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According to the ARISTOTLE trial, apixaban was superior to warfarin because it was associated with fewer strokes, systemic embolism, and bleeding. Hemopericardium was one of the major bleeding events reported in this trial. However, the percentage of patients that developed hemopericardium was not stated in the trial results. We present a case of hemopericardium in an 80-year-old man admitted for dyspnea, cough, and lower extremity edema. He was recently diagnosed with paroxysmal atrial fibrillation and started on apixaban for stroke prevention. Prior to admission, he was taking metoprolol succinate and amiodarone for atrial fibrillation. His symptoms resolved after undergoing successful pericardiocentesis. Although hemopericardium is a rare side effect associated with the use of non-vitamin K oral anticoagulants (NOACs), we suspect that a drug-drug interaction between apixaban and amiodarone (via the cytochrome p450 system and p-glycoprotein efflux pumps), the patient's advanced age, and borderline creatinine are possible risk factors.

Spontaneous spinal epidural hematoma (SSEH) is a rare clinical entity that can result in severe neurological deficit and warrants emergent neurosurgical evaluation and management. The exact etiology of this entity remains unknown, but certain risk factors exist, including the use of anticoagulant medications. There are few published reports of the association of SSEH with direct factor Xa inhibitors. We aimed to present 2 cases of SSEH in patients on chronic apixaban therapy. To the best of our knowledge, there is only 1 other report of SSEH in the setting of apixaban therapy. A comparison between the cases suggests the importance of rapid recognition and management of SSEH in order to achieve favorable neurological outcomes.

Apixaban is the only NOA the administration of which is associated with a reduction in the incidence of both stroke and major bleeding. Therefore, apixaban is the drug of choice in patients with non-valvular AF, including elderly patients, patients with a high risk of bleeding complications, as well as in patients with impaired renal function. In clinical practice, the efficacy and safety of apixaban are not inferior to those obtained in the ARISTOTLE trial. Apixaban is safe when used during cardioversion and catheter ablation. The results of pre-clinical studies provide implications for further investigation into the possibility of administration of apixaban in patients with «valvular» AF.

Background: Review of clinical data on andexanet alfa for the reversal of factor Xa (FXa) inhibitor associated anticoagulation. Data sources: In the present review, we identified articles via PubMed using the combined keywords andexanet alfa, apixaban, enoxaparin, edoxaban, and rivaroxaban. Additional online searches via PubMed, Google Scholar, and Lexicomp were conducted for both prescribing and cost information. Portola Pharmaceuticals was contacted for information used for United States Food and Drug Administration approval of andexanet alfa. Study selection and data extraction: English-language clinical trials and reviews published between January 2008 and April 2019 were included for review. Bibliographies of selected articles were reviewed manually for relevant publications, focusing on reversal strategies for apixaban, enoxaparin, edoxaban, or rivaroxaban associated anticoagulation using andexanet alfa. Review articles were excluded. Data synthesis: The safety and tolerability of andexanet alfa were evaluated in one phase I, two phase II, and one phase III clinical trials. The use of andexanet alfa for reversing FXa inhibitor-associated anticoagulation were evaluated in the phase III ANNEXA-4 study. Conclusions: Studies evaluating laboratory parameters for coagulation show that andexanet alfa rapidly neutralizes the anticoagulant effects of apixaban, enoxaparin, edoxaban, and rivaroxaban. Clinical studies show that andexanet alfa improves markers related to coagulation, and reverses major bleeding in healthy volunteers and patients with life-threatening bleeding. Interruption of anticoagulation may result in thromboembolic and ischemic events. The use of andexanet alfa requires close monitoring for signs and symptoms of thromboembolic events, ischemic events, and cardiac arrest. Furthermore, anticoagulation should be resumed following the administration of andexanet alfa as soon as medically appropriate.

Atraumatic adrenal hemorrhage is a rare injury, often due to the disruption of normal hemostasis secondary to sepsis, autoimmune disease, or chronic anticoagulation. We present a case of recurrent adrenal hemorrhage in a patient with antiphospholipid syndrome previously maintained on warfarin for deep vein thrombosis and pulmonary embolism prophylaxis who worsened shortly after transition to apixaban therapy. Initial left-sided adrenal hemorrhage occurred four weeks after beginning apixaban, followed by the development of retinal hemorrhage and later right-sided adrenal hemorrhage. This is, to date, the first reported case of adrenal hemorrhage in a patient receiving chronic anticoagulation with apixaban.

Charles Frost,1 Andrew Shenker,1 Stanford Jhee,2 Zhigang Yu,1 Jessie Wang,3 Alexander Bragat,1 Janice Pursley,4 Frank LaCreta1 1Exploratory Clinical and Translational Research, Bristol-Myers Squibb, Princeton, NJ, USA; 2PAREXEL International Early Phase, Glendale, CA, USA; 3Exploratory Development Global Biometric Sciences, Bristol-Myers Squibb, Princeton, NJ, USA; 4Analytical and Bioanalytical Development, Bristol Myers Squibb, Princeton, NJ, USA Purpose: This double-blind, placebo-controlled, intra-subject, dose-escalation study assessed single-dose safety, pharmacokinetics, and pharmacodynamics of apixaban in healthy Japanese and Caucasian subjects. Subjects and methods: Sixteen healthy male Japanese and sixteen healthy male Caucasian subjects, matched for age, weight, and smoking status were randomized to receive four sequential single oral doses of either apixaban (2.5, 10, 25, and 50mg) or matched placebo. Doses were separated by a ≥5-day washout. Blood samples were collected for the determination of apixaban plasma concentration, clotting times (international normalized ratio [INR], activated partial thromboplastin time, and modified prothrombin time [mPT]), and ex vivo thrombin generation (TG). Urine samples were collected for the analysis of apixaban concentration. Results: Ascending single doses of apixaban 2.5–50mg were safe and well tolerated by all subjects. Apixaban exposure increased the dose proportionally up to 10mg. Apixaban reached maximum concentrations (Cmax) 3–4h postdose, with mean Cmax ranging from 52.5–485.0 to 44.8–494.3ng/mL in Japanese and Caucasian subjects. The mean half-life was ~8 and ~13h and the renal clearance was 1.1 and 0.8L/h in Japanese and Caucasian subjects, respectively. Pharmacodynamic assessments were similar between ethnic groups, with comparable dose-related prolongation of INR and mPT and inhibition of TG. Conclusion: Ascending single doses of apixaban over a 20-fold dose range were safe and well tolerated in Japanese and Caucasian subjects in this study. The consistency between pharmacokinetic and pharmacodynamic measures in Japanese and Caucasian subjects indicates that apixaban may be administered as a fixed dose with no need for adjustment in Japanese patients. Keywords: safety, pharmacokinetics, pharmacodynamics, Japanese, apixaban, anticoagulation, Asian, novel, Eliquis