Dabigatran Etexilate and Sertraline: Interaction Details

a) According to a retrospective cohort study (n=234), there was an increased risk of clinically relevant bleeding (hospital admission due to bleeding) in patients receiving warfarin for atrial fibrillation during concomitant SSRI therapy or within 2 weeks following SSRI therapy termination. Patients with a mean age of 72 +/- 7 years receiving warfarin plus SSRI (n=117) were matched with randomly selected patients who received warfarin only (n=117). SSRI included FLUoxetine, citalopram, PARoxetine, sertraline, fluvoxaMINE, or escitalopram. Nine patients experienced 11 bleeding episodes during 213.9 treatment years in the warfarin plus SSRI group, and 10 patients experienced 14 bleedings during 586.4 treatment years in the warfarin-only group. The corresponding total incidences of bleedings were 51.4 and 23.9 per 1000 treatment years, respectively. The hazard ratio for first bleedings during treatment with warfarin plus SSRI was 3.49 (95% CI; 1.37 to 8.91, p=0.009) compared with warfarin only. The SSRI implicated in patients experiencing bleeding at the time of concomitant administration were sertraline or citalopram. The addition of an SSRI was not associated with a change in warfarin dose or INR (p=0.48 and p=0.31 respectively). The results of the study may be limited by earlier bleeding events, unknown patient adherence, and exclusion of clopidogrel, dipyridamol, corticosteroids and anticoagulants other than warfarin in the model ³.

b) A population-based, case-controlled study of new coumarin users (acenocoumarol and phenprocoumon) with concomitant selective serotonin reuptake inhibitors (SSRIs) resulted in an increased risk of hospitalization due to non-gastrointestinal bleeding. Using national pharmacy and hospitalization records in the Netherlands, researchers identified 1848 cases that were admitted for abnormal bleeding and compared them with 5818 control subjects who were also taking a coumarin. Median duration of treatment in patients was 220 days (range, 1 to 4690 days). Patients on SSRIs showed greater risk for hospitalization for non-gastrointestinal bleeding (adjusted odds ratio (OR) 1.7, 95% confidence interval (CI), 1.1 to 2.5); however, the rate of gastrointestinal bleeding (adjusted OR 0.8, 95% CI, 0.4 to 1.5) was not significantly different ¹.

c) In a non-blinded, randomized, placebo-controlled trial involving 12 healthy volunteers, the effect of sertraline on the plasma protein binding of warfarin was assessed. On days and 32 of the study, all participants received warfarin 0.75 mg/kg. Beginning on day 11, each volunteer was randomized to either the sertraline or placebo group; the sertraline was gradually increased from 50 mg/day to 200 mg/day. Prothrombin time was measured prior to each dose of warfarin and periodically thereafter. The researchers concluded that the anticoagulant effects of warfarin were not enhanced by sertraline to a clinically significant degree, despite the fact that sertraline was given in a higher-than-usual dose ⁴.

d) Case reports and epidemiological studies (case-control and cohort studies) have demonstrated an association between the use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Based on data from published observational studies, exposure to SSRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage. Bleeding events related to SSRIs and SNRIs have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages ².