FDA panel rejects ximelagatran as an oral anticoagulant

AstraZeneca proposed the drug as an alternative to warfarin and asked for a three-part indication.

Issue: October 2004

BETHESDA, Md. – A Food and Drug Administration advisory panel rejected ximelagatran as an oral anticoagulant.

Representatives from AstraZeneca had requested the following three-part indication for ximelagatran (Exanta): prevention of venous thromboembolism in patients undergoing knee replacement surgery, prevention of stroke and other thromboembolic complications associated with atrial fibrillation, and long-term secondary prevention of venous thromboembolism after standard treatment of an episode of acute venous thromboembolism.

Hamish Cameron, MD, vice president of Exanta at AstraZeneca, presented ximelagatran as an alternative to warfarin based on the results of the THRIVE III (Thrombin Inhibitor in Venous Embolism III), EXULT A & B (Exanta Used to Lessen Thrombosis) and SPORTIF III and SPORTIF V (Stroke Prevention Using the Oral Direct Thrombin Inhibitor Ximelagatran in Patients with Nonvalvular Atrial Fibrillation) trials.

“Ximelagatran provides predictable kinetics and dynamics allowing fixed dosing, there is no need for anticoagulation monitoring, there is a low risk of food and drug interactions, there is a rapid onset of action, and there is an acceptable bleeding profile,” Cameron said.

The committee disagreed. Panel members rejected all three for reasons of safety. While the nearly unanimous rejection of the Cardiovascular and Renal Drugs Advisory Committee is not binding, the FDA usually follows the advisory panel’s advice.

The committee was concerned about the safety of ximelagatran. Ximelagatran patients had about a one in 2000 chance of developing liver failure, which lead committee reviewer Steven E. Nissen, MD, vice chairman of the department of cardiology at the Cleveland Clinic Foundation, called too high.

“I’m troubled by the nature of this liver injury in that it is difficult to predict. My judgment from hearing the cases is that it is almost certainly drug-related,” Nissen said. He conceded that the risk of liver toxicity was lower with short-term use, suggesting that ximelagatran might be approved for treatment following knee surgery, but he said he was concerned about “duration creep.”

“We hear a lot about dose creep, but what about duration creep? You can use this drug for 12 days, but not for 13, 14, 15 or longer? What if someone is on it, they seem to be doing well, and they stay on the drug for 20 or 30 days or six months? We don’t have a lot of data on the prolonged risk profile, and while my risk concerns are lower for short-term use, they do not entirely go away,” Nissen said.

Panel chairman Jeffrey S. Borer, MD, chief of the division of cardiovascular pathophysiology at Weill Medical College of Cornell University agreed with Nissen, but said the risk should be considered along with the benefits.

“It’s hard for me to talk about safety without putting it in the context of benefit. ... Having an alternative would be very attractive. The risk may be one in 2000, but to prevent a major event you only have to treat 15 patients so this has to be considered,” said Borer, who ultimately voted no on all three parts of the indication.

Representatives from AstraZeneca presented separate data sets for each part of their requested indication.

For the long-term secondary prevention of venous thromboembolism after standard treatment for an episode of venous thromboembolism, the sponsor presented results from the THRIVE III study, which randomized 1223 patients to either 24 mg of ximelagatran or placebo for 18 months. Results showed a significant reduction in the number of recurrent events with approximately 10 patients treated to prevent one event.

For the prevention of venous thromboembolism in patients undergoing knee replacement surgery, researchers presented the EXULT A & B trials, which compared ximelagatran at 24 mg and 36 mg to adjusted dose warfarin. After seven to 12 days of treatment and a follow-up period of four to six weeks, researchers assessed a primary composite outcome of total venous thromboembolism and all-cause mortality. Ximelagatran significantly outperformed warfarin in reducing this outcome.

For the prevention of stroke and other venous and thromboembolic complications associated with atrial fibrillation, researchers presented the SPORTIF III and SPORTIF V trials, which enrolled approximately 7500 patients and randomized them to 36 mg of ximelagatran or dose adjusted warfarin. Researchers concluded that ximelagatran was noninferior.