Subscribe to RSS
Concomitant Use of Selective Serotonin Reuptake Inhibitors and Oral Anticoagulants and Risk of Major Bleeding: A Systematic Review and Meta-analysisFunding There was no funding for this study.
Background Selective serotonin reuptake inhibitors (SSRIs), the most prescribed antidepressants, are associated with a modestly increased risk of major bleeding. However, in patients treated with both SSRIs and oral anticoagulants (OACs), the risk of major bleeding may be substantial.
Objective To assess the risk of major bleeding associated with concomitant use of SSRIs and OACs, compared with OAC use alone.
Methods We searched MEDLINE, Embase, PsycINFO, and the Cochrane Central Register of Controlled Trials (from inception to December 1, 2021) for clinical trials and observational studies assessing the association between concomitant use of SSRIs and OACs and the risk of major bleeding. Given sufficient homogeneity of studies, we conducted a random-effects meta-analysis to estimate a pooled hazard ratio (HR) of major bleeding associated with concomitant use of SSRIs and OACs, compared with OAC use alone.
Results The review comprised 14 studies, including 7 cohort and 7 nested case–control studies. Following assessment of clinical and methodological heterogeneity, eight studies with a total of 98,070 patients were eligible for the meta-analysis. The pooled HR of major bleeding associated with concomitant use of SSRIs and OACs was 1.35 (95% confidence interval [CI]: 1.14–1.58). In secondary analyses, the pooled HR for concomitant use of SSRIs and direct OACs was 1.47 (95% CI: 1.03–2.10).
Conclusion Concomitant use of SSRIs and OACs was associated with an increased risk of major bleeding. Overall, our findings suggest that physicians may need to tailor treatment according to individual patient risk factors for bleeding when prescribing SSRIs to patients using OACs.
A.A.R. and C.R. conceived the study. A.A.R., C.R., and R.W.P. developed the design and methodology of the study. A.A.R., N.H., and C.R. were involved in the acquisition, analysis, or interpretation of data. A.A.R. and C.R. drafted the manuscript, and all authors critically revised the manuscript.
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
Received: 13 May 2022
Accepted: 23 August 2022
Accepted Manuscript online:
29 August 2022
Article published online:
28 October 2022
© 2022. Thieme. All rights reserved.
Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany
- 1 Canadian Institute for Health Information. Drug Use Among Seniors in Canada, 2016. ON, Ottawa: CIHI; 2018
- 2 de Abajo FJ. Effects of selective serotonin reuptake inhibitors on platelet function: mechanisms, clinical outcomes and implications for use in elderly patients. Drugs Aging 2011; 28 (05) 345-367
- 3 Peretti S, Judge R, Hindmarch I. Safety and tolerability considerations: tricyclic antidepressants vs. selective serotonin reuptake inhibitors. Acta Psychiatr Scand Suppl 2000; 403: 17-25
- 4 Anderson IM. Selective serotonin reuptake inhibitors versus tricyclic antidepressants: a meta-analysis of efficacy and tolerability. J Affect Disord 2000; 58 (01) 19-36
- 5 de Abajo FJ, Rodríguez LA, Montero D. Association between selective serotonin reuptake inhibitors and upper gastrointestinal bleeding: population based case-control study. BMJ 1999; 319 (7217): 1106-1109
- 6 van Walraven C, Mamdani MM, Wells PS, Williams JI. Inhibition of serotonin reuptake by antidepressants and upper gastrointestinal bleeding in elderly patients: retrospective cohort study. BMJ 2001; 323 (7314): 655-658
- 7 Dalton SO, Johansen C, Mellemkjaer L, Nørgård B, Sørensen HT, Olsen JH. Use of selective serotonin reuptake inhibitors and risk of upper gastrointestinal tract bleeding: a population-based cohort study. Arch Intern Med 2003; 163 (01) 59-64
- 8 Barbui C, Andretta M, De Vitis G. et al. Antidepressant drug prescription and risk of abnormal bleeding: a case-control study. J Clin Psychopharmacol 2009; 29 (01) 33-38
- 9 Renoux C, Vahey S, Dell'Aniello S, Boivin JF. Association of selective serotonin reuptake inhibitors with the risk for spontaneous intracranial hemorrhage. JAMA Neurol 2017; 74 (02) 173-180
- 10 Hackam DG, Mrkobrada M. Selective serotonin reuptake inhibitors and brain hemorrhage: a meta-analysis. Neurology 2012; 79 (18) 1862-1865
- 11 Movig KLL, Janssen MWHE, de Waal Malefijt J, Kabel PJ, Leufkens HGM, Egberts ACG. Relationship of serotonergic antidepressants and need for blood transfusion in orthopedic surgical patients. Arch Intern Med 2003; 163 (19) 2354-2358
- 12 Salkeld E, Ferris LE, Juurlink DN. The risk of postpartum hemorrhage with selective serotonin reuptake inhibitors and other antidepressants. J Clin Psychopharmacol 2008; 28 (02) 230-234
- 13 Andrade C, Sandarsh S, Chethan KB, Nagesh KS. Serotonin reuptake inhibitor antidepressants and abnormal bleeding: a review for clinicians and a reconsideration of mechanisms. J Clin Psychiatry 2010; 71 (12) 1565-1575
- 14 Laporte S, Chapelle C, Caillet P. et al. Bleeding risk under selective serotonin reuptake inhibitor (SSRI) antidepressants: a meta-analysis of observational studies. Pharmacol Res 2017; 118: 19-32
- 15 Douros A, Ades M, Renoux C. Risk of intracranial hemorrhage associated with the use of antidepressants inhibiting serotonin reuptake: a systematic review. CNS Drugs 2018; 32 (04) 321-334
- 16 Comoretto RI, Rea F, Lucenteforte E. et al; Italian Group for Appropriate Drug prescription in the Elderly (I-GrADE). Bleeding events attributable to concurrent use of warfarin and other medications in high-risk elderly: meta-analysis and Italian population-based investigation. Eur J Clin Pharmacol 2018; 74 (08) 1061-1070
- 17 Shamseer L, Moher D, Clarke M. et al; PRISMA-P Group. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ 2015; 350: g7647
- 18 Moher D, Liberati A, Tetzlaff J, Altman DG. PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ 2009; 339: b2535
- 19 EndNote X9 [computer program]. Niles Software; 2018
- 20 Sterne JA, Hernán MA, Reeves BC. et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ 2016; 355: i4919
- 21 Stroup DF, Berlin JA, Morton SC. et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA 2000; 283 (15) 2008-2012
- 22 IntHout J, Ioannidis JP, Borm GF. The Hartung-Knapp-Sidik-Jonkman method for random effects meta-analysis is straightforward and considerably outperforms the standard DerSimonian-Laird method. BMC Med Res Methodol 2014; 14: 25
- 23 Essebag V, Platt RW, Abrahamowicz M, Pilote L. Comparison of nested case-control and survival analysis methodologies for analysis of time-dependent exposure. BMC Med Res Methodol 2005; 5 (01) 5
- 24 Langan D, Higgins JPT, Jackson D. et al. A comparison of heterogeneity variance estimators in simulated random-effects meta-analyses. Res Synth Methods 2019; 10 (01) 83-98
- 25 Veroniki AA, Jackson D, Bender R. et al. Methods to calculate uncertainty in the estimated overall effect size from a random-effects meta-analysis. Res Synth Methods 2019; 10 (01) 23-43
- 26 Sidik K, Jonkman JN. A comparison of heterogeneity variance estimators in combining results of studies. Stat Med 2007; 26 (09) 1964-1981
- 27 Viechtbauer W, Cheung MW. Outlier and influence diagnostics for meta-analysis. Res Synth Methods 2010; 1 (02) 112-125
- 28 Cochran KA, Cavallari LH, Shapiro NL, Bishop JR. Bleeding incidence with concomitant use of antidepressants and warfarin. Ther Drug Monit 2011; 33 (04) 433-438
- 29 Hauta-Aho M, Tirkkonen T, Vahlberg T, Laine K. The effect of drug interactions on bleeding risk associated with warfarin therapy in hospitalized patients. Ann Med 2009; 41 (08) 619-628
- 30 Jobski K, Hoffmann F, Herget-Rosenthal S, Dörks M. Drug interactions with oral anticoagulants in German nursing home residents: comparison between vitamin K antagonists and non-vitamin K antagonist oral anticoagulants based on two nested case-control studies. Clin Res Cardiol 2020; 109 (04) 465-475
- 31 Komen JJ, Hjemdahl P, Mantel-Teeuwisse AK, Klungel OH, Wettermark B, Forslund T. Concomitant anticoagulant and antidepressant therapy in atrial fibrillation patients and risk of stroke and bleeding. Clin Pharmacol Ther 2020; 107 (01) 287-294
- 32 Kurdyak PA, Juurlink DN, Kopp A, Herrmann N, Mamdani MM. Antidepressants, warfarin, and the risk of hemorrhage. J Clin Psychopharmacol 2005; 25 (06) 561-564
- 33 Lee MT, Park KY, Kim MS, You SH, Kang YJ, Jung SY. Concomitant use of NSAIDs or SSRIs with NOACs requires monitoring for bleeding. Yonsei Med J 2020; 61 (09) 741-749
- 34 Quinn GR, Singer DE, Chang Y. et al. Effect of selective serotonin reuptake inhibitors on bleeding risk in patients with atrial fibrillation taking warfarin. Am J Cardiol 2014; 114 (04) 583-586
- 35 Quinn GR, Hellkamp AS, Hankey GJ. et al. Selective serotonin reuptake inhibitors and bleeding risk in anticoagulated patients with atrial fibrillation: an analysis from the ROCKET AF trial. J Am Heart Assoc 2018; 7 (15) e008755
- 36 Sajan F, Conte JV, Tamargo RJ, Riley LH, Rock P, Faraday N. Association of selective serotonin reuptake inhibitors with transfusion in surgical patients. Anesth Analg 2016; 123 (01) 21-28
- 37 Schalekamp T, Klungel OH, Souverein PC, de Boer A. Increased bleeding risk with concurrent use of selective serotonin reuptake inhibitors and coumarins. Arch Intern Med 2008; 168 (02) 180-185
- 38 Scheitz JF, Turc G, Kujala L. et al; TRISP Collaboration. Intracerebral hemorrhage and outcome after thrombolysis in stroke patients using selective serotonin-reuptake inhibitors. Stroke 2017; 48 (12) 3239-3244
- 39 Schelleman H, Brensinger CM, Bilker WB, Hennessy S. Antidepressant-warfarin interaction and associated gastrointestinal bleeding risk in a case-control study. PLoS One 2011; 6 (06) e21447
- 40 Zhang Y, Souverein PC, Gardarsdottir H, van den Ham HA, Maitland-van der Zee AH, de Boer A. Risk of major bleeding among users of direct oral anticoagulants combined with interacting drugs: a population-based nested case-control study. Br J Clin Pharmacol 2020; 86 (06) 1150-1164
- 41 Kennedy SH, Lam RW, McIntyre RS. et al; CANMAT Depression Work Group. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: section 3. pharmacological treatments. Can J Psychiatry 2016; 61 (09) 540-560
- 42 Gelenberg AJ, Freeman MP, Markowitz JC. et al. Practice guideline for the treatment of patients with major depressive disorder. 2010 . Available at: https://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/mdd.pdf
- 43 Andrade JG, Aguilar M, Atzema C. et al; Members of the Secondary Panel. The 2020 Canadian Cardiovascular Society/Canadian Heart Rhythm Society comprehensive guidelines for the management of atrial fibrillation. Can J Cardiol 2020; 36 (12) 1847-1948
- 44 Hindricks G, Potpara T, Dagres N. et al; ESC Scientific Document Group. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): the Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J 2021; 42 (05) 373-498
- 45 January CT, Wann LS, Calkins H. et al. 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration With the Society of Thoracic Surgeons. Circulation 2019; 140 (02) e125-e151
- 46 Baumgartner C, Fan D, Fang MC. et al. Anxiety, depression, and adverse clinical outcomes in patients with atrial fibrillation starting warfarin: cardiovascular research network WAVE study. J Am Heart Assoc 2018; 7 (08) e007814
- 47 Ray WA, Chung CP, Murray KT. et al. Association of oral anticoagulants and proton pump inhibitor cotherapy with hospitalization for upper gastrointestinal tract bleeding. JAMA 2018; 320 (21) 2221-2230
- 48 Ray WA. Evaluating medication effects outside of clinical trials: new-user designs. Am J Epidemiol 2003; 158 (09) 915-920