Selective Serotonin Reuptake Inhibitors and Bleeding Risk in Anticoagulated Patients With Atrial Fibrillation: An Analysis From the ROCKET AF Trial

Gene R Quinn, Anne S Hellkamp, Graeme J Hankey, Richard C Becker, Scott D Berkowitz, Günter Breithardt, Maurizio Fava, Keith A A Fox, Jonathan L Halperin, Kenneth W Mahaffey, Christopher C Nessel, Manesh R Patel, Jonathan P Piccini, Daniel E Singer, Gene R Quinn, Anne S Hellkamp, Graeme J Hankey, Richard C Becker, Scott D Berkowitz, Günter Breithardt, Maurizio Fava, Keith A A Fox, Jonathan L Halperin, Kenneth W Mahaffey, Christopher C Nessel, Manesh R Patel, Jonathan P Piccini, Daniel E Singer

Abstract

Background There is concern that selective serotonin reuptake inhibitors ( SSRI s) substantially increase bleeding risk in patients taking anticoagulants. Methods and Results We studied 737 patients taking SSRI s in the ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Embolism and Stroke Trial in Atrial Fibrillation) trial of rivaroxaban compared with warfarin for the prevention of stroke/systemic embolism in patients with atrial fibrillation. These patients were propensity score matched 1:1 to 737 patients not taking SSRI s. The primary outcome measure was major and nonmajor clinically relevant bleeding events, the principal safety outcome in ROCKET AF . Over a mean 1.6 years of follow-up, the rate of major/ nonmajor clinically relevant bleeding was 18.57 events/100 patient-years for SSRI users versus 16.84 events/100 patient-years for matched comparators, adjusted hazard ratio ( aHR ) of 1.16 (95% confidence interval [CI], 0.95-1.43). The aHR s were similar in patients taking rivaroxaban ( aHR 1.11 [95% CI, 0.82-1.51]) and those taking warfarin ( aHR 1.21 [95% CI, 0.91-1.60]). For the rarer outcome of major bleeding, the aHR for SSRI users versus those not taking SSRI s was 1.13 (95% CI, 0.62-2.06) for rivaroxaban; for warfarin, the aHR was higher, at 1.58 (95% CI , 0.96-2.60) but not statistically significantly elevated. Conclusions We found no significant increase in bleeding risk when SSRI s were combined with anticoagulant therapy, although there was a suggestion of increased bleeding risk with SSRI s added to warfarin. While physicians should be vigilant regarding bleeding risk, our results provide reassurance that SSRI s can be safely added to anticoagulants in patients with atrial fibrillation . Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique identifier: NCT 00403767.

Trial registration: ClinicalTrials.gov NCT00403767.

Keywords: anticoagulation; atrial fibrillation; bleeding risk; rivaroxaban; selective serotonin reuptake inhibitors.

References

    1. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials. Arch Intern Med. 1994;154:1449–1457.
    1. Ageno W, Gallus AS, Wittkowsky A, Crowther M, Hylek EM, Palareti G. Oral anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence‐Based Clinical Practice Guidelines. Chest. 2012;141:e44S–e88S.
    1. Pratt LA, Brody DJ, Gu Q. Antidepressant use in persons aged 12 and over: United States, 2005–2008. NCHS Data Brief. 2011;(76):1–8.
    1. Chemali Z, Chahine LM, Fricchione G. The use of selective serotonin reuptake inhibitors in elderly patients. Harv Rev Psychiatry. 2009;17:242–253.
    1. Qaseem A, Snow V, Denberg TD, Forciea MA, Owens DK; Clinical Efficacy Assessment Subcommittee of American College of Physicians . Using second‐generation antidepressants to treat depressive disorders: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2008;149:725–733.
    1. Go AS, Hylek EM, Phillips KA, Chang Y, Henault LE, Selby JV, Singer DE. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA. 2001;285:2370–2375.
    1. de Abajo FJ, Rodríguez LA, Montero D. Association between selective serotonin reuptake inhibitors and upper gastrointestinal bleeding: population based case‐control study. BMJ. 1999;319:1106–1109.
    1. Kharofa J, Sekar P, Haverbusch M, Moomaw C, Flaherty M, Kissela B, Broderick J, Woo D. Selective serotonin reuptake inhibitors and risk of hemorrhagic stroke. Stroke. 2007;38:3049–3051.
    1. de Abajo FJ, García‐Rodríguez LA. Risk of upper gastrointestinal tract bleeding associated with selective serotonin reuptake inhibitors and venlafaxine therapy: interaction with nonsteroidal anti‐inflammatory drugs and effect of acid‐suppressing agents. Arch Gen Psychiatry. 2008;65:795–803.
    1. Meijer WEE, Heerdink ER, Nolen WA, Herings RMC, Leufkens HGM, Egberts ACG. Association of risk of abnormal bleeding with degree of serotonin reuptake inhibition by antidepressants. Arch Intern Med. 2004;164:2367–2370.
    1. 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;28:345–367.
    1. Roose SP, Rutherford BR. Selective serotonin reuptake inhibitors and operative bleeding risk: a review of the literature. J Clin Psychopharmacol. 2016;36:704–709.
    1. Laporte S, Chapelle C, Caillet P, Beyens M‐N, Bellet F, Delavenne X, Mismetti P, Bertoletti L. Bleeding risk under selective serotonin reuptake inhibitor (SSRI) antidepressants: a meta‐analysis of observational studies. Pharmacol Res. 2017;118:19–32.
    1. Auerbach AD, Vittinghoff E, Maselli J, Pekow PS, Young JQ, Lindenauer PK. Perioperative use of selective serotonin reuptake inhibitors and risks for adverse outcomes of surgery. JAMA Intern Med. 2013;173:1075–1081.
    1. Mortensen JK, Larsson H, Johnsen SP, Andersen G. Post stroke use of selective serotonin reuptake inhibitors and clinical outcome among patients with ischemic stroke: a nationwide propensity score‐matched follow‐up study. Stroke. 2013;44:420–426.
    1. Andrade C, Sharma E. Serotonin reuptake inhibitors and risk of abnormal bleeding. Psychiatr Clin North Am. 2016;39:413–426.
    1. Lexapro Highlights of Prescribing Information. Available at: . Accessed July 3, 2017.
    1. Hergovich N, Aigner M, Eichler HG, Entlicher J, Drucker C, Jilma B. Paroxetine decreases platelet serotonin storage and platelet function in human beings. Clin Pharmacol Ther. 2000;68:435–442.
    1. Reikvam A‐G, Hustad S, Reikvam H, Apelseth TO, Nepstad I, Hervig TA. The effects of selective serotonin reuptake inhibitors on platelet function in whole blood and platelet concentrates. Platelets. 2012;23:299–308.
    1. Hallbäck I, Hägg S, Eriksson AC, Whiss PA. In vitro effects of serotonin and noradrenaline reuptake inhibitors on human platelet adhesion and coagulation. Pharmacol Rep. 2012;64:979–983.
    1. Bykov K, Schneeweiss S, Donneyong MM, Dong Y‐H, Choudhry NK, Gagne JJ. Impact of an interaction between clopidogrel and selective serotonin reuptake inhibitors. Am J Cardiol. 2017;119:651–657.
    1. Andrade C. Selective serotonin reuptake inhibitor drug interactions in patients receiving statins. J Clin Psychiatry. 2014;75:e95–e99.
    1. Dong Y‐H, Bykov K, Choudhry NK, Donneyong MM, Huybrechts KF, Levin R, Schneeweiss S, Gagne JJ. Clinical outcomes of concomitant use of warfarin and selective serotonin reuptake inhibitors: a multidatabase observational cohort study. J Clin Psychopharmacol. 2017;37:200–209.
    1. Renoux C, Vahey S, Dell'Aniello S, Boivin J‐F. Association of selective serotonin reuptake inhibitors with the risk for spontaneous intracranial hemorrhage. JAMA Neurol. 2017;74:173–180.
    1. 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:e21447.
    1. Quinn GR, Singer DE, Chang Y, Go AS, Borowsky LH, Udaltsova N, Fang MC. Effect of selective serotonin reuptake inhibitors on bleeding risk in patients with atrial fibrillation taking warfarin. Am J Cardiol. 2014;114:583–586.
    1. 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;168:180–185.
    1. Wallerstedt SM, Gleerup H, Sundström A, Stigendal L, Ny L. Risk of clinically relevant bleeding in warfarin‐treated patients–influence of SSRI treatment. Pharmacoepidemiol Drug Saf. 2009;18:412–416.
    1. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, Halperin JL, Hankey GJ, Piccini JP, Becker RC, Nessel CC, Paolini JF, Berkowitz SD, Fox KAA, Califf RM; ROCKET AF Investigators . Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883–891.
    1. ROCKET AF Study Investigators . Rivaroxaban‐once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation: rationale and design of the ROCKET AF study. Am Heart J. 2010;159 :340–347.e1.
    1. Rosenbaum P, Rubin D. Constructing a control group using multivariate matched sampling methods that incorporate the propensity score. Am Stat. 1985;39:33–38.
    1. Lee EW, Wei LJ, Amato DA, Leurgans S. Cox‐type regression analysis for large numbers of small groups of correlated failure time observations. Survival analysis: State of the art. 1992;211:237–247.
    1. Rosendaal FR, Cannegieter SC, van der Meer FJ, Briët E. A method to determine the optimal intensity of oral anticoagulant therapy. Thromb Haemost. 1993;69:236–239.
    1. Teichert M, Visser LE, Uitterlinden AG, Hofman A, Buhre PJ, Straus S, De Smet PAGM, Stricker BH. Selective serotonin re‐uptake inhibiting antidepressants and the risk of overanticoagulation during acenocoumarol maintenance treatment. Br J Clin Pharmacol. 2011;72:798–805.

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