Choosing Wisely:

Don’t use two or more medications that are known to increase the risk of bleeding without evaluating the potential risks and benefits. These medications include direct oral anticoagulants, warfarin, aspirin, selective serotonin reuptake inhibitors (SSRIs), antiplatelet agents, NSAIDs, and corticosteroids.

Rationale and Comments: Prescribing more than one of these medications concurrently may result in an enhanced risk of bleeding. This heightened risk of bleeding may be mediated through complex pharmacokinetic and/or pharmacodynamic mechanisms. It is well established that the combination of anticoagulants and NSAIDs increase the risk of bleeding. A combination of warfarin with either single or dual antiplatelet therapy significantly increases the risk of major bleeding by two- to four-fold, respectively. The most commonly prescribed antidepressant therapeutic class (SSRIs), may decrease platelet serotonin uptake, leading to impaired platelet aggregation, and thereby increased risk of bleeding. Specific to gastrointestinal bleeding, SSRIs may also increase gastric acid secretion. Bleeding has been observed in association with other antidepressants in some observational studies; however, recent systematic reviews give weight to SSRIs in combination with NSAIDs for increased vigilance for risk of upper gastrointestinal bleeding. In patients where benefits outweigh the risks of the combination, appropriate education of patient and caregivers and appropriate follow-up monitoring for early detection of any signs and symptoms of bleeding is highly recommended.
Sponsoring Organizations:
  • American Society of Consultant Pharmacists
  • Sources:
  • Systematic reviews
  • Disciplines:
  • Gastroenterologic
  • References: • Juurlink DN. Antidepressants, antiplatelets and bleeding: one more thing to worry about? CMAJ. 2011;183(16):1819-1820.
    • Chang S-H, Chou I-J, 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(13):1250-1259.
    • Spina E, Barbieri MA, et al. Clinically relevant drug interactions between newer antidepressants and oral anticoagulants. Expert Opin Drug Metab Toxicol. 2020;16(1):31-44.
    • Vazquez SR. Drug-drug interactions in an era of multiple anticoagulants: a focus on clinically relevant drug interactions. Hematology Am Soc Hematol Educ Program. 2018;2018(1):339-347.
    • Liu L, Huang J, et al. Efficacy and safety of triple therapy versus dual antiplatelet therapy in patients with atrial fibrillation undergoing coronary stenting: a meta-analysis. PLoS ONE. 2018;13(6):e0199232.
    • Kumar S, Danik SB, et al. Non-vitamin K antagonist oral anticoagulants and antiplatelet therapy for stroke prevention in patients with atrial fibrillation: a meta-analysis of randomized controlled trials. Cardiol Rev. 2016;24(5):218-223.
    • Lin C-C, Hu H-Y, et al. Risk factors of gastrointestinal bleeding in clopidogrel users: a nationwide population-based study. Aliment Pharmacol Ther. 2013;38(9):1119-1128.
    • Labos C, Dasgupta K, et al. Risk of bleeding associated with combined use of selective serotonin reuptake inhibitors and antiplatelet therapy following acute myocardial infarction. CMA. 2011;183(16):1835-1843.
    • Hansen ML, Sørensen R, et al. Risk of bleeding with single, dual, or triple therapy with warfarin, aspirin, and clopidogrel in patients with atrial fibrillation. Arch Intern Med. 2010;170(16):1433-1441.
    • Anglin R, Yuan Y, et al. Risk of upper gastrointestinal bleeding with selective serotonin reuptake inhibitors with or without concurrent nonsteroidal anti-inflammatory use: a systematic review and meta-analysis. Am J Gastroenterol. 2014;109(6):811-819.

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