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 significant adverse effects of injectable anticoagulants such as heparin and enoxaparin. This undesirable effect needs close monitoring of their use for clinically relevant drug-drug interactions. Objectives: To study the rate of hemorrhagic events, the anatomical site, and the severity of the bleeding in patients receiving heparin or enoxaparin in combination with clopidogrel, Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), and warfarin. Methods: We designed a prospective, multi-center, case-series study. Patients admitted to two teaching hospitals who received either an NSAID, or warfarin, or clopidogrel were evaluated. Any hemorrhagic event was recorded by Yellow Card Scheme. Also, the Naranjo scale was utilized for causality assessment.Results: A total of 123 patients were eligible for inclusion. They were admitted between November 2014 and April 2015. Sixty-five patients (52.5%) received heparin and 58 patients (47.2%) received enoxaparin. Of 123 patients, 115 patients (93.5%) received aspirin, 69 (56.1%) warfarin, 34 (27.6%) an antiplatelet medication, and 121 (98.4%) NSAIDs in combination with heparin or enoxaparin. Overall, 26 cases (21.1%) of the hemorrhagic incident were reported, of whom six cases (4.9%) were categorized as major bleeding. Patients receiving heparin constituted the largest proportion among all 26 hemorrhagic incidents (57.7%). All patients with the hemorrhagic incident had aspirin in their medication regimen, while 19 patients (73.0%) were concomitantly receiving warfarin as well. Hematuria (46.2%), hematoma in the injection site (38.5%), and hematoma (34.6%) were the top three types of hemorrhagic events. In Naranjo scale analysis, 19 patients scored more than 9 points, indicating a definite Adverse Drug Reaction (ADR) causality. Moreover, seven patients scored 5 to 8, affirming a possible association with ADR. Conclusion: The risk of hemorrhagic 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.