Hemorrhagic events in patients receiving heparin or enoxaparin in combination with Oral antithrombotics, NSAIDs, and antiplatelet medications: A multi-center case-series study

Background: Hemorrhagic events are amongst the major adverse effects of injectable anticoagulants such as heparin and enoxaparin. This necessitates close monitoring of their use for clinically relevant drug-drug interactions. Aim: To study the rate of hemorrhagic events, the anatomical site, and the severity of the hemorrhage in patients receiving heparin or enoxaparin in combination with clopidogrel, non-steroidal anti-inflammatory drugs (NSAIDs), and warfarin.  Methods: A prospective, multi-center, case-series study was designed. Patients admitted to two teaching hospitals who received either an NSAID, and/ or warfarin, and/or clopidogrel were evaluated. Yellow Card Scheme was applied to record any hemorrhagic events. Naranjo scale was utilized for causality assessment.  Results: 123 patients were eligible for inclusion between November 2014 and April 2015. Sixty-five patients (52.5%) received heparin and 58 patients (47.2%) received enoxaparin. Of 123 patients 115 (93.5%) patients received aspirin, 69 (56.1%) patients received warfarin, 34 (27.6%) patients received an antiplatelet medication, and 121 (98.4%) patients received NSAIDS in combination with heparin or enoxaparin. Overall, 26 (21.1%) cases of hemorrhagic incident were reported of which six (4.9%) cases were categorized as major bleeding. Patients receiving heparin constituted the largest proportion among all 26 haemorrhagic incidents (57.7%). All patients with hemorrhagic incident had aspirin in their medication regimen while 19 (73.0%) patients were concomitantly receiving warfarin as well. Hematuria (46.2%), hematoma in injection site (38.5%) and hematoma (34.6%) were the top three types of the hemorrhagic events. In Naranjo scale analysis, 19 patients scored more than 9 points, indicating a definite ADR causality. Moreover, seven patients scored 5 to 8 affirming a probable association with ADR.  Conclusions: The risk of hemorrhagic events can be influenced by undesirable drug-drug interactions. Close monitoring of high-risk patients is advised to prevent adverse hemorrhagic reactions. Further studies to detect the explanatory factors associated with the hemorrhagic events are recommended.