Download PDF
CC BY 4.0 · Thromb Haemost 2023; 123(02): 245-254
DOI: 10.1055/a-1957-6305
Stroke, Systemic or Venous Thromboembolism

Selective Serotonin Reuptake Inhibitor Use and Risk of Major Bleeding during Treatment with Vitamin K Antagonists: Results of A Cohort Study

Sanne Bakker‡   *
1   Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands
,
Johanna Louise I. Burggraaf  ‡   *
2   Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
,
Marieke J. H. A. Kruip
3   Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands
4   Star-shl Thrombosis Service, Rotterdam, The Netherlands
,
Felix J. M. van der Meer
5   Department of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, The Netherlands
,
Willem M. Lijfering
2   Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
,
Nienke van Rein
1   Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands
2   Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
› Author Affiliations Funding/Acknowledgments This study was performed by S.B. within the master's degree program in Pharmacy of Leiden University. J.L.I.B. is funded by a ZonMw grant (848017007). This study was not funded.
› Further Information
Also available at
   Permissions and Reprints


Abstract

Background Selective serotonin reuptake inhibitors (SSRIs) may increase the risk of major bleeding by decreasing platelet function or decreasing vitamin K antagonist (VKA) metabolism via cytochrome P450 (CYP) inhibition.

Aims To determine whether SSRIs are associated with major bleeding during VKA treatment and investigate the possible mechanisms.

Methods In this cohort study, information on SSRI use and bleeding complications was obtained from patient records of VKA initiators between 2006 and 2018 from two anticoagulation clinics. Conditional logistic regression and time-dependent Cox regression were used to estimate the effect of SSRIs on a high international normalized ratio (INR ≥ 5) within 2 months after SSRI initiation and on major bleeding during the entire period of SSRI use, respectively. SSRI use was stratified for (non-)CYP2C9 inhibitors.

Results A total of 58,918 patients were included, of whom 1,504 were SSRI users. SSRI initiation versus nonuse was associated with a 2.41-fold (95% confidence interval [CI]: 2.01–2.89) increased risk for a high INR, which was 3.14-fold (95% CI: 1.33–7.43) among CYP2C9-inhibiting SSRI users. The adjusted hazard ratio of major bleeding was 1.22 (95% CI: 0.99–1.50) in all SSRI users and 1.31 (95% CI: 0.62–2.72) in CYP2C9-inhibiting SSRI users compared with nonusers.

Conclusion SSRI use is associated with an increased risk of high INR and might be associated with major bleeding. The risk of a high INR was slightly more elevated for CYP2C9-inhibiting SSRI users, suggesting there might be a pharmacokinetic interaction (by CYP2C9 inhibition) next to a pharmacodynamic effect of SSRIs on platelet activation.

Keywords

SSRI - serotonin reuptake inhibitors - cohort study - drug interactions - hemorrhages - coumarins

Author Contributions

S.B. and J.L.I.B. contributed equally to this article. N.vR., S.B., J.L.I.B., and W.M.L. designed the research. M.J.H.A.K. and F.J.M.vdM. provided data from the anticoagulation clinics. S.B., J.L.I.B., and N.vR. analyzed the data. S.B. and J.L.I.B. wrote the first manuscript draft. J.L.I.B. and N.vR. revised the manuscript. All authors gave final approval of the version to be published.


Data Availability Statement

The deidentified data that support the findings of this study are available from the corresponding author upon reasonable request.


* These authors contributed equally to the manuscript.


Supplementary Material



Publication History

Received: 01 June 2022

Accepted: 29 September 2022

Accepted Manuscript online:
08 October 2022

Article published online:
30 December 2022

© 2022. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133 (6, Suppl): 160S-198S
    CrossrefPubMedGoogle Scholar
  • 2 Schulman S, Beyth RJ, Kearon C, Levine MN. Hemorrhagic complications of anticoagulant and thrombolytic treatment: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133 (6, Suppl): 257S-298S
    CrossrefPubMedGoogle Scholar
  • 3 Smith DJ, Court H, McLean G. et al. Depression and multimorbidity: a cross-sectional study of 1,751,841 patients in primary care. J Clin Psychiatry 2014; 75 (11) 1202-1208 , quiz 1208
    CrossrefPubMedGoogle Scholar
  • 4 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
    CrossrefPubMedGoogle Scholar
  • 5 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
    CrossrefPubMedGoogle Scholar
  • 6 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
    CrossrefPubMedGoogle Scholar
  • 7 Dong YH, Bykov K, Choudhry NK. et al. Clinical outcomes of concomitant use of warfarin and selective serotonin reuptake inhibitors: a multidatabase observational cohort study. J Clin Psychopharmacol 2017; 37 (02) 200-209
    CrossrefPubMedGoogle Scholar
  • 8 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
    CrossrefPubMedGoogle Scholar
  • 9 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
    CrossrefPubMedGoogle Scholar
  • 10 Hemeryck A, De Vriendt C, Belpaire FM. Inhibition of CYP2C9 by selective serotonin reuptake inhibitors: in vitro studies with tolbutamide and (S)-warfarin using human liver microsomes. Eur J Clin Pharmacol 1999; 54 (12) 947-951
    CrossrefPubMedGoogle Scholar
  • 11 Schmider J, Greenblatt DJ, von Moltke LL, Karsov D, Shader RI. Inhibition of CYP2C9 by selective serotonin reuptake inhibitors in vitro: studies of phenytoin p-hydroxylation. Br J Clin Pharmacol 1997; 44 (05) 495-498
    CrossrefPubMedGoogle Scholar
  • 12 Teichert M, Visser LE, Uitterlinden AG. et al. Selective serotonin re-uptake inhibiting antidepressants and the risk of overanticoagulation during acenocoumarol maintenance treatment. Br J Clin Pharmacol 2011; 72 (05) 798-805
    CrossrefPubMedGoogle Scholar
  • 13 Ufer M. Comparative pharmacokinetics of vitamin K antagonists: warfarin, phenprocoumon and acenocoumarol. Clin Pharmacokinet 2005; 44 (12) 1227-1246
    CrossrefPubMedGoogle Scholar
  • 14 van der Meer FJ, Rosendaal FR, Vandenbroucke JP, Briët E. Bleeding complications in oral anticoagulant therapy. An analysis of risk factors. Arch Intern Med 1993; 153 (13) 1557-1562
    CrossrefPubMedGoogle Scholar
  • 15 Burggraaf JLI, van Rein N, van der Meer FJM, Lijfering WM. Perioperative management in patients using vitamin K antagonists: observational cohort study. Thromb Haemost 2020; 120 (03) 495-504
    Article in Thieme ConnectPubMedGoogle Scholar
  • 16 van Rein N, Cannegieter SC, le Cessie S. et al. Statins and risk of bleeding: an analysis to evaluate possible bias due to prevalent users and healthy user aspects. Am J Epidemiol 2016; 183 (10) 930-936
    CrossrefPubMedGoogle Scholar
  • 17 van Rein N, Lijfering WM, Bos MH. et al. Objectives and design of BLEEDS: a cohort study to identify new risk factors and predictors for major bleeding during treatment with vitamin K antagonists. PLoS One 2016; 11 (12) e0164485
    CrossrefPubMedGoogle Scholar
  • 18 Lipsitch M, Tchetgen Tchetgen E, Cohen T. Negative controls: a tool for detecting confounding and bias in observational studies. Epidemiology 2010; 21 (03) 383-388
    CrossrefPubMedGoogle Scholar
  • 19 Tatsumi M, Jansen K, Blakely RD, Richelson E. Pharmacological profile of neuroleptics at human monoamine transporters. Eur J Pharmacol 1999; 368 (2–3): 277-283
    CrossrefPubMedGoogle Scholar
  • 20 Walker GA, Heidenreich PA, Phibbs CS. et al. Mental illness and warfarin use in atrial fibrillation. Am J Manag Care 2011; 17 (09) 617-624
    PubMedGoogle Scholar
  • 21 Maki ED, Miesner AR, Grady SE, Marschall LM. Effects of depressive and other psychiatric disorders on anticoagulation control in a pharmacist-managed anticoagulation clinic. Ann Pharmacother 2013; 47 (10) 1292-1300
    CrossrefPubMedGoogle Scholar
  • 22 Paradise HT, Berlowitz DR, Ozonoff A. et al. Outcomes of anticoagulation therapy in patients with mental health conditions. J Gen Intern Med 2014; 29 (06) 855-861
    CrossrefPubMedGoogle Scholar
  • 23 Fihn SD, Gadisseur AA, Pasterkamp E. et al. Comparison of control and stability of oral anticoagulant therapy using acenocoumarol versus phenprocoumon. Thromb Haemost 2003; 90 (02) 260-266
    PubMedGoogle Scholar
  • 24 Gadisseur AP, van der Meer FJ, Adriaansen HJ, Fihn SD, Rosendaal FR. Therapeutic quality control of oral anticoagulant therapy comparing the short-acting acenocoumarol and the long-acting phenprocoumon. Br J Haematol 2002; 117 (04) 940-946
    CrossrefPubMedGoogle Scholar
  • 25 Ufer M, Svensson JO, Krausz KW, Gelboin HV, Rane A, Tybring G. Identification of cytochromes P450 2C9 and 3A4 as the major catalysts of phenprocoumon hydroxylation in vitro. Eur J Clin Pharmacol 2004; 60 (03) 173-182
    CrossrefPubMedGoogle Scholar
  • 26 Thijssen HH, Flinois JP, Beaune PH. Cytochrome P4502C9 is the principal catalyst of racemic acenocoumarol hydroxylation reactions in human liver microsomes. Drug Metab Dispos 2000; 28 (11) 1284-1290
    PubMedGoogle Scholar
  • 27 Anglin R, Yuan Y, Moayyedi P, Tse F, Armstrong D, Leontiadis GI. 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 (06) 811-819
    CrossrefPubMedGoogle Scholar
  • 28 Jiang HY, Chen HZ, Hu XJ. et al. Use of selective serotonin reuptake inhibitors and risk of upper gastrointestinal bleeding: a systematic review and meta-analysis. Clin Gastroenterol Hepatol 2015; 13 (01) 42-50.e3
    CrossrefPubMedGoogle Scholar
  • 29 Green Jr FW, Kaplan MM, Curtis LE, Levine PH. Effect of acid and pepsin on blood coagulation and platelet aggregation. A possible contributor prolonged gastroduodenal mucosal hemorrhage. Gastroenterology 1978; 74 (01) 38-43
    CrossrefPubMedGoogle Scholar
  • 30 Abdel Salam OM. Fluoxetine and sertraline stimulate gastric acid secretion via a vagal pathway in anaesthetised rats. Pharmacol Res 2004; 50 (03) 309-316
    CrossrefPubMedGoogle Scholar
  • 31 van den Heuvel JM, Hövels AM, Büller HR, Mantel-Teeuwisse AK, de Boer A, Maitland-van der Zee AH. NOACs replace VKA as preferred oral anticoagulant among new patients: a drug utilization study in 560 pharmacies in The Netherlands. Thromb J 2018; 16 (01) 7
    CrossrefPubMedGoogle Scholar
  • 32 Foerster KI, Hermann S, Mikus G, Haefeli WE. Drug-drug interactions with direct oral anticoagulants. Clin Pharmacokinet 2020; 59 (08) 967-980
    CrossrefPubMedGoogle Scholar
  • 33 Spina E, Barbieri MA, Cicala G, Bruno A, de Leon J. Clinically relevant drug interactions between newer antidepressants and oral anticoagulants. Expert Opin Drug Metab Toxicol 2020; 16 (01) 31-44
    CrossrefPubMedGoogle Scholar
  • 34 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
    CrossrefPubMedGoogle Scholar