Diabetes Care Volume 41, August 2018 1757 Effect of Aspirin on Cancer Sadanori Okada,1,2 Takeshi Morimoto,3 Hisao Ogawa,4 Mio Sakuma,3 Chemoprevention in Japanese Chisa Matsumoto,3 Hirofumi Soejima,5 Masafumi Nakayama,6 Naofumi Doi,7 Patients With Type 2 Diabetes: Hideaki Jinnouchi,8 Masako Waki,9 Izuru Masuda,10 and Yoshihiko Saito,2 for 10-Year Observational Follow-up the JPAD Trial Investigators* of a Randomized Controlled Trial Diabetes Care 2018;41:1757–1764 | https://doi.org/10.2337/dc18-0368 OBJECTIVE This study analyzed the efficacy of low-dose aspirin in cancer chemoprevention in patients with diabetes. 1Department of Diabetology, Nara Medical Uni- RESEARCH DESIGN AND METHODS versity, Kashihara, Nara, Japan 2 This study was a posttrial follow-up of the Japanese Primary Prevention of Department of Cardiovascular Medicine, Nara Medical University, Kashihara, Nara, Japan Atherosclerosis with Aspirin for Diabetes (JPAD) trial. Participants in the JPAD 3Department of Clinical Epidemiology, Hyogo trial (2,536 Japanese patients with type 2 diabetes and without preexisting College of Medicine, Nishinomiya, Hyogo, Japan 4 cardiovascular disease) were randomly allocated to receive aspirin (81 or 100 mg National Cerebral and Cardiovascular Center, PATHOPHYSIOLOGY/COMPLICATIONS daily) or no aspirin. After that trial ended in 2008, we followed up with the Osaka, Japan 5Department of Cardiology, Graduate School of participants until 2015, with no attempt to change the previously assigned ther- Medical Science, Kumamoto University, Chuo, apy. The primary end point was total cancer incidence. We investigated the effect Kumamoto, Japan of low-dose aspirin on cancer incidence. 6Nakayama Cardiovascular Clinic, Amakusa, Kumamoto, Japan RESULTS 7Department of Cardiovascular Medicine, Nara Prefectural Seiwa Medical Center, Sango, Ikoma, During the median follow-up period of 10.7 years, a total of 318 cancers occurred. Nara, Japan The cancer incidence was not significantly different between the aspirin and 8Department of Internal Medicine, Jinnouchi no-aspirin groups (log-rank, P = 0.4; hazard ratio [HR], 0.92; 95% CI, 0.73–1.14; P = Hospital Diabetes Care Center, Chuo, Kumamoto, Japan 0.4). In subgroup analyses, aspirin did not affect cancer incidence in men, women, 9 ‡ Department of Internal Medicine, Shizuoka City or participants aged 65 years. However, it decreased cancer incidence in partici- Shizuoka Hospital, Aoi, Shizuoka, Japan pants aged <65 years (log-rank, P = 0.05; HR, 0.67; 95% CI, 0.44–0.99; P = 0.048). 10Medical Examination Center, Takeda Hospital, Shimogyo, Kyoto, Japan After adjusting for sex, hemoglobin A1c, smoking status, and administration of metformin and statins, aspirin significantly reduced cancer incidence in participants Corresponding author: Yoshihiko Saito, yssaito@ aged <65 years (adjusted HR, 0.66; 95% CI, 0.43–0.99; P = 0.04). naramed-u.ac.jp. Received 19 February 2018 and accepted 7 May CONCLUSIONS 2018. Low-dose aspirin did not reduce cancer incidence in Japanese patients with type 2 This article contains Supplementary Data online diabetes. at http://care.diabetesjournals.org/lookup/suppl/ doi:10.2337/dc18-0368/-/DC1. *A complete list of the JPAD Trial Investigators Malignant neoplasms have been the leading cause of death in Japan since 1981 (1). can be found in the Supplementary Data online. Mortality due to malignant neoplasms has been ;30% in the Japanese general © 2018 by the American Diabetes Association. population since the 2000s but has gradually increased up to 38% in patients with Readers may use this article as long as the work is properly cited, the use is educational and not diabetes (2). Cumulative evidence supports the fact that diabetes is associated with a for profit, and the work is not altered. More infor- high incidence of cancer (3–7). A meta-analysis in a Japanese population showed that mation is available at http://www.diabetesjournals patients with diabetes had a 1.7-fold higher risk of cancer than those without diabetes .org/content/license. 1758 Aspirin for Cancer Prevention in Diabetes Diabetes Care Volume 41, August 2018 (8). This risk varied among cancers, how- Participant enrollment in the JPAD trial points were colorectal cancer incidence ever, with hepatic, pancreatic, endome- started in December 2002 and was com- and total cancer mortality. Total cancer trial, and colorectal cancers demonstrating pleted in May 2005. After the JPAD trial incidence and mortality were composite a higher incidence in patients with dia- was completed in April 2008, all partic- end points of all types of cancer, in betes (8–10). This evidence shows that ipants were monitored until the day of accordance with previous studies to eval- patients with diabetes are at high risk not any fatal event or July 2015, even if car- uate aspirin’s cancer chemoprevention only for cardiovascular diseases but also diovascular events occurred. The JPAD (16,22). Because aspirin’s chemopreven- for cancer. trial and its follow-up observational tive effect on colorectal cancer was A chemopreventive effect of aspirin period together constitute the JPAD2 previously reported in people without against cancer has been suggested by a cohort study (Supplementary Fig. 1). Par- diabetes (17,18), we analyzed colorectal series of studies during the past few ticipants who were not monitored until cancer incidence as a secondary end point. decades (11–13). Several meta-analyses July 2015 were censored on the day of These end points were defined after the of randomized controlled trials (RCTs) their last visit. start of the JPAD trial. We collected data recently reported reductions in cancer The JPAD trial and JPAD2 cohort study on cancer occurrence by contacting each incidence and mortality with long-term were performed according to the Dec- treating physician. When these physicians use of aspirin (14–16). In particular, laration of Helsinki and were approved reported the cancer occurrence, the study aspirin’s chemopreventive efficacy against by the ethics committee of each partici- secretariat asked them about the detailed colorectal cancer was well investigated pating hospital (Nara Medical University information of the cancers (i.e., onset by RCTs (17,18). In 2016, the U.S. Preven- Ethics Committee and Graduate School date, site, and tissue type). We excluded tive Services Task Force recommended of Medical Science, and Kumamoto Uni- cancer events that occurred before the use of low-dose aspirin for preven- versity Ethics Committee). Written in- the enrollment. Hemorrhagic events, tion of colorectal cancer in selected formed consent was obtained from each consisting of gastrointestinal bleeding, patients, taking into consideration age, participant. hemorrhagic stroke, and bleeding from cardiovascular risk, bleeding risk, and life any other sites, were reported previously expectancy (19). Most evidence, how- Study Participants (21). All potential end points were ad- ever, has been derived from studies of In the JPAD trial we recruited 2,539 judicated by a central independent com- people without diabetes; therefore, Japanese patients with type 2 diabetes, mittee that was blinded to the group – whether low-dose aspirin can prevent age 30 85 years, and no history of car- assignments. cancer in patients with diabetes remains diovascular disease. The detailed inclu- uncertain. sion and exclusion criteria in the JPAD Statistical Analysis We previously conducted an RCT, the trial were described previously (20). After Categorical variables are expressed as Japanese Primary Prevention of Athero- the JPAD trial was completed, three numbers and percentages. Continuous sclerosis with Aspirin for Diabetes (JPAD) participants were excluded because variables are expressed as means (SD) trial, to evaluate the efficacy of low-dose they were found to have a history of car- or medians (interquartile range). Based aspirin in the primary prevention of car- diovascular disease before enrollment on their distribution, continuous variables fi diovascular events in Japanese patients in the JPAD trial. A nal total of 2,536 were compared using the Student t test with type 2 diabetes (20). The JPAD trial participants were enrolled in the JPAD2 or the Wilcoxon rank sum test as appro- began in 2002. We reported the original cohort study. priate. Comparisons between the aspirin results in 2008 (20) and the follow-up and no-aspirin groups were made on the Intervention fi results in 2017 after a median follow-up The JPAD trial randomly allocated par- basis of time to the rst event, according period of more than 10 years (JPAD2 ticipants (1:1) to receive aspirin (81 mg to the intention-to-treat principle, be- cohort study) (21). The current study or 100 mg daily; aspirin group) or no cause 85% of participants retained their used the JPAD2 cohort study data to aspirin (no-aspirin group). All participants original allocation at the time of analy- analyze the effect of low-dose aspirin were allowed to undergo any concur- sis and previous studies indicated that on cancer incidence and mortality in rent treatments. At the end of the JPAD the long-term effect of aspirin on cancer Japanese patients with type 2 diabetes. trial, participants were administered low- chemoprevention persisted despite dis- dose aspirin according to the decision continuing aspirin (15,22). Because the RESEARCH DESIGN AND METHODS of each physician during the follow-up mortality from cardiovascular events Study Design period. We checked whether partici- was low in the JPAD2 cohort study and The detailed designs of the JPAD trial pants were administered low-dose aspi- we monitored all participants after these fi and JPAD2 cohort study have been pre- rin during follow-up. On July 2015, 2,160 events, the cause-speci c cumulative in- viously described (20,21). In brief, the JPAD participants (85%) had retained their cidence of each end point was estimated trial was a multicenter, randomized, stan- original allocation (21). using the Kaplan-Meier method in each dard care–controlled, open-label, blinded group, and differences between groups end point assessment trial conducted Primary and Secondary End Points were assessed with the log-rank test.