ORLANDO -- For preventing venous thromboembolism following a total knee replacement, the investigational oral anticoagulant dabigatran etexilate was comparable to Lovenox, investigators reported here.
ORLANDO, Dec. 11 -- The investigational oral anticoagulant dabigatran etexilate was comparable to Lovenox at preventing venous thromboembolism following a total knee replacement, investigators reported here.
In a phase III randomized trial of the drug in more than 2,000 patients, dabigatran at either of two oral doses was as effective as Lovenox (an injectable low molecular weight heparin) at preventing venous thromboembolic events, reported Bengt Eriksson, M.D., on behalf of investigators in the multinational RE-MODEL trial.
There was no significant difference in all-cause mortality or bleeding risk, said Dr. Eriksson, an orthopedic surgeon in Gothenburg, Sweden, at the of the American Society of Hematology meeting.
If the drug is approved, he said, it would be a significant improvement over conventional anticoagulation therapy with injectable heparins or oral vitamin K antagonists such as Coumadin (warfarin), because dabigatran is delivered orally in a fixed daily dose and does not require INR monitoring.
But the drug was given for only six to 10 days and follow-up was for only three months, and it isn't yet clear whether dabigatran, a direct thrombin inhibitor, will turn out to have liver toxicity, one of the fatal flaws that doomed Exanta (ximelagatran), another oral direct thrombin inhibitor, Dr. Eriksson acknowledged.
The RE-MODEL Study was a multinational randomized, double-blind placebo controlled trial pitting dabigatran against Lovenox in 2,076 patients undergoing total knee replacement.
Patients were randomized to dabagitran at either 150 mg or 229 mg once daily, with half of the assigned dose being given on the day of surgery, one to four hours post-operatively, or to Lovenox at 40 mg once-daily by subcutaneous injection, beginning 12 hours before the start of surgery.
Patients were treated for six to 10 days, and were followed up for three months after surgery. The goal of the study was to show non-inferiority for dabagitran, measured by the primary efficacy endpoint of venous thromboembolism and all-cause mortality.
The presence of venous thromboembolism was determined by centrally adjudicated objective clinical testing for symptomatic events, and centrally adjudicated bilateral venograms on the last day of treatment for asymptomatic events.
The investigators found that the primary efficacy endpoint of total venous thromboembolism and all cause mortality, were similar among all groups, occurring in 40.5% of patients on dabigatran at 150 mg, 36.4% on dabigatran at 220 mg, and 37.7% on Lovenox (P for non-inferiority versus enoxaparin for both doses <0.05).
Proximal deep vein thrombosis and/or pulmonary embolism occurred in 3.8% of patients on dabigatran 150 mg, 2.6% on dabigatran 220 mg, and 3.5% of those on Lovenox. Symptomatic DVT occurred in one patient given dabigatran at 150 mg, in three on dabigatran 220 mg, and in eight on Lovenox. Asymptomatic DVTs occurred in 36.0%, 39.5%, and 35.9% of patients in the respective groups. There were three deaths, one in each group.
In the safety analysis, they found that were no significant differences in major bleeding rates in 1.3% of patients on dabigatran at 150 mg, 1.5% on dabigatran at 220 mg, and 1.3% on enoxaparin.
Elevated levels of alanine aminotransferase three times the upper limit of normal occurred in 3.7% and 2.8% of patients on dabigatran 150 and 220 mg, respectively, and in 4.0% of patients on Lovenox; these differences were not statistically significant.
"Dabigatran etexilate is a new anticoagulant that provides safe and reliable protection combined with convenience," Dr. Eriksson said. "Both concerning oral dosing and lack of coagulation monitoring, there are strong reasons to believe there will be considerable benefit of the drug in other medical indications where there is a risk of life-threatening thrombosis or thromboembolism."
Dr. Eriksson noted that the three-month follow-up period in the study was implemented at the recommendation of the FDA, following trial results with Exanta, which in late stage clinical trials was shown to have both hepatic and cardiac toxicities. That drug was deemed unapprovable by the FDA.
The RE-MODEL study was supported by Boehringer Ingleheim, manufacturer of dabigatran exetilate. Dr. Eriksson did not disclose any conflicts of interest.