Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors (ANNEXA-4)
Presenter:
Stephanie Dwyer, PharmD
TRIAL SUMMARY
Background
Direct oral anticoagulants (DOACs) such as apixaban and rivaroxaban reduce the risk of bleeding relative to warfarin. However, concerns remain regarding the management of bleeding related to DOAC use. Before the U.S. FDA’s approval of idarucizumab (PRAXBIND®), a reversal agent for the direct thrombin inhibitor dabigatran, the lack of reversal agents was a consistent concern associated with the use of all DOACs. Currently, there is no approved specific reversal agent for factor Xa inhibitors, although late phase clinical trials of reversal agents are ongoing1. Andexanet alfa is a recombinant modified human factor Xa decoy protein that is catalytically inactive. It retains the ability to bind factor Xa inhibitors in the active site with high affinity. It was also designed to neutralize the anticoagulant effect of both direct and indirect factor Xa inhibitors2,3. Two parallel trials called Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of FXA Inhibitors Apixaban (or ANNEXA-A) and Rivaroxaban (or ANNEXA-R) were designed to establish the efficacy and safety of andexanet for the reversal of anticoagulation with apixaban or rivaroxaban in older healthy volunteers. The authors concluded from these trials that andexanet rapidly restored factor Xa activity and thrombin generation and reduced unbound factor Xa inhibitor concentrations in apixaban and rivaroxaban treated older patients. The objective of ANNEXA-4 trial was to evaluate the use of andexanet in patients with acute major bleeding that was potentially life-threatening4,5.
Methods
ANNEXA-4 is an ongoing, multicenter, prospective, open-label, single-group study of andexanet alfa in patients with acute major bleeding. The interim analysis was performed for patients enrolled between April 10, 2015 and June 17, 2016 in 20 centers in the United States, 1 center in the United Kingdom, and 1 center in Canada. Patients were included if they had potentially life-threatening acute overt bleeding with signs and symptoms of hemodynamic compromise, acute overt bleeding with hemoglobin decrease of at least 2 g/dL, hemoglobin ≤ 8 g/dL without baseline hemoglobin or investigators opinion that hemoglobin level would fall to ≤ 8 g/dL with resuscitation, or acute symptomatic bleed in critical organs (retroperitoneal, intraarticular, pericardial, intracranial, intramuscular) and received one of the factor Xa inhibitors within 18 hours (apixaban, rivaroxaban, edoxaban, and enoxaparin at least 1 mg/kg/day).
Patients with acute major bleeding ≤18 hours of last dose of apixaban, edoxaban, rivaroxaban, or enoxaparin were included in the study to receive andexanet IV bolus and infusion. All patients receiving apixaban despite time from last dose to presentation, or who received rivaroxaban more than 7 hours ago received 400 mg bolus followed by 480 mg infusion at 4 mg/min for 2 hours. For patients who received enoxaparin, edoxaban or a dose of rivaroxaban within 7 or less hours or at an unknown time, they received 800 mg IV bolus and infusion of 960 mg at 8 mg/minute for 2 hours. If there was a delay between medical presentation and start of andexanet of more than 7 hours, the patient received the 480 mg infusion dose.
Outcomes:
The co-primary outcomes were percent change in the anti-factor Xa activity and rate of excellent or good hemostatic efficacy in 12 hours after infusion. Only patients whose baseline anti-factor Xa activity was ≥75 ng/mL or ≥0.5 IU/mL for enoxaparin were included in the efficacy analysis. For hemostatic efficacy, the independent adjudication committee reviewed each case to determine hemostatic efficacy on the basis of pre-determined criteria. The objective of safety outcome was to evaluate the overall safety of andexanet, including adjudicated thromboembolic events and antibodies to factor X, factor Xa, and andexanet. All patients who received andexanet were included in the safety assessment.
Results
For the interim analysis, 67 patients were included in the study. Forty-seven patients were enrolled in the efficacy population. For the baseline characteristics, the mean age of the patients was 77 years. The mean (±SD) time from emergency department presentation to the administration of the andexanet bolus was 4.8±1.8 hours and approximately 9% of the patients had creatinine clearance <30 mL/minute. Most patients had substantial cardiovascular disease. Of the 67 patients in the safety population, 31 patients were receiving apixaban, 32 patients were receiving rivaroxaban, and 4 were receiving enoxaparin. The study is still on-going and will enroll patients until there are 162 patients for efficacy analysis with an expected safety population of approximately 230. Among the 26 patients who received rivaroxaban, the median value for anti-factor Xa activity decreased by 89% from baseline to the end of the infusion administration (277 ng/mL at baseline to 16.8 ng/mL). At the end of the 2-hour infusion, the median value for anti-factor Xa activity was 30.6 ng/mL. Four hours later, the median anti-factor Xa activity relatively decreased by 39% from baseline (177.7 ng/mL). For the 20 patients who received apixaban, the median value for anti-factor Xa activity relatively decreased by 93% from baseline to the end of the bolus infusion administration (149.7 ng/mL to 10.3 ng/mL). At the end of the 2 hour infusion, there was a relative decrease of 92% in the median value for anti-factor Xa. Four hours later, the median value decreased by 30% from baseline (103.0 ng/mL). At 8 hours and 12 hours, the value for anti-factor Xa activity remained at similar levels. For the clinical outcomes, 37 patients (79%) were adjudicated as having excellent or good hemostasis based on the pre-defined criteria. Fifteen percent of the patients died (n=10) with 6 adjudicated as cardiovascular events and 4 as non-cardiovascular events. Thrombotic events occurred in 12 patients. Four patients had a thrombotic event within 3 days after andexanet. The rest were between 4 and 30 days.
Conclusions
For patients with major cardiovascular disease and had acute major bleeding due to the use of factor Xa inhibitor, the administration of andexanet alfa resulted in rapid reversal of anti-factor Xa activity. Seventy-nine percent of the patients had excellent or good hemostatic efficacy and clinical response in 12 hours after the administration of andexanet alfa.
KEY DISCUSSION POINTS:
· If approved, andexanet will most likely be added to the hospital’s formulary. Hospitals should develop protocol for the management of bleeding and reversal.
· Since ANNEXA-4 only included patients with acute bleeding, the question regarding the role of andexanet for patients who require emergent surgery remains unknown.
· If clinically relevant re-bleeding occurs along with elevated coagulation parameters, an additional 5 gram dose of idarucizumab may be considered. Should a re-dose of andexanet be given if clinical relevant bleeding re-occurs?
· Providers should balance the need for complete anticoagulant reversal and the resulting increased risk of thromboembolism from the patient’s underlying disease. Anticoagulant therapy should be restarted as soon as medically appropriate.
QUESTIONS & ANSWERS:
1. Given the rebound Xa activity that is seen, do you propose that an extended infusion beyond 2 hours should be used? If so, how do you justify the potential thrombotic risk associated with it? Should we be dosing this based on hemostatic response as opposed to a pre-specified time period?
· The andexanet alfa pharmacokinetic data have shown that factor Xa inhibitors do not get cleared with andexanet alfa. Upon release from the andexanet alfa, the factor Xa inhibitor returns to the central compartment. Due to the half-life of approximately 1 hour for andexanet, this may explain why there is a return of Xa activity. There is not enough data to justify extended infusion beyond two hours. Thrombotic events occurred in 18 % of the patients. However, measurements of endogenous thrombin potential immediately after administration of the antidote did not differ to any degree from those measured at later time points. This indicates that andexanet probably did not overcorrect leaving the patients in a hypercoaguable state. The dosing of andexanet should be based on hemostatic response and not a pre-specified time period as the patients had substantial cardiovascular diseases and thromboembolic and bleeding risks.
2. When were patients started on anticoagulation following andexanet alfa administration? Was this reported?
· Anticoagulation was resumed in 18 patients within 30 days. The study did not report the exact time anticoagulation was restarted. Per the study’s protocol, “investigators may choose to re-start anticoagulation or antiplatelet agents with any agent at any time based on clinical judgment. If anticoagulation or an antiplatelet agent is restarted during the study, the date, time, and agent(s) used should be recorded on the case report forms.”
3. If approved, what would be the expected cost of this drug?
· The price of andexanet alfa is still unknown as the medication is pending FDA approval. However, the president of Viewpoint Consulting predicted andexanet alfa will cost around $7,500-$8000 per dose.6
4. Was thromboembolism monitored with any screening tests or just on the basis of clinical signs and symptoms?
· According to the supplementary data, thromboembolic events were monitored based on different criteria.
o Transient ischemic attack (TIA): A transient episode of neurological dysfunction caused by focal brain, spinal cord, or retinal ischemia, with signs or symptoms lasting < 24 hours and no evidence of new infarct on neuroimaging if performed.
o Stroke is defined as the rapid onset of signs and symptoms with specialist evaluation or imaging.
o Myocardial infarction: cardiac biomarkers and imaging
o Venous thromboembolism: objective confirmation with venography, ultrasound, CT, or V/Q scan.
References:
1. Brown et al. Nonvitamin K antagonist oral anticoagulant activity: challenges in measurement and reversal. Critical Care. 2016; 20:273
2. Milling TJ, Kaatz S. Preclinical and clinical data for factor Xa and “universal” reversal agents. Am J Med. 2016. pii: S0002-9343(16)30665 9.[Epub ahead of print]
3. Sarode R et al. Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study. Circulation. 2013; 128: 1234-1243.
4. Siegal D et al. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med. 2015; 373:25
5. Connolly et al. Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. N Engl J Med. 2016.
6. Thompson A. BioPharm Insight [Internet]. Available from: http://www.biopharminsight.com/portola-s-andexanet-alfa-factor-xa-inhibitor-reversal-likely-see-high-price-prompt-conservative. Accessed 2016 October 20.