Phase II clinical trial results published today in Circulation (2006;114:2374-2381) highlight the potential of a simple, once-daily dosing regimen of the novel, oral anticoagulant rivaroxaban (BAY 59-7939), a direct Factor Xa inhibitor. In this trial, rivaroxaban demonstrated that it may have similar safety and efficacy to subcutaneous enoxaparin (the current standard), for the prevention of venous thromboembolism (VTE) in patients undergoing elective total hip replacement surgery.
?These data show that we could be another step closer to the clinical reality of an oral, once-daily anticoagulant that is not associated with limitations of current standard therapies such as regular monitoring or administration by injection. The work done with rivaroxaban is important in the field of anticoagulation, and we hope to confirm these results in ongoing, extensive phase III studies,? said Bengt Eriksson MD, PhD, from Sahlgrenska University Hospital in Gothenburg, Sweden, the principal investigator in this phase II trial, and one of the principal investigators in the ongoing phase III programme.
Today?s publication completes the phase II programme with rivaroxaban for the prevention of VTE after major orthopaedic surgery, and contains the full data set from the once-daily dosing trial; results from twice-daily trials in hip and knee replacement surgery have already been published (Eriksson et al. J Thromb Haemost 2006;4:121?128; Turpie et al. J Thromb Haemost 2005;3:2479?86). These data taken together formed the basis of the decision to initiate the phase III programme with rivaroxaban for the prevention of VTE after orthopaedic surgery, using a once-daily dosing regimen.
The ODIXa-HIP od trial, a multi-center, randomized, international trial, evaluated 873 patients undergoing elective total hip replacement surgery for related VTE and bleeding. Study drugs were oral, once-daily rivaroxaban 5?40 mg, or the current standard, once-daily subcutaneous enoxaparin 40 mg, each continued for a further 5?9 days after surgery. The primary efficacy endpoint was the incidence of VTE (deep vein thrombosis [DVT] or pulmonary embolism [PE]), or death from any cause. The incidence of VTE was observed in 6.4?14.9% of patients receiving oral, once-daily rivaroxaban, compared with 25.2% of enoxaparin patients.
In this trial, oral rivaroxaban was shown to have similar safety to injected enoxaparin when administered once daily, as reported with twice daily rivaroxaban in earlier phase II trials. The incidence of major, post-operative bleeding was similar with the lower rivaroxaban doses and enoxaparin: major, post-operative bleeding was observed in 0.7% of patients receiving oral rivaroxaban 10 mg once daily, compared with 1.9% of patients given daily injections of enoxaparin 40 mg.
Currently, low molecular weight heparins (LMWHs; including enoxaparin) and vitamin K antagonists (VKAs, including warfarin) are used for the prevention of VTE after orthopaedic surgery. The parenteral (intravenous) administration of LMWHs limits their use, and an oral drug is more convenient for patients and physicians alike.
Clinicians currently have no alternative oral anticoagulant to VKAs, which have a slow onset of action, inter-patient variability, and several drug?drug and food?drug interactions, so their effects must be monitored carefully (with the dose increased or decreased accordingly), or the patient is at increased risk of suffering a VTE or major haemorrhage (Ansell and Berqvist. Drugs 2004 64;suppl 1:1?5).
In the United States alone, approximately 700,000 hip and knee replacements are carried out each year. If approved, the availability of a once-daily tablet could effectively protect patients against VTE, without the inherent disadvantages of current drugs.
Phase III RECORD Programme
Based on the full results published today, rivaroxaban 10 mg once daily offers the optimum combination of safety and efficacy, and was chosen as the dose for the phase III studies for the prevention of VTE after elective major orthopaedic surgery. The RECORD (REgulation of Coagulation in major Orthopaedic surgery reducing the Risk of DVT and PE) programme is currently enrolling and will evaluate over 10,000 patients. The first regulatory filing for market authorization in this indication is planned for late 2007 in Europe and 2008 in the United States.
Alexander GG Turpie, Professor of Medicine at McMaster University, Hamilton, Canada, and lead investigator of one of the RECORD studies said, ?We are delighted with the progress being made in the RECORD programme, and look forward to the results next year.?
About rivaroxaban:
Rivaroxaban is a first-in-class, oral, once-daily, direct Factor Xa inhibitor. It is an anticoagulant (a drug that limits blood clotting) in advanced clinical development for the effective prevention and treatment of venous and arterial thrombosis, in both the acute and chronic settings. It acts at the central point in the coagulation cascade, to regulate thrombin generation, which leads to clot formation.