The direct factor Xa inhibitor rivaroxaban

Since the 1920s, when heparin was discovered by a medical student in liver cell extracts and warfarin was synthesised from the dicoumarol found in spoiled cattle feed, these two agents have remained the mainstays of anticoagulation treatment. The broad range of indications for these medications, including prophylaxis of thromboembolic disease in surgical patients, as well as in patients with atrial fibrillation, prosthetic heart valves or unstable coronary syndromes,1 has made these drugs frequently prescribed among patients aged 65 years or older. Unfractionated heparin has now been superseded by its low-molecular-weight counterparts (such as enoxaparin) in many clinical applications, and, although they facilitate outpatient therapy, there are significant limitations and complications of both heparin and warfarin therapies.2 Heparins require parenteral administration and their use is associated with haemorrhage. Similarly, the risks of bleeding, the delayed onset of action, the numerous interactions with food and other medications, and the complexity of individualised dosing make warfarin a dangerous and inconvenient medication for patients and their treating doctors.3,4

The lack of efficacy of heparin and warfarin for certain indications (such as arterial thromboembolic disease), the bleeding risks, and the inconvenience of therapy have provided much impetus for research into alternative anticoagulants. In recent years, a number of novel anticoagulant agents have emerged. These new anticoagulants, developed in an era of greater fundamental knowledge of haemostasis, involve the use of small, specific molecules designed to directly inhibit clotting factors within the clotting pathway, such as thrombin or activated factor X (Xa).

One novel anticoagulant to emerge recently was ximelagatran, an orally active direct thrombin inhibitor. Clinical trials demonstrated that ximelagatran’s effectiveness in preventing strokes in patients with atrial fibrillation was similar to warfarin, with suggestions that it offered a comparable safety profile, as well as easier dose administration and a decreased need for monitoring.5 However, ximelagatran was dramatically withdrawn from the market in February 2006 when it was shown that some 6% of patients demonstrated abnormal liver functions subsequent to therapy.6 Other drugs that also inhibit thrombin have emerged, such as dabigatran etexilate, and this drug is currently in advanced clinical trials and limited clinical use in some countries.7-9

Rivaroxaban is an oxazolidinone derivative that is a potent and selective direct inhibitor of factor Xa (see Box 1), binding the enzyme competitively and reversibly. Inhibition of factor Xa increases clotting times and decreases the formation of thrombin, the pivotal enzyme required for generation of fibrin, platelet activation and thrombus formation in venous thromboembolic disease and deep vein thrombosis (DVT).11 Rivaroxaban has an oral bioavailability of about 80% and is well absorbed from the gastrointestinal tract, with food having no major effect on its absorption.12 Plasma levels of rivaroxaban peak around 2.5–4 hours, and the drug has a terminal half-life of about 5–9 hours in young people and 11–13 hours in older people.13 Rivaroxaban exhibits dual excretion, primarily by the kidneys (66%) but also by the biliary-faecal route (28%).12,13

The espoused advantages of rivaroxaban, although similar to many novel anticoagulants in development, are numerous compared with warfarin and heparins (Box 2). Rivaroxaban has a rapid onset of action, high oral bioavailability (thus avoiding parenteral administration), and has predictable pharmacokinetic properties. Rivaroxaban can be administered without concurrent heparin, once daily in a fixed dose, without the need for individual monitoring and dose titration.3,11-13

While the complete therapeutic properties of rivaroxaban remain to be fully elucidated, current available evidence suggests it is a sound candidate to potentially replace enoxaparin and warfarin for certain indications. Rivaroxaban is currently undergoing multinational, multicentre, phase III clinical trials for a number of clinical indications, with recently published phase III studies in arthroplasty thromboprophylaxis demonstrating promising results.

While the efficacy and safety of rivaroxaban have been demonstrated by phase III trials, there have also been numerous studies to assess potential interactions of rivaroxaban with foods and other drugs. Kubitza and colleagues performed four randomised studies, two of which assessed the interaction of rivaroxaban with food.20 No significant food–drug interactions were found, nor were there any major disturbances to any of the pharmacological parameters studied (E3).20

In another phase II study performed by the same researchers, the safety, tolerability and pharmacokinetics of the combination of rivaroxaban and the non-steroidal anti-inflammatory drug (NSAID) naproxen were investigated.21 Patients were allocated to receive naproxen alone, rivaroxaban alone or a combination of both drugs. The results demonstrated no interactions in the mechanisms between rivaroxaban and naproxen, and also showed that the addition of naproxen did not affect prothrombin time or platelet aggregation, although a significant increase in bleeding was observed in the combination group. However, this increase in bleeding was less than when naproxen was administered alone, and further studies are underway to confirm the safety of this drug combination.21

An important phase I trial was performed to determine if aspirin influenced the safety and efficacy of rivaroxaban.22 In all the subjects studied, this combination was tolerated, and aspirin did not affect either the factor Xa inhibition activity of rivaroxaban or prolongation of the prothrombin time. Additionally, it was determined that rivaroxaban did not interfere with the effects of aspirin on platelet aggregation, suggesting this combination should pose no appreciable clinical interaction (E3).22

Clinical trials undertaken thus far to assess potential interactions of rivaroxaban with common drugs have found no significant interactions with aspirin, NSAIDs, antacids, histamine H2-receptor antagonists or digoxin (E3).20-22 However, recent evidence has shown that rivaroxaban demonstrates pharmacological interactions with potent inhibitors of cytochrome P450 3A4, including drugs such as ketaconazole, macrolides (such as clarithromycin) and protease inhibitors (such as the antiretroviral drug atazanavir).23 Further studies are required to determine potential interactions between rivaroxaban and other drugs, but the results so far demonstrate that rivaroxaban appears to be largely clinically safe (E3).

Given that research to date has shown rivaroxaban to be a viable anticoagulant, the manufacturers have sought licensing approval in Europe. As licensing in Australia may soon follow, it is important that all clinicians treating patients with anticoagulants be aware of the potential advantages of rivaroxaban. A summary of rivaroxaban’s medicinal profile is provided in Box 4.

The high level of evidence published in the clinical studies of rivaroxaban indicates that it is a promising alternative anticoagulant. Large, multicentre, multinational randomised controlled trials have shown that rivaroxaban is clearly superior to enoxaparin in the prevention of VTE after orthopaedic surgery (E2), and that there is no appreciable increase in the incidence of major or fatal bleeding (E2). The safety of rivaroxaban for mainstream clinical use has also been illustrated by its few interactions with other drugs (E3) and few side effects (E3) in studies so far.

A salient observation is that a number of patient groups have been excluded from the clinical evaluation of rivaroxaban, including pregnant and lactating women, patients being treated for HIV, patients with renal impairment (calculated creatinine clearance < 30 mL/min), and patients with clinically significant liver disease. Further studies of the use of rivaroxaban in patients with varying degrees of renal and liver dysfunction are necessary.

The ease of dosing and administration and decreased need for monitoring of patients treated with rivaroxaban, combined with superior outcomes, make it an attractive anticoagulant for the future. Clinical trials are underway studying the use of rivaroxaban for various indications, such as the treatment of vein thromboses and the prevention of stroke in patients with atrial fibrillation and acute coronary syndromes, and it is hoped that rivaroxaban will reduce the burden of disease caused by these conditions. However, in the interim, rivaroxaban has been proven to be a highly effective and exciting new oral anticoagulant drug. With the concurrent development of other orally active direct factor Xa inhibitors, such as apixaban, rivaroxaban will potentially benefit many patients at risk of venous thromboembolic disease. Important messages for patients are shown in Box 5.

1 Mechanisms of action of new and current anticoagulant therapies within the coagulation cascade*

* Adapted from Brighton TA.5 Printed with permission.