Clopidogrel IBS Patients Have Higher Incidence of Gastrointestinal Symptoms Influenced by Age and Gender

Background: Clopidogrel is an irreversible antagonist of P2Y₁₂ receptors (P2Y₁₂Rs) used as an antiplatelet drug to reduce risk of thrombosis. P2Y₁₂Rs are expressed in gastrointestinal (GI) tract where they might regulate GI function. Aim: To evaluate if blockade of P2Y₁₂Rs by clopidogrel is associated with higher incidence of GI symptoms in patients with irritable bowel syndrome (IBS). Methods: A retrospective analysis of our institutional database was conducted for a 13-year period. IBS patients were identified, and their demographics, GI symptoms and clopidogrel therapy were collected. Logistic regression models were used to characterize symptoms in clopidogrel versus no-clopidogrel IBS-groups, adjusting for Age and Sex differences. An additional study characterized the P2Y₁₂R distribution in human gut. Results: The search identified 7217 IBS patients (6761 no-clopidogrel/456 clopidogrel). There were a higher proportion of patients with GI symptoms on clopidogrel (68%) compared to controls (60%, p = 0.0011) that were Females (70 vs. 60%, p = 0.0003) not Males (61 vs. 60%; p = 0.8312). In Females, clopidogrel was associated with higher incidence of GI symptoms (Age adjusted; p < 0.0001) for pain, constipation, gastroparesis (p ≤ 0.0001) and psychogenic pain (p = 0.0006). Age or Sex (adjusted models) influenced one or more GI symptoms (i.e., pain, p < 0.0001; constipation, p < 0.0001/p = 0.008; diarrhea, flatulence, p = 0.01). P2Y₁₂R immunoreactivity was abundant in human ENS; glial-to-neuron ratio of P2Y₁₂Rs expressed in Females ≫ Males. Conclusions: Irreversible blockade of P2Y₁₂R by clopidogrel is associated with higher incidence of GI symptoms in Female IBS patients, although Age or Sex alone contributes to symptomatology. Prospective studies can determine clinical implications of P2Y₁₂Rs in IBS.