Dose-response study of recombinant factor VIIa/tissue factor inhibitor recombinant nematode anticoagulant protein c2 in prevention of postoperative venous thromboembolism in patients undergoing total knee replacement

Background-With the best prophylactics now available, venous thromboembolism after total knee replacement remains substantial (25% to 27%). Recombinant nematode anticoagulant protein c2 (rNAPc2) is a potent inhibitor of factor VIIa/tissue factor complex that has the potential to reduce this risk. The present study was performed to determine an efficacious and safe dose of rNAPc2 for prevention of venous thromboembolism after elective unilateral total knee replacement. Methods and Results-This open-label, sequential dose-ranging study was conducted in 11 centers in Canada, Europe, and the United States. Five regimens were tested. Injections were administered subcutaneously on the day of surgery (day I) and days 3, 5, and optionally, day 7, Primary efficacy outcome was a composite of overall deep vein thrombosis based on mandatory unilateral venography (day 7 +/-2) and confirmed symptomatic venous thromboembolism recorded less than or equal to 48 hours after the last dose of rNAPc2. Primary safety outcome was major bleeding less than or equal to 72 hours after the last dose, An independent, blinded Central Adjudication Committee assessed all outcome events. Of 293 patients studied, 251 (86%) could be evaluated for primary efficacy analysis. A dosage of 3.0 mug/kg administered within 1 hour after surgery provided the best observed results, with an overall deep vein thrombosis rate Of 12.2%, a proximal deep vein thrombosis rate of 1.3%, and a major bleeding rate of 2.3%. Conclusions-A randomized, double-blind trial that compared rNAPc2 with current best prophylactics is warranted based on encouraging, first-reported clinical results for a factor VIIa/tissue factor inhibitor evaluated for thrombosis prophylaxis.