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Association Between Nonsteroidal Anti-Inflammatory Drugs and Colorectal Cancer: a Population-Based Case–Control Study

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Association Between Nonsteroidal Anti-Inflammatory Drugs and Colorectal Cancer: a Population-Based Case–Control Study Published OnlineFirst April 25, 2018; DOI: 10.1158/1055-9965.EPI-17-0876 Research Article Cancer Epidemiology, Biomarkers Association between Nonsteroidal Anti- & Prevention Inflammatory Drugs and Colorectal Cancer: A Population-Based Case–Control Study Chun-Nan Kuo1,2, Jen-Jung Pan3, Ya-Wen Huang4, Hui-Ju Tsai4,5, and Wei-Chiao Chang1,2,6,7 Abstract Background: COX-2 overexpression may contribute to Results: A total of 65,208 colorectal cancer cases and 65,208 colorectal cancer occurrence. Aspirin and nonsteroidal anti- matched controls were identified. Patients with aspirin use had a inflammatory drugs (NSAIDs) can reduce colorectal cancer recur- lower risk of colorectal cancer compared with nonusers [adjusted rence, but the efficacy of primary prevention in Asian populations OR (AOR) ¼ 0.94, 95% confidence interval (CI) ¼ 0.90–0.99]. is still elusive. Thus, we examined the primary preventive efficacy NSAID use was associated with lower incidence of colorectal of aspirin and NSAIDs on colorectal cancer incidence in Taiwan. cancer (AOR ¼ 0.96; 95% CI ¼ 0.92–1.00). When examining Methods: A nested case–control study was conducted using colon or rectal cancer, similar decreased risks were observed. the National Health Insurance Research Database (NHIRD) in Patients taking more cumulative days of NSAIDs use tended to Taiwan. We identified patients with diagnosis of colorectal cancer experience a more protective effect on colorectal cancer, but no from 2005 to 2013 in the Registry of Catastrophic Illness Patient dose–response effects were noted. Database. We selected patients without colorectal cancer from the Conclusions: Aspirin and NSAIDs were associated with a Longitudinal Health Insurance Database as the controls and reduced risk of colorectal cancer development among a study matched them with cases. NSAID exposure was defined as at least cohort in an Asian population. two prescriptions 13 to 48 months prior to the index date. Impact: This study provided a possible chemoprevention for Conditional logistic regression models were performed to eval- colorectal cancer in an Asian population. Cancer Epidemiol Biomarkers uate the association between NSAID use and colorectal cancer. Prev; 27(7); 1–9. Ó2018 AACR. Introduction dence and death are even higher in Taiwan than in the Western world (4). Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely It is known that the mechanisms by which the enzymes or COX used as symptomatic treatment for conditions such as acute pain, cause inflammation are related to inhibition of the formation of chronic inflammatory, and degenerative joint diseases (1). Gen- prostaglandins, prostacyclins, and thromboxanes (5). Previous erally, NSAIDs are divided into nonselective and selective NSAIDs studies have documented that COX-2 plays an important role in depending on whether or not the inhibitory target is on COX-2 the pathogenesis of colorectal cancer (6, 7). Given the association selectivity. Colorectal cancer is the third deadliest cancer between COX-2 and colorectal cancer, many studies have inves- in America (2), and also the second most common cancer in tigated the efficacy of NSAIDs as chemoprevention for colorectal Taiwan (3). The age-standardized rates of colorectal cancer inci- cancer. For example, several studies have shown that aspirin reduces the recurrence of adenomatous polyps among patients – 1Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical Univer- with a history of colorectal cancer (8 10). However, other ran- sity, Taipei, Taiwan. 2Department of Pharmacy, Wan Fang Hospital, Taipei domized trials failed to show that low-dose aspirin given as Medical University, Taipei, Taiwan. 3Division of Gastroenterology and Hepatol- primary prevention lowered the risk of colorectal cancer (11, 12). ogy, Department of Medicine, The University of Arizona, Tucson, Arizona. Although, numerous studies have examined the role of aspirin 4Institute of Population Health Sciences, National Health Research Institutes, 5 or NSAIDs on colorectal cancer chemoprevention, data regarding Miaoli, Taiwan. Department of Pediatrics, Feinberg School of Medicine, primary prevention among Asian populations are still unclear. Northwestern University, Chicago, Illinois. 6Master Program for Clinical Pharmacogenomics and Pharmacoproteomics, School of Pharmacy, Taipei Furthermore, dose and duration response data are also limited. To Medical University, Taipei, Taiwan. 7Center for Biomarkers and Biotech Drugs, extend our understanding in this area, we conducted a nested Kaohsiung Medical University, Kaohsiung, Taiwan. case–control study to examine the primary preventive efficacy of Corresponding Authors: Hui-Ju Tsai, Division of Biostatistics and Bioinformat- aspirin and NSAIDs on colorectal cancer incidence in a large ics, Institute of Population Health Sciences National Health Research Institutes, nationwide population-based cohort in Taiwan. Zhunan, Miaoli 35053, Taiwan. Phone: 886-3724-6166, ext. 36150; Fax: 886- 3758-6467; E-mail: [email protected]; and Wei-Chiao Chang, Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical University, Taipei, Materials and Methods Taiwan. Phone: 8862-2736-1661, ext. 6188; E-mail: [email protected] Data source doi: 10.1158/1055-9965.EPI-17-0876 The data used in this study were derived from the National Ó2018 American Association for Cancer Research. Health Insurance Research Database (NHIRD) in Taiwan. The www.aacrjournals.org OF1 Downloaded from cebp.aacrjournals.org on September 30, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst April 25, 2018; DOI: 10.1158/1055-9965.EPI-17-0876 Kuo et al. National Health Insurance (NHI) program in Taiwan was nac, aceclofenac, acemetacin, nabumetone, diclofenac, etodo- launched in 1995 and the NHIRD has been released for research lac, ketorolac, sulindac, and tolmetin; (v) enolic acid deriva- purposes since 1998. NHIRD has collected demographic char- tives: piroxicam, meloxicam, and tenoxicam; (vi) anthranilic: acteristics, outpatient visits and inpatient claims data, and pre- flufenamic, mefenamic, niflumic, and tolfenamic; and (vii) scription records and disease diagnoses for approximately 99% of sulphonailide: nimesulide. the entire population of 23 million people residing in Taiwan. However, the data in NHIRD before 2001 were not comprehen- NSAID exposure sive for research purpose. Therefore, in this study, we set 2005 as In this study, we examined the long-term effects of NSAID index year and evaluated 4-year exposure duration for cases in (including aspirin, selective, and nonselective NSAIDs) use. 2005, starting from 2001. Specifically, we de fined users, recent or former users were based on a previous population-based case–control Demark study Cases of colorectal cancer and matched controls (14). We accounted for the duration of exposure to NSAID use The incident cases of colorectal cancer were defined as patients that was between 13 months and 48 months prior to the index diagnosed with colorectal cancer from 2005–2013 (ICD-9-CM date. Study participants were categorized on the basis of their codes: 153 and 154) who were identified from the Registry of NSAID exposure status. First, patients exposed to NSAIDs were Catastrophic Illness Patient Database (RCIPD). The date of the classified as users (definedasatleasttwoprescriptionsof first diagnosed record of colorectal cancer was defined as the index NSAIDs during the 13–48 months prior to the index date) or date. In detail, patients were mandated to have histologic, radio- nonusers. Patients with only one prescription would be exclud- graphic, and/or pathologic confirmations for cancer diagnosis ed from the subsequent analyses. Next, we classified patients before catastrophic illness certificates were issued and included in as recent users (defined as at least two prescriptions of NSAIDs the RCIPD. Of note, in this study, we did not include those with in the 13–24 months prior to the index date), former users in situ malignancies because such early-stage diseases do not (defined as at least two prescriptions of NSAIDs in the 25–48 qualify for catastrophic illness certificates and hence are not months prior to the index date, but not in the 13–24 months captured by the RCIPD. As we intended to analyze the association prior to the index date), or nonusers. Furthermore, we grouped between NSAID and colorectal cancer incidence, we excluded patients into continuous users (definedasatleasttwoprescrip- nearly 80,000 cases before the year 2005. tions of NSAIDs per months and continuing for over 6 months For each case, we randomly selected one control from the in the period of 13–48 months prior to the index date), Longitudinal Health Insurance Database for the year 2005 noncontinuous users (defined as not meeting the criteria of (LHID2005) who did not have a colorectal cancer diagnosis at continuous use, but with identified prescriptions of aspirin or the time when the matched case was diagnosed with colorectal NSAIDs in the period of 13–48 months prior to the index date), cancer. The LHID2005 is a subset derived from the NHIRD and or nonusers (14). includes medical claims data of 1,000,000 individuals randomly sampled from the 2005 NHI Registry for Beneficiaries. Previous Adjustment of potential confounding factors studies have reported that there is no difference of distributions in We took into account the potential confounding effects age and gender between LHID 2005 and NHIRD (13). Therefore, caused by comorbid medical disorders, concomitant medica- the LHID2005
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