Rivaroxaban

Rivaroxaban (BAY 59-7939) is an oral anticoagulant invented and manufactured by Bayer; in a number of countries it is marketed as Xarelto. In the United States, it is marketed by Janssen Pharmaceutica. It is the first available orally active direct factor Xa inhibitor. Rivaroxaban is well absorbed from the gut and maximum inhibition of factor Xa occurs four hours after a dose. The effects lasts 8–12 hours, but factor Xa activity does not return to normal within 24 hours so once-daily dosing is possible.

Regulatory approval and indications
In September 2008, Health Canada granted marketing authorization for rivaroxaban as one 10 mg tablet taken once daily for the prevention of venous thromboembolism (VTE) in patients who have undergone elective total hip replacement or total knee replacement surgery.

In September 2008, the European Commission granted marketing authorization of rivaroxaban for the prevention of venous thromboembolism in adult patients undergoing elective hip and knee replacement surgery.

On July 1, 2011, the U.S. Food and Drug Administration (FDA) approved rivaroxaban for prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE), in adults undergoing hip and knee replacement surgery.

On September 8, 2011, an independent FDA Advisory Panel recommended approval (9-2 [1 abstaining]) of Xarelto for stroke prophylaxis in patients with atrial fibrillation. The dissenting votes suggested the direct Xa inhibitor needed more studies to determine safety and comparison to clinical dosing of warfarin and dabigatran.

Mechanism of action
Rivaroxaban is an oxazolidinone derivative optimized for inhibiting both free Factor Xa and Factor Xa bound in the prothrombinase complex. It is a highly selective direct Factor Xa inhibitor with oral bioavailability and rapid onset of action. Inhibition of Factor Xa interrupts the intrinsic and extrinsic pathway of the blood coagulation cascade, inhibiting both thrombin formation and development of thrombi. Rivaroxaban does not inhibit thrombin (activated Factor II), and no effects on platelets have been demonstrated.

Rivaroxaban has predictable pharmacokinetics across a wide spectrum of patients (age, gender, weight, race) and has a flat dose response across an eightfold dose range (5–40 mg). Clinical trial data have shown that it allows predictable anticoagulation with no need for dose adjustments and routine coagulation monitoring. However, these trials have excluded patients with liver disease and end-stage liver disease and use of rivaroxaban may be unsafe in these populations.

Clinical development
Four clinical studies with a total enrollment of over 12,000 patients have shown that oral rivaroxaban has non-inferior and possibly superior efficacy compared to 40 mg per day of the subcutaneous low molecular weight heparin (LMWH) enoxaparin in preventing VTE in adult patients undergoing total hip or knee replacement surgery. However, the risk of bleeding was greater in patients randomized to rivaroxaban (10 mg/day) rather than enoxaparin (40 mg/day) and one patient (out of > 6000) randomized to rivaroxaban died of liver toxicity. The four studies include RECORD1 and 2 (hip replacement) and RECORD3 and 4 (knee replacement). The RECORD4 study concluded that rivaroxaban was significantly more effective in reducing the occurrence of venous blood clots following knee replacement surgery than enoxaparin.

In addition, rivaroxaban has been studied in phase III clinical trials for stroke prevention in non-valvular atrial fibrillation (AF or afib) (ROCKET-AF), prevention of VTE in hospitalized medically ill patients (MAGELLAN), treatment and secondary prevention of VTE (EINSTEIN), and secondary prevention of major cardiovascular events in patients with acute coronary syndrome (ACS) (ATLAS ACS TIMI 51). More than 8,000 patients have been enrolled in the rivaroxaban clinical development program overall. The study has been completed and shows that taking rivaroxaban once daily for 35 days was associated with a reduction in the risk of venous thrombosis, compared with standard 10-day treatment with enoxaparin by subcutaneous injection, in acutely ill medical patients. However, bleeding rates were significantly increased with rivaroxaban.

A study in December 2010 shows that rivaroxaban can be a single-drug approach to the short-term and continued treatment of venous thrombosis and can also improve the benefit-to-risk profile of anticoagulation. The study compared oral rivaroxaban alone (15 mg twice daily for 3 weeks, followed by 20 mg once daily) with subcutaneous enoxaparin followed by a vitamin K antagonist (either warfarin or acenocoumarol) for 3, 6, or 12 months in patients with acute, symptomatic DVT. The study also carried out a double-blind, randomized, event-driven superiority study that compared rivaroxaban alone (20 mg once daily) with placebo for an additional 6 or 12 months in patients who had completed 6 to 12 months of treatment for venous thromboembolism.

Rivaroxaban had noninferior efficacy with respect to the primary outcome (36 events [2.1%], vs. 51 events with enoxaparin–vitamin K antagonist [3.0%]; hazard ratio, 0.68; 95% confidence interval [CI], 0.44 to 1.04; P<0.001). The principal safety outcome occurred in 8.1% of the patients in each group. In the continued-treatment study, which included 602 patients in the rivaroxaban group and 594 in the placebo group, rivaroxaban had strong efficacy (8 events [1.3%], vs. 42 with placebo [7.1%]; hazard ratio, 0.18; 95% CI, 0.09 to 0.39; P<0.001). Four patients in the rivaroxaban group had nonfatal major bleeding (0.7%), versus none in the placebo group (P=0.11).

Chemistry


Rivaroxaban bears a striking structural similarity to the antibiotic linezolid: both drugs share the same oxazolidinone-derived core structure. Accordingly, rivaroxaban was studied for any possible antimicrobial effects and for the possibility of mitochondrial toxicity, which is a known complication of long-term linezolid use. Studies found that neither rivaroxaban nor its metabolites have any antibiotic effect against Gram-positive bacteria. As for mitochondrial toxicity, in vitro studies found the risk to be low, and not likely to be of clinical consequence because rivaroxaban is only meant (and approved) for short-term use.

Related drugs
A number of anticoagulants inhibit the activity of Factor Xa. Unfractionated heparin (UFH), low molecular weight heparin (LMWH), and fondaparinux inhibit the activity of factor Xa indirectly by binding to circulating antithrombin (AT III). These agents must be injected. Warfarin, phenprocoumon, and acenocoumarol are orally active vitamin K antagonists (VKA) which decrease hepatic synthesis of a number of coagulation factors, including Factor X. In recent years, a new series of oral, direct acting inhibitors of Factor Xa have entered clinical development. These include rivaroxaban, apixaban, betrixaban, LY517717, YM150, and DU-176b.