Bleeding Incidence With Concomitant Use of Antidepressants and Warfarin

Abstract

Introduction Bleeding is the major complication associated with warfarin therapy. Some antidepressants are also associated with increased bleeding risk. Warfarin and antidepressants are used frequently in combination, but it is unclear whether concomitant use increases the risk of bleeding beyond that with warfarin alone. The primary goal of this study was to determine whether use of warfarin and an antidepressant increases the risk for bleeding outcomes compared to warfarin use alone. The secondary goal was to characterize the risk of bleeding in warfarin-treated patients taking one specific class of antidepressant, selective serotonin reuptake inhibitors (SSRIs). Materials and Methods This was a retrospective, single-center, study of warfarin-treated patients prescribed (n=46) and not prescribed (n=54) an antidepressant. Medical records over six months were reviewed for INR values, medical history, bleeding type and incidence, and hospitalization due to bleeding. Patients were included in the antidepressant group if taking concomitant warfarin and antidepressant therapy consistently for a period of 6 months and in the control group if not taking an antidepressant with warfarin. Results Use of any antidepressant with warfarin was not associated with the incidence of any bleeding or major bleeding during the 6-month period. However, use of an SSRI with warfarin was associated with an increase in any bleeding event (OR 2.6, 95% CI, 1.01–6.4 p=0.04). Use of a SSRI remained a significant predictor of bleeding after accounting for other factors associated with bleeding risk. Conclusion This data suggest it is important to clarify the interaction between warfarin and SSRIs in regard to bleeding risk given the high frequency of their concomitant use.

Management of Depression After Myocardial Infarction

“…In another study, warfarin users taking fluoxetine, citalopram, paroxetine, amitriptyline, and mirtazapine all had increased likelihood (odds ratios 1.63-1.75) of gastrointestinal bleeding [53]. Serotonin reuptake inhibitors increase the risk of bleeding in patients taking warfarin more than do other antidepressants [54]. In patients taking warfarin for atrial fibrillation, the risk of bleeding events was increased about twofold in patients also taking serotonin reuptake inhibitors, with a number-needed-to-harm of 36 treatment-years per extra event [55], although addition of serotonin reuptake inhibitors to warfarin did not change the INR or warfarin dosing.…”

Lack of effect of multiple doses of vortioxetine on the pharmacokinetics and pharmacodynamics of aspirin and warfarin

“…[1][2][3][4] The bleeding risk increases further when SSRIs/SNRIs are used concomitantly with NSAIDs, anticoagulants, and antiplatelet agents. 1,[5][6][7][8] Potential mechanisms that underlie the bleeding risk associated with medications that affect the serotonergic system may include inhibition of serotonin uptake by platelets, SRI-induced increases in gastric acid secretion, and modulation of the CYP450 metabolism. 9,10,26 Certain SSRIs and SNRIs with high protein binding (eg, fluoxetine, duloxetine), when coadministered with another highly bound drug (eg, warfarin), may also increase the free plasma drug concentrations via displacement of proteinbound drug, potentially increasing the risk of adverse events.…”

“…The study also evaluated the effects of vortioxetine coadministration on the pharmacokinetics of aspirin and vice versa. In period 1, 28 subjects were randomized to 1 of the 2 sequences in which vortioxetine 10 mg or matching placebo was administered once daily in the morning for 14 days (days [1][2][3][4][5][6][7][8][9][10][11][12][13][14], followed by coadministration with aspirin 150 mg once daily for 6 days (days [15][16][17][18][19][20]. Following a 21-day washout, in period 2, subjects received the alternative treatment.…”

“…[1][2][3][4] This bleeding risk increases further with concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs), anticoagulants, and antiplatelet agents. 1,[5][6][7][8] This effect is thought to be related to platelet serotonin depletion. …”

“…25 SSRIs and SNRIs are reported to potentially increase the risk of bleeding events, and concomitant use of aspirin, NSAIDs, warfarin, and other anticoagulants with these drugs may potentiate this risk. [1][2][3][4][5][6][7][8] The objectives of the current studies were to evaluate the effects of multiple vortioxetine doses on the pharmacokinetics and pharmacodynamics of aspirin/salicylic acid and the (R)-and (S)-warfarin enantiomers.…”