Post Implantation Syndrome and Administration on NSAIDs in Patients Undergoing EVAR for AAA

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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