InPaFis – results of an open monocenter single-arm phase II study to evaluate the safety of a modified analgesia with indomethacin during pancreatectomy and its influence on clinically relevant postoperative pancreatic fistula

Background: Clinically relevant postoperative pancreatic fistula (CR-POPF) is a common complication after pancreatoduodenectomies, probably caused by local inflammation around the pancreas anastomosis. During endoscopic retrograde cholangio-pancreatography (ERCP), indomethacin is applied in order to prevent post-ERCP pancreatitis. Our single-arm phase II study aimed at evaluating the safety of indomethacin during pancreatoduodenectomies and its influence on CR-POPF. Methods: A total of 58 patients were enrolled in the InPaFis study and received a suppository of indomethacin at the beginning and the end of surgery. Primary endpoint was the development of CR-POPF, and secondary endpoints were further complications. Besides the evaluation of safety of indomethacin, we analyzed clinical efficacy by comparing InPaFis patients with a historical patient cohort. Results: A total of 50 patients of the InPaFis collective completed the study. Compared to the 186 patients of the control cohort, we found a non-significantly reduced rate of CR-POPF in InPaFis patients (34.0% vs. 41.9%, P = 0.197), but significantly more severe complications ( P = 0.010). After propensity score matching, the trend toward a lower fistula rate in the InPaFis cohort remained consistent (28.6% vs. 42.9%, P = 0.271), but there was no difference concerning severe complications anymore ( P = 0.209). We found a significantly reduced trypsin activation in drain fluid despite initial elevated lipase activity in the InPaFis cohort ( P = 0.029), corresponding to less CR-POPF in these patients. Conclusion: The anti-inflammatory effect of indomethacin might prevent the formation of a CR-POPF by inhibiting the activation of digestive enzymes. Further randomized trials are warranted to evaluate the potential inhibition of pancreatic fistulas by indomethacin.