Bristol-Myers Squibb Company and Pfizer Inc. 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 (VTE) 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 orthopaedic surgery, including total hip replacement, are at high risk for venous thromboembolism. In fact, venous thromboembolism occurs in 40 per cent to 60 per cent of patients undergoing orthopaedic 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 orthopaedic 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."
ADVANCE-3, a randomized, double-blind, multi-centre, 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 per cent of patients in the apixaban group and 3.9 per cent of patients in the enoxaparin group, demonstrating a statistically significant relative risk reduction for apixaban of 64 per cent (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 per cent of patients in the apixaban group compared with 1.1 per cent in the enoxaparin group, demonstrating a statistically significant relative risk reduction for apixaban of 60 per cent (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 per cent and 5.0 per cent of patients in the apixaban and enoxaparin groups, respectively (P=0.72). The safety measure of major bleeding occurred in 0.8 per cent of patients who received apixaban, and in 0.7 per cent 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.
Venous thromboembolism encompasses two serious conditions: deep vein thrombosis, a blood clot in a vein, usually in the leg that partially or totally blocks the flow of blood; and pulmonary embolism, a blood clot blocking a vessel in the lungs. Deep vein thrombosis causes multiple symptoms including pain, swelling and redness and, more importantly, can progress to pulmonary embolism, which carries the risk of sudden death.
Apixaban is being investigated within the EXPANSE Clinical Trials Program, which is projected to include nearly 60,000 patients worldwide across multiple indications and patient populations and includes a total of nine completed or ongoing, randomized, double-blind Phase 3 trials, including ADVANCE-3.
The dose and regimen for apixaban were informed by Phase 2 apixaban clinical trial data and data modeling results, which suggest 2.5 mg twice daily dosing provides the optimal balance of safety and efficacy in the prevention of venous thromboembolism.
In addition to prevention of venous thromboembolism, apixaban is in phase 3 trials studying the prevention of stroke and other thromboembolic events in patients with atrial fibrillation and the treatment of venous thromboembolism.
In 2007, Pfizer and Bristol-Myers Squibb entered into a worldwide collaboration to develop and commercialize apixaban, an investigational oral anticoagulant discovered by Bristol-Myers Squibb. This global alliance combines Bristol-Myers Squibb's long-standing strengths in cardiovascular drug development and commercialization with Pfizer's global scale and expertise in this field.
Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases.