Ignite Creation Date:
2024-05-06 @ 12:17 PM
Last Modification Date:
2024-10-26 @ 12:57 PM
Study NCT ID:
NCT03727412
Status:
UNKNOWN
Last Update Posted:
2018-11-26
First Post:
2018-10-30
Brief Title:
Post Implantation Syndrome and Administration on NSAIDs in Patients Undergoing EVAR for AAA
Sponsor:
University of Thessaly
Organization:
University of Thessaly
Study Overview
Official Title:
Post Implantation Syndrome and Administration on NSAIDs in Patients Undergoing Endovascular Repair of an Abdominal Aortic Aneurysm Under General Anesthesia
Status:
UNKNOWN
Status Verified Date:
2018-11
Last Known Status:
RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
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 endografts 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 12000 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 12000mL
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
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 endografts 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 12000 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 12000mL
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 aneurysm1 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 602-5 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 endografts 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 patients 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 259 of the PIS group compared to 29 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 172 and in 188 of patients in the PIS group and in 43 and 51 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 ie 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 12000 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 10000 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 Crohns 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 5000 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 PiperacillinTazobactam 2025 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 385oC 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 12000mL 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 changes13 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 005 mV new or T wave inversion of 03 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 p125 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 p210 Interactions between the main effects of the final model will then be examined The enter method with significance level p305 will be used to obtain p values and odds ratios for the main effects and interactions All analyses will be carried out with SPSS 200 statistical package for Windows IBM Corporation Armonk New York
The relation of PIS with patients 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 259 of the PIS group compared to 29 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 172 and in 188 of patients in the PIS group and in 43 and 51 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 ie 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 12000 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 10000 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 Crohns 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 5000 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 PiperacillinTazobactam 2025 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 385oC 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 12000mL 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 changes13 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 005 mV new or T wave inversion of 03 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 p125 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 p210 Interactions between the main effects of the final model will then be examined The enter method with significance level p305 will be used to obtain p values and odds ratios for the main effects and interactions All analyses will be carried out with SPSS 200 statistical package for Windows IBM Corporation Armonk New York
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None