Rivaroxaban: A potential replacement for warfarin?

Millions of people in the United States require chronic anticoagulation to prevent thromboembolism secondary to chronic atrial fibrillation (AF), pulmonary hypertension, mechanical valve replacements, and other prothrombotic conditions. Warfarin, the most commonly prescribed anticoagulant, has many drawbacks, such as medication and dietary interactions, the need for frequent clinician monitoring, and bleeding complications. Other disadvantages of this therapy involve financial and clinical complexities of bridging therapy with subcutaneous heparinoids, necessary in some instances for even short pauses in treatment. A great deal of research has been devoted to finding a replacement agent for warfarin due to these requirements. Characteristics of an “ideal agent” include reversibility, dose-response predictability, lack of need to monitor dose, and efficacy without risk of major bleeding. In 2004, the experimental oral direct thrombin inhibitor, ximelagatron, was close to achieving this goal. Ximelagatron, which was approved for use in Europe, made it to phase 3 clinical trials in the United States. Further development of the drug was halted when evidence of significant hepatotoxicity surfaced. Now, several new oral anticoagulants are in the final stages of development, including rivaroxaban.

Pharmacology

Rivaroxaban is an oxazolidinone derivative that exerts its action by binding to the active site of factor Xa. Factor Xa acts at the convergence point of the extrinsic and intrinsic coagulation pathways and catalyzes the conversion of prothrombin to thrombin; therefore, by inhibiting factor Xa, rivaroxaban blocks thrombin generation and decreases formation of fibrin clots. Radiographic examination of the rivaroxaban-factor Xa complex reveals rivaroxaban is bound to 2 pockets of the factor Xa active site.¹ This activity also results in decreased activation of platelets and increased prothrombin time and activated partial thromboplastin time.^2,3

Pharmacokinetics

Rivaroxaban is well absorbed orally, with an approximate bioavailability of 80%. The pharmacokinetic and pharmacodynamic characteristics of rivaroxaban are moderately altered by food, resulting in delayed absorption and increased peak concentration, but are unaffected by changes in gastric pH induced by ranitidine or an antacid. Absorption appears to be increased in the presence of food by approximately 28%, with time to peak concentrations being delayed from 2.75 to 4.0 hours.⁴ Dose-ranging trials of once-daily oral rivaroxaban doses of 5, 10, 20, 30, or 40 mg for venous thromboembolism prophylaxis have been completed.⁵ Although pharmacokinetic studies have shown plasma concentrations of rivaroxaban increase proportionally with increasing dose,⁶ no significant dose-efficacy relationship was found for the composite end point of deep vein thrombosis, pulmonary embolism, and all-cause mortality; however, larger doses resulted in increased bleeding.^5,7 Extremes in body weight (≤50 or >120 kg) have been examined, and serum concentrations of rivaroxaban were unaffected in subjects weighing more than 120 kg but were increased by 24% in subjects weighing 50 kg or less, resulting in a small (15%) increase in prolongation of prothrombin time, which is not considered clinically relevant. Based on these results, phase 3 clinical trials for venous thromboembolism prophylaxis have studied rivaroxaban at a fixed 10-mg oral dose and without monitoring.

Rivaroxaban has been reported to be highly protein bound. Approximately half of the circulating dose of the drug is metabolized hepatically to inactive compounds. Rivaroxaban is excreted via 2 distinct pathways, with the majority of the drug being excreted renally (36% unchanged) and the remaining third excreted via the biliary route. The elimination half-life of rivaroxaban is 6 to 7 hours. The Table compares the pharmacokinetics of rivaroxaban with enoxaparin, warfarin, and fondaparinux.

Safety

Rivaroxaban appears to be generally well tolerated. As with any anticoagulant, the risk of hemorrhage is a chief safety concern. Trials to date have not shown an increased risk of major or minor bleeding compared with conventional therapies.^10-12 Rivaroxaban has not induced hepatotoxicity or other major adverse events,^10-12 nor has it demonstrated interactions with aspirin, naproxen, ranitidine, or antacids in randomized controlled trials.^13,14 Rivaroxaban also does not appear to prolong the QTc interval.¹⁵

Patient populations at high risk of bleeding and those with renal failure (calculated creatinine clearance of <30 mL/min) have not been included in large clinical trials to date. Dose adjustments for decreased renal function (calculated creatinine clearances of 30-49 mL/ min) are being used in the ongoing ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonist for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) trial.

Efficacy in orthopedic patients

Patients undergoing knee and hip arthroscopy are at high risk of developing thrombotic complications. Prophylactic anticoagulant therapy with warfarin, low-molecular-weight heparin, and fondaparinux are the current standard of therapy to reduce this complication. Current guidelines recommend extending the duration of therapy beyond 10 days, up to a maximum of 35 days postoperatively.¹⁶ Although each of the current therapies significantly decreases the rate of thromboembolic complications, they also put the patient at risk of potential bleeding complications. In addition, warfarin therapy requires close monitoring due to variable patient response, and low-molecular-weight heparin and fondaparinux require daily subcutaneous (SQ) injections. Three studies supporting the use of rivaroxaban for venous thromboembolism prophylaxis in the setting of orthopedic surgery were recently published by the RECORD (Regulation of Coagulation in Orthopedic Surgery to Prevent Deep Venous Thrombosis and Pulmonary Embolism) Study Group.^10-12

RECORD 1 and 2 compared rivaroxaban (10 mg orally once daily) with enoxaparin (40 mg [SQ]) in patients after hip replacement surgery.^10,11 RECORD 3 focused on patients undergoing knee replacement surgery. As in RECORD 1 and 2, rivaroxaban was administered at 10 mg daily versus 40 mg enoxaparin SQ daily.¹² All 3 trials enrolled a total of more than 9500 patients, with the primary outcome being the composite of new-onset deep vein thrombosis, nonfatal pulmonary embolism, or death from any cause. Rivaroxaban showed a significant reduction in the incidence of this composite end point as compared with enoxaparin (Figure). This benefit was observed without a subsequent increase in bleeding events between groups. There was also no increase in the incidence of liver dysfunction or other major adverse events. The RECORD studies add to the current evidence that demonstrates the importance of extended duration venous thromboembolism prophylaxis in the orthopedic population, and suggest that rivaroxaban is a safe, effective alternative to enoxaparin for the prevention of venous thromboembolism in these patients.

RECORD 4 trial data were presented at the European Federation of National Associations of Orthopaedics & Traumatology annual meeting on June 1, 2008.¹⁷ RECORD 4 included 3148 individuals who were undergoing knee replacement surgery (as in RECORD 3). Patients received rivaroxaban 10 mg versus the US Food and Drug Administration (FDA)-approved dose of enoxaparin for this indication (30 mg twice daily SQ injection), which was a larger dose than RECORD 3. Both treatments were administered for 10 to 14 days. Patients were followed for 40 days. The primary end point was the composite of deep vein thrombosis, nonfatal pulmonary embolism, and all-cause mortality. As in the previous RECORD studies, rivaroxaban showed a significant reduction in the incidence of venous thromboembolism as compared with enoxaparin (Figure).¹⁷

Ongoing trials

Current studies will likely lead to the FDA approving rivaroxaban as an alternative to low-molecular-weight heparin or unfractionated heparin for the prophylaxis of venous thromboembolism following hip orthopedic surgeries. While this will have a large impact on orthopedic populations, the most anticipated trial results in cardiac patients are still pending. Currently, there are ongoing trials for prevention of thromboembolic events in patients with AF and for the medical management of acute coronary syndrome (ACS).

Stroke prophylaxis in AF

Over 2.2 million Americans currently have AF, and 10 million Americans are estimated to develop the disease by 2050. The most common complication of AF is stroke, with recent estimates attributing 15% to 20% of all strokes to AF.¹⁸ Risk of thromboembolic events is increased in the presence of heart failure, hypertension, diabetes, advanced age (>75 years), and history of stroke.¹⁹ Warfarin is the preferred agent for treating patients with AF because it reduces stroke risk; however, the drug is associated with a risk for bleeding, and a great deal of resources are required to ensure that patients remain in a safe and effective range for this indication. Because of the need for constant monitoring and dosage titration, new anticoagulants that can effectively reduce the risk for stroke and not require intense monitoring are needed.

The ongoing ROCKET AF study may offer a new solution.²⁰ The primary outcome of this randomized, double-blind, active-control study comparing rivaroxaban (20 mg once daily) with warfarin (adjusted to an international normalized ratio target of 2.5) is a composite of major and nonmajor clinically relevant bleeding and any stroke or non—central nervous system systemic embolism. All patients in this study were adults with documented AF and with risk factors that put them at increased risk of stroke. Like other rivaroxaban studies, patients were excluded from this study if they had active bleeding, hemorrhagic disorders, history of debilitating strokes, or intracranial hemorrhage. Interestingly, patients with calculated creatinine clearances of 30 to 49 mL/min were included, but these patients will receive a rivaroxaban dose of 15 mg daily. ROCKET AF results are anticipated in December 2009, and about 14,000 patients are expected to participate.

ACS

Anticoagulation for the acute management of non-ST-segment elevation myocardial infarction (NSTEMI) and unstable angina is well established.^21-24 Following percutaneous coronary intervention (PCI), discontinuation of anticoagulation with intravenous or SQ heparinoids is recommended; however, there are also clinical trial data to support the long-term use of warfarin (in addition to aspirin) after PCI.²⁵ Despite the supportive evidence, use of warfarin in either of these settings has been limited because of advancements of dual antiplatelet therapies and the complexities of warfarin therapy. Rivaroxaban is currently being studied in this setting as well. ATLAS ACS-TIMI (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Aspirin With or Without Thienopyridine Therapy in Subjects with Acute Coronary Syndrome)-46 is a randomized, double-blind, placebo-controlled, tri-armed trial.²⁰ Patients will receive rivaroxaban (once or twice daily) in addition to antiplatelet therapy 1 to 7 days after experiencing an ACS (STEMI, NSTEMI, or unstable angina). Approximately 3600 patients are being monitored for the 7-month (including follow-up) duration of the study. Results from the ATLAS study are expected to be released this fall.

Clinical implications

Based on the results of the RECORD trials, rivaroxaban shows great promise as an effective and safe anticoagulant. Thus far, rivaroxaban has demonstrated improved efficacy with a similar risk profile when compared with enoxaparin for the prevention of venous thromboembolism following orthopedic surgeries. Ongoing trials examining rivaroxaban’s efficacy and safety for preventing stroke in patients with AF and for the medical management of ACS will further illuminate its scope of use. Rivaroxaban researchers, however, are not alone in the pursuit of the anticoagulant panacea. Currently, apixaban, another oral-factor Xa inhibitor, is undergoing phase 3 trials, while other oral-factor Xa inhibitors (PRT054021, LY517717, YM150, and DU-176b) are in earlier stages of investigation. Also, dabigatran, an oral direct thrombin inhibitor, is currently being studied for use in similar settings as the oral-factor Xa inhibitors. All of this leaves many questions regarding the future role and scope of rivaroxaban, but if FDA approval is granted, it will likely supplant warfarin as the outpatient anticoagulant of choice, provided alternative agents do not show greater promise.