Anti-Xa activity in apixaban overdose: a case report.

Barton J ，Wong A ，Graudins A 《-》

An Observational Study of the Factor Xa Inhibitors Rivaroxaban and Apixaban as Reported to Eight Poison Centers.

Rivaroxaban and apixaban are part of a new group of oral anticoagulants targeting factor Xa and approved by the Food and Drug Administration in 2011 and 2012. These oral anticoagulants are administered at fixed daily doses, without the need for laboratory-guided adjustments. There are limited data available on supratherapeutic doses or overdose of the oral Xa inhibitors. This study characterizes the clinical effect in patients exposed to rivaroxaban and apixaban. A retrospective study collected data from 8 regional poison centers covering 9 states. Cases were initially identified by a search of the poison centers' databases for case mentions involving a human exposure to Xarelto, rivaroxaban, Eliquis, or apixaban. Inclusion criteria included single-substance exposure. Exclusion criteria were animal exposure, polysubstance exposure, or information call. Data for the study were collected by individual chart review, including case narratives, and compiled into a single data set. There were 223 patients: 124 (56%) were female patients, mean age was 60 years, and 20 were children younger than 12 years (9%). One hundred ninety-eight patients ingested rivaroxaban (89%) and 25 ingested apixaban (11%). Dose was reported in 182 rivaroxaban patients, with a mean dose of 64.5 mg (range 15 to 1,200 mg), and in 21 apixaban patients, with a mean dose of 9.6 mg (range 2.5 to 20 mg). For rivaroxaban, prothrombin time was measured in 49 patients (25%) and elevated in 7; partial thromboplastin time, measured in 49 (25%) and elevated in 5; and international normalized ratio, measured in 61 (31%) and elevated in 13. For apixaban, prothrombin time was measured in 6 patients (24%) and elevated in none; partial thromboplastin time, measure in 6 (24%) and elevated in none; and international normalized ratio, measured in 5 patients (20%) and elevated in none. Bleeding was reported in 15 patients (7%): 11 rivaroxaban and 4 apixaban. The site of bleeding was gastrointestinal (8), oral (2), nose (1), bruising (1), urine (1), and subdural (1). The subdural bleeding occurred after fall and head injury. All cases with bleeding involved long-term ingestions. Coagulation test results were normal in most patients with bleeding: prothrombin time 5 of 6 (83%), partial thromboplastin time 5 of 6 (83%), and international normalized ratio 5 of 9 (55%). Blood products were used in 7 rivaroxaban patients (1 suicide) and 3 apixaban patients. No bleeding or altered coagulation test results occurred in children, which all involved a one-time ingestion. All 12 suicide attempts involved rivaroxaban: altered coagulation test results occurred for 5 patients (42%), no bleeding occurred in any suicide attempt patient, 1 patient was treated with fresh frozen plasma (international normalized ratio 12.47), and dose by patient history did not predict risk of altered coagulation or bleeding. Two rivaroxaban patients experienced elevation of hepatic transaminase levels greater than 1,000 U/L. Bleeding after Xa inhibitor ingestion as a single agent is uncommon. Prothrombin time, partial thromboplastin time, or international normalized ratio may be elevated in a minority of cases but appears unreliable to measure risk of bleeding. Massive acute ingestion in suicide attempt may result in significant anticoagulation. Single exploratory ingestion by children was not associated with toxicity.

Spiller HA ，Mowry JB ，Aleguas A Jr ，Griffith JR ，Goetz R ，Ryan ML ，Bangh S ，Klein-Schwartz W ，Schaeffer S ，Casavant MJ ... -  《-》

The X factor: Lack of bleeding after an acute apixaban overdose.

We present an acute apixaban overdose without reported coingestants; it is the first such case report associated with multiple serum drug levels to assist in determining overdose kinetics. A 62 year old female presented to an emergency department (ED) 2 hours after ingesting sixty 5 mg tablets (5mg/kg) of her spouse's apixaban medication. She denied coingestants, and did not take her prescribed medications that day. Her vital signs were normal and she denied symptoms. Chemistry and hematology labs were unremarkable. Plasma apixaban concentrations were 2765.6 ng/ml at 14 hours post ingestion with a non-linear half life. There was no utilization of blood products or factor replacement. There was never any bleeding, and her hemoglobin did not decrease. This case demonstrates that a single ingestion of apixaban can occur without any complications occurring.

Leikin SM ，Patel H ，Welker KL ，Leikin JB ... -  《-》

Self-poisoning with 60 tablets of Apixaban, a pharmacokinetics case report.

A 67-year-old man was admitted to the emergency department about 5 h after deliberate self-poisoning with 300 mg of Apixaban. The clinical examination did not show any organ dysfunctions or haemorrhagic signs, and the patient's life was not in danger. The first analysis, upon admission, showed a concentration of 2655 μg l-1 of Apixaban. The Cmax was observed 17 h after the intake (3654 μg l-1 ), about four times the classical Tmax value (median [range]: 4 h [2-4]). The Apixaban was then eliminated following a first order elimination with a calculated half-life of 10.8 h. The anti-Xa activity seems to be linearly related to concentration up to 4000 μg l-1 . This report suggests that the use of activated charcoal should be effective up to 17 h after a massive intake.

Franck B ，Dulaurent S ，El Balkhi S ，Monchaud C ，Picard N ，Couderc S ，Marquet P ，Saint-Marcoux F ，Woillard JB ... -  《-》

Influence of apixaban on antifactor Xa levels in a patient with acute kidney injury.

The case of a patient requiring conversion from apixaban to heparin in the setting of acute kidney injury is reported. A 70-year-old man was initiated on apixaban 5 mg twice daily for new-onset, nonvalvular atrial fibrillation with a CHA2DS2-VASc score of 4, indicating a high risk of stroke. Soon after starting apixaban, he experienced pulmonary edema with pneumonia requiring hospitalization. During the course of hospitalization, the patient developed acute kidney injury requiring hemodialysis, and apixaban was stopped due to concerns about altered pharmacokinetics and impaired drug elimination in this setting. A heparin infusion was started 36 hours after the last dose of apixaban was administered. Antifactor Xa levels were monitored consistent with the hospital's standard practice protocols. The initial and repeat antifactor Xa concentrations were elevated (1.8-4.4 IU/mL) for up 72 hours after stopping the heparin infusion. Given the suspected interference of apixaban with standard antifactor Xa level monitoring, the heparin protocol was modified to reflect drip-rate adjustments based on activated partial thromboplastin times (aPTTs). The hospital protocol for heparin infusions was reinstituted on hospital day 7, with dosage adjustments based on antifactor Xa levels. The patient remained on a continuous heparin infusion for atrial fibrillation for the remainder of his hospitalization without complications or bleeding events. A 70-year-old man with new-onset nonvalvular atrial fibrillation and receiving apixaban discontinued this therapy and was given heparin instead due to acute kidney injury. His heparin dosage was successfully adjusted based on antifactor Xa levels and aPPTs.

Wendte J ，Voss G ，VanOverschelde B 《-》