New oral agents appear effective for preventing VTE in orthopedic surgery patients

Agents are oral inhibitors of Factor Xa — the common point between extrinsic pathways that initiate clotting and intrinsic pathways that amplify clotting.

Issue: March 2006

ATLANTA — New oral agents are on the horizon to prevent thromboembolic events after surgical procedures, and they appear as safe and effective as existing products, according to recent research reports.

The risk of a thromboembolic event, such as deep vein thrombosis (DVT) and pulmonary embolism, is high after major orthopedic surgery.

BAY 59-7939 (Bayer) and LY517717 (Eli Lilly) are oral Xa inhibitors being tested as alternatives to the other anticoagulants. Factor Xa is the common point between extrinsic pathways that initiate clotting and intrinsic pathways that amplify clotting, according to a press statement from ASH. The agents appear to interrupt thrombus formation without impairing platelet hemostatic function.

Alexander G.G. Turpie, MD, of Hamilton Health Sciences-General Hospital in Ontario, provided data from two multinational, randomized, double-blind clinical trials comparing five doses of BAY 59-7939 with enoxaparin (Lovenox, Sanofi-Aventis) for prophylaxis at the 47th Annual Meeting of the American Society of Hematology.

Researchers conducted the first trial of patients undergoing elective total hip replacement surgery in Europe and the second trial of patients undergoing total knee replacement in North America, Turpie said.

They also studied the same regimen of the Bayer compound in both trials. Patient characteristics, such as age, weight and gender, were similar in all treatment groups, according to Turpie.

“[The studies] were designed as dose-finding trials looking at efficacy and safety in comparison to enoxaparin,” Turpie said.

Test design

The researchers randomized 1343 patients to receive either oral BAY 59-7939, given twice daily in total daily doses of 2.5 mg to 60 mg, or subcutaneous enoxaparin at 40 mg once daily starting 12 hours before hip surgery or 30 mg twice daily starting 12 hours after knee surgery.

“The average time to the first oral dose of the test agent was seven hours. And 89% of the patients received this first dose between six to eight hours after surgery. The average duration of treatment was eight days,” he said.

“The assessment for efficacy was a composite of DVT, detected by a standardized bilateral venogram five to nine days after surgery, or earlier if the patients were symptomatic, had objectively confirmed pulmonary embolism and all-cause mortality,” Turpie said.

The secondary efficacy endpoint was major venous thromboembolism (VTE). The primary safety endpoint was major, postoperative bleeding, and researchers analyzed this in 1317 patients.

The risk of higher dosing

Although all doses of the Bayer compound were effective, the risk for major, postoperative bleeding increased with higher doses (P=.001), according to Turpie.

“In respect to safety, there is a clear dose-response relationship with increased risk of bleeding with the higher doses of the Bayer compound, which was highly statistically significant,” he said. “Looking at the three lower doses, where the risk of bleeding was no different or less than that observed with enoxaparin, the rate of venous thromboembolism was at least equivalent or less than that observed with the comparator.”

As far as other safety and tolerability measures were concerned, there was a low incidence of nausea and vomiting despite early postoperative administration of the oral agent. The Bayer compound had no effect on electrocardiogram parameters, including the QT interval. There were no incidences of clinically relevant thrombocytopenia, and the increases in liver enzymes were less than those seen with the comparator, and there was no evidence of a dose-dependent increase in liver abnormalities, Turpie siad.

Turpie said that the study showed that the optimum dose for phase-3 studies should be a total daily dose between 5 mg/day and 20 mg/day.

More investigation

Giancarlo Agnelli, MD, professor of internal medicine at the University of Perugia in Italy, reported data from a double-blind, placebo-controlled, dose-escalation study that investigated the safety and efficacy of LY517717 compared with enoxaparin in preventing VTE in patients undergoing total knee or total hip replacement.

In the study, researchers randomized 511 patients undergoing total knee or total hip replacement to receive either one of six oral doses of LY517717 — 25 mg, 50 mg, 75 mg, 100 mg, 125 mg or 150 mg — or 40 mg of enoxaparin once daily. “The seven groups were well balanced concerning gender, age and body mass index, and there was a slight increased prevalence of hip [surgeries] in the study population,” Agnelli said.

Both treatments were continued for six to 10 doses. Three hundred and ninety-one patients had an evaluable bilateral venogram or experienced an objectively confirmed clinical VTE and were included in the efficacy analyses. Agnelli and colleagues stopped the three lowest doses early due to lack of efficacy, and the study was completed with the three higher doses of LY517717.

“There was a trend of increased efficacy with increased dose,” Agnelli said. “The last three doses, 100, 125 and 150, satisfied the criteria for noninferiority.”

Bilateral venography

Patients underwent bilateral venography within 12 hours of the last dose of the oral study drug, and researchers assessed them for symptomatic DVT, pulmonary embolism and bleeding events through day 30. Symptomatic DVT and pulmonary embolism events were included in the combined VTE endpoint. The 100-mg, 125-mg and 150-mg doses of LY517717 were comparable with enoxaparin in the incidence of symptomatic or venographic DVT or pulmonary embolism. Bleeding events were uncommon in both treatment groups.

“The rate of major bleeding was 1.1% in the enoxaparin group, and 0.9%, 0.9% and 0% in the patients receiving the three highest doses of the Lilly compound. So, there was no difference concerning bleeding, and there was no increase in bleeding associated with the use of the Lilly compound,” Agnelli said.

“We believe that based on the data shown today, we can conclude that at least three doses of LY are as efficacious as enoxaparin in preventing VTE in patients undergoing major orthopedic surgery. We did not observe any apparent increase in bleeding with the use of the LY compound as compared with enoxaparin. The LY was safe and well tolerated,” he said, adding that it would be a good candidate for more clinical trials.

The companies developing the agents provided financial support for the studies.

Dr. Turpie is a paid consultant for Bayer.

For more information:
Turpie AGG, Bauer KA, Borris L, et al. Thromboprophylaxis after orthopedic surgery with an oral, direct factor Xa inhibitor: pooled results of two phase Iib clinical trials. #277. Agnelli G, Haas SK, Krueger KA, et al. A phase II study of the safety and efficacy of a novel oral fXa inhibitor (LY517717) for the prevention of venous thromboembolism following TKR or THR. #278. Both presented at the 47th Annual Meeting of the American Society of Hematology. Dec. 10-13, 2005. Atlanta.