麻豆传媒

A novel anti-factor XI agent was at least as good as low-molecular-weight heparin for prevention after knee arthroplasty, without significant differences in bleeding risk, according to a phase II trial.

Injections of the second-generation antisense oligonucleotide FXI-ASO yielded a venous thromboembolism rate that was noninferior to enoxaparin (Lovenox) when the novel agent was given at 200 mg (27% versus 30%), , of the University of Amsterdam Academic Medical Center, and colleagues found.

The 300-mg dose of the factor XI-reducing agent significantly lowered that rate of events discovered by symptoms or mandatory bilateral venography to 4% (P<0.001 for superiority), the researchers reported online in the New England Journal of Medicine and at the American Society of Hematology meeting in San Francisco.

Major or clinically relevant bleeding events were nonsignificantly lower with the novel agent as well (3% in both dose groups versus 8% with enoxaparin) in the Factor XI-ASO Total Knee Arthroplasty study.

"FXI-ASO has the potential to reduce the rate of postoperative thrombosis to a greater extent than conventional anticoagulants, without increasing bleeding," the researchers concluded. "These findings support the concept that with the use of strategies targeting factor XI, thrombosis and hemostasis can be dissociated."

Factor XI falls in the intrinsic pathway that triggers clotting in response to DNA, RNA, and inorganic phosphates that are released by tissue damage.

By contrast, factor Xa (targeted by some of the newer oral anticoagulants) is on the extrinsic pathway triggered by tissue factors released by an event like surgery.

That FXI-ASO, which reduces human factor XI messenger RNA expression in the liver to block its role in the clotting cascade, reduced venous thromboembolism "challenges the concept that tissue factor is the main driver of thrombosis among patients undergoing surgery," Buller's group wrote.

FXI-ASO prolonged the activated partial-thromboplastin time in the trial but had no effect on the prothrombin time or the levels of factors VIII, IX, and XII, the other components of the intrinsic pathway.

, a hematologist-oncologist and medical director of the Clot Connect education program of the University of North Carolina at Chapel Hill, called the findings the most significant at the conference.

"It is fascinating that the lowering of factor XI can decrease the risk for thrombosis, yet not lead to an increase in bleeding," he told 麻豆传媒. "In other words, an anticoagulant does not necessarily need to lead to an increased bleeding risk. It is this dissociation of bleeding and protection from thrombosis that is so impressive, intriguing, and promising."

While agreeing that the concept is tantalizing, , of Harvard and Beth Israel Deaconess Medical Center in Boston, didn't find the FXI-ASO data convincing.

"These results also do not make a compelling case for the clinical use of the factor XI antisense oligonucleotide over anticoagulants that are currently used for prophylaxis in patients undergoing knee arthroplasty," he wrote in an accompanying editorial.

The trial was too small and in a setting (elective primary unilateral total knee arthroplasty) where the incidence of clinically relevant bleeding is already low, even when patients are on anticoagulants, to really prove anything about reduced bleeding risk, he proposed.

And inconvenience and questions over reversibility could dampen enthusiasm, Flaumenhaft suggested.

In the 300-patient trial, FXI-ASO had to be started 36 days before surgery (three times in the first week then four once-weekly doses).

And the subcutaneous injections were associated with a high incidence of injection site reactions, with rates of 32% in the 200-mg dose group and 25% in the 300-mg dose group compared with 2% in the enoxaparin group, although the researchers emphasized that these were "mild and did not result in discontinuation of the study drug."

The drug dramatically knocked down factor XI levels to 0.38 and 0.20 units/mL for the lower and higher dose groups, respectively, at the time of surgery compared with 0.93 units/mL in the enoxaparin group.

Even more than a month after the last FXI-ASO dose, factor XI levels "remained reduced by approximately 60% without evidence of recovery," Flaumenhaft noted.

But there could be a subset of patients for whom such a drug would makes sense, he pointed out."Many conditions require long-term primary or secondary antithrombotic prophylaxis," he wrote. "Factor XI antisense oligonucleotide, with its prolonged activity and possibility of decreased bleeding risk, may represent a useful therapy in this context."

The researchers agreed that "although the slow onset of action of FXI-ASO precludes its use as the sole therapy when a rapid antithrombotic effect is needed, its profile renders it an appealing option for the management of a wide range of chronic thrombotic conditions."

There were no symptomatic pulmonary embolism cases in the trial and no symptomatic deep vein thrombosis in the follow-up period after venography.

Symptomatic venous thromboembolism rates were low across the groups, at 1% in the 200-mg FXI-ASO group, 0% in the 300-mg dose group, and 1% in the enoxaparin group.

The researchers cautioned about the modest sample size and the open-label design but noted that all outcomes were adjudicated by a panel blind to treatment assignments.

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