Asundexian confers lower bleeding rates vs. apixaban for stroke prevention in AF
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WASHINGTON — In patients with atrial fibrillation requiring stroke prevention, the novel factor XIa inhibitor asundexian was associated with lower bleeding rates compared with apixaban, according to the results of the PACIFIC-AF trial.
Results of the randomized, double-blind, phase 2 PACIFIC-AF trial were presented at the American College of Cardiology Scientific Session and simultaneously published in The Lancet.
The researchers randomly assigned 755 patients (mean age, 74 years; 41% women; 29% with chronic kidney disease) with AF, a CHA2DS2-VASc score of at least 2 if male or 3 if female (mean, 3.9) and elevated bleeding risk to asundexian (Bayer) 20 mg daily, asundexian 50 mg daily or apixaban (Eliquis, Bristol Myers Squibb/Pfizer).
Manesh R. Patel, MD, FACC, FAHA, FSCAI, chief of the divisions of cardiology and clinical pharmacology and Richard Sean Stack, MD Distinguished Professor at Duke University School of Medicine and member in the Duke Clinical Research Institute, said during a presentation that factor Xa inhibitors such as apixaban prevent pathological thrombi but can also prevent the benefits of blood clots, whereas “the hypothesis biologically for factor XI inhibition is to hopefully uncouple this hemostasis from thrombosis in such a way that, when factor XI inhibition happens through that contact pathway, no pathological thrombosis can occur, or at least some of it can be prevented, while potentially preserving some of the tissue factor pathway thrombin generation that would lead to the beneficial blood clots that form.”
Asundexian 20 mg inhibited factor XIa activity by 81% at trough concentrations and 90% at peak concentrations, whereas asundexian 50 mg inhibited factor XIa activity by 92% at trough concentrations and 94% at peak concentrations, Patel said during the presentation.
The primary endpoint of major or clinically relevant nonmajor bleeding by International Society on Thrombosis and Haemostasis criteria occurred in three patients from the asundexian 20 mg group, one patient from the asundexian 50 mg group and six patients from the apixaban group, and there were no major bleeding events in any group, according to the researchers.
Compared with the apixaban group, the ratio of incidence proportion was 0.5 for the asundexian 20 mg group (90% CI, 0.14-1.68), 0.16 for the asundexian 50 mg group (90% CI, 0.01-0.99) and 0.33 (90% CI, 0.09-0.97) for the pooled asundexian group, Patel and colleagues found.
Rates of any adverse event were 47% in both asundexian groups and 49% in the apixaban group, according to the researchers.
“Asundexian, a small oral factor XIa inhibitor, was well tolerated in this phase 2 study of more than 750 patients with atrial fibrillation,” Patel said during the presentation. “It had significantly lower bleeding rates for patients randomized to either dose compared to apixaban. The factor XI inhibition data represent a promising strategy to prevent pathologic thrombi while potentially minimizing bleeding risk in our AF patients. Of course, a phase 3 trial will be required.”
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Chirag R. Barbhaiya, MD, FHRS
What we seem to know so far from this relatively small study is that there seems to be less bleeding with asundexian than there is with apixaban, and that drug levels are less likely to be influenced by kidney disease than currently available direct oral anticoagulants. These are appealing characteristics, but the missing link is going to be whether or not asundexian is as effective as currently available therapies in reducing risk for stroke and thromboembolic events related to AF. If effectiveness is established, asundexian could become an important medication for reducing risk for stroke and thromboembolism in patients with AF.
Asundexian effectively inhibited factor XI activity without causing more bleeding than apixaban, which is the direct oral anticoagulant with the lowest bleeding risk among the commercially available oral anticoagulant medications.
Approximately half of patients who would benefit from anticoagulant medications for prevention of stroke related to AF do not take anticoagulant medications. One of the main barriers to patients’ accepting anticoagulant medications is their perception that they are at significantly increased risk for bleeding when taking these medications. A medication that can prevent stroke without significantly increasing risk for bleeding would be a game changer, and it is possible that asundexian could be just such a medication.
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Patel MR, et al. Featured Clinical Research II. Presented at: American College of Cardiology Scientific Session; April 2-4, 2022; Washington, D.C. (hybrid meeting).
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