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Comparative Safety of Nsaids for Gastrointestinal Events in Asia-Pacific Populations: a Multi-Database, International Cohort Study

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Comparative Safety of Nsaids for Gastrointestinal Events in Asia-Pacific Populations: a Multi-Database, International Cohort Study Comparative Safety of NSAIDs for Gastrointestinal Events in Asia-Pacific Populations: A Multi-Database, International Cohort Study Edward Chia-Cheng Lai,a,b,c Ju-Young Shin,d Kiyoshi Kubota,e Kenneth K. C. Man,f Byung Joo Park,d,g Nicole Pratt,h Elizabeth E. Roughead,h Ian C. K. Wong,i Yea-Huei Kao Yang,a,i Soko Setoguchic,j,k* Author Affiliations: aSchool of Pharmacy, Institute of Clinical Pharmacy and Pharmaceutical Sciences, National Cheng Kung University, Tainan, Taiwan; bDepartment of Pharmacy, National Cheng Kung University Hospital, Tainan, Taiwan; cDuke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina, USA; dDepartment of Preventive Medicine, Seoul National University College of Medicine, Seoul, South Korea; eDepartment of Pharmacoepidemiology, University of Tokyo, Tokyo, Japan; fCentre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, University of Hong Kong, Hong Kong; gOffice of Drug Utilization Review, Korea Institute of Drug Safety and Risk Management, Seoul, South Korea; hQuality Use of Medicines and Pharmacy Research Centre, Sansom Institute for Health Research, University of South Australia, Adelaide, Australia; iHealth Outcome Research Center, National Cheng-Kung University, Tainan, Taiwan; and jDepartment of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA; and kRutgers Center for Pharmacoepidemiology and Treatment Science, Institute for Health, Rutgers University, New Brunswick, New Jersey, USA. * Authors 3 through 9 are listed in alphabetical order. Funding/Support: This work was supported by a research agreement between Duke University and Janssen Research & Development, LLC. Dr Kubota was supported by grant 11-2-021 from the Pfizer Health Research Foundation. Corresponding Author: Soko Setoguchi, MD, DrPH, Institute for Health, Rutgers University, 112 Paterson St, New Brunswick, NJ 08901, USA; telephone: 848-932-6507; email: [email protected]. Key Words: Anti-Inflammatory Agents, Non-Steroidal; Pharmacoepidemiology Key Points: Study of nonsteroidal anti-inflammatory drugs (NSAIDs) commonly used in Asia-Pacific countries is limited. Compared with diclofenac, loxoprofen was associated with a lower risk of gastrointestinal hospitalizations in Korea and mefenamic acid with a lower risk in Taiwan and Korea. Our study provides lessons for future multinational pharmacoepidemiologic studies in the Asia- Pacific region. Conflict of Interest Disclosures: Dr. Setoguchi is served as a consultant and receiving a research grant from Pfizer Inc. and Janssen Inc. Dr Kubota was supported by grant 11-2-021 from the Pfizer Health Research Foundation. Prof. Wong reported receiving a research grant from the Pfizer Health Research Foundation to the University of Hong Kong to investigate the use of biologics in Hong Kong. All other authors declared that they have no conflicts of interest. 2847 words Comparative Safety of NSAIDs August 1, 2018 Abstract Purpose: The safety of nonsteroidal anti-inflammatory drugs (NSAIDs) commonly used in Asia-Pacific countries has had limited study. We assessed the risk of hospitalization for gastrointestinal events with loxoprofen and mefenamic acid compared with other NSAIDs in Asia-Pacific populations. Methods: We conducted a cohort study using a distributed network with a common data model in Australia, Hong Kong, Japan, Korea, and Taiwan. We included patients who initiated diclofenac, loxoprofen, mefenamic acid, or celecoxib and followed them until their first gastrointestinal hospitalization, switch or discontinuation of medication, disenrollment, or end of database coverage. We used Cox proportional hazards models to assess hospitalization risk. Results: We identified 9879 patients in Japan, 70,492 in Taiwan, 263,741 in Korea, and 246 in Hong Kong who initiated an NSAID, and 44,013 patients in Australia, a predominantly Caucasian population. The incidence of gastrointestinal hospitalization was 25.6 per 1000 person-years in Japan, 32.8 in Taiwan, 11.5 in Korea, 484.5 in Hong Kong, and 35.6 in Australia. Compared to diclofenac, the risk of gastrointestinal events with loxoprofen was significantly lower in Korea (hazards ratio [HR], 0.37; 95% CI, 0.25-0.54) but not in Japan (1.65; 95% CI, 0.47-5.78). The risk of gastrointestinal events with mefenamic acid was significantly lower in Taiwan (0.45; 95% CI, 0.26-0.78) and Korea (0.11; 95% CI, 0.05-0.27) but not Hong Kong (2.16; 95% CI, 0.28-16.87), compared with diclofenac. Conclusions: Compared with diclofenac, loxoprofen was associated with a lower risk of gastrointestinal hospitalizations in Korea and mefenamic acid with a lower risk in Taiwan and Korea. 2 Introduction The Asian Pharmacoepidemiology Network (AsPEN) was formed to support the conduct of international pharmacoepidemiologic research and to facilitate prompt identification and validation of emerging safety concerns in Asian countries.1,2 Analyses have been conducted through this research network to build experience in using databases from AsPEN countries using a variety of methodological approaches, including sequence symmetry analysis (SSA).3 AsPEN consists of research groups based in the Asia-Pacific region, including Australia, China, Hong Kong, Japan, Korea, Singapore, Taiwan, and Thailand. It is well known that the use of nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with higher risks of upper and lower gastrointestinal events.4,5 Cyclooxygenase-2 (COX-2) inhibitors, a selective NSAID, reduce the risk of gastrointestinal events because the inhibition of COX-2 does not affect the synthesis of prostaglandins that protect the gastrointestinal tract.6,7 However, the safety of NSAIDs that are commonly or solely used in the Asia-Pacific region, including loxoprofen and mefenamic acid, has not been well studied. Also, the majority of evidence comes from countries with predominantly Caucasian populations. It is unclear whether ethnic differences between Asian and Caucasian populations play a role in the comparative safety profiles of NSAIDs.7-9 This international, multi-database cohort study aimed to compare the safety of loxoprofen and mefenamic acid with the safety other NSAIDs in terms of the risk of hospital admission for peptic ulcer diseases or upper and lower gastrointestinal bleeding. We compared patients who initiated loxoprofen or mefenamic acid with patients who initiated diclofenac, one of the commonly used and previously studied NSAIDs. We also included celecoxib in the study to benchmark the effect for COX-2 inhibitors with nonselective NSAIDs. 3 Method Distributed Network Approach With a Common Data Model We conducted a retrospective, multi-database, international pharmacoepidemiologic study using a distributed network approach10-12 and developed a study-specific common data model consisting of 8 tables, including patient demographic characteristics, eligibility, drug, inpatient encounter, inpatient diagnosis, outpatient diagnosis, inpatient procedures, and outpatient procedures (eMethods). Teams from all participating countries converted their original data structures to the common data model before analyses. The coordinating center generated a systematic SAS program based on the study protocol and distributed it to each site. The results of the analyses were then returned to the coordinating center for collating. Participating Databases Participating countries included Australia, Hong Kong, Japan, Korea, and Taiwan. We included data from the Japan Medical Data Centre insurance claims database (JMDC) for 2005 through 2010; the Korea Health Insurance Review and Assessment Service database (HIRA) for 2006 through 2008; the Taiwan National Health Insurance Research Database (NHIRD) for 2002 through 2008; the Hong Kong Clinical Data Analysis and Reporting System (CDARS) for 2008 through 2012; and the Australian Department of Veterans’ Affairs health care claims database for 2001 through 2012. These databases have been described in detail elsewhere.2 Study Cohort Definitions We selected patients who initiated NSAIDs (ie, diclofenac, loxoprofen, mefenamic acid and celecoxib). We considered the first dispensed NSAID to be the index medication, and we 4 used the dispensing date as the index date. We included only new users of NSAIDs, which we defined as patients who received no dispensing of an NSAID during the 6 months before the index date. Although use of nonprescription NSAIDs is not common in Asian countries,13 some patients in the study may have used over-the-counter NSAIDs. To minimize exposure misclassification, we further restricted the study population to patients who had certain chronic conditions (ie, diabetes mellitus, hypertension, myocardial infarction or acute coronary syndrome, stroke, and rheumatoid arthritis). These patients are more likely to seek medical care on a regular basis and, therefore, more likely to receive prescriptions for NSAIDs. Also, these patients are at high risk for gastrointestinal complications of NSAID use.14 Furthermore, we excluded patients with a history of cancer (other than non-melanoma skin cancer), human immunodeficiency virus infection, renal failure, liver injury, respiratory failure, or transplant to make the results more generalizable to patients who are chronically ill but not at the end of life. Finally, we excluded patients with history of liver cirrhosis, esophageal varices, chronic alcoholism, or bariatric or other surgery resulting in gastrojejunal anastomosis, because
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