Article Title/CitationSiegal DM, Curnutte JT, Connolly SJ, et al. Andexanet alfa for the reversal of factor Xa inhibitor activity. New Engl J Med 2015; 373(25): 2413-2424.
Brief Background
Traditionally, warfarin (Coumadin), a vitamin K antagonist, has been the treatment of choice for the prevention/treatment of DVT and pulmonary embolism, venous thrombosis after surgery, and clot formation due to nonvalvular atrial fibrillation. Although warfarin is effective for these purposes, the required dosage varies widely between patients, so they must have weekly blood tests until the dose is stabilized, and then monthly maintenance testing.1 The newer anti-coagulants, including direct factor Xa inhibitors, have largely supplanted the use of warfarin due to their fixed dosing.2 However, when they were first approved there was no means of reversing their effects analogous to administration of vitamin K to reverse warfarin. This was considered a serious limitation, especially in the context of emergency surgery.3 Andexanet alfa is a specific neutralizing agent for factor Xa inhibitors because it attaches to the inhibiting molecule and prevents it from limiting thrombin generation.4
Study Objective or Purpose
The ANNEXA-A and ANNEXA-R clinical trials were conducted to assess the safety and efficacy of andexanet alfa in reversing the factor Xa inhibition caused by apixaban (ANNEXA-A) and rivaroxaban (ANNEXA-R).
Funding Sources and Disclosures
Funding for the study was provided by Portola Pharmaceuticals, Bayer, Bristo-Myers Squibb, Johnson & Johnson, and Pfizer. Drs. Siegal, Connolly, Mathur, and Crowther served on advisory boards for several pharmaceutical companies including the funding companies. Drs. Curnutte, Lu, Conley, Wiens, Bronson, Leeds, Mar, and Gold are Portola employees; Cornutte, Conley, and Wiens hold stock options in Portola.
Methods
Study Design and Methodology
The ANNEXA-A and ANNEXA-R trials were randomized, double-blind, placebo-controlled studies.
Patient Selection and Enrollment
Patients were healthy volunteers aged 50 to 75 who were randomly assigned in a 3:1 ratio (ANNEXA-A) or 2:1 ratio (ANNEXA-R) to receive Andexanet or placebo.
Study Intervention
Participants were given apixaban (5 mg twice a day) or rivaroxaban (20 mg once daily) for 3.5 days. On the fourth day the Andexanet was administered. Each study was conducted in two ways – the first, with a bolus of 400 (apixaban) or 800 (rivaroxaban) mg Andexanet and the second, a bolus as above plus 2-hour infusion (4 mg/min. for apixaban, 8 mg/min. for rivaroxaban). They lived on site for eight days so researchers could watch for side effects. Additional assessments were conducted on days 15, 36, and 43.
Outcome Measures/Endpoints
The primary outcome measure was the percent change in anti-factor Xa activity from baseline to nadir. Secondary efficacy endpoint was the proportion of participants who had a reduction of 80% or more in anti-factor Xa activity.5 Additional secondary endpoints were the occurrence of clots, bleeding, or other adverse effects.6
Data Handling
The total number of participants was 145 and they were assigned randomly to the drug or placebo in a 3:1 (apixaban) or 2:1 (rivaroxaban) ratio. The samples were large enough to have over 99% power to detect percent change from baseline to nadir. The two-sided alpha level was 0.05. The primary end point was tested first in order to avoid Type 1 error.
Statistical Analysis
Efficacy analysis was based on an intent-to-treat protocol, randomized for Andexanet or placebo. The primary and secondary end points were compared using the Wilcoxon rank-sum test.
Results
Baseline Characteristics
The 14-month study resulted in 101 participants in the Andexanet condition and 44 participants in the placebo condition. Mean age was 57.9 years, with 39% of the sample female. Treatment groups were balanced.
Outcomes
In both studies, anti-factor Xa activity decreased quickly after Andexanet administration compared to placebo, with a 94% reduction with apixaban and 92% reduction with rivaroxaban. In the bolus-only condition, reversal lasted two hours. The bolus plus infusion resulted in level that remained low for up to two hours after the infusion was ended. All Andexanet participants had at least 80% reversals; none of the placebo participants did.7 Thrombin generation was significantly increased in the Andexanet condition. No severe or serious adverse effects were reported, and no thrombosis occurred. Adverse effects were mild (e.g. hives). No antibodies against factor Xa, factor X, or Andexanet were detected.8
Conclusions
Authors’ Conclusions
The two trials discussed here provided evidence for the efficacy and safety of Andexanet as a reversal therapy against the factor Xa inhibitors apixaban and rivaroxaban. Reversal occurred rapidly and length of reversal was in line with known pharmacodynamics. No serious adverse events or development of antibodies was noted.
Strengths and Weaknesses
The power of analysis which resulted from the sample size suggests that this study is statistically sound. The authors noted that, although there were no clinically significant thromboses, there were temporary increases in D-dimer and prothrombin fragments. Previous studies using animals have indicated that these substances are not relevant in the case of factor Xa inhibitors. However, this has not been studied in humans.
Applicability
This study reported on the safety and efficacy of Andexanet in healthy volunteers. It is unknown whether the drug would be safe and effective for patients who were taking anti-clotting drugs due to atrial fibrillation or DVT. Further trials will consider this population before the drug can be unequivocally approved for widespread use.
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