Original Article Yonsei Med J 2020 Sep;61(9):741-749 https://doi.org/10.3349/ymj.2020.61.9.741 pISSN: 0513-5796 · eISSN: 1976-2437 Concomitant Use of NSAIDs or SSRIs with NOACs Requires Monitoring for Bleeding Min-Taek Lee1, Kwang-Yeol Park2, Myo-Song Kim1, Seung-Hun You1, Ye-Jin Kang1, and Sun-Young Jung1 1College of Pharmacy, Chung-Ang University, Seoul; 2Department of Neurology, Chung-Ang University Hospital, Chung-Ang University College of Medicine, Seoul, Korea. Purpose: Non-vitamin K antagonist oral anticoagulants (NOACs) are widely used in patients with atrial fibrillation (AF) because of their effectiveness in preventing stroke and their better safety, compared with warfarin. However, there are concerns for an in- creased risk of bleeding associated with concomitant use of non-steroidal anti-inflammatory drugs (NSAIDs) or selective sero- tonin reuptake inhibitors (SSRIs) with NOACs. In this study, we aimed to evaluate the risk of bleeding events in individuals taking concomitant NSAIDs or SSRIs with NOACs after being diagnosed with AF. Materials and Methods: A nested case-control analysis to assess the safety of NSAIDs and SSRIs among NOAC users with AF was performed using data from Korean National Health Insurance Service from January 2012 to December 2017. Among patients who were newly prescribed NOACs, 1233 cases hospitalized for bleeding events were selected, and 24660 controls were determined. Results: The risk of bleeding events was higher in patients receiving concomitant NSAIDs [adjusted odds ratio (aOR) 1.41; 95% confidence interval (CI) 1.24–1.61] or SSRIs (aOR 1.92; 95% CI 1.52–2.42) with NOACs, compared to no use of either drug, respec- tively. The risk of upper gastrointestinal bleeding was higher in patients receiving concomitant NSAIDs or SSRIs without proton pump inhibitors (PPIs) (NSAIDs: aOR 2.47; 95% CI 1.26–4.83, SSRI: aOR 10.8; 95% CI 2.41–2.48) compared to no use. Conclusion: When NSAIDs or SSRIs are required for NOAC users with AF, physicians need to monitor bleeding events and con- sider the use of PPIs, especially for combined use of both drugs or when initiating NOACs treatment. Key Words: ‌Non-vitamin K antagonist oral anticoagulants, atrial fibrillation, nested case-control study, hemorrhages, drug interactions INTRODUCTION the only OAC used for patients with AF.1 Because of the disad- vantages of using warfarin, including a narrow therapeutic range, Non-vitamin K antagonist oral anticoagulants (NOACs), intro- interaction with various foods and drugs, and the requirement duced to the market in 2010, have been used to treat patients of frequent monitoring for bleeding,3 NOACs have been pre- with atrial fibrillation (AF) instead of warfarin. About 85% of pa- ferred in clinical settings. tients with AF take oral anticoagulants (OACs),1 because treat- However, although to lesser degrees than warfarin, NOACs ment with OACs markedly decreases the risk of ischemic stroke have also been reported to pose a risk of bleeding complications, in patients with AF.2 Before the launch of NOACs, warfarin was which may be influenced by pharmacokinetic or pharmacody- namic interactions. Whereas an increased risk of bleeding in Received: May 27, 2020 Revised: July 10, 2020 warfarin has been well studied, there is still insufficient evidence Accepted: July 14, 2020 Corresponding author: Sun-Young Jung, PhD, College of Pharmacy, Chung-Ang about the risk of bleeding events associated with drug-drug University, 84 Heukseok-ro, Dongjak-gu, Seoul 06974, Korea. interactions with NOACs. To date, several studies have assessed Tel: 82-2-820-5678, Fax: 82-2-816-7338, E-mail: [email protected] the numbers of potentially interacting drugs on the risk of com- •The authors have no potential conflicts of interest to disclose. posite bleeding events in patients using NOAC using databases © Copyright: Yonsei University College of Medicine 2020 in Taiwan,4 the United Kingdom,5 and German nursing homes.6 This is an Open Access article distributed under the terms of the Creative Com- However, interactions with drugs inhibiting platelet aggregation, mons Attribution Non-Commercial License (https://creativecommons.org/licenses/ by-nc/4.0) which permits unrestricted non-commercial use, distribution, and repro- including non-steroidal anti-inflammatory drugs (NSAIDs) and duction in any medium, provided the original work is properly cited. selective serotonin reuptake inhibitors (SSRIs), were not as- www.eymj.org 741 Use of NSAID or SSRI with NOAC Increases Bleeding sessed4 or showed conflicting results with previous studies.5,6 Study population NSAIDs are commonly used in short- or long-term treatment We conducted a nested case-control analysis among patients for several indications, including osteoarthritis and rheumatic with AF (ICD-10, I48) who were first prescribed NOACs during diseases. A Danish study reported that 21% of NOACs users took the study period from January 1, 2013, to December 31, 2017. concomitant NSAIDs,7 and a post hoc analysis of the RE-LY trial NOACs included in this study were apixaban, rivaroxaban, edox- revealed an increased risk of major bleeding associated with aban (factor Xa inhibitors), and dabigatran (direct thrombin in- NSAIDs in NOAC users.8 SSRIs are a first-line pharmaceutical hibitor). The date of the first NOAC prescription after AF was set treatment for major depressive disorder and anxiety disorders as the cohort entry. For each cohort population, at least 1 year and have relatively favorable safety profiles. However, studies of look-back period was applied before the first NOAC prescrip- have reported an increased risk of intracranial9 or gastrointesti- tion (2012.1.1.–2017.12.31.) to define new-users of NOACs with- nal (GI) hemorrhage10 associated with use of SSRIs. Furthermore, out any history of bleeding events. We also excluded patients combined use of NSAIDs and SSRIs concomitantly with NOACs diagnosed with cancer at least once and those who switched may pose an additional increase in the risk of bleeding. One from NOACs to warfarin during the study period. We determined study has shown that SSRIs combined with NSAIDs increases the cohort endpoint as 1) hospitalization or emergency depart- the risk of intracranial bleeding,11 and a meta-analysis has re- ment visit due to bleeding, 2) death, or 3) end of the study pe- ported a synergistic effect on GI bleeding with combined use of riod, whichever came first. NSAIDs and SSRIs.12 To date, however, population-based stud- In order to define an NOAC treatment episode, we allocated ies quantifying the degree of risk of bleeding associated with con- a grace period of 14 days. If a new prescription started less than comitant use of NSAIDs or SSRIs, especially for combined use 14 days from the end of the previous prescription and days of of the two drugs, remain scarce. supply, we defined the two prescriptions as the same treatment Concerning the risk of upper GI bleeding with NOACs, using episode, which began from the date of the previous prescrip- proton pump inhibitors (PPIs) when prescribing NOACs has tion and ended with the days of supply of the new prescription. been recommended in the 2018 European Heart Rhythm As- We defined the first NOACs treatment episode at cohort entry sociation guideline, especially in patients with a history of GI as the “incident episode” and the NOACs episode after exiting bleeding or ulcer and patients requiring concomitant use of the incident episode without hospitalization or emergency de- antiplatelet therapy.13 However, real-world data on the gastro- partment visit for bleeding as the “prevalent episode”. Thus, each protective effect in patients with NOACs, especially with con- cohort individual had only one incident episode and potentially comitant use of NSAIDs or SSRIs, is limited. several prevalent episodes. Accordingly, this study’s objective was to evaluate the risk of bleeding events in individuals taking concomitant NSAIDs or Definition of cases and controls SSRIs with NOACs after being diagnosed with AF and to iden- Cases were defined as patients that underwent hospitalization tify the risk of bleeding events. The second goal was to assess the or emergency department visit for major bleeding events. The risk of upper GI bleeding after the use of NSAIDs or SSRIs com- major bleeding events were categorized as upper GI bleeding, bined with PPIs. Finally, we performed subgroup analyses to lower GI bleeding, intracranial bleeding, and other bleedings, determine high-bleeding risk groups. including urinary tract bleeding, airway bleeding, and others, based on previous reports in the literature (Supplementary Ta- ble 1, only online).4,6,14 For each case, up to 20 controls at risk of MATERIALS AND METHODS the bleeding event were randomly selected by age (±5 years), sex, episode status, and duration from diagnosis of AF to the pre- Data source scription of NOACs (±1 year) using risk-set sampling. In the risk- This study used National Health Information Database (NHIS- set sampling, patients could serve as controls for multiple cas- 2019-1-402) made by National Health Insurance Service (NHIS), es, and patients were eligible to be selected as controls before a single-payer organization that is mandatory for all residents becoming a case. For each control, an index date was assigned in Korea. For this reason, the NHIS obtains information on pa- to have the same length of follow-up as that for a correspond- tient demographics, insurers’ payment coverage, medical use/ ing case. This approach resembles Cox regression with time- transactions, diagnoses, claims of procedures, and inpatient/ varying covariates and is reported to produce comparable and outpatient prescriptions. All diagnoses are coded according to unbiased estimates of hazard ratios compared by Cox regres- the international classification of disease, 10th revision, clinical sion on the full cohort, with superior computational efficiency modification (ICD-10 CM) established by the World Health Or- when studying time-dependent exposure, such as drug-drug ganization.