Rivaroxaban (Johnson & Johnson (JNJ) and Bayer AG (BAY)) is one of a new class of oral anticoagulants in development for the prevention and treatment of venous and arterial thromboembolic disease. Rivaroxaban is an orally available small molecule which selectively inhibits factor Xa and prothrombinase activity leading to predictable inhibition of the hemostatic mechanism. The hope is that Rivaroxaban will prove safer and more efficacious than enoxaparin (Lovenox, Sanofi-Aventis (SNY)) now widely used to reduce the risk of dangerous blood clots in the legs and lungs after major surgery. But the real promise of Rivaroxaban is as a replacement for warfarin (Coumadin, Bristol-Myers Squibb Co. (BMY)), a pill used for atrial fibrillation for many years. Coumadin is now widely available as a generic and notoriously difficult to tolerate because of a litany of interactions with food and other medicines. Currently, patients taking warfarin endure constant blood tests to ensure levels are sufficient to prevent strokes, but not high enough to cause dangerous bleeding or brain hemorrhages. Additionally, to avoid serious bleeding, patients scheduled for surgery must stop taking warfarin days ahead of time. Overall, not an ideal situation.
The results of Phase II and III clinical trials presented at the XXIst Congress of the International Society of Thrombosis and Haemostasis (ISTH) continue the positive outlook for this drug. The Phase III RECORD 3 study demonstrated that once daily oral Rivaroxaban was superior to daily subcutaneous Lovenox for the prevention of venous thromboembolism (VTE) after total knee replacement.
There was a 50% reduction in the primary endpoint of symptomatic VTE and all cause mortality, and a 40% reduction in the secondary endpoints of proximal deep venous thrombosis, pulmonary embolism, and VTE related death. This data adds to four large dose-ranging studies including 2861 patients which have been completed in the indication of VTE prevention in major orthopedic surgery in which Rivaroxaban prevented total VTE in a manner comparable to that observed with Lovenox.
Also presented were Phase II data from the ODIXa-DVT and EINSTEIN-DVT studies comparing Rivaroxaban to standard
therapy with Lovenox and Coumadin in the treatment and secondary prevention of DVT. Both studies demonstrated similar efficacy and rates of major bleeding as compared to standard therapy. BAY is presently enrolling patients in a Phase III study EINSTEIN-VTE (Oral direct factor Xa inhibitor rivaroxaban in patients with acute symptomatic deep-vein thrombosis or pulmonary embolism) and EINSTEIN-Extension (once-daily oral direct factor Xa inhibitor rivaroxaban in the long-term prevention of recurrent symptomatic venous thromboembolism in patients with symptomatic deep-vein thrombosis or pulmonary embolism). Phase II studies are enrolling for the prevention of stroke in patients with atrial fibrillation and the treatment of acute coronary syndromes.
Apixiban (BMY and Pfizer Inc. (PFE)) is a competing oral factor Xa inhibitor. In a Phase II DVT treatment study presented at ISTH, Apixiban demonstrated similar efficacy and safety to standard therapy during a 12 week study in the treatment of acute DVT.
Bottom Line - Rivaroxaban is a novel anticoagulant that continues to have favorable results in ongoing clinical trials. The ability to administer an oral anticoagulant with a rapid onset of action which does not require monitoring is very attractive to clinicians, and bodes well for the use of this medication. Apixiban appears to have similar favorable characteristics, but it may suffer if Rivaroxaban remains on track to be first to market.
In other ISTH news, Dabigatran, an oral factor IIa inhibitor (Rendix, Boehringer Ingelheim GmbH), failed to achieve the primary endpoint of a composite of total VTE and all-cause mortality when compared to enoxaparin in the prevention of VTE after knee replacement surgery. With lingering concerns about liver toxicity associated with oral direct thrombin inhibitors and poor oral bioavailability, Dabigatran is facing an uphill battle.
David Feinbloom, M.D. is an academic hospitalist at Beth Israel Deaconess Medical Center and an instructor in medicine at Harvard Medical School. His research focus is on arterial and venous thrombosis with a particular interest in anticoagulation.