Over the last decade, several direct oral anticoagulants have become available for thromboembolic prophylaxis, as an alternative to the Vitamin K antagonist warfarin. These agents are either direct thrombin inhibitors (dabigatran) or Factor Xa inhibitors (rivaroxaban, apixaban, edoxaban). In my clinical practice, I frequently prescribe these medications for stroke prophylaxis from atrial fibrillation. During these discussions with patients, I provide information from clinical trials comparing warfarin and the DOACs. These medications have shown similar stroke prophylaxis efficacy and safety in terms of hemorrhage risk when compared to warfarin. One of the concerns for patients and clinicians has been a lack of a reversal agent for the DOACs. There is some evidence to suggest that patients have better outcomes in case of hemorrhagic events while on DOACs as compared to warfarin1.
Prothrombin complex concentrate along with Vitamin K is used to treat warfarin associated major bleeding. Idaruzicumab was approved by the FDA in 2015 for reversal of dabigatran related major hemorrhages. Still acute life threatening hemorrhage while on Factor Xa inhibitors remains difficult to treat due to a lack of a specific reversal agent.
Final results from the ANNEXA-4 study were presented at the International Stroke Conference 2019 held at Honolulu earlier this month. The results were simultaneously published in the NEJM2. This trial investigated Andexanet alfa, a modified recombinant inactive form of human factor Xa. This binds to and sequesters factor Xa inhibitor molecules. This leads to rapid lowering of factor Xa inhibitor activity. ANNEXA-4 investigators enrolled 352 adult patients who presented due to acute major bleeding in the setting of using a factor Xa inhibitor within the last 18 hours. Patients were eligible if they had an acute major bleeding in a critical organ, such as intracranial or retroperitoneal hemorrhage, bleeding associated with significant hemodynamic compromise, or significant drop in the hemoglobin level. 64% of the patients enrolled had an intracranial hemorrhage as their qualifying event. Patients with severe intracranial hemorrhage (GCS<7 or hematoma volume>60 ml) were excluded from the trial. The drug was infused as an initial bolus dose followed by a 2 hour infusion. Blood levels of Factor Xa inhibitor and anti-Factor Xa activity was measured before, during and after the infusion. Patients with intracranial hemorrhage received a follow up brain CT or MRI at 1 hour and 12 hours after the infusion.
There was a 92% reduction in the median values of anti-Factor Xa activity after administration of the bolus dose in patients who were on rivaroxaban or apixaban. At 12 hours after the infusion, 82% patients were noted to have an excellent or good hemostatic efficacy as determined by pre-specified criteria. This is comparable to the 72% rate noted with prothrombin complex concentrate treatment given for reversal of warfarin related major bleeding. Thrombotic events occurred in 10% of patients within 30 days after the infusion, with almost half of these events being ischemic stroke. Interestingly, this study did not show a direct correlation between anti-Factor Xa activity reduction and clinical response. Among patients with intracranial hemorrhage, there was a weak relationship that was observed between hemostatic efficacy and anti-Factor Xa activity reduction. Therefore the investigators do not recommend using the anti-Factor Xa activity level as a predictor of clinical response. This study was limited due to its non randomized design. A randomized clinical trial is currently being initiated by the study sponsors to overcome this limitation3.
The FDA approved andexanet alpha in May 2018 for reversal of anticoagulation in case of severe life threatening bleeding related to apixaban or rivaroxaban. Intracranial hemorrhage is one of the most feared complications of long term anticoagulation and now we have available, effective and safe reversal agents for all the prescribed oral anticoagulants. This provides a significant benefit and reassurance for patients who are taking these medications for thromboembolic prophylaxis.
- Compared to warfarin, direct oral anticoagulants are associated with lower mortality in patients with blunt traumatic intracranial hemorrhage: A TQIP study. J Trauma Acute Care Surg. 2016 Nov;81(5):843-848.
- Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors. February 7, 2019 DOI: 10.1056/NEJMoa1814051
- ClinicalTrials.gov number (NCT03661528)