A Rare Case of Apixaban-Induced Subdural Hematoma in Elderly Heart Failure Patient

Introduction

New oral anticoagulants (NOACs) that either inhibit thrombin (dabigatran) or inhibit coagulation factors (F Xa), such as rivaroxaban, apixaban, edoxaban, and betrixaban, have become more popular in the last few decades.¹ Apixaban, used to prevent systemic embolism and stroke in patients with atrial fibrillation and deep venous thrombosis (DVT), has been proven to be safer than warfarin.² However, apixaban, like other anticoagulants, carries the risk of fatal bleeding issues, including gastrointestinal, subarachnoid, and potentially subdural bleeding.

A subdural hematoma is the collection of blood between the dura mater and the arachnoid mater. It can happen as a result of trauma or spontaneously in certain people. The most common cause of chronic subdural hematomas (cSDHs) is bridging vein tears as they cross the dural cell layer. Inertial brain injury, both severe and minor, is recorded in two-thirds of patients and can cause tears in those vulnerable arteries.³ Chronic subdural hematoma (cSDH) is more common in elderly people with a history of minor head injuries, whereas acute subdural hematoma (ASDH) is more common in patients who have suffered severe head trauma.⁴

Very few cases of apixaban-induced subdural hematomas have been reported in the literature, and mostly in these cases, the subdural hematomas are in the spine and not in the cranium. These cases highlight the importance of considering this potential complication in patients receiving apixaban therapy, especially elderly individuals who may be at a higher risk of bleeding. According to one study, a 60-year-old man with a history of hypertension and oligodendroglioma suffered cranial subdural hemorrhage when taking apixaban for deep venous thrombosis.⁵ We present an 81-year-old male patient with spontaneous subdural hemorrhage due to the use of apixaban for apical thrombus, and we also describe the related literature review.

Case Presentation

An 81-year-old male came to the cardiology outpatient clinic with shortness of breath, fatigue, and coughing at night. He had diabetes, for which he was on medication. His vital signs were normal. On examination, he had crackles in both lungs and S3 on the auscultation in the heart, as well as mild bilateral lower limb edema. His electrocardiography showed a complete right bundle branch block, while echocardiography demonstrated an ejection fraction of 30–35 associated with an apical thrombus of 0.93×1.29 cm and moderate mitral regurgitation (Figure 1A and B). The patient was managed with ramipril 2.5mg, carvedilol 6.25 mg, furosemide 40 mg, spironolactone 25 mg, and apixaban of 2.5mg BID. Unfortunately, the patient lost follow-up and presented again with a cognitive decline, slurred speech, and right hemiparesis. The patient did not have a recent history of head trauma, or seizure event. He was disoriented, dysarthric and had difficulty in obeying commands. Motor examination showed right side weakness (2/5 based on MRC). Pupils were isochoric, and reactive to light. There was no facial asymmetry. Likewise, other cranial examinations were normal. Extensive laboratory examinations, including full blood count, renal and liver function tests and coagulation profile were in the normal limits. A non-contrast brain CT showed chronic subdural hematoma of 2.6 cm thickness in the left parietal region (Figure 2A and B). The apixaban was discontinued. Following neurosurgery, cardiology, and anesthesiology discussions, the surgery was deferred due to the patient’s age and coexisting comorbidities and the risk of general anesthesia. The patient was managed conservatively. Up on the next follow-up, the patient’s condition improved massively with an improved cognitive state, normal speech and also had an improved motor status with power of 4/5 (based on MRC score) and as a result, he was referred for physiotherapy and rehabilitation center.

Figure 1 (A) Electrocardiogram (ECG) with complete right bundle branch block (RBBB). (B) Echocardiogram showing apical thrombus 0.93×1.29cm.

Figure 2 Brain computed tomography (CT) showing subdural hematoma of 2.6 cm in both axial (A) and coronal (B) views.

Discussion

Apixaban, a novel oral anticoagulant, is a direct factor Xa inhibitor that has gained popularity due to its efficacy and safety profile when compared with traditional anticoagulants such as warfarin. But unfortunately, apixaban, like other anticoagulants, has a tendency to cause bleeding diathesis, including subdural hematoma. It is the only new oral anticoagulant (NOAC) approved by Food and Drug Administration (FDA) for hemodialysis (HD) patients.⁶ Gastrointestinal, cerebral, and soft tissue bleeding have all been well-documented events, but subdural bleeding was infrequently reported in the literature.^7–9 An uncommon occurrence of spinal subdural hematoma caused by apixaban medication for non-rheumatic atrial fibrillation was described in a case study.¹⁰ Another case report by reported a spontaneous thoracic spinal subdural hematoma associated with apixaban therapy.¹¹ These cases highlight the importance of considering subdural hematoma as a potential complication in patients receiving apixaban therapy.

It is important to note that subdural bleeding with apixaban is infrequent relative to other bleeding problems. Apixaban had the lowest prevalence of cerebral haemorrhage among a similar class of inhibitors, according to a literature study.¹² This highlights that, while apixaban may cause subdural hematomas, the overall risk of bleeding with this medication is relatively uncommon.

The exact mechanism through which apixaban can cause subdural hematomas is unknown. However, it is suspected that apixaban’s anticoagulant activity may raise the risk of bleeding, particularly bleeding into the subdural region. Furthermore, older age, renal impairment, and concurrent use of other drugs like anticoagulant drugs, non-steroidal anti-inflammatory drugs (NSAIDs), or selective serotonin reuptake inhibitors (SSRIs) could raise the risk of subdural hematoma in individuals on apixaban therapy; therefore, care should be taken with those susceptible patients, which requires monitoring.¹³

The clinical manifestation of apixaban-induced subdural hemorrhage varies depending on its location and degree of associated mass effect. Headaches, neurological impairments, changes in mental status, and, in severe cases, loss of consciousness are common symptoms.⁵ Prompt diagnosis and care are critical for avoiding complications and improving patient outcomes.

In terms of therapy, apixaban-induced subdural hematoma is normally treated with a multidisciplinary approach. In cases of substantial mass impact or neurological impairment, neurosurgical intervention is required. A large craniotomy is the standard approach for acute subdural hematoma (ASDH); a decompressive craniotomy may also be performed if necessary to prevent subsequent brain injury.^12,14 In less severe cases like this case, conservative therapy with constant monitoring and anticoagulation reversal may be sufficient.¹⁵ Due to his age and concomitant comorbidities, the patient was managed conservatively with follow-up.

The US Food and Drug Administration (FDA) approved andexanet alfa as an antidote for patients using rivaroxaban or apixaban who require anticoagulation reversal due to life-threatening or uncontrolled bleeding. Andexanet alfa (also known as coagulation factor Xa) reverses factor Xa inhibition by acting as a decoy factor Xa with no procoagulant characteristics, thereby competing with naturally synthesized and circulating factor Xa.¹⁶

Conclusion

In conclusion, while apixaban is generally considered a safe and effective anticoagulant, it carries a risk of bleeding complications, including subdural hematoma. Frequency of apixaban-induced subdural hematoma is relatively low compared to other bleeding complications associated with this medication. Healthcare providers should be aware of this potential complication, especially in elderly patients or those with underlying risk factors. Close monitoring and prompt management are essential to ensure optimal patient outcomes.