stronger inflammatory response. Moulakakis et al.,
 observing a milder inflammatory activation in patients with a PTFE endograft, have confirmed
 this finding in a later report. Accordingly a previous study found that the use of polyester
 endograft independently predicted PIS and was correlated with an above 10 times higher risk
 for an inflammatory response. Based on the results of the above 3 mentioned studies the type
 of endograft's material seems to play an important role in PIS development and may have a
 predictive role for a significant number of patients undergoing endovascular repair of
 abdominal aortic aneurysm ( EVAR ).

 The relation of PIS with patient's outcome has not been adequately established. In most
 studies PIS is considered a benign condition, although it may lead to a more demanding
 postoperative care characterized by prolonged hospitalization. In a prospective study of 214
 patients after EVAR this group found that patients with PIS were more likely to suffer from
 an adverse event during the 30 days after the procedure. Adverse events occurred in 25.9% of
 the PIS group compared to 2.9% of the non- PIS group and included any major cardiovascular
 event, acute renal failure, readmission, and death by any cause. For the same cohort, at the
 1-year follow-up, high-sensitivity C-reactive protein and interleukin 6 were attenuated
 toward the values of the non-PIS group. During the one-year follow-up period, MACE and
 adverse events occurred, respectively, in 17.2% and in 18.8% of patients in the PIS group and
 in 4.3% and 5.1% of the non-PIS group. The occurrence of PIS was the only independent
 predictor of a MACE or an adverse event during the follow-up period.

 Current available literature data certainly raise the question of altering current
 therapeutic approach and treat patients with PIS by focusing on the reduction of the
 inflammatory response by administration of steroid or non-steroidal drugs. Motte et al
 published recently a prospective trial of 150 EVAR patients who were randomized to receive a
 single preoperative dose of methylprednisolone or placebo. The inflammatory response, as
 assessed by the inflammatory biomarkers levels, was reduced in the methylprednisolone group,
 although no differences were noted in patient outcomes between the two groups during a
 3-month follow-up period. Data on postoperative use of anti-inflammatory drugs are absent.

 Because PIS was the only independent predictor of an adverse event during the first year
 after EVAR, it seems that even a strong inflammatory stimulus at the immediate postoperative
 period could probably affect the cardiovascular health of these patients at the long term.
 Any therapeutic measurements that might thus focus on PIS acute treatment or even prevention
 seem reasonable.

 The aim of the present randomized placebo-controlled study is to evaluate whether the
 perioperative administration of Naproxen (NPR) an anti-inflammatory drug with a beneficial
 cardiovascular safety profile17 in patients with an abdominal aortic aneurysm undergoing
 endovascular repair could have any effect on the inflammatory response and patients outcome
 during the first year of follow-up after surgery.

 Patient quality of life will also be studied by completing the SF36 questionnaire
 preoperatively and in the first year post-operative follow-up.

 METHOD According to the definition of PIS, it must fulfill at least two of the criteria of
 the Systemic Inflammatory Response Syndrome (SIRS), i.e. fever and leukocytosis. Therefore,
 PIS will be considered as the presence of fever (persisting body temperature > 38 ° C lasting
 more than 1 day during hospitalization) and leukocytosis ( white blood cell count > 12,000 /
 mL ) with negative blood and urine culture. All patients with AAA that will be subjected to
 EVAR from February 2018 and who will receive an endograft made from polyester will be
 included in this study.

 Exclusion criteria will be clinical and / or laboratory indications of an infection
 preoperatively, including:

 -  Leukocytosis (white blood cell count [WBC]> 10,000 / mL) and elevated body temperature

 -  Signs of gangrene

 -  Previous trauma or surgery two months before enrolling in the study

 -  Previous implantation of endoprothesis

 -  Any autoimmune disease or systemic inflammatory condition

 -  Any malignancy

 -  Use of anti-inflammatory drugs, chemotherapeutic agents, immunosuppressants or
 anticoagulants

 -  Severe severe renal impairment (GFR < 30 ml / min) and

 -  Absolute contraindications of NSAIDs such as: NSAID-allergic patients, patients who have
 experienced asthma attacks following the use of acetylsalicylic acid or other
 anti-inflammatory nonsteroidal drugs, patients with nasal polyps, patients with
 anaphylactic or other severe NSAID allergies, severe hepatic insufficiency, heart
 failure patients (moderate to severe), patients with ischemic heart disease or other
 vascular diseases, presence of old or active gastric or ulcer of duodenum, history of
 gastrointestinal haemorrhage in the past, proctitis or recent rectal bleeding, a history
 of inflammatory bowel disease (ulcerative colitis, Crohn's disease).

 After approval by the Scientific Council of the University Hospital of Larissa and written
 consent of all patients after being informed pre-operatively about the way and the purpose of
 the clinical study, the patients will be randomly selected to receive either Naproxen (NPR )
 500 mg x 2 or placebo, starting the previous day before the procedure and for 3 days
 postoperatively. The NPR has a half-life of 12-17 hours and reaches a maximum concentration
 at 1 to 4 hours after administration. All regimens will be given during patient
 hospitalization. A computer algorithm will be used in the randomization. The NPR was selected
 due to the expected significant anti-inflammatory activity and favorable cardiovascular
 safety profile.

 All patients will be treated by the same surgical and anesthesiology team . Every effort will
 be made to follow the selection criteria recommended by the manufacturer of the stent graft,
 however, the surgeon' s decision as to which device to use will be based on the anatomical
 characteristics of the proximal neck, the iliac artery configuration, and the presence of
 thrombus or calcifications. Systemic heparinization will be achieved with 5,000 IU of
 heparin. Every effort will be made to deploy the endovascular device just below the level of
 the lowest renal artery. All the devices will be bifurcated systems. All patients will
 receive antibiotic prophylaxis (Daptomycin 500mg and Piperacillin/Tazobactam 2/0.25 gr) half
 an hour pre-operatively and for the day of operation, as well as 3500 IU of low molecular
 weight heparin (tinzaparin) from the first postoperative day until discharge.

 In all patients, demographics, intra-operative and post-operative complications, the
 incidence of PIS, the diameter of the aneurysm, the type of the graft deployed, the operation
 time, the amount of contrast media administered and length of postoperative stay, will be
 recorded. Temperature will be recorded eight times daily for the duration of hospitalization.
 Blood tests including troponin levels will be measured on the first and second post-operative
 day and the day before discharge. Post-operative pain will be controlled with intravenous
 tramadol, while in cases of fever > 38.5oC lasting more than 2 hours intravenous paracetamol
 ( 1 g ) will be administered. All patients presenting with fever during the post-operative
 period, whether or not fulfilling the PIS criteria, will undergo a thorough work up for
 possible infection. If any of these tests reveal evidence of an early pulmonary, urinary
 tract or any other kind of infection, the patient will not be considered to suffer from PIS.
 Patients will be discharged in the absence of any complications, with a body temperature <
 38oC for at least 24 hours and a WBC < 12.000/mL. Outpatient follow-up will be performed at
 1, and 12 months after surgery.

 Adverse events will include any major adverse cardiovascular events ( MACE ), acute renal
 failure, readmission, and death by any cause. MACE is defined as a composite of death from
 cardiac causes, non-fatal acute myocardial infarction ( ST and non-ST ), ischemic stroke, or
 transient ischemic attack. Death is considered due to cardiac causes if the patient died of
 MI, cardiac arrhythmia, or congestive heart failure caused primarily by a cardiac condition.
 The diagnosis of MI requires elevated troponin concentration with at least one of two 12-lead
 electrocardiogram changes, including development of new Q waves or new persistent ST-T
 segment or T wave changes.13 Unstable angina is defined as severe chest pain lasting for at
 least 30 minutes, unresponsive to standard therapeutic intervention, and associated with
 transient ST segment deviation of 0.05 mV, new or T wave inversion of 0.3 mV, without
 development of Q waves, or creatinine kinase-MB elevation. Stroke is defined according to the
 current World Health Organization definition as rapidly developing clinical signs of focal
 (or global) disturbance of cerebral function, lasting >24 hours or leading to death, with no
 apparent cause other than that of a vascular origin. Transient ischemic attack includes brief
 episodes of neurologic dysfunction resulting from focal cerebral ischemia, not associated
 with a permanent cerebral infarction, lasting < 24 hours. Acute kidney failure is defined as
 impaired renal function according to the Kidney Disease Improving Global Outcomes clinical
 practice guidelines.

 All patients will be on antiplatelet therapy (aspirin 100 mg once daily) for at least 3 weeks
 prior to the procedure. Preoperative medications will be continued immediately after surgery.
 Patients who will become enrolled and will be already receiving a statin will continue their
 medication. For patients not already on statin, atorvastatin ( 20 mg once daily ) will be
 initiated at the screening visit.

 Venous blood will be collected without a tourniquet preoperatively, at days 1 and 2
 postoperatively. Besides the traditional inflammatory markers (WBC, hs-CRP, and fibrinogen )
 interleukin 6 (IL-6) will be evaluated as it was the only marker significantly altered in PIS
 patients in a previous study.

 STATISTICAL ANALYSIS Power analysis: Assuming the frequency of PIS after elective EVAR with a
 polyester endograft is 50%, the study will required 186 patients in both groups to have the
 80 % power to detect a decrease in frequency to 30%.

 Data will be expressed as mean ± standard deviation ( SD ) as appropriate, except for
 non-Gaussian parameters, which are presented as median (range). Comparisons of continuous
 variables will be performed by Student t test for normally distributed variables and Mann-
 Whitney U test for non-normally distributed variables, while the chi-square test was used for
 categorical variables. To assess the effect of the independent variables observed within the
 study context, each one will be initially examined separately and the significant predictors
 at level p1=.25 will be identified. These will be used in a binary logistic regression model.
 The formerly non-significant factors will then be considered again at level p2=.10.
 Interactions between the main effects of the final model will then be examined. The enter
 method with significance level p3=.05 will be used to obtain p values and odds ratios for the
 main effects and interactions. All analyses will be carried out with SPSS 20.0 statistical
 package for Windows (IBM Corporation, Armonk, New York).
Inclusion Criteria:

 -  patients suffering from infrarenal abdominal aortic aneurysm undergoing endovascular
 aneurysm repair

 Exclusion Criteria:

 -  Leukocytosis (white blood cell count [WBC]> 10,000 / mL) and elevated body temperature

 -  Signs of gangrene

 -  Previous trauma or surgery two months before enrolling in the study

 -  Previous implantation of endoprothesis

 -  Any autoimmune disease or systemic inflammatory condition

 -  Any malignancy

 -  Use of anti-inflammatory drugs, chemotherapeutic agents, immunosuppressants or
 anticoagulants

 -  Severe severe renal impairment (GFR < 30 ml / min) and

 -  Absolute contraindications of NSAIDs such as: NSAID-allergic patients, patients
 who have experienced asthma attacks following the use of acetylsalicylic acid or
 other anti-inflammatory nonsteroidal drugs, patients with nasal polyps, patients
 with anaphylactic or other severe NSAID allergies, severe hepatic insufficiency,
 heart failure patients (moderate to severe), patients with ischemic heart disease
 or other vascular diseases, presence of old or active gastric or ulcer of
 duodenum, history of gastrointestinal haemorrhage in the past, proctitis or
 recent rectal bleeding, a history of inflammatory bowel disease (ulcerative
 colitis, Crohn's disease).