Less Bleeding With Factor XI Inhibitor Anticoagulant? PACIFIC-AF

April 06, 2022

A new antithrombotic agent in development that targets a novel pathway — inhibition of activated coagulation factor XI — might be able to reduce thromboembolic events with a lower risk of bleeding than currently available anticoagulants, new data suggest.

Results from the PACIFIC-AF phase 2 study of asundexian, a small-molecule oral inhibitor of activated factor XI, in patients with atrial fibrillation (AF) showed the drug to be well tolerated and associated with significantly lower bleeding rates than apixaban.

"Factor XI inhibition is a promising strategy to prevent pathologic thrombi while minimizing bleeding risk in AF patients," study investigator, Manesh Patel, MD, Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina, concluded.

Patel presented the results of the PACIFIC-AF trial on April 3 at the American College of Cardiology (ACC) 2022 Scientific Session. The study was simultaneously published online in the Lancet.

In the Lancet publication, the researchers note that current guidelines recommend non-vitamin K antagonists — also called novel oral anticoagulants (NOACs) or direct oral anticoagulants (DOACs), which mainly inhibit factor X — for stroke prevention in patients with AF because of their improved safety and efficacy over vitamin K antagonists. But use of these agents is still limited because of concerns around bleeding, particularly in vulnerable or older patients with renal dysfunction.

They report that epidemiologic and animal data have identified inhibition of activated factor XI as a new target to prevent thrombosis with minimal effect on hemostasis and bleeding.

Activated factor XI is thought to contribute to clot progression, which can lead to vessel occlusion and pathologic manifestations of thrombosis, but, in contrast to other clotting factors, activated factor XI has only a minor effect on clot consolidation during hemostasis, the authors explain.

Consistent with this hypothesis, most people with factor XI deficiency do not experience spontaneous bleeding or hematomas, and data suggest that they have lower rates of cardiovascular events, including cardioembolic stroke.

Asundexian, in development by Bayer, is a direct, potent inhibitor of activated coagulation factor XI. It is dosed once daily and has a mean terminal half-life of 15.8 to 17.8 hours, with less than 15% renal elimination, Patel noted.

The current PACIFIC-AF study was conducted to determine the optimal dose of asundexian and to compare the incidence of bleeding between asundexian and apixaban in patients with AF.

The study was conducted at 93 sites in 14 countries — 12 European countries, Canada, and Japan — in 755 patients (41% women; mean age, 73 years) with AF, a CHA2DS2-VASc score of at least 2 in males or at least 3 in females (mean score, 3.9), and increased bleeding risk. Of the patients enrolled, 29% had chronic kidney disease and 45% had previously taken DOACs.

They were randomized to 12 weeks of treatment with one of three regimens: asundexian 20 mg once daily; asundexian 50 mg once daily; or apixaban 5 mg twice daily.

Both doses of asundexian resulted in high levels of factor XI inhibition (between 81% and 94% inhibition at trough and peak).

The primary endpoint was the composite of major or clinically relevant non-major bleeding, according to International Society on Thrombosis and Haemostasis (ISTH) criteria.

This occurred in three patients in the asundexian 20 mg group, one patient in the asundexian 50 mg group, and six patients in the apixaban group.

Ratios of incidence proportions for the primary endpoint were 0.50 (90% CI, 0.14 - 1.68) for asundexian 20 mg, 0.16 (90% CI, 0.01 - 0.99) for asundexian 50 mg, and 0.33 (90% CI, 0.09 - 0.97) for pooled asundexian, compared with apixaban.

Noting that the bleeding rate in the study was lower than expected, the researchers say that "although it appears that asundexian leads to less bleeding than apixaban, the magnitude of this effect cannot be defined due to the low event rates."

The rate of any adverse event occurring was similar in the three treatment groups.

The study was not powered to look at thrombotic or cardiovascular events, but an exploratory thrombotic composite endpoint of cardiovascular death, MI, ischemic stroke, and systemic embolism showed two events in the asundexian 20 mg group, four events in the asundexian 50 mg group, and three events in the apixaban group.

"These findings add to increasing evidence around activated factor XI as a therapeutic target, and specifically provide rationale for larger clinical outcome studies with asundexian," the researchers say.

They note that "although DOACs provide safer and more reliable stroke prevention compared with vitamin K antagonism, the risk of bleeding is a persistent and troubling clinical problem. The risk of bleeding often dissuades use of oral anticoagulation, bleeding events lead to discontinuation, discontinuation of oral anticoagulation leads to stroke, and some bleeding events are fatal."

They point out that activated factor XI inhibition with subcutaneous antisense oligonucleotides, human monoclonal antibodies, or orally administered inhibitors, compared with low-molecular-weight heparin, has been shown to prevent venous thromboembolism with a low risk of bleeding after total knee arthroplasty. However, this is the first study to have compared oral anticoagulation with factor XI inhibitors and factor Xa inhibition with DOACs in patients with AF at risk for stroke.

The researchers say the lower rate of bleeding with asundexian is notable, given the lower-than-expected rates of bleeding in the current study, despite enrichment criteria for bleeding risk factors. "Therefore, the potential reduction in bleeding with asundexian might be even greater in general clinical practice, where bleeding rates are higher outside of the controlled setting of a clinical trial," they add.

They also suggest that asundexian might also be particularly beneficial and useful early after an ischemic stroke related to atrial fibrillation.

"Because atrial fibrillation-related strokes often involve a large territory of brain compared with other stroke subtypes, the risk of hemorrhagic transformation is higher and leads to greater disability than other stroke subtypes. Therefore, having a medication with a lower risk of bleeding to use very soon after the initial stroke would be valuable," they say.

Patel reported that other phase 2 trials of asundexian in combination with antiplatelet therapy are underway in patients with noncardioembolic ischemic stroke and acute MI, with results expected later this year.

During discussion of the trial after the ACC presentation, Michael Gold, MD, Medical University of South Carolina, Charleston, congratulated Patel on these "exciting findings."

Gold asked whether the lower dose would be sufficient, given that both doses in this study gave high levels of factor XI inhibition. Patel replied: "We've learned from the factor Xa inhibitors that dose really matters." He added that if hematosis and thrombosis can really be uncoupled by inhibiting factor XI, it might be possible to push the dose to maximize efficacy.

Gold also asked whether any groups had been identified that might need a lower dose of asundexian.

Patel replied that most patients with AF have both thrombotic and bleeding risk. "We are trying to understand what factors increase bleeding risk, as well as thrombotic risk. But we do know that 40% of our AF population is not being treated with any anticoagulation. We need to understand what these patients' risk factors are, and then try to get them into the factor XI inhibitor program."

PACIFIC-AF was funded by Bayer. Patel reports research grants from Bayer and serving as an advisory board member/consultant to the company.

American College of Cardiology (ACC) 2022 Scientific Session. Presented April 3, 2022. 

Lancet. Published online April 3, 2022. Abstract

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