What are the possible causes of hemorrhagic stroke in an 89-year-old patient on apixaban (Apixaban) for atrial fibrillation (AF), with well-controlled hypertension and no significant medical history?

From the Guidelines

Hemorrhagic stroke in an 89-year-old patient on apixaban for atrial fibrillation is most likely due to the anticoagulation therapy itself, as apixaban increases bleeding risk, especially in elderly patients, as shown in the ARISTOTLE trial 1. The patient's age and anticoagulation therapy are significant risk factors for hemorrhagic stroke. Age-related cerebral amyloid angiopathy, which causes fragile blood vessels, is a common cause of hemorrhagic stroke in the elderly. Despite well-controlled hypertension, the patient may experience sudden blood pressure spikes that can rupture weakened vessels. Other potential causes include:

• Undiagnosed cerebral microbleeds
• Medication interactions that enhance the anticoagulant effect of apixaban (such as NSAIDs, certain antibiotics, or antifungals)
• Falls resulting in head trauma
• Undiagnosed coagulopathies
• Kidney dysfunction affecting apixaban clearance Additionally, the patient might have an undetected brain aneurysm or arteriovenous malformation. According to the 2017 European Heart Rhythm Association (EHRA) consensus document, optimal blood pressure control is crucial for both stroke and bleeding risk reduction in AF patients taking OAC 1. Management should include immediate discontinuation of apixaban, blood pressure control, reversal of anticoagulation if appropriate, neuroimaging, and supportive care. After stabilization, reassessment of stroke and bleeding risks would determine if anticoagulation should be resumed, possibly at a lower dose or with an alternative agent. It is essential to note that the ARISTOTLE trial demonstrated that apixaban was significantly better than warfarin, with fewer overall strokes (both ischemic and hemorrhagic), systemic emboli, and major bleeding events 1. However, the patient's advanced age and potential comorbidities may require careful consideration of the benefits and risks of anticoagulation therapy.

From the FDA Drug Label

Apixaban can cause bleeding which can be serious and rarely may lead to death. You may have a higher risk of bleeding if you take apixaban tablets and take other medicines that increase your risk of bleeding, including: aspirin or aspirin-containing products long-term (chronic) use of nonsteroidal anti-inflammatory drugs (NSAIDs) warfarin sodium (COUMADIN®, JANTOVEN®) any medicine that contains heparin selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) other medicines to help prevent or treat blood clots

Some reasons for hemorrhagic stroke in an 89-year-old patient on apixaban for atrial fibrillation may include:

• Bleeding risk: Apixaban can cause bleeding which can be serious and rarely may lead to death.
• Concomitant medication use: The patient may be taking other medicines that increase the risk of bleeding, such as aspirin, NSAIDs, or SSRIs.
• Age-related factors: The patient's age (89 years old) may increase the risk of bleeding due to decreased renal function or other age-related comorbidities.
• Underlying medical conditions: Although the patient has well-controlled hypertension, other underlying medical conditions may increase the risk of bleeding. 2

From the Research

Hemorrhagic Stroke in 89-Year-Old Patient on Apixaban

Some possible reasons for hemorrhagic stroke in an 89-year-old patient on apixaban for atrial fibrillation, with well-controlled hypertension and no other medical history, include:

• Advanced age, as older patients are at higher risk of bleeding complications 3, 4
• Renal impairment, as apixaban is partially renally excreted and may accumulate in patients with renal impairment, increasing the risk of bleeding 3, 5
• Interaction with other medications, although not specified in the patient's history, could potentially increase the risk of bleeding 6
• The dose of apixaban, as higher doses may increase the risk of bleeding, although the standard dose is usually 5 mg twice daily 4, 6

Renal Impairment and Apixaban

Studies have shown that:

• Patients with stage III chronic kidney disease (CKD) are at higher risk of major hemorrhage when taking apixaban compared to those with preserved renal function 3
• Apixaban may be a reasonable alternative to warfarin in patients with severe renal impairment, with lower rates of major bleeding and mortality 6, 7
• The risk of bleeding with apixaban in patients with mild renal impairment is significantly less compared to conventional anticoagulants, while in patients with moderate to severe renal impairment, the risk of bleeding is similar 5

Bleeding Risk with Apixaban

The bleeding risk with apixaban has been evaluated in several studies, including:

• A meta-analysis that found the risk of bleeding with apixaban in patients with mild renal impairment to be significantly less compared to conventional anticoagulants, while in patients with moderate to severe renal impairment, the risk of bleeding was similar 5
• A study that found no significant difference in major bleeding events between patients with preserved renal function and those with impaired renal function taking apixaban 5 mg or 2.5 mg twice daily 4