Antithrombotic therapy for stroke prevention in patients with atrial fibrillation (AF) has dramatically shifted from warfarin, a vitamin K antagonist, to the direct oral anticoagulants (DOACs) such as dabigatran, apixaban, and rivaroxaban. In patients with contraindications to oral anticoagulation, left atrial appendage occlusion (LAAO) devices, such as the Watchman™ device, may be considered; however, temporary postimplantation antithrombotic therapy is still a recommended practice. We present a case of complex antithrombotic management, post LAAO device implantation, designed to avoid drug interactions with concomitant rifampin use and remained necessary secondary to subsequent device leak. This case highlights the challenges of antithrombotic therapy post LAAO device placement in a complex, but representative, patient.