bs_bs_banner Therapeutic Apheresis and Dialysis 2016; 20(2):197–204 doi: 10.1111/1744-9987.12357 © 2016 The Authors. Therapeutic Apheresis and Dialysis published by John Wiley & Sons Australia, Ltd on behalf of International Society for Apheresis, Japanese Society for Apheresis, and Japanese Society for Dialysis Therapy Safety and Tolerability of Nafamostat Mesilate and Heparin as Anticoagulants in Leukocytapheresis for Ulcerative Colitis: Post Hoc Analysis of a Large-Scale, Prospective, Observational Study Koji Sawada,1 Maiko Ohdo,1 Tomoko Ino,2 Takashi Nakamura,2 Toyoko Numata,2 Hiroshi Shibata,2 Jun-ichi Sakou,2 Masahiro Kusada,2 and Toshifumi Hibi3 1Dojima General & Gastroenterology Clinic, Osaka, 2Scientific and Technical Affairs Department, Japan Operation Division, Blood Purification Business Unit, Asahi Kasei Medical Co. Ltd., and 3Center for Advanced IBD Research and Treatment, Kitasato University, Kitasato Institute Hospital, Tokyo, Japan Abstract: Nafamostat mesilate is the first anticoagulant of reactions (8.6% vs. 7.1%) and intrafilter pressure in- choice for leukocytapheresis (LCAP) with a Cellsorba E creases (12.7% vs. 16.8%) between the nafamostat column for treating ulcerative colitis (UC). However, mesilate and heparin groups. Adverse reactions of hemor- because of complications, mainly due to allergy to rhage or blood pressure decreases associated with heparin nafamostat mesilate, heparin may be used as a substitute. use were not observed. There were no significant differ- To evaluate the safety and tolerability of nafamostat ences in rates of clinical remission (69.1% vs. 68.1%) and mesilate and heparin as anticoagulants in LCAP for UC, mucosal healing (62.9% vs. 63.6%) between the we conducted post hoc analysis of data from a large- nafamostat mesilate and heparin groups. Thus, the safety scale, prospective, observational study of LCAP, which and tolerability were comparable in the nafamostat was conducted at 116 medical facilities in Japan between mesilate and heparin groups, indicating that both May 2010 and December 2012. Of 832 patients included nafamostat mesilate and heparin can be well tolerated as in this analysis, nafamostat mesilate and heparin were anticoagulants in LCAP for UC. Key Words: Anticoag- used in 676 (81.3%) and 113 (13.6%), respectively. There ulant, Heparin, Leukocytapheresis, Nafamostat mesilate, were no significant differences in the incidence of adverse Ulcerative colitis. Ulcerative colitis (UC) is a disease of unknown or- We established previously that leukocytapheresis igin that causes chronic inflammation in the mucosa (LCAP), a type of apheresis, is an effective treat- of the colon. The clinical symptoms are recurrent or ment for active UC (6,7). LCAP is an extracorpo- continuous diarrhea with bloody mucus in the stool, real circulation therapy that uses the Cellsorba E abdominal pain, and the presence of diffuse lesions column (Asahi Kasei Medical, Tokyo, Japan), that originate in the rectum and typically advance which is filled with a nonwoven polyester fiber that continuously in a proximal direction (1). removes activated leukocytes and activated plate- The main medical treatment for active UC is the lets from the peripheral blood to elicit anti- oral and topical administration of 5-aminosalicylic acid inflammatory effects (8–10). LCAP for active UC (5-ASA) (2); however, corticosteroids are often used received approval for medical insurance coverage in patients refractory to 5-ASA (3). Patients who are in Japan in 2001. also refractory to corticosteroids receive concurrent Our previous study revealed that the efficacy rate immunosuppressants or biological agents (4,5). of LCAP was 74% among 39 patients with steroid- resistant UC (6). In addition, the efficacy was 80% in a double-blind sham column control study of 19 Received March 2015; revised June 2015. patients with steroid-resistant active UC, which indi- Address correspondence and reprint requests to Dr. Koji Sawada, fi fi Dojima General & Gastroenterology Clinic, 2-4-27 Dojima, Kita-ku, cated that LCAP had a signi cantly higher ef cacy Osaka 530–0003, Japan. Email: [email protected] than a sham column (7). 197 This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. 198 K Sawada et al. These studies used nafamostat mesilate, which has remove leukocytes. LCAP was performed 5–10 times a relatively short half-life, as the anticoagulant in the during the treatment period with a blood flow rate of LCAP treatment because UC is a hemorrhagic ill- 30–50 mL/min and a blood processing volume ness. In addition, polyester fiber has a negative elec- ≥30 mL/kg bodyweight. tric charge, which may induce the production of bradykinin in blood and thereby decrease blood Assessment of treatment outcomes pressure (11). Because nafamostat mesilate can in- The surveyed patient demographic data included hibit the production of bradykinin (12), it may be age, weight, gender, UC disease duration, response more suitable as an anticoagulant during LCAP to corticosteroids, and concomitant medications. treatment. However, several studies have reported The information from each LCAP session included that nafamostat mesilate is associated with adverse the date that LCAP was performed, the amount of events such as allergic symptoms and anaphylactic processed blood, the anticoagulant used, the reason shock (13,14). Thus, in an actual clinical setting, hep- for the change, the dose if the anticoagulant was arin could be used as a substitute anticoagulant in pa- changed, and the reason for discontinuation of tients who develop adverse events associated with LCAP where applicable. The following reasons for nafamostat mesilate. However, the tolerability of the discontinuation of LCAP were defined as heparin as an anticoagulant in LCAP for UC has “intrafilter pressure increase”: increased intrafilter not been investigated using data from a large-scale pressure or blood clotting. In addition, all adverse study. events noted during the observation period were re- We previously conducted a large-scale, prospec- corded in the CRFs, and any events for which a tive, observational study to evaluate the safety and causal relationship with LCAP could not be ruled efficacy of LCAP for active UC (15). In this large- out were considered adverse reactions (ARs) to scale study, nafamostat mesilate was used as the anti- LCAP. The AR terminology followed the Medical coagulant for LCAP treatment in 676 patients Dictionary for Regulatory Activities (MedDRA/J (81.3%), while heparin was used in 113 patients version 15.1). The incidence of all ARs and intrafilter (13.6%). Therefore, we analyzed the results of this pressure increases was investigated according to the study to evaluate the safety and tolerability of number of patients. nafamostat mesilate and heparin as anticoagulants The Lichtiger Clinical Activity Index (CAI) (16) in LCAP for UC. was used to determine efficacy and was assessed be- fore the start of LCAP and 2 weeks after the last PATIENTS AND METHODS LCAP session. Clinical remission was defined as a CAI score ≤4 at 2 weeks after the last LCAP session. In addition, clinical improvement was defined as clin- Study design ical remission or a final CAI score at least 50% lower The present study used data from a large-scale, than that obtained before the start of LCAP. Mucosal prospective, observational study of LCAP, which in- healing was assessed in all patients with an endo- cluded 847 patients with active UC (15). The study scopic index (EI) within the disease activity index was conducted in accordance with the Good (DAI) (17) and was defined as an EI of ≤1or0at Postmarketing Study Practice (GPSP) ordinance 2 weeks after the last LCAP session. The of the Japanese Ministry of Health, Labor, and hematochezia scores before the start of LCAP and Welfare. All patients in this study underwent LCAP 2 weeks after the last LCP session were compared at one of the 116 participating medical facilities be- for those patients with a DAI hematochezia score. tween May 2010 and December 2012. The treatment strategy for each patient, including the course of LCAP, was determined by the attending physician. Statistical analysis The observation period began 2 weeks prior to the Patient demographic data, the incidence of AR start of LCAP and ended 2 weeks following the and intrafilter pressure increases, and treatment effi- conclusion of treatment. The treating physicians cacy were compared by analyzing continuous data then filled out a case report form (CRF) after the using Wilcoxon rank-sum tests and categorical data observation period. using Fisher’s exact test. The hematochezia scores before and after treatment were compared using LCAP treatment Wilcoxon signed-rank test. Any missing data were Leukocytapheresis was performed using Cellsorba excluded. In all the analyses, P < 0.05 (two-sided) E, a column filled with nonwoven polyester fiber to was considered to be statistically significant. © 2016 The Authors. Therapeutic Apheresis and Dialysis published by John Wiley & Sons Australia, Ltd on behalf Ther Apher Dial, Vol. 20, No 2, 2016 of International Society for Apheresis, Japanese Society for Apheresis, and Japanese Society for Dialysis Therapy Anticoagulants in LCAP for UC 199 RESULTS appropriate treatment. The main ARs in the heparin group were a decreased platelet count (2.7%, 3 of 113), nasal congestion (1.8%, 2 of 113), and pain in Anticoagulant use and demographic profiles the vascular access site (1.8%, 2 of 113). No serious Of the 847 patients enrolled in this study, the ARs, including exacerbated hemorrhagic stool or de- data from 832 were analyzed after 15 patients creased blood pressure, were observed. No ARs were excluded because the anticoagulant used fi were observed in the two patients who received could not be identi ed. The anticoagulants used LMWH in all sessions or in the five individuals who in the 832 patients are shown in Table 1.