Updating the Evidence of the Interaction Between Clopidogrel and CYP2C19-Inhibiting Selective Serotonin Reuptake Inhibitors: A Cohort Study and Meta-Analysis

We previously found that patients who initiate clopidogrel while treated with a cytochrome P450 (CYP) 2C19-inhibiting selective serotonin reuptake inhibitor (SSRI) have a higher risk of subsequent ischemic events than patients treated with other SSRIs. It is not known whether initiating an inhibiting SSRI while treated with clopidogrel will also increase risk of ischemic events. The aim of this study was to assess clinical outcomes following initiation of a CYP2C19-inhibiting SSRI versus initiation of other SSRIs among patients treated with clopidogrel and to update existing evidence on the clinical impact of clopidogrel-SSRI interaction. Using five US databases (1998-2013), we conducted a cohort study of clopidogrel initiators who encountered treatment with SSRI during their clopidogrel therapy. Patients were matched by propensity score (PS) and followed for as long as they were exposed to both clopidogrel and index SSRI group. Outcomes were a composite ischemic event (myocardial infarction, ischemic stroke, or a revascularization procedure, whichever came first) and a composite major bleeding event (gastrointestinal bleed or hemorrhagic stroke, whichever came first). Results were combined via random-effects meta-analysis with previous evidence from subjects initiating clopidogrel while on SSRI therapy. The PS-matched cohort comprised 2346 clopidogrel users starting CYP2C19-inhibiting SSRI therapy and 16,115 starting other SSRIs (mean age 61 years; 59% female). Compared with those treated with a non-inhibiting SSRI, the hazard ratio (HR) for patients treated with a CYP2C19-inhibiting SSRI was 1.07 (95% confidence interval [CI] 0.82-1.40) for the ischemic outcome and 1.00 (95% CI 0.42-2.36) for bleeding. The pooled estimates were 1.11 (95% CI 1.01-1.22) for ischemic events and 0.80 (95% CI 0.55-1.18) for bleeding. We observed similar estimates of association between the two studies. The updated evidence still indicates a small decrease in clopidogrel effectiveness associated with concomitant exposure to clopidogrel and CYP2C19-inhibiting SSRIs.