Single-Dose Anticoagulant Promising in Knee Replacement

A monoclonal antibody against coagulation factor XI is being studied to prevent venous thromboembolism (VTE) after knee arthroplasty, with a phase II study suggesting that a single, modest dose could be on par with standard therapy.

Factor XI inhibitor osocimab was associated with VTE rates from 15.7% to 29.9% at 10-13 days postoperatively, varying by dose (0.3-1.8 mg/kg) and whether the single IV infusion was given before or after knee replacement surgery, researchers showed in a paper published online in JAMA.

The three highest postoperative doses showed noninferiority in efficacy against enoxaparin (Lovenox; 26.3%) with a noninferiority margin of 5%, according to the FOXTROT study team led by Jeffrey Weitz, MD, of the Thrombosis and Atherosclerosis Research Institute in East Hamilton, Ontario.

The highest preoperative dose (1.8 mg/kg) actually met the threshold for superiority against the control, but its 4.7% rate of adjudicated major or clinically relevant non-major bleeding led the investigators to conclude that the intermediate (0.6 and 1.2 mg/kg) doses are more promising for future investigation.

That bleed risk was 5.9% with enoxaparin and 2% with apixaban (Eliquis) in the 10-13 postoperative day period. Across all arms of the study, bleeding events were limited to the surgical site through day 13 without any intracranial bleeding or bleeding into another critical site, Weitz’s group reported.

Antithrombotic agents, such as aspirin, currently used for thromboprophylaxis in knee surgery demonstrate low rates of symptomatic VTE and bleeding, Kenneth Bauer, MD, of Beth Israel Deaconess Medical Center, Boston, noted in an accompanying editorial. For example, the apixaban arm had fairly low 14.5% incident VTE rate, he pointed out.

“Based on the results of this dose-finding study, it is not possible to conclude that the risk of bleeding using osocimab … is less than that of currently available anticoagulants or to conclude that osocimab is any more effective in preventing VTE than apixaban,” he commented.

Nevertheless, there is an unmet need where agents targeting factor XI or factor XII may have a role: higher-risk populations needing safer anticoagulant agents, according to Bauer, who cited as examples older patients, those with renal dysfunction, and the acutely ill on extracorporeal membrane oxygenation or left ventricular assist devices.

“In the last 15 years, considerable interest has developed in targeting factor XII, a component of the contact activation pathway, and factor XI in the intrinsic coagulation cascade as an antithrombotic strategy,” according to the editorialist.

Previous work has been done to inhibit factor XI by an antisense oligonucleotide, dubbed FXI-ASO, which was shown in a phase III trial to match enoxaparin in its reduction of VTE elective knee replacement.

FOXTROT included 813 people randomized open-label to various osocimab regimens by IV (before or after unilateral knee arthroplasty) or a control regimen of enoxaparin by subcutaneous injection or oral apixaban for at least 10 days or until the mandatory venography.

Participants had a mean age of 66.5 years, with 74.2% being women.

Of the total cohort, 600 took their assigned medication and had valid venograms and were therefore included in the main per-protocol analysis.

VTE was assessed by bilateral venography or confirmed symptomatic deep vein thrombosis or pulmonary embolism.

“No patient experienced pulmonary embolism during the period between randomization and completion of venography at 10 to 13 days postoperatively, and no deaths occurred during the study,” Weitz and colleagues noted.

Among the limitations of FOXTROT were the open-label design, lack of a placebo group, and exclusion of people who had their procedures with spinal anesthesia.

Moreover, most of the thrombotic events in the trial were asymptomatic deep vein thrombosis found by bilateral venography, which are a surrogate for symptomatic thrombosis, Bauer added.