Article, Surgery

Emergency neurosurgical care in patients treated with apixaban: report of 2 cases

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Case Report

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American Journal of Emergency Medicine

journal homepage: www. elsevier. com/ locate/ajem

American Journal of Emergency Medicine 33 (2015) 858.e5-858.e7

Emergency neurosurgical care in patients treated with apixaban: report of 2 cases?

Abstract

A debate has emerged regarding the safety profile of direct anticoagu- lants, which are increasingly prescribed for the prevention of thrombo- embolic events. Despite favorable safety data derived from Controlled clinical trials, the absence of specific antidotes for the management of hemorrhagic complications represents a major challenge for emergency physicians. Here, we present the first report on patients treated with the direct factor Xa inhibitor apixaban and conditions requiring urgent neurosurgical intervention (intracerebral hemorrhage, n= 1; subdural hematoma, n = 1). prothrombin complex concentrates were adminis- tered before surgery, and both patients had a favorable postsurgical course without bleeding or thromboembolic complications. Further stud- ies are needed, but this approach seems to be suitable for the emergency management of apixaban-associated intracranial hemorrhage.

A 78-year-old woman (Patient 1) was treated at a center for ortho- pedic surgery because of an osteoporotic lumbar vertebral body fracture. Because of atrial fibrillation, she received apixaban (Eliquis; Pfizer, Berlin, Germany) 5 mg twice daily. The patient suddenly complained of nausea followed by repetitive vomiting, severe aphasia, and decreased vigilance with right-sided hemiparesis. Urgent comput- ed tomography (CT) revealed left-sided parieto-occipital hemorrhage with significant mass effect on surrounding brain tissue (Figure). After patient transfer to our hospital, blood was drawn for laboratory examina- tion of hemostatic parameters and demonstrated values within normal limits (Table). prothrombin complex concentrates (Beriplex P/N 500; CSL Behring, Marburg, Germany) (3000 IU) were administered ac- cording to available guidelines. The patient underwent surgical hemato- ma evacuation through craniotomy, and no increased bleeding tendency was observed during surgery. No further hemostatic measures were undertaken, and no thromboembolic event occurred during the fur- ther inhospital treatment. After surgery, the patient recovered well with significant regression of the hemiparesis and aphasia. Computed tomo- graphic imaging obtained postoperatively was unremarkable. She was transferred to a neurologic rehabilitation unit on the 14th day after surgery. A 76-year-old man (Patient 2) was admitted to our department with Gait Ataxia and psychomotor retardation. computed tomographic imaging demonstrated a left-sided chronic subdural hematoma with significant Midline shift. Clinical examination was remarkable for right-sided hemiparesis (grade 4/5) and gait ataxia. No further focal neurologic deficits were present. The patient was treated with apixaban 5 mg twice daily because of atrial fibrillation. Blood examination showed normal laboratory values of hemostatic parameters, but anti-

? Sources of support: None.

Xa levels were significantly increased (Table). We opted for administra- tion of 1500 IU PCC and performed surgical evacuation of the hematoma through burr hole trepanation 14 hours after admission of the patient. After surgery, the patient recovered well, and a postoperative CT scan was unremarkable without signs of remnant or rebleeding (Figure). Clinical symptoms had completely resolved when he was discharged on the fifth day after hospital admission.

Antithrombotic medication is increasingly prescribed in the aging population of industrialized countries. Direct anticoagulants–also re- ferred to as “new generation” or “novel” anticoagulants–have signifi- cant advantages compared with anticoagulation therapy with coumadins, which has been the standard of care treatment for the last decades. Monitoring of coagulation parameters is not necessary; more- over, a prospective multicenter study on apixaban has demonstrated superiority of apixaban in preventing stroke or systemic embolism with less bleeding and lower mortality compared with warfarin [1]. When compared with other direct anticoagulants (dabigatran and rivaroxaban), treatment with apixaban not only resulted in similar rates of Stroke prevention but also was associated with a lower risk of major hemorrhage [2]. A major disadvantage of all direct anticoagulants is the lack of established laboratory examinations to assess the degree of anticoagulation, and most importantly, there are no specific antidotes for anticoagulation reversal in cases of Bleeding complications. Several case reports have demonstrated the potential of the direct anticoagu- lants dabigatran and rivaroxaban to exacerbate intracranial hemorrhage with fatal patient outcomes [3-5]. To the best of our knowledge, no cases regarding the management of apixaban-related intracranial hemor- rhage have yet been reported.

Both patients required emergency neurosurgery, as clinical symp-

toms were present and intracranial hemorrhage had exerted mass effect on brain tissue. Standard laboratory values were within reference ranges despite proof of anti-Xa activity in patient 2. It is well recognized that apixaban may exhibit variable effects on coagulation assays and normal prothrombin time or activated partial thromboplastin time may not exclude clinically relevant levels of apixaban [6]. We opted for administration of prothrombin complex concentrates before surgery in both patients, as preclinical and clinical studies have suggested effec- tiveness in stabilizing hemostasis in patients treated with direct antico- agulants [7]. Other agents that have been reported for reversal of direct anticoagulants include fresh frozen plasma, factor eight inhibitor bypassing activity, and recombinant factor VIIa [8].

Surgical procedures and further courses of both patients were uneventful without bleeding complications, and postoperative CT imaging had unre- markable findings. It is not possible to conclude that PCC administration has prevented bleeding complications because the patients’ course if PCC had not been administered is unknown. Prothrombin complex concentrate

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image of Figure

Figure. computed tomography scans of patient 1 (on admission: A, after surgery: B) and patient 2 (on admission: C, after surgery: D).

administration has been associated with a considerable risk of thromboem- bolic events such as myocardial infarction [9]. Although both patients had no symptoms suggestive of Thromboembolic events, this risk has to be taken into account when considering administration of PCC. In the absence of specific antidotes, at this point of time, administration of prohemostatic substances is justified in cases of potentially Life-threatening hemorrhage. Current research focuses on specific antidotes (eg, andexanet alfa) that se- quester direct anticoagulants in patients’ blood and prevent interactions with factor Xa [10]. Results of Efficacy studies are currently carried out, and re- sults are eagerly awaited.

Our report demonstrates that emergency neurosurgical intervention without bleeding complications in patients treated with apixaban is fea- sible and a favorable outcome can be achieved. Administration of PCC may have beneficial effects in avoiding bleeding complications, but

Table

Laboratory results and administration of PCC

Reference range values Patient 1 Patient 2

further studies are clearly needed to optimize Treatment protocols for respective patients.

Conflict of interest

CB and OWS have received speaker honoraria from CSL Behring.

Christopher Beynon, MD?

Anna Potzy, MD Andreas W. Unterberg, MD, PhD Oliver W. Sakowitz, MD, PhD

Department of neurosurgery, Heidelberg University Hospital

Heidelberg Germany

?Corresponding author. Department of Neurosurgery, Heidelberg University Hospital, Im Neuenheimer Feld 400, 69120 Heidelberg

Germany Tel.: +49 6221 5636173

E-mail address: [email protected]

Before surgery

INR b1.2 1.06 1.02

Quick 70%-125% 87.1 95

aPTT b35 s 23.9 s 24.9 s

Anti-factor Xa negative N/A 77.4 ng/mL Platelet count 150’000-440’000/uL 299’000/uL 177’000/uL PCC administration 3000 IU 1500 IU

After surgery

INR b1.2 0.98 NA

Quick 70%-125% 106% NA

aPTT b35 s 23.0 s NA

Platelet count 150-440/uL 302’000/uL NA

Abbreviations: INR, international normalized ratio; aPTT, activated partial throm- boplastin time.

http://dx.doi.org/10.1016/j.ajem.2014.12.017

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