This paper illustrates an example of delayed, recurrent, spontaneous intracranial hemorrhage in a patient on a new irreversible, direct factor-Xa inhibitor. With the increasing use of newer anticoagulation agents in patients with atrial fibrillation, the occurrence of such events may increase. It is incumbent on neurosurgeons to document the occurrence of such events and develop management protocols.
Recent studies have shown that even subclinical atrial fibrillation can place a person at a significantly increased risk of stroke [6
]. The last two decades have witnessed a robust interest in new anticoagulation agents. Agents such as fractionated/low-molecular-weight heparin and direct thrombin inhibitors provided advantages over warfarin but had limited use because of their parenteral administration [7
]. Therefore, while oral vitamin K antagonists have many disadvantages, they remained the mainstay of therapy in patients requiring chronic anticoagulation. Newer direct factor-Xa (e.g., rivaroxaban, apixaban, and edoxaban) and thrombin (e.g., dabigatran) inhibitors, however, demonstrate comparative efficacy and decreased major bleeding rates compared with warfarin while also being amenable to oral administration [2
Edoxaban is one of three new direct factor-Xa inhibitors currently in phase 3 clinical trials for the prevention of stroke in patients with nonvalvular atrial fibrillation and the prevention of systemic embolization [2
]. Edoxaban has been shown to be an effective inhibitor of factor-Xa because it has a 10,000-fold greater affinity for the receptor than thrombin without other relevant inhibitory effects [10
]. Bolstered by comparable or lower bleeding rates than warfarin in phase II trials that appear dose dependent, the phase III ENGAGE AF-TIMI 48 trial is currently underway comparing edoxaban 30
mg once daily, edoxaban 60
mg once daily, and dose-dependent warfarin in primary stroke prevention.
Other direct factor-Xa inhibitors have shown promising results in regards to intracranial hemorrhage. In the event of intracranial hemorrhage, however, there are no data on the morbidity and mortality surrounding the bleed or discussion of effective reversal agents such as exist for warfarin [5
As DBS has been used in over 80,000 patients and perioperative hemorrhage events are well documented, it seems delayed hemorrhage is likely a rare event. A recent PUBMED review of the English literature on this topic revealed only a single case of reported delayed hemorrhage with aspirin being identified as the likely causative agent [12
]. To our knowledge, the current report is novel in that the hemorrhage was recurrent and in the setting of edoxaban use.
Only general guidelines are available to help the neurosurgeon in regards to resumption of anti-platelet or anticoagulation therapy after trauma or intracranial procedures [13
]. When used for stroke prevention in the setting of atrial fibrillation, anti-coagulation is routinely reinitiated in our DBS practice 6–12 weeks after elective surgery.
The use of novel direct anti-coagulants will certainly increase rapidly in the near future as these agents are, in general, proving to be safer than warfarin therapy. Given the rarity with which delayed hemorrhage usually occurs following DBS surgery, however, it is extremely concerning that edoxaban might pose a significant risk in this particular patient population. Further reports on the use of novel anti-coagulants after intracranial surgery are acutely needed to help assess the true relative risk they pose.