Brief Title
Post Implantation Syndrome and Administration on NSAIDs in Patients Undergoing EVAR for AAA
Official Title
Post Implantation Syndrome and Administration on NSAIDs in Patients Undergoing Endovascular Repair of an Abdominal Aortic Aneurysm Under General Anesthesia
Brief Summary
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.
Detailed Description
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).
Study Type
Interventional
Primary Outcome
major cardiovascular events after endovascular aneurysm repair
Secondary Outcome
post implantation syndrome
Condition
Aneurysm Abdominal
Intervention
Drugs, Generic (Naprosyn)
Study Arms / Comparison Groups
Naproxen Group
Description: patients with an abdominal aortic aneurysm undergoing endovascular epair and taking preoperatively naproxen (Naprosyn, tab 500 mg twice/day for 4 days)
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
186
Start Date
August 1, 2018
Completion Date
October 1, 2021
Primary Completion Date
October 1, 2021
Eligibility Criteria
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).
Gender
All
Ages
N/A - N/A
Accepts Healthy Volunteers
No
Contacts
, +306974301352, [email protected]
Location Countries
Greece
Location Countries
Greece
Administrative Informations
NCT ID
NCT03727412
Organization ID
01
Responsible Party
Principal Investigator
Study Sponsor
University of Thessaly
Study Sponsor
, ,
Verification Date
November 2018