What is the probability of intracranial hemorrhage (ICH) in a patient taking Apixaban (apixaban) who has suffered a fall, initially denying head injury but later found to have a minor head injury?

From the Guidelines

If someone on apixaban experiences a fall with a small head injury, the risk of intracranial bleeding is approximately 1-2%. This risk is supported by a recent study published in 2023 1, which found that the incidence of delayed intracranial hemorrhage (ICH) in patients on novel oral anticoagulants (NOACs) like apixaban is relatively low. The study, which included patients with minor head injuries, reported a delayed ICH incidence of 1.5% to 2% in those on NOACs. Symptoms of intracranial bleeding can develop within hours to days after the injury, and life-threatening complications typically emerge within the first 24-48 hours, though they can occasionally develop later.

• Key factors influencing the risk of intracranial bleeding include the type of anticoagulant used, the severity of the head injury, and the patient's overall health status.
• The study by Nishijima et al. 1 suggests that patients on warfarin have a higher risk of delayed ICH compared to those on NOACs, but the risk is still relatively low for NOAC users.
• It is essential for anyone on apixaban who experiences a head injury to seek immediate medical evaluation, even if they initially feel fine, as symptoms may be subtle or delayed.
• Warning signs requiring emergency care include severe headache, confusion, weakness, slurred speech, vomiting, seizures, or loss of consciousness.
• Healthcare providers may perform CT scans to detect bleeding and might consider temporarily stopping apixaban depending on the injury severity and bleeding risk.
• The increased bleeding risk with apixaban occurs because it inhibits Factor Xa in the clotting cascade, preventing the formation of blood clots that would normally stop bleeding after injury.
• Clear discharge instructions with return precautions are warranted due to the potential for up to approximately 5% of these patients to develop delayed ICH, as noted in the study 1.

From the FDA Drug Label

The most common reason for treatment discontinuation in both studies was for bleeding-related adverse reactions; in ARISTOTLE this occurred in 1.7% and 2.5% of patients treated with apixaban tablets and warfarin, respectively, and in AVERROES, in 1.5% and 1. 3% on apixaban tablets and aspirin, respectively. Table 1: Bleeding Events in Patients with Nonvalvular Atrial Fibrillation in ARISTOTLE* Apixaban N=9088 n(per 100 pt-year) Warfarin N=9052 n(per 100 pt-year) Hazard Ratio (95% CI) P-value Major † 327(2.13) 462(3.09) 0.69(0.60,0.80) <0.0001 Intracranial(ICH)‡52( 0.33) 125(0.82) 0.41(0.30,0.57) - Hemorrhagic stroke§38 (0.24) 74(0.49) 0.51(0.34,0.75) - Other ICH15 (0.10) 51(0.34) 0.29(0.16,0. 51) -

The probability of intracranial bleed in patients taking apixaban is 0.33% per 100 patient-years. The time until it becomes life-threatening is not directly stated in the label, but fatal intracranial bleeding occurred in 0.03% of patients per year. 2

From the Research

Probability of Intracranial Bleed

• The probability of intracranial bleed in patients taking apixaban after a ground-level fall is relatively low, with one study reporting no cases of traumatic intracranial hemorrhage in 31 subjects taking a direct oral anticoagulant, including apixaban 3.
• Another study found that apixaban was associated with a lower rate of traumatic brain injury (TBI) compared to no antithrombotic therapy, with a rate of 15.7% versus 21.25% 4.
• However, the risk of intracranial bleed is still present, and patients taking apixaban should be closely monitored for signs of bleeding, especially after a fall.

Time to Become Life-Threatening

• The time it takes for an intracranial bleed to become life-threatening can vary depending on the severity of the bleed and the individual patient's condition.
• One study reported that patients with traumatic intracranial hemorrhage on factor Xa inhibitors, including apixaban, had a low risk of hematoma expansion, with 87% of patients having excellent or good hemostasis on repeat imaging 5.
• Another study found that the use of 3-factor prothrombin complex concentrate (PCC3) to manage nonoperable intracranial bleeding associated with apixaban resulted in minimal or no progression of lesions measured by repeat computed tomography (CT) after treatment 6.
• The study 7 describes a case where andexanet alfa was administered approximately 18 hours after presentation, followed by repeat craniotomy with evacuation of the hematoma, and no further expansion of the intracranial hemorrhage was observed.

Management of Intracranial Bleed

• The management of intracranial bleed in patients taking apixaban typically involves reversal of anticoagulation using agents such as andexanet alfa or 3-factor prothrombin complex concentrate (PCC3) 7, 6.
• Close monitoring of the patient's condition and repeat imaging are also crucial in managing intracranial bleed 5.
• The use of andexanet alfa, PCC, and aPCC in the management of traumatic hemorrhage in the setting of an acute massive apixaban overdose requires further research 7.