Prevalence of drug–drug interaction in atrial fibrillation patients based on a large claims data

Autoři: Kenji Momo aff001;  Haruna Kobayashi aff002;  Yuuka Sugiura aff002;  Takeo Yasu aff001;  Masayoshi Koinuma aff002;  Sei-ichiro Kuroda aff001
Působiště autorů: Department of Pharmacy, The Institute of Medical Science Hospital, The University of Tokyo, Minato-ku, Tokyo, Japan aff001;  Faculty of Pharmaceutical Sciences, Teikyo Heisei University, Nakano-ku, Tokyo, Japan aff002;  Department of Hospital Pharmaceutics, School of Pharmacy, Showa University, Shinagawa-ku, Tokyo, Japan aff003
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article


This study aimed to compare and determine the prevalence of drug–drug interaction (DDI) and bleeding rate in atrial fibrillation (AF) patients receiving anticoagulants in a clinical setting. We used large claims data of AF patients obtained from the Japan Medical Data Center. The prevalence of DDIs and cases leading to bleeding events were surveyed clinically relevant DDIs extracted from 1) reported from a spontaneous adverse event reporting system (Japanese Adverse Drug Events Report system; JADER) ≥4 patients; 2) DDIs cited in the package inserts of each anticoagulant (each combination assessed according to “Drug interaction 2015” list; 3) warfarin and quinolone antibiotics DDIs. DDIs were categorized the mechanisms for pharmacokinetic DDI (Cytochrome P450 (CYP) or transporter etc. that modulate blood concentration of anticoagulants)/pharmacodynamic DDI (combination with similar pharmacological actions) or both in the analysis for each patients’ prescriptions obtained from a claims data. AF patients were compared between cases with and without bleeding after administered of anticoagulants. Bleeding was observed in 220/3290 (6.7%) AF patients. The bleeding rate in patients with both pharmacokinetic and pharmacodynamic DDI mechanisms (26.3%) was higher than that in patients with either mechanism (8.6% and 9.2%, respectively) or without DDIs (4.9%). The odds ratio for bleeding in AF patients with both of pharmacokinetic and pharmacodynamic was (7.18 [4.69–11.00], p<0.001). Our study concluded multi mechanism based DDIs leads serious outcome as compared to that of single mechanism based DDIs in AF patients. We determined the prevalence and frequency of bleeding for anticoagulant-related DDIs. To manage DDIs, both pharmacokinetic and pharmacodynamic DDI mechanisms should be closely monitored for initial symptoms of bleeding within the first 3 months.

Klíčová slova:

Adverse events – Anticoagulant therapy – Anticoagulants – Atrial fibrillation – Japan – Pharmacodynamics – Pharmacokinetics


1. Life expectancies at birth in some countries, Abridged Life Tables for Japan 2017, Vital, Health and Social Statistics Office, Director-General for Statistics and Information Policy, Ministry of Health and Welfare. Available from: Cited 22 Aug 2018.

2. McDonnell PJ, Jacobs MR. Hospital admissions resulting from preventable adverse drug reactions. Ann Pharmacother. 2002;36: 1331–1336. doi: 10.1345/aph.1A333 12196047

3. Reimche L, Forster AJ, van Walraven C. Incidence and contributors to potential drug-drug interactions in hospitalized patients. J Clin Pharmacol. 2011;51: 1043–1050. doi: 10.1177/0091270010378858 20926752

4. Bergendal L, Friberg A, Schaffrath A. Potential drug-drug interactions in 5,125 mostly elderly out-patients in Gothenburg, Sweden. Pharm World Sci. 1995;17: 152–157. doi: 10.1007/bf01879709 8574210

5. Dewilde WJ, Oirbans T, Verheugt FW, Kelder JC, De Smet BJ, Adriaenssens T, et al. WOEST study investigators. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet. 2013;381(9872): 1107–1115. doi: 10.1016/S0140-6736(12)62177-1 23415013

6. Chang SH, Chou IJ, Yeh YH, Chiou MJ, Wen MS, Kuo CT, et al. Association between use of non-vitamin k oral anticoagulants with and without concurrent medications and risk of major bleeding in nonvalvular atrial fibrillation. JAMA. 2017;318: 1250–1259. doi: 10.1001/jama.2017.13883 28973247

7. JMDC inc. last accessed November/16/2019 (

8. Japanese Adverse Drug Event Report database, Pharmaceutical and Medical Devices Agency. last accessed November/16/2019 (

9. Sugiyama Y. Medical Tribune Inc. Drug interaction list 2015:

10. Ohe K. Kampo Med 61, 203–212 (2010) (

11. Suzuki Y, Suzuki H, Umetsu R, Uranishi H, Abe J, Nishibata Y, et al. Analysis of the interaction between clopidogrel, aspirin, and proton pump inhibitors using the FDA Adverse Event Reporting System Database. Biol Pharm Bull. 2015;38: 680–686. doi: 10.1248/bpb.b14-00191 25947914

12. Nakamura M. Analysis of spontaneously reported adverse events. Yakugaku Zasshi. 2016;136: 549–556. doi: 10.1248/yakushi.15-00224-5 27040337

13. Miki A, Ohtani H, Sawada Y. Warfarin and miconazole oral gel interactions: analysis and therapy recommendations based on clinical data and a pharmacokinetic model., J Clin Pharm Ther. 2011;36 (6): 642–650. doi: 10.1111/j.1365-2710.2010.01229.x 21143257

14. Martin-Perez M, Gaist D, de Abajo FJ, Rodriguez LAG. Population impact of drug interactions with warfarin: a real-world data approach. Thromb Haemost. 2018;118: 461–470. doi: 10.1055/s-0038-1627100 29433149

15. Pemberton MN, Oliver RJ, Theaker ED. Miconazole oral gel and drug interactions. Br Dent J. 2004;196: 529–531. doi: 10.1038/sj.bdj.4811224 15131616

16. Pharmaceuticals and Medical Devices Safety Information, MHLW pharmaceutical and Medical Devices Safety information (FY2016), 2016;338: 3–7.

17. Sakaguchi H. Treatment and Prevention pf Oral Candidiasis in Elderly Patietns. Med. Mycol. J. 2017; 58: 43–49

18. Gibson CM, Mehran R, Bode C, Halperin J, Verheugt FW, Wildgoose P, et al. Prevention of bleeding in patients with atrial fibrillation undergoing PCI. N Engl J Med. 2016;375: 2423–2434. doi: 10.1056/NEJMoa1611594 27959713

19. Goto K, Nakai K, Shizuta S, Morimoto T, Shiomi H, Natsuaki M, et al. CREDO-Kyoto Registry Cohort-2 Investigators. Anticoagulant and antiplatelet therapy in patients with atrial fibrillation undergoing percutaneous coronary intervention. Am J Cardiol. 2014;114: 70–78. doi: 10.1016/j.amjcard.2014.03.060 24925801

20. Hisaka A, Kusama M, Ohno Y, Sugiyama Y, Suzuki H. A proposal for a Pharmacokinetic Interaction Significance Classification System (PISCS) based on predicted drug exposure changes and its potential application to alert classifications in product labelling. Clin Pharmacokinet. 2009;48: 653–666. doi: 10.2165/11317220-000000000-00000 19743887

21. Ohno Y, Hisaka A, Ueno M, Suzuki H. General framework for the prediction of oral drug interactions caused by CYP3A4 induction from in vivo information. Clin Pharmacokinet. 2008;47: 669–680. doi: 10.2165/00003088-200847100-00004 18783297

22. Ohno Y, Hisaka A, Suzuki H. General framework for the quantitative prediction of CYP3A4-mediated oral drug interactions based on the AUC increase by coadministration of standard drugs. Clin Pharmacokinet. 2007;46: 681–696. doi: 10.2165/00003088-200746080-00005 17655375

23. Over view of medical insurance in Japan, Ministry of Health, Labor and Welfare. Last accessed 17/Oct/2018 (

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2019 Číslo 12
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