In Woong Han 1, O Choel Kwon 1, Min Gu Oh 1, Yoo Shin Choi 2, and Seung Eun Lee 2. Departments of Surgery, Dongguk University College of Medicine 2

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1 Effect of Rowachol on Prevention of Postcholecystectomy Syndrome after Laparoscopic Cholecystectomy - Prospective multicenter Randomized controlled trial- In Woong Han 1, O Choel Kwon 1, Min Gu Oh 1, Yoo Shin Choi 2, and Seung Eun Lee 2 1 Departments of Surgery, Dongguk University College of Medicine 2 Departments of Surgery, Chung- Ang University College of Medicine

2 Introduction The postcholecystectomy syndrome (PCS): heterogeneous group of diseases usually presenting as abdominal symptoms following gallbladder removal Pathogenesis of the PCS: not well known The derangement of bile acid metabolism No consensus of medical treatment on PCS- Prevention important To determine whether Rowachol is useful in the prevention of PCS and symptoms improvement after laparoscopic cholecystectomy (LC)

3 Patients & Methods A prospective multicenter trial Dongguk University Ilsan Hospital / Chung-Ang University Hospital Registered on clinicaltrials.gov as NCT A single-blind, placebo-controlled design Rowachol Inhibited hepatic HMG-CoA reductase and cholesterol nucleation in bile Promote biliary lipid secretion Rowachol or placebo mg tid for 3 months after LC Patients: performed LC d/t various GB diseases LC : multiports (mostly 3-ports) or single port (SILS) Biochem Pharmacol Gut Klin Wochenschr Calculated sample size: 138 patients for both arms by MRCC in DUIH Level of significance, α = 0.05 / β= 0.20, power of the test= 80% Target: Reduction of 20% of pain score (superiority trial) / 10% cut-off values

4 Definition Postcholecystectomy Syndrome Persistence of gastrointestinal symptoms after cholecystectomy Abdominal discomfort and bloating Nausea and vomiting Diarrhea RUQ pain or abdominal colic Jaundice or yellow discoloration of the skin Fever develops as a sign of infection Definition of PCS in this study: Primary end-point RUQ pain on EORTC QLQ C points at postoperative 3 months If suspected PCS, radiologic diagnosis would be performed

5 Evaluation Patient F/U at postoperative 3 months after completion of medication Questionnaire: EORTC QLQ C-30 version 3.0 Korean validated version Changing pattern of liver function test Difficulty Scores to perform LC (0-5) Difficult access into peritoneal cavity ( 0/ 1) Difficult dissection of adhesions from GB ( 0/ 1) Difficult dissection of Calot s triangle ( 0/ 1) Difficult dissection of GB bed ( 0/ 1) Difficult GB extraction from abdomen ( 0/ 1) Han HS et al, J Clin Ultrasound Data collection: Automatic system by MedicalDB database system

6 Eligibility criteria Inclusion criteria Age 18, 85 years Patients with pathologic diseases scheduled for laparoscopic cholecystectomy: Gallstone disease c/s inflammation Neoplastic GB disease Exclusion criteria Current immunosuppressive therapy Chemotherapy within 4 weeks before operation Radiotherapy completed longer than 4 weeks before operation Inability to follow the instructions given by the investigator Severe psychiatric or neurologic diseases Drug- and/or alcohol-abuse according to local standards Participation in another intervention-trial with interference of a primary or secondary endpoint of this study Lack of compliance Lack of informed consent

7 Patients flow Intention-To-Treat Analysis 160 patients were screened 138 Underwent randomization 22 were excluded from randomization 1 noncompliance 4 loss of follow-up 71 were received Rowachol and included in ITT analysis 64 completed 3 months follow-up 67 were received placebo and included in ITT analysis 63 completed 3 months follow-up 1 noncompliance 3 loss of follow-up

8 Clinical characteristics Rowachol (n = 71) Placebo (n = 67) p Age 51.5 ± ± Sex (male: female) 26: 45 33: BMI (kg/m 2 ) 24.6 ± ± ASA class (minimal/ moderate/ severe) 46/ 25/ 0 43/ 24/ Preoperative ERCP stone removal (n, %) 8 (11.3) 6 (9.0) GB stone (n, %) 66 (93.0) 62 (92.5) *Combined comorbid diseases(n, %) 22 (31.2) 21 (31.3) Single port cholecystectomy (n, %) 5 (7.0) 7 (10.4) Difficulty score in LC 0.5 ± ± # Postoperative complication (n, %) 0 1 (1.5) Open conversions Pathology (acute: chronic) (n, %) 6: 61 13: Operative time (min) 51.9 ± ± *Cardiovascular, Cerebrovascular, Diabetes mellitus, Chronic obstructive lung disease, Chronic renal failure, etc. # 1 case of minor bile leak only, no other complication occurred 3 cases xanthogranulomatous cholecystitis, 2 cases T1 GB cancer

9 Comparison of Laboratory Results at Postoperative 3 months after Rowachol (n = 64) Placebo (n = 63) P Total bilirubin (mg/dl) 0.7 ± ± Direct bilirubin (mg/dl) 0.3 ± ± Alkaline phosphatase (IU/L) ± ± Aspartate aminotransferase (IU/L) ± ± Alanine aminotransferase (IU/L) 44.3 ± ± White blood cells (x 10 6 /µl) 6.8 ± ±

10 Post-cholecystectomy syndrome Incidence of Abdominal pain on postoperative 3 months after *PCS No PCS p Rowachol (n, %) 3 (4.7) (%) 100 Placebo (n, %) 9 (14.3) Rowachol Placebo 20 0 PCS *Definition of PCS in this study: No PCS RUQ pain on EORTC QLQ C points at postoperative 3 months

11 Rowachol vs. Placebo Incidence of the other symptoms on postoperative 3 months after Rowachol (n = 64) Placebo (n = 63) p *Highly presented Symptom scales (n, %) Fatigue 42 (65.6) 37 (58.7) Nausea and vomiting 21 (32.8) 20 (31.7) Dyspnea 12 (18.8) 13 (20.6) Insomnia 39 (60.9) 35 (55.6) Appetite loss 39 (60.9) 38 (60.3) Constipation 28 (43.8) 22 (34.9) Diarrhea 44 (68.8) 35 (55.6) Financial difficulties 4 (6.3) 5 (7.9) # Impaired Functional Scale (n, %) Physical function 1 (1.6) 1 (1.6) Role function 1 (1.6) 2 (3.2) Emotional function 2 (3.1) 2 (3.2) Cognitive function 5 (7.8) 2 (3.2) Social function 0 1 (1.6) Global health status/ QoL 17 (26.6) 15 (23.8) *Symptom scales 30 points at postoperative 3 months, # Functional scales 50 points at postoperative 3 months

12 Age/ Sex Group Postcholecystectomy syndrome Detailed characteristics for each patient Difficulty score pathology Combined CBD stone Postoperative complication Radiologic diagnosis using USG Management for pain 44/ M Placebo 3 Chronic - - nonspecific conservative 41/ M Rowachol 0 Chronic - - nonspecific conservative 61/ F Placebo 3 Acute - - nonspecific conservative 70/ F Rowachol 0 Chronic - - nonspecific conservative 36/ F Rowachol 0 Chronic - - nonspecific conservative 64/ M Placebo 2 Acute - Bile leak Mild BD dilatation conservative 66/ F Placebo 4 Acute Yes - nonspecific conservative 44/ F Placebo 2 Acute - - nonspecific conservative 46/ F Placebo 2 Acute - - nonspecific conservative 35/ M Placebo 4 Chronic - - nonspecific conservative 51/ F Placebo 0 Chronic - - nonspecific conservative 58/ M Placebo 1 Chronic - - nonspecific conservative

13 Postcholecystectomy syndrome Risk factor analysis, Abdominal pain on postoperative 3 months after PCS (n = 12) No PCS (n= 115 ) p Age 51.3 ± ± Sex (male: female) 5:7 48: BMI (kg/m 2 ) 26.4 ± ± ASA class (minimal/ moderate/ severe) 7: 5 75: 40: Preoperative ERCP stone removal (n, %) 1 (8.3) 11 (9.6) GB stone (n, %) 12 (100) 105 (91.3) *Combined comorbid diseases(n, %) 4 (33.3) 36 (31.3) Single port cholecystectomy (n, %) 0 11 (9.6) Difficulty score to perform LC 1.8 ± ± 1.0 < # Postoperative complication (n, %) 1 (8.3) Open conversions 0 0 Pathology (acute: chronic) (n, %) 5 (41.7) 12 (10.4) Operative time (min) 52.1 ± ± Postoperative Rowachol treatment (n, %) 3 (25.0) 61 (53.0) *Cardiovascular, Cerebrovascular, Diabetes mellitus, Chronic obstructive lung disease, Chronic renal failure, etc. # 1 case of minor bile leak only, no other complication occurred 3 cases xanthogranulomatous cholecystitis, 2 cases T1 GB cancer

14 Risk factor analysis Multivariate analysis: multiple logistic regression analysis HR 95 % Confidence intervals Higher difficulty score in LC ( 3) Pathology (acute cholecystitis) p Absence of Postoperative Rowachol treatment

15 Summary & Conclusion There are no significant differences in aspect of demographics, preoperative clinical findings, and surgical findings between Rowachol and placebo group Rowachol group showed significantly lower postoperative RUQ pain (PCS) compared to placebo group The risk factors of PCS were revealed as higher difficulty score to perform LC, and absence of postoperative Rowachol treatment after multivariate analysis Rowachol can be beneficial for prevention of postcholecystectomy syndrome after laparoscopic cholecystectomy