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Perioperative anti-TNF biologics are not safe because they increase complications associated with surgery. Feza H. Remzi FACS, FASCRS, FTTS ( Hon ) Chairman Department of Colorectal Surgery Professor of Surgery Ed and Joey Story Chair Digestive Disease Institute Cleveland Clinic - PowerPoint PPT Presentation
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Perioperative anti-TNF biologics are not safe because they increase complications
associated with surgery
Feza H. Remzi FACS, FASCRS, FTTS ( Hon ) Feza H. Remzi FACS, FASCRS, FTTS ( Hon ) Chairman Chairman
Department of Colorectal SurgeryDepartment of Colorectal SurgeryProfessor of SurgeryProfessor of Surgery
Ed and Joey Story Chair Ed and Joey Story Chair Digestive Disease InstituteDigestive Disease Institute
Cleveland ClinicCleveland Clinic Cleveland, OHCleveland, OH
Disclosure
• None
Crohn’s Disease Operative IncidenceJejunoileitis50% at 5 years; 70% at 10 yearsIleocolitis75% at 5 years; 90% at 10 yearsColitis50% at 5 years; 70% at 10 years
Immunosuppressives
Malnutrition/overall health
Patient perceptions of surgery
Surgical Plan
infliximabinfliximabCsACsA
prednisoneprednisone
6-MP6-MP
induce remission…rescue them from
surgery
Anastomotic leaks!Anastomotic leaks!Wound Wound
complications!!complications!!
Infliximab and Surgical Outcome in Crohn’s Disease
• Is Infliximab use associated with a higher Risk of postoperative complications?
• Earlier studies were good but not without some limitations
Colombel et al. Am J Gastroenterol.
Marchal et al Alimentary Pharmacology & Therapeutics
Infliximab and Surgical Outcome in Crohn’s Disease
Colombel et al. IFX No IFX N 52 218No difference in complicationsSmall sample sizeHeterogenous study sampleLimited stratification for risk factors
Marchal et al IFX No IFX N 39 40 No difference in complicationsSmall sample sizeHeterogenous study sampleLimited stratification for risk factors
Malnutrition/Overall Health
• More difficult to quantify and examine
• Related to • length and severity of illness• delayed referral for surgery
• Hypoalbuminemia (<2.0 mg/dL)• Relative contraindication to IPAA,
strictureplasty, ileocolic anastomosis
Emergent/Urgent Surgery
• Fistulas• Abscesses• Bleeding• Acute obstruction
Increased post-operative complications in these situations
Use of Infliximab within Three Months Of Ileocolonic Resection Is Associated With Adverse Postoperative Outcomes In Crohn's Patients
Appau et al, Journal of Gastrointestinal surgery 2008Journal of Gastrointestinal surgery 2008
The Digestive Disease Institute Cleveland Clinic Foundation. Cleveland, Ohio
Infliximab and Surgical Outcome in Crohn’s Disease
• Limit to Ileocolic resection
• Limit to IFX use within 3 months before surgery
• Increase sample size
Methods
• Retrospective Cohort Study with both historical and contemporary controls
• Include: -only patients having ileocolic resection at Cleveland Clinic.-first surgery for Crohn’s disease.
• Exclude: -Infliximab used postoperatively.• - Infliximab used more than 3
months preoperatively.
Infliximab and Surgical Outcome in Crohn’s Disease
Study design• IFX group: IFX within 3 months Ileocolic Res (1998 to 2007)
• Contemporary Controls: No IFX Ileocolic Res (CC = 1998 to 2007)
• Historical control: Ileocolic resection before IFX came to (HC = 1991 to 1997) market
Infliximab and Surgical Outcome in Crohn’s Disease
End Points•Any 30-day post operative complication:•Abscess•Sepsis•Anastomotic Leak•30-day readmission rate
Infliximab and Surgical Outcome in Crohn’s Disease
ResultsResultsnn M:FM:F Mean AgeMean Age
IFXIFX 6060 29:3129:31 35.8 +/- 11.935.8 +/- 11.9
CCCC 329329 151:178151:178 36.8 +/- 14.436.8 +/- 14.4
HCHC 6969 36:3336:33 38.0 +/- 12.538.0 +/- 12.5
Infliximab and Surgical Outcome in Crohn’s Disease
Variable Odds Ratio(95% CI)
CCInfliximab 2.00 (0.96 – 4.18)Immunomo 0.53 (0.17 - 1.62)Steroids 1.59 (0.83 - 3.04)Stoma 0.49 (0.22 - 1.09)
Multivariable logistic regression Model-Factors Associated with any post-operative complications
Adjusted for Age, Sex, Comorbidity, and behavior of disease
Multivariable logistic regression Model-Factors Associated with 30-day Sepsis.
VariableVariableOdds RatioOdds Ratio
(95% CI)(95% CI)CCCC
InfliximabInfliximab 2.62 (1.12 – 6.13)2.62 (1.12 – 6.13)Immunomod. Immunomod. 1.40 (0.66 – 2.98)1.40 (0.66 – 2.98)Steroids Steroids 1.10 (0.50 – 2)1.10 (0.50 – 2)Stoma Stoma 0.28 (0.09 - 0.84)0.28 (0.09 - 0.84)
Adjusted for Age, Sex, Comorbidity, and behavior of diseaseAdjusted for Age, Sex, Comorbidity, and behavior of disease
Multivariable logistic regression Model-Factors Associated with 30-day Abscess.
VariableOdds Ratio(95% CI)
CCInfliximab 5.78 (1.69 - 19.7)Immunomod. 0.41 (0.11 - 1.52)Steroids 2.94 (0.63 - 13.6)Stoma 0.16 (0.02 - 1.25)
Adjusted for Age, Sex, Comorbidity, and behavior of disease
Conclusion
• Use of IFX three months before ileocolonic resection in CD patients appears to be associated with increased risk of post operative complications
(especially: -Sepsis,abscess, and readmission rate) • However, the presence of stoma above
anastomosis seems to decrease these risks.
Infliximab in Ulcerative Colitis Is Associated with an Increased Risk of Post-operative Complications after
Restorative Proctocolectomy
Mor et al Disease Colon rectum 2008
Introduction2-stage procedure
• Total proctocolectomy and fashioning of ileal pouch with covering ileostomy
• Ileostomy closure
3-stage procedure• Sub-total colectomy• Completion proctectomy and pouch with ileostomy• Ileostomy closure
Aims
• Assess rate of post-operative complications in infliximab-treated UC patients undergoing RP
• To investigate whether there has been an increase in the requirement for subtotal colectomy and three-stage procedure
Methods
• Case-matched comparison of post-op complications Jan 2000 – Dec 2006
• Patients identified from Ileal Pouch Registry
• 2 stage patients only• Patients with pre-op diagnosis of Crohn’s
Disease excluded
Methods
• Percentage of patients requiring initial colectomy (3 stage procedure) in those treated with infliximab compared with those not treated with infliximab
• Results adjusted for extent and severity of colitis, steroid dose & use of other immunomodulator
Results
• Over 3000 patients underwent IPAA since 1983 • 523 RP performed for UC
• 85 patients treated with infliximab• 46 2-stage• 39 3 stage
• Infliximab administered within a median of 16 weeks preoperatively
• Median of 3.2 infusions • Six patients suffered side effects attributable to infliximab• One patient developed lymphoma in the pouch
ResultsEarly post-op complications, multivariate analysis
Infliximab (n=46)
Non-infliximab
(n=46)p-value
Sepsis Leak
10 (22%) 8 (17.4%)
1 (2.2%) 1* (2.2%)
0.016 0.043
Post-op hemorrhage
3 (6.5%) 1 (2.2%) 0.21
Thrombotic event
4 (8.7%) 1 (2.2%) 0.07
Ileus 2 (4.3%) 3 (6.5%) 0.58Overall 16 (35%) 7 (15%) 0.022
* Sub-clinical leak not associated with pelvic sepsis* Sub-clinical leak not associated with pelvic sepsis
ResultsLate post-operative complications, multivariate analysis
Infliximab (n=46)
Non-infliximab
(n=46)p-value
Pouchitis 18 (39%) 7 (15%) 0.011
Stricture 5 (11%) 9 (20%) 0.3
SBO 3 (6.5%) 6 (13%) 0.44
Overall 24 (52%) 17 (37%) 0.08
RESULTS
• 3-stage RP performed in 46% (39/85) patients who received infliximab compared with 28% (122/438) who did not• Odds ratio 2.07 (95% CI 1.18, 3.63)
Conclusion
• Infliximab use in UCSeems to increase the risk of early and late post-operative complicationsGreater need for unplanned 3-stage RP
• Risks of both infliximab and surgery should be presented to patients failing conventional medical therapy
Author (year of ublication) Ref. Study
periodStudy design
Diagnosis
Biologics (cut-off value)
Impact on initial surgery
Patient Number
(user/non-user)
End point Risk factor
Selvasekar ( 2007) 5 2002-
2005 RC UC IFX (None) TPC/IPAA 301 (47/254) 30-day complication Yes
Schluender (2007) 6 2000-
2005 RC UC IFX (None) TPC/IPAA 151(17/134) 30-day complication No
Mor (2008) 7 2000-2006 RCM UC/IC IFX (None) TPC/IPAA 92 (46/46) 30-day
complication Yes
Ferrante (2009) 8 1998-
2008 RC UC/IC IFX (< 12 weeks) TPC/IPAA 144 (22/119) 30-day complication No
Coquet-Reinier (2010) 9 1999-
2008 RCM UC IFX (None) Laparoscopic TPC/IPAA 26 (13/13) 30-day
complication No
Gainsbury (2011) 10 2005-
2009 RC UC IFX (< 12 weeks) TPC/IPAA 81(29/52) 30-day complication No
Bregnbak (2012) 11 2005-
2010 RC UC IFX (< 12 weeks) Colectomy 71 (20/51) 30-day complication No
Nørgård (2012) 12 2003-
2010 RC UC IFX (< 12 weeks) Colectomy 1200 (199/1027)
30- and 60- day complication No
Eshuis (2012) 13 2006-2009 RC UC IFX (None) TPC/IPAA 72 (38/34) 30-day
complication Yes *
Present study 2006-2010 RC UC/IC
IFX (<12 weeks); adalimumab or certolizumab
pegol (<4 weeks)
STC/EI or TPC/IPAA 588 (167/421)
Long-term f/u, pouch function,
QOLYes *
Time after surgery (month) 0 3 6 9 12 Time after surgery (month) 0 3 6 9 12 No pelvic sepsis (---- biologics) 25 19 18 17 No pelvic sepsis (---- biologics) 25 19 18 17 17 No pelvic sepsis ( no-biologics) 156 142 137 135 17 No pelvic sepsis ( no-biologics) 156 142 137 135 131 131
Patie
nt fr
ee o
f pel
vic
seps
is
Patie
nt fr
ee o
f pel
vic
seps
is
(%)
(%)
Kaplan-Meier Estimate of Pelvic Sepsis-free SurvivalKaplan-Meier Estimate of Pelvic Sepsis-free Survival
Gu et al unpublished data 2012Gu et al unpublished data 2012
Early active Early active diseasedisease
RemissionRemission
ComplicationsComplications
??SurgerySurgery
MaintenanceMaintenance
= = A good time to operateA good time to operate= = A bad time to operateA bad time to operate
Patie
nt h
ealth
Patie
nt h
ealth
timetime
Referring to the Surgeon
Early active Early active diseasedisease
RemissionRemission
ComplicationsComplicationsEarly surgeryEarly surgery
Medical Medical treatmenttreatment
High riskHigh risk
Low riskLow risk
Patient Perceptions
• Most frustrating aspect for the surgeon
• Unique to patients with IBD
Impact of Surgery on Quality of LifeCleveland Clinic Data
Ulcerative Colitis• Functional results and QOL rated as good
to excellent in 93% of patients • Only 18% with less than full daytime
continence• Sexual dysfunction in 3%
Crohn’s Disease• QOL improves over baseline by 30 days
post-op
Solutions
• Early discussion of surgical options and outcomes with patient by both gastroenterologist and surgeon
• Clearly defining the goals of continued medical therapy
• Clearly defined criteria for referral to surgery• Better understanding of contributing factors
Recommended