Rivaroxaban

Rivaroxaban (Xarelto®), an oral oxazolidinone-based anticoagulant, is a potent, selective direct inhibitor of factor Xa that is used in the prevention of venous thromboembolism (VTE) in adult patients after total hip replacement (THR) or total knee replacement (TKR) surgery. In four large, clinical trials, oral rivaroxaban was more effective than subcutaneous enoxaparin in preventing postoperative VTE in patients undergoing THR or TKR surgery. Notably, the superior efficacy of rivaroxaban was achieved with a low but not significant increase in the incidence of major bleeding episodes. In addition, preliminary pharmacoeconomic analyses in several countries indicate that rivaroxaban is a cost-effective treatment strategy versus enoxaparin. Although the position of rivaroxaban relative to other therapies remains to be fully determined, it is an effective emerging option for the prevention of VTE following THR and TKR.

Rivaroxaban is a potent oral direct inhibitor of the serine endopeptidase factor Xa and inhibits both free factor Xa and factor Xa bound in the prothrombinase complex. The potency of factor Xa inhibition occurs primarily as a result of rivaroxaban binding with high selectivity to the S1 and S4 pockets of the serine endopeptidase.

In healthy volunteers and in orthopaedic surgery patients, rivaroxaban prophylaxis dose-dependently inhibited factor Xa and prolonged prothrombin (PT) and activated partial thromboplastin times confirming data from animal models. Plasma rivaroxaban concentrations correlated with both factor Xa inhibition and PT, following a maximum effect and linear model, respectively. Rivaroxaban prophylaxis did not prolong the corrected QT interval using the Fridericia formula.

Rivaroxaban pharmacokinetics following oral administration are best described by a one-compartment model and are characterized by rapid absorption (peak plasma concentration reached within 2–4 hours) and high bioavailability (80–100%). The apparent volume of distribution of rivaroxaban at steady state is ≈50 L. Rivaroxaban can be classified as a low-clearance drug, with a mean apparent oral clearance rate in orthopaedic surgery patients of 5.5 L/h on the day of surgery, increasing to 7.5 L/h at steady state, and mean terminal half-life of between 7 and 11 hours.

Approximately two-thirds of an administered rivaroxaban dose is metabolized via cytochrome P450 (CYP) enzymes (CYP3A4 and CYP2J2) and CYP-independent mechanisms, with one-third excreted as unchanged drug in the urine. The metabolized fraction of the drug is eliminated in approximately equal amounts via the renal and faecal routes.

In four large, randomized, double-blind (double-dummy), multicentre, phase III trials, known as RECORD1, 2, 3 and 4 studies, oral rivaroxaban 10 mg once daily regimens were more effective than subcutaneous enoxaparin at preventing postoperative VTE in patients undergoing THR or TKR surgery. Rivaroxaban was shown to be superior to enoxaparin regimens, with significantly lower incidences of the primary endpoint, total VTE (composite of deep vein thrombosis [DVT], nonfatal pulmonary embolism [PE] or death from any cause) observed in all four studies. For example, in the largest study (RECORD1), the primary endpoint occurred in 1.1% of rivaroxaban recipients and 3.7% of enoxaparin recipients.

Furthermore, a significantly lower incidence of the main secondary endpoint, major VTE (composite of proximal DVT, nonfatal PE or death from VTE), was observed with rivaroxaban regimens compared with enoxaparin regimens in RECORD1, 2 and 3. In a pooled analysis of the four RECORD trials, rivaroxaban regimens significantly reduced the incidence of the composite endpoint of symptomatic VTE and death compared with enoxaparin regimens, both over the total study duration and during the enoxaparin-controlled period.

Generally similar bleeding events were observed in the individual RECORD trials, with no significant between-group differences in major bleeding events, on-treatment non-major bleeding events and any on-treatment, bleeding events with rivaroxaban and enoxaparin treatments. Bleeding events were the most frequently reported adverse events associated with rivaroxaban prophylaxis across the four RECORD trials.

The most common adverse events (apart from bleeding) during rivaroxaban treatment across the RECORD trials were pyrexia, vomiting, nausea and constipation, and these events occurred at a similar frequency to that with enoxaparin treatment. Generally similar incidences of elevated liver enzymes were observed in rivaroxaban recipients compared with enoxaparin recipients across the four RECORD trials.

In several modelled cost-effectiveness analyses conducted from a Canadian, Spanish, US and UK healthcare payer perspective, rivaroxaban was predicted to be cost effective relative to enoxaparin. Cost effectiveness was demonstrated irrespective of surgical procedure (THR or TKR), duration of treatment or dosage regimen.