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Treatment with the bleeding reversal agent andexanet (Andexxa) in people with acute intracerebral hemorrhage on factor Xa inhibitors led to less expansion of hematoma volume but was associated with thrombotic events, the trial showed.

A composite measure of hemostatic efficacy was achieved in 67% of patients receiving andexanet compared with 53.1% of those receiving usual care (adjusted difference, 13.4 percentage points; 95% CI 4.6-22.2, P=0.003), reported Stuart Connolly, MD, of McMaster University in Ontario, Canada, and colleagues in the .

Hemostatic efficacy, the primary endpoint, was defined by three measures at 12 hours: expansion of hematoma by 35% or less, an increase of less than 7 points on the National Institutes of Health Stroke Scale (), and no receipt of rescue therapy. The median percent change in anti-factor Xa activity between baseline and the 1-to-2-hour nadir was 94.5% with andexanet and 26.9% with usual care (P<0.001).

However, 10.3% of participants receiving andexanet experienced thrombotic events, compared with 5.6% in the usual care group (difference 4.6 percentage points; 95% CI 0.1-9.2, P=0.048). Ischemic stroke occurred in 6.5% and 1.5% of participants, respectively. Differences between groups in disability scores assessed by the modified Rankin scale, or in death within 30 days, didn't differ appreciably.

"We did see that the drug -- although it reduces expansion, which is a benefit -- actually increases the risk of thrombotic events, in particular ischemic stroke," Connolly told MedPage Today. "That's the fly in the ointment."

Acute cerebral hemorrhage is associated with high morbidity and mortality, and hematoma expansion is a complication that can occur in patients taking oral anticoagulants, including factor Xa inhibitors like apixaban (Eliquis) and rivaroxaban (Xarelto).

Andexanet alfa is a form of human factor Xa, a reversal agent that binds and sequesters Xa inhibitor molecules, restoring thrombin generation. A previous study, ANNEXA-4, found that in patients on a factor Xa inhibitor with acute major bleeding in any site, 82% had excellent or good hemostatic efficacy at 12 hours.

That study, however, lacked a control group, so the researchers set out to conduct the randomized controlled ANNEXA-I trial. (Andexanet received accelerated approval from the FDA in May 2018 after an interim analysis from ANNEXA-4.)

In ANNEXA-I, outcomes "were assessed in patients with small hematoma volumes and mild-to-moderate neurologic deficits at baseline -- enrollment criteria for the trial -- although this is the population that could perhaps benefit most from avoiding hematoma expansion," noted Wade Smith, MD, PhD, and J. Claude Hemphill, MD, both of the University of California San Francisco, in an .

ANNEXA-I assessed efficacy at 12 hours after baseline, and "although three efficacy measures were used as part of the primary endpoint, only hematoma expansion, not early clinical deterioration or the need for rescue therapy, differed appreciably between the trial groups," Smith and Hemphill pointed out.

In addition, "longer-term outcomes at 3 or more months, a standard measure in most stroke clinical trials, including those for intracerebral hemorrhage, were not reported," they added.

Longer-term data might be difficult to achieve, Connolly noted, but physicians could use the trial outcomes to inform clinical risk-benefit analyses.

"Probably the kind of decision-making that will go on will be, if you're at very high risk for expansion, then you're probably going to treat and take your risk on ischemic stroke," Connolly said. "So patients who come in a little bit later on, with not such a big hematoma, maybe you don't treat them because of the risk of having a thrombotic event like ischemic stroke."

ANNEXA-I included participants who had intracerebral hemorrhage, were on a factor Xa inhibitor most recently taken within 15 hours of randomization, and had not received andexanet before. Patients with a score of less than 7 or a score of more than 35 on the NIHSS were excluded, along with anyone with surgery planned within 12 hours after enrollment, or a thrombotic event within 2 weeks before enrollment.

Overall, 530 people were enrolled in the trial from 2019-2023, including 263 patients randomized to andexanet and 267 to usual care. All were included in the safety analysis, but efficacy was assessed in an interim analysis of 452 participants. The average age in the efficacy analysis was about 79, and just under half of participants were female.

Of those in the usual care group, 85.5% received prothrombin complex concentrate within 3 hours after randomization. Patients in the andexanet group received either a high-dose or low-dose bolus over 15 to 30 minutes followed by a continuous infusion over 2 hours, with bolus dose based on FDA labeling and type, amount, and timing of their most recent factor Xa inhibitor dose.

Atrial fibrillation was the most frequent indication for factor Xa inhibitors. Most participants were on apixaban (62.5%) or rivaroxaban (28.6%).

The trial was not designed for subgroup analyses, the researchers acknowledged. Relative clinical effects of andexanet are difficult to assess, they noted, and the mechanism of thrombotic events with andexanet is uncertain.

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