ANNEXA-I: Andexanet Alfa Shows Efficacy, Safety for Factor Xa Reversal in Acute ICH

A postmarketing study of the bleeding reversal agent andexanet alfa (Andexxa; AstraZeneca) demonstrated safety and efficacy in patients experiencing acute intracerebral hemorrhage while on oral factor Xa (FXa) inhibitors. Results were presented during a plenary session at the 15th World Stroke Congress (WSC) held in Toronto, Canada, from October 10-12, 2023.

Brain illustration | Image credit: jolygon - stock.adobe.com

The phase 4 ANNEXA-I trial (NCT03661528) was stopped early based on the achievement of prespecified criteria for superior hemostatic efficacy and the capability to limit potentially life-threatening brain bleeding compared with usual care in patients on oral FXa inhibitors.^1,2 Andexanet alfa was initially granted accelerated approval by the FDA in 2018 based on the change from baseline in anti-FXa activity in healthy volunteers in previous trials.³

“Andexanet is a specific reversal agent for FXa inhibitors. It is a decoy molecule that resembles FXa itself but has been modified such that it lacks the catalytic activity, and it lacks the anticoagulant effect through modifications of this protein,” lead investigator Stuart Connolly, MD, FRCPC, explained during his presentation of the findings at WSC 2023. “Thus, it's able to bind rapidly to FXa inhibitors in the circulation, thus drawing them off native FXa and allowing native FXa to go back to do what it's supposed to do.”

ANNEXA-I, a randomized, multicenter clinical trial aimed to determine the safety and efficacy of andexanet alfa vs usual care for the treatment of ICH within 6 hours of symptom onset to baseline scan and within 15 hours of taking an oral FXa inhibitor. The trial utilized a prospective, randomized, open-label design with a primary outcome measure of effective hemostasis, which was defined as:

• A National Institutes of Health Stroke Scale (NIHSS) change of +6 or less from baseline to 12 hours
• A hematoma volume increase of 35% or less at 12 hours compared with baseline on a repeat CT or MRI scan
• No rescue therapies given between 3 and 12 hours after randomization

The secondary outcome was andexanet alfa’s effect on anti-FXa activity, defined as the percent change from baseline to nadir in anti-FXa activity in the first 2 hours following randomization.

A planned interim assessment of efficacy was conducted after 450 patients were randomized and followed for 1 month, and the independent data and safety monitoring board recommended that the trial be stopped when the interim analysis showed reversal benefits earlier than anticipated. Although the trial was intended to enroll 900 patients, the predetermined threshold for early termination for efficacy was a P value lower than .031 at interim analysis. A blinded end point adjudication committee adjudicated the primary efficacy outcome, and a blinded imaging core laboratory reviewed available scans.

The interim analysis was performed May 30, 2023, and the results presented at WSC 2023 encompassed 530 patients, including additional patients before the study close out and final database lock on September 18, 2023.

The mean ages in the andexanet alfa and usual care groups were 79.4 and 78.7 years, respectively, and the populations were well balanced between male and female patients. This population had a heavy burden of underlying vascular disease, including myocardial infarction, stroke, and atrial fibrillation. Median time from symptom onset to baseline scan was 2.2 hours in the andexanet alfa group and 2.4 hours in the usual care group. Median scan to randomization times were 1.1 and 1.2 hours, respectively.

In terms of hemostatic efficacy, an excellent (hematoma expansion of 20% or less) or good result was seen in 63.9% (n = 168) of patients in the andexanet alfa cohort compared with 52.4% (n = 140) in the usual care group. The increase in good or excellent efficacy per 100 patients with andexanet alfa vs usual care was 11.0% (P = .008). Most of the hemostatic efficacy outcomes in both cohorts were considered excellent (55.9% in the andexanet alfa group and 45.3% in the usual care group).

Andexanet alfa also produced a substantial reduction in median FXa inhibitor activity, which is consistent with previous findings. The median reduction in anti-FXa activity with andexanet alfa was 94.4%, while patients treated with usual care saw a 23.5% reduction (P < .0001).

Regarding safety, 10.3% of patients (n = 27) experienced at least 1 thrombotic event (TE) following treatment with andexanet alfa vs 5.6% (n = 15) in the usual care group. The increase in TE incidence with andexanet alfa was 4.6 per 100 patients (P = .048). Ischemic stroke occurred in 6.5% (n = 17) of patients treated with andexanet alfa and 1.5% (n = 4) of patients given usual care. Myocardial infarction was also more common in the andexanet alfa group (4.2% [n = 11] vs 1.5% [n = 4]). On the other hand, slight trends toward higher deep vein thrombosis and pulmonary embolism incidence were seen with usual care. There were no significant differences in deaths between groups.

“Andexanet rapidly reduced anti-factor Xa activity and increased the rate of hemostatic efficacy. Andexanet also increased the rate of thrombotic events compared to usual care,” Connolly concluded. “Thus, andexanet can be considered for patients with acute intracerebral hemorrhage associated with factor Xa inhibitor therapy. As with many treatments, we will need to weigh the benefits and the risks and use careful risk stratification and patient selection.”

References

1. Trial of andexanet alfa in ICH patients receiving an oral FXa inhibitor. ClinicalTrials.gov. Updated September 13, 2023. Accessed October 26, 2023. https://clinicaltrials.gov/study/NCT03661528

2. Andexxa Phase IV trial stopped early after achieving pre-specified criteria on haemostatic efficacy versus usual care. News release. AstraZeneca. June 5, 2023. Accessed September 26, 2023. https://www.astrazeneca.com/media-centre/press-releases/2023/andexxa-phase-iv-trial-stopped-early-after-achieving-pre-specified-criteria-on-haemostatic-efficacy-versus-usual-care.html

3. Andexxa. Prescribing information. AstraZeneca; 2022. Accessed October 26, 2023. https://medicalinformation.astrazeneca-us.com/home/prescribing-information/andexxa.html