The following are key points to remember about this review of anticoagulant-associated intracranial hemorrhage (ICH) in the era of reversal agents:

1. Among patients taking oral anticoagulants (OACs), the annual rate of ICH is 0.3%-0.6% (primarily for warfarin). Of those, 46%-86% are intracerebral, while 13%-45% are subdural and 1%-8% are subarachnoid. Mortality rates are 40%-65% over 30-90 days. Annual rates of ICH for patients taking the direct oral anticoagulants (DOACs) are 0.1%-0.2%, a 50% reduction as compared to warfarin.
2. In general, intracerebral bleeding that occurs in patients taking OAC reflects spontaneous bleeding that is exacerbated by anticoagulation. OACs sustain intracerebral hematoma formation, but do not cause it.
3. Hematoma expansion, which is often fatal, occurs in 30%-40% of patients not on OACs within 3-6 hours after symptom onset. Rates of hematoma expansion are approximately 35%-55% for patients on warfarin and 38% in one prospective DOAC trial.
4. To test for anticoagulant effect, an international normalized ratio (INR) is rapidly available for warfarin-treated patients. The thrombin time is the most sensitive test for excluding the presence of dabigatran, but cannot be used to detect its clinical level. Calibrated anti-factor Xa assays are becoming more routinely available to measure the clinical effect of apixaban, edoxaban, and rivaroxaban (reversal is likely indicated if anti-factor Xa level is >30 ng/ml).
5. Warfarin reversal in the setting of an ICH should be done using intravenous vitamin K (10 mg) and prothrombin complex concentrate (25-50 U/kg). Recombinant factor VIIa is not a first-line agent given the risk of thromboembolic events.
6. Dabigatran can be rapidly reversed with the administration of idarucizumab (Praxbind), a noncompetitive, specific humanized antibody against dabigatran. This should be given as a 5 mg intravenous bolus.
7. Andexanet alfa (AndexXa) is a recombinant factor Xa that competes with native factor Xa to bind apixaban, edoxaban, rivaroxaban, and other factor Xa inhibitors (e.g., heparin, low molecular weight heparin, and fondaparinux). It is not yet approved by the Food and Drug Administration (FDA), but has been shown to reduce anticoagulant effect after an initial bolus followed by an infusion. The dose tested in studies is drug-specific: 400 mg intravenous bolus followed by 480 mg infusion over 2 hours for apixaban, 800 mg bolus followed by 960 mg infusion over 2 hours for rivaroxaban.
8. Ciraparantag is a synthetic, water-soluble, cationic small molecule that has been shown in preliminary studies to bind heparin, low molecular weight heparin, dabigatran, rivaroxaban, apixaban, and edoxaban. Phase III studies have not been initiated and FDA review is not imminent.
9. Until a specific reversal agent is available, use of PCCs 25-50 U/kg intravenous is recommended for patients with active use of apixaban, edoxaban, or rivaroxaban who present with ICH.
10. If there is reliable evidence that DOAC medications were taken >48 hours prior to presentation, then reversal is likely unnecessary unless significant renal dysfunction is present.

Keywords: Antibodies, Monoclonal, Humanized, Arrhythmias, Cardiac, Anticoagulants, Antithrombins, Blood Coagulation Factors, Factor VIIa, Factor Xa Inhibitors, Hematoma, Heparin, Heparin, Low-Molecular-Weight, Intracranial Hemorrhages, Secondary Prevention, Subarachnoid Hemorrhage, Thromboembolism, Vascular Diseases, Vitamin K, Warfarin

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