PFE/BMY are presumably going to submit an NDA for Apixaban in VTE prevention following hip or knee surgery, but this could be tricky because one of the two knee studies (ADVANCE-1) failed to show non-inferiority to Lovenox (#msg-31742223).
By combining the ADVANCE-2 study in knee surgery (#msg-47461590) with the ADVANCE-3 study in hip surgery (the study you just posted about), PFE/BMY may be able to persuade the FDA to use the pooled results for both hip and knee. However, there are also questions regarding the dose of Lovenox used in the comparator arms of these studies, as discussed in the prologue of #msg-47461590.
This is BMY/PFE’s PR on the Apixaban ADVANCE-3 study in VTE prevention (which has more detail than the Bloomberg newswire in #msg-58061287). Please see #msg-58061618 for a discussion of what these data mean in the context of the overall VTE-prevention program.
›Newly Published Investigational Apixaban ADVANCE-3 Study Results Demonstrate Statistical Superiority to Enoxaparin with Comparable Rates of Bleeding in the Prevention of Venous Thromboembolism Following Total Hip Replacement Surgery
Wednesday December 22, 2010, 5:05 pm EST
PRINCETON, N.J. & NEW YORK--(BUSINESS WIRE)-- Bristol-Myers Squibb Company (NYSE:BMY) and Pfizer Inc. (NYSE:PFE) today announced that the ADVANCE-3 study results, published in The New England Journal of Medicine, showed apixaban was statistically superior to 40 mg once daily enoxaparin in reducing the incidence of venous thromboembolism in patients undergoing elective total hip replacement surgery. The study results also showed comparable rates of the composite of major and clinically relevant non-major bleeding, including surgical site bleeding, in patients treated with apixaban compared with those treated with enoxaparin.
Patients undergoing major orthopedic surgery, including total hip replacement, are at high risk for venous thromboembolism. In fact, venous thromboembolism occurs in 40 percent to 60 percent of patients undergoing orthopedic surgery who do not receive preventive care. With close to 200,000 hip replacement surgeries performed each year in the United States, the threat of venous thromboembolism and its associated morbidity and mortality risk represent a growing challenge to physicians.
Apixaban is an investigational, oral, highly selective Factor Xa inhibitor, part of a class of agents being studied for their potential to prevent and treat blood clots in the veins and arteries. Results of ADVANCE-3 were first presented in July 2010, at the 21st International Congress on Thrombosis in Milan, Italy.
“One of the major concerns for orthopedic surgeons using oral anticoagulants for venous thromboembolism prevention in hip surgery is the significant risk of bleeding,” said Michael Rud Lassen, M.D., Hoersholm Hospital in Copenhagen, Denmark, lead investigator for the study. “We are encouraged by the ADVANCE-3 data, which demonstrated that apixaban provides more effective thromboprophylaxis without an increased risk of bleeding, when compared with enoxaparin, and has the advantages of oral administration, which is particularly beneficial once patients leave the hospital.”
About ADVANCE-3
ADVANCE-3, a randomized, double-blind, multicenter, head-to-head trial was designed to evaluate the efficacy and safety of oral, twice daily apixaban 2.5 mg compared with subcutaneous enoxaparin 40 mg once daily, over a 35-day treatment period for reducing the risk of venous thromboembolism in patients undergoing elective total hip replacement surgery.
Of the 5,407 patients from 21 countries (Europe, Asia/Pacific, Latin America, Africa) randomized in the study, 3,866 patients were eligible for the analysis of the primary efficacy endpoint defined as the composite of adjudicated asymptomatic or symptomatic deep vein thrombosis, nonfatal pulmonary embolism or death from any cause during study treatment.
When apixaban was compared with enoxaparin, the primary efficacy endpoint occurred in 1.4 percent of patients in the apixaban group and 3.9 percent of patients in the enoxaparin group, demonstrating a statistically significant relative risk reduction for apixaban of 64 percent (one-sided P<0.001 for noninferiority and two-sided P<0.001 for superiority).
The secondary efficacy outcome of major venous thromboembolism – defined as the composite of adjudicated asymptomatic or symptomatic proximal deep vein thrombosis, nonfatal pulmonary embolism, or death related to venous thromboembolism – occurred in 0.5 percent of patients in the apixaban group compared with 1.1 percent in the enoxaparin group, demonstrating a statistically significant relative risk reduction for apixaban of 60 percent (one-sided P<0.001 for noninferiority and two-sided P=0.01 for superiority).
A principal safety measure, the composite of major and clinically relevant non-major bleeding, occurred in 4.8 percent and 5.0 percent of patients in the apixaban and enoxaparin groups, respectively (P=0.72). The safety measure of major bleeding occurred in 0.8 percent of patients who received apixaban, and in 0.7 percent of patients who received enoxaparin (P=0.54).
In ADVANCE-3, the overall safety profiles (i.e., bleeding, adverse events, serious adverse events, discontinuations due to adverse events, liver function test increases) of apixaban and enoxaparin were similar. In addition, the number of deaths, myocardial infarctions, strokes and episodes of thrombocytopenia (low platelet count) in the study was low.‹
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