Clinicians treating patients with anticoagulants have to walk a fine line in preventing blood clot formation while also minimizing bleeding risk. Targeting factor XI, an important enzyme in the coagulation pathway, could provide a safer way to reduce clot formation, according to a study by Harry Roger Büller, MD, PhD, and colleagues, which found that FXI-ASO, a novel factor XI inhibitor, significantly reduced the risk of post-operative venous thromboembolism (VTE) in patients undergoing knee surgery.
Results of their study were simultaneously published in The New England Journal of Medicine and presented as one of the late-breaking abstracts at ASH’s 56th Annual Meeting.
People who have a level of Factor XI that is naturally reduced also have a lower risk of VTE. The investigators thus hypothesized that minimizing factor XI in patients undergoing a surgical knee replacement would lead to a lower rate of VTE.
To test this concept, Dr. Büller, of the Academic Medical Center of the University of Amsterdam, the Netherlands, and colleagues compared the safety and efficacy of FXI-ASO (an injectable nucleic acid engineered to reduce factor XI expression) with the anticoagulant enoxaparin in 274 patients undergoing elective total knee arthroplasty:
- 134 patients received 200 mg FXI-ASO
- 71 patients received 300 mg FXI-ASO
- 69 patients received 40 mg enoxaparin
Treatment with FXI-ASO, a second-generation antisense oligonucleotide, was initiated 36 days before surgery to allow time for the treatment to interfere with factor XI production; the final dose was given three days after surgery. For patients receiving enoxaparin, the drug was administered subcutaneously once daily.
Injections of the lower dose of FXI-ASO yielded a rate of VTE (the study’s primary efficacy outcome) similar to enoxaparin, while the higher-dose group had a significantly lower VTE rate:
- 200 mg FXI-ASO: 27% (95% CI 20–35), or 36 VTEs
- 300 mg FXI-ASO: 4% (95% CI 1–12), or 3 VTEs
- Enoxaparin: 30% (95% CI 20–43), or 21 VTEs
Both FXI-ASO regimens met the pre-specified criteria for noninferiority to enoxaparin, but the 300-mg dose of FXI-ASO was found to be superior to enoxaparin (p<0.001).
“Only three clots were present in the 300-mg group,” Dr. Büller said during his presentation of results at the ASH Annual Meeting. “This rate, 4.2 percent, has never been seen in the setting of knee surgery, where the best evidence is around 10 or 15 percent.”
FXI-ASO was also considered safe, with three percent of patients in the 200-mg group (4 of 144 patients) and 3 percent in the 300-mg group (2 of 77 patients) experiencing clinically relevant bleeding, versus 8 percent (6 of 72 patients) of the enoxaparin group.
“Our observation that the 300-mg dose regimen of FXI-ASO markedly reduced the rate of venous thrombosis, as compared with enoxaparin, and that any clots that formed were small, raises the possibility that factor XI may be involved not only in the propagation of thrombosis, but also in its initiation,” researchers wrote in their NEJM paper, challenging “the concept that tissue factor is the main driver of thrombosis among patients undergoing surgery.”
The ability to dissociate thrombosis and hemostasis is “the Holy Grail” of anticoagulant therapy, Dr. Büller said, and has the opportunity to revolutionize surgical care and reduce medical costs.
Büller HR, Bethune C, Bhanot S, et al. Factor XI antisense oligonucleotide for prevention of venous thrombosis. N Engl J Med. 2015;372:232-40.