SAN FRANCISCO – Reducing factor XI levels with the experimental antisense oligonucleotide FXI-ASO lowered venous thromboembolism rates after total knee arthroplasty without increasing bleeding in a phase II study.

Venous thromboembolism (VTE) rates were 30% among controls (21/69) on enoxaparin (Lovenox) 40 mg, compared with 27% for patients (36/134) given FXI-ASO 200 mg and 4% for those (3/71) given FXI-ASO 300 mg. Low-dose FXI-ASO was noninferior to enoxaparin (P = .59), while the high-dose regimen was superior (P < .001).

A 4% VTE rate “has never ever been seen before in patients undergoing knee surgery,” Dr. Harry Büller said during the late-breaking abstract session at the annual meeting of the American Society of Hematology.

The strategy of targeting factor XI is based on the understanding that patients with factor XI deficiency (plasma levels < 20% of normal) have a reduced risk of deep vein thrombosis (DVT). Experimental data in mice and primates also suggest that reducing factor XI attenuates thrombosis without excess bleeding.

Among the 300 patients in the open-label study, major or clinically relevant bleeding occurred in 3% of both FXI-ASO groups and 8% of the enoxaparin group (P = .09).

The findings provide the first evidence in humans that the factor XI intrinsic pathway is one of the drivers of postoperative thrombosis and support the concept that thrombosis and hemostasis can be dissociated, said Dr. Büller of the Academic Medical Center, Amsterdam.

“FXI-ASO is a promising new investigational antithrombotic agent and I believe you are witnessing the birth of a new class of antithrombotic agents,” he concluded.

During a press conference, Dr. Büller confided to reporters that he felt like a boy in a candy store, finally able to reveal the superb study findings.

Dr. Robert Flaumenhaft of Harvard Medical School, Boston, was far less effusive in an editorial that accompanied the simultaneous publication of the study in the New England Journal of Medicine.

“Do these finding prove that reduction in factor XI levels inhibits thrombosis without affecting bleeding? The conservative answer is no,” he wrote.

Dr. Flaumenhaft observed that the incidence of clinically relevant bleeding is relatively low after knee arthroplasty, even when patients receive anticoagulants, and that this safety outcome did not differ significantly between the enoxaparin and 300-mg FXI-ASO groups.

“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.

Central to this argument are issues of convenience and questions regarding reversibility. Treatment began 36 days before surgery and was associated with a high incidence of adverse events at the injection site and factor XI levels remained about 60% lower 70 days after initiation of therapy.

The half-life of FXI-ASO is about 22 days, “which in the classical setting in terms of bleeding could be seen as something of a disadvantage,” Dr. Büller told reporters. “But if we do the next study and it shows to be safe, it turns into an advantage” … because there is the possibility of giving FXI-ASO once every 3 weeks.

Dr. Flaumenhaft closed the editorial by acknowledging that the study challenges “the current paradigm” regarding the primary mechanism responsible for fibrin formation during thrombosis. “The striking observation that reducing factor XI levels prevents thrombosis after knee arthroplasty provides the best clinical evidence to date that the intrinsic pathway is essential for thrombus formation,” he wrote.

The study was conducted at 19 centers in five countries and randomly assigned 300 patients scheduled for elective primary unilateral total-knee arthroplasty to daily enoxaparin 40 mg or three doses of FXI-ASO. The protocol was amended early on to exclude a 100-mg FXI-ASO dose.

FXI-ASO 200 mg or 300 mg was given subcutaneously beginning 36 days before surgery on days 1, 3, 5, 8, 15, 22, and 29, and 6 hours postoperatively, with a final dose on day 39.

Enoxaparin 40 mg was given subcutaneously once daily, beginning the evening before or 6-8 hours after surgery, according to investigator preference, and was continued for at least 8 days postoperatively.

The primary efficacy point was a composite of asymptomatic DVT, detected by venography, and confirmed symptomatic VTE.

At baseline, the average factor XI level was 1.23 units/mL in the enoxaparin group, 1.20 U/mL in the 200-mg group, and 1.16 U/mL in the 300-mg group.

In patients with an average factor XI level of 0.2 U/mL or less, the incidence of the primary efficacy outcome was 5%.

Isis Pharmaceuticals funded the study. Dr. Büller disclosed ties with Isis, Daiichi-Sankyo, Bayer Healthcare, Pfizer, and Bristol-Myers Squibb. Dr. Flaumenhaft reported having no disclosures.

pwendling@frontlinemedcom.com

Factor XI inhibitor trims DVTs after knee replacement surgery