Rivaroxaban: A direct factor Xa inhibitor for VTE prophylaxis in patients undergoing total knee or hip replacement surgery

Key Points

Abstract

Rivaroxaban is a highly potent direct factor Xa inhibitor with competitive and reversible activity that is pending FDA approval for the indication of venous thromboembolism (VTE) prophylaxis in patients undergoing total knee replacement (TKR) or total hip replacement (THR) surgery. Unlike the currently prescribed VTE prophylactic agents, which require subcutaneous (SC) administration or exhibit an undesirable drug interaction/monitoring profile, this agent offers the convenience of once-daily oral dosing, without the inconvenience of laboratory monitoring. In multiple phase 3 trials, rivaroxaban has demonstrated superior efficacy compared with enoxaparin in preventing VTE in patients undergoing THR and TKR, with comparable rates of major bleeding. The most commonly reported adverse events associated with rivaroxaban treatment include anemia, nausea, elevations in liver transaminases (short-term, with comparable incidence to that of enoxaparin), and postprocedural hemorrhage. Unresolved issues include the long-term hepatotoxicity profile of rivaroxaban and a potential risk of precipitating adverse cardiovascular events. (Formulary. 2009;44:226–236.)

Thrombosis is the process through which a fibrin blood clot is formed via activation of platelets and the clotting cascade. Clot formation in response to injurious stimuli acts to preserve the structure and normal function of the vasculature. Disruption of the normal clotting response may lead to pathologic clots that can result from 1 or a combination of factors as described by Virchow's triad. According to the triad, the 3 main causes of thrombosis include abnormalities of blood flow, clotting components, or changes in the vessel wall.¹

Several nonpharmacologic thromboprophylaxis methods have been studied in patients who have undergone THR or TKR, including graded compression stockings (GCS), intermittent pneumatic compression devices (IPC), and venous foot pumps (VFP). The American College of Chest Physicians (ACCP) Practice Guidelines (2008) recommend the initial use of IPC for patients undergoing either THR or TKR who have a high risk of bleeding (alternative is VFP).³

The ACCP Practice Guidelines recommend the use of a single pharmacologic thromboprophylactic agent for patients at lower risk of bleeding who are undergoing elective THR or TKR.³ Anticoagulant options for VTE prophylaxis include low molecular weight heparin (LMWH), fondaparinux, or an adjusted-dose vitamin K antagonist. Enoxaparin and other LMWHs bind to and enhance the activity of antithrombin III, inhibiting factor Xa and factor IIa (thrombin). The recommended subcutaneous (SC) dose for enoxaparin for the indication of THR ranges from 40 mg once/d up to 30 mg twice/d.⁴ Patients undergoing TKR should receive enoxaparin 60 mg/d, divided into 2 doses. In addition to the relative inconvenience associated with SC administration of enoxaparin and other LMWHs, anti-factor Xa-level monitoring may be warranted in patients with moderate (creatinine clearance [CrCl], 30–50 mL/min [product labeling] or 30–60 mL/min [at some institutions]) or severe (CrCl <30 mL/min) renal impairment or in obese patients (weight >150 kg). Moreover, high acquisition costs of LMWH contribute to escalating pharmacy drug expenditures, because daily costs can range from $23 to $34 (Novation contract pricing; Santa Clara Valley Medical Center [SCVMC], San Jose, California; April 2009). Fondaparinux, an indirect factor Xa inhibitor, offers the advantage of once-daily dosing but also requires parenteral administration and should be avoided in patients with severe renal impairment or in patients with body weight <50 kg.⁵ Acquisition costs associated with fondaparinux (2.5 mg/d) have been demonstrated to be approximately 30% lower than those for enoxaparin (Novation contract pricing; SCVMC, San Jose, California; April 2009). Adjusted-dose vitamin K antagonists such as warfarin inhibit the synthesis of vitamin K-dependent coagulation factors II, VII, IX, and X, along with anticoagulant proteins C and S. Warfarin offers the convenience of oral dosing, but this advantage is offset by its narrow therapeutic index along with its tendency to interact with many medications (>100), thereby necessitating frequent laboratory monitoring.⁶ The recommended duration of prophylaxis is different for TKR than for THR. The ACCP recommendation is for patients undergoing TKR to receive thromboprophylaxis for ≥10 days and for patients undergoing THR to receive extended prophylaxis for up to 35 days.³

Several anticoagulants currently in development target individual coagulation factors, including thrombin and activated factor X (factor Xa). Dabigatran (Boehringer Ingelheim) is an oral direct thrombin inhibitor.^7–9 At present, the safety and efficacy of this agent as prophylaxis for VTE in patients undergoing THR or TKR, as well as for stroke prevention in patients with atrial fibrillation (AF), are being evaluated in phase 3 trials. Over the past decade, fondaparinux has been studied for numerous indications such as DVT, surgical thromboprophylaxis, and PE.⁵ The clinical success of this agent has led to the development of 2 oral factor Xa inhibitors, apixaban (Pfizer/Bristol-Myers Squibb) and rivaroxaban (Bayer/Ortho-McNeil).^10–12 Rivaroxaban, a direct factor Xa inhibitor, is awaiting FDA approval for the indications of thromboprophylaxis after THR or TKR. In late March 2009, FDA's Cardiovascular and Renal Drugs Advisory Committee voted in favor of approving this agent for the indication of VTE prophylaxis. In May 2009, FDA issued a complete response letter for this agent; the manufacturer has since announced that a response will likely not be submitted to FDA until the fourth quarter of 2009 at the earliest. Other indications currently being evaluated in ongoing phase 3 trials include VTE treatment; stroke prevention in patients with AF; VTE prevention in hospitalized, medically ill patients; and secondary prevention of acute coronary syndrome (ACS).¹² This agent is currently approved for use in both Canada and the European Union.

CHEMISTRY AND PHARMACOLOGY

Rivaroxaban belongs to a new class of oxazolidinone-based, active-site directed, factor Xa inhibitors, characterized by highly potent, competitive, and reversible activity. This agent is also characterized by high bioavailability, in excess of 80%.¹³

Factor Xa plays a central role in thrombin generation because of its position at the start of the common pathway of the extrinsic and intrinsic coagulation systems. Activation of the extrinsic pathway of the clotting cascade occurs through the release of thromboplastin (tissue factor) from endothelial cells. Tissue factor activates factor VII, which mediates the conversion of factor X to factor Xa. Activation of the intrinsic pathway of the clotting cascade occurs after exposure of factor XII to subendothelial components exposed during vessel injury. The intrinsic pathway mediates the activation of factor X via a chain of events initiated by factor XI. Once stimulated, both pathways activate the common pathway of the clotting cascade, with eventual formation of a stable fibrin clot.¹

Rivaroxaban exhibits selective inhibition of factor Xa as demonstrated by a 10,000-fold-higher affinity for factor Xa inhibition than that of other serine proteases, including thrombin, trypsin, plasmin, factor VIIa, factor IXa, urokinase, and activated protein C. Rivaroxaban inhibits factor Xa whether it is clot-bound or incorporated within the prothrombin complex.¹⁴ This pharmacologic property may confer an advantage to using rivaroxaban in lieu of alternative anticoagulants for the treatment of patients with a preexisting clot.¹⁵

Because rivaroxaban exerts its effect at the junction of the extrinsic and intrinsic pathways, it would be expected to alter prothrombin time (PT) and activated partial thromboplastin time (aPTT). Samama et al¹⁶ conducted a study of the effects of varying concentrations of rivaroxaban (50–300 ng/mL) on PT and aPTT of pooled human platelet-poor plasma (PPP). The investigators assessed aPTT by mixing 50 mcL of PPP with 50 mcL of CK Prest, a reagent comprising rabbit cerebral tissue and kaolin. The aPTT increased nearly 1.5-fold as the concentration of rivaroxaban increased from 50 ng/mL to 200 ng/mL. Assessments of PT using 4 different thromboplastin reagents (International Sensitivity Index of 0.9–1.8) revealed a concentration-dependent increase in PT, with ratios (PT with rivaroxaban : PT without rivaroxaban) increasing from 1.05–1.13 to 1.44–2.21 as rivaroxaban concentrations increased from 50 ng/mL to 300 ng/mL. Of note, in clinical studies of healthy male participants, rivaroxaban did not increase bleeding times or signs and symptoms of bleeding across a wide range of oral doses.¹⁷

PHARMACOKINETICS

Multiple preclinical trials have been conducted to determine the pharmacokinetic profile of rivaroxaban.^15,17–22 This agent exhibits a high degree of protein binding (92%–95%), 80% to 100% bioavailability, a volume of distribution of 50 liters, a terminal half-life of 7 to 11 hours, and a time to maximum concentration (C_max) of 2 to 4 hours.¹⁹ Rivaroxaban undergoes metabolism through cytochrome P450 pathways, primarily CYP3A4 and CYP2J2, and it serves as a substrate for p-glycoprotein and breast cancer resistance protein.¹⁹ Approximately one-third of the drug is renally secreted as unchanged drug, and the remainder undergoes metabolic degradation.¹⁹ Rivaroxaban exhibits linear pharmacokinetics up to a daily oral dose of 15 mg, but at higher doses, a lower magnitude of increases in bioavailability and absorption rate is observed.¹⁹ Kubitza et al¹⁵ suggested that limited solubility may be responsible for incomplete absorption of higher doses of the tablet formulation of rivaroxaban, as demonstrated by lower proportions of rivaroxaban excreted unchanged in the urine at the highest doses (60 and 80 mg) compared with the lowest dose (1.25 mg). The authors suggested that a benefit of the decreased bioavailability observed with higher doses of rivaroxaban may be a reduced propensity for bleeding.

An open-label, crossover study conducted by Kubitza et al²¹ demonstrated that, compared with fasting patients, those who were fed had a slower increase in plasma concentration at 4 hours compared with 2.75 hours, indicative of slower absorption. However, area under the plasma concentration-time curve (AUC) (fasted, 888 ng•h/mL; fed, 1,107 ng•h/mL) and C_max (fasted, 113 mcg•h/mL; fed, 158 mcg•h/mL) significantly increased with the administration of food (P<.05). Pharmacodynamic parameters such as maximal PT prolongation and inhibition of factor Xa did not differ significantly between patients in the fed or fasted state.²¹ Despite the changes found in AUC and C_max after coadministration of rivaroxaban (10–20 mg/d) with food, the changes are not considered clinically significant; therefore, the EU manufacturer states that this agent can be taken with or without food.¹⁹ Kubitza et al²¹ also demonstrated that increases in gastric pH caused by H₂ blockers such as ranitidine (oral 150 mg twice/d) or antacids (10 mL) such as aluminum hydroxide and magnesium hydroxide had no effect on the pharmacokinetic or pharmacodynamic properties of rivaroxaban (20 mg once/d).

In another preclinical study conducted by Kubitza et al,²² the effects of rivaroxaban 10 mg/d on PT and aPTT were assessed in patients with varying body weights (≤50, 70–80, or >120 kg). Patients with higher body weights demonstrated a lower degree of PT prolongation or had minor decreases in rivaroxaban AUC along with a decrease in maximal inhibition of factor Xa. Patients with lower body weights demonstrated slightly elevated C_max, a 2-fold increase in half-life, and a slightly more prolonged aPTT. As none of the pharmacokinetic or pharmacodynamic changes were considered clinically significant, the EU manufacturer of rivaroxaban does not require dose adjustment of this drug in underweight or overweight patients.¹⁹

CLINICAL TRIALS

Rivaroxaban has been assessed in multiple phase 3 clinical trials for the prevention of VTE in patients undergoing THR and TKR. Furthermore, nearly 50,000 patients will be enrolled in ongoing phase 3 clinical trials assessing the safety and efficacy of this agent for VTE prevention in medically ill, hospitalized patients; VTE treatment; stroke prevention in patients with AF; and secondary prevention of ACS (phase 2 completed; progressing toward phase 3).¹¹

The Regulation of Coagulation in Major Orthopedic Surgery Reducing the Risk of DVT and PE (RECORD) trials all featured the same primary efficacy end point of composite DVT, nonfatal PE, and all-cause mortality, along with the same main safety end point of major bleeding.^23–26 The investigators of the RECORD trials classified major bleeding events as 1) fatal bleeding or bleeding involving critical organs (eg, intracranial, intraocular, intraspinal, or retroperitoneal); 2) extrasurgical bleeding or reoperation; 3) bleeding associated with a decrease in hemoglobin level of ≥2 g/dL; or 4) bleeding that required transfusion of ≥2 units of whole blood or packed cells. Other outcome measures assessed included elevations in alanine aminotransferase (>3 times the upper limit of normal [ULN]) and adverse cardiovascular outcomes such as myocardial infarction (MI), ischemic stroke, and cardiovascular death. RECORD 1 and 2 included patients undergoing THR, whereas RECORD 3 and 4 included patients undergoing TKR.

In the RECORD 1 and 2 trials, patients were randomized to receive oral rivaroxaban 10 mg once/d (initiated 6–8 h after wound closure) or SC enoxaparin 40 mg once/d for 31 to 39 days. Both studies enrolled approximately 55% women aged 61 to 63 years and with similar mean body weights of 75 to 78 kg. RECORD 1 featured a predominantly white patient population, whereas Asian and Hispanic patients accounted for 31% of the patient population in RECORD 2.^23,24

Compared with enoxaparin, the rivaroxaban group in the RECORD 1 study demonstrated a significantly lower risk of experiencing the primary outcome (1.1% vs 3.7%; relative risk reduction, 70%; 95% CI, 49%–82%; P<.001). Similarly, the RECORD 2 trial demonstrated that treatment with rivaroxaban resulted in a lower risk for experiencing the primary outcome compared with enoxaparin (2% vs 9.3%; absolute risk reduction, 7.3%; 95% CI, 5.2%–9.4%; P<.0001). For both RECORD 1 and RECORD 2, the difference in the primary outcome was driven strictly by the lower rates of DVT (both proximal and distal) observed with rivaroxaban treatment.^23,24 In RECORD 1, the absolute risk reduction in DVT incidence was 2.7% (95% CI, –3.7% to –1.7%; P<.001). In RECORD 2, the absolute risk reduction in DVT incidence was 6.5% (95% CI, –8.5% to –4.5%; P<.0001). The RECORD 2 investigators commented on the high rate of invalid venograms in the study (~25%) but stated that sensitivity analyses demonstrated that the missing data did not affect the power of the trial or bias outcomes.

The incidence of major bleeding did not differ significantly between the 2 treatment groups in the RECORD 1 and 2 studies.^23,24 Of note, the incidence of major bleeding did not exceed 0.3%, as the definition of major bleeding used by the RECORD study investigators may have resulted in bleeding rates lower than the typically reported frequency in other VTE prophylaxis studies (according to package labeling, fondaparinux is associated with bleeding rates of 2.2% for hip fracture, 3% for hip replacement, and 2.1% for knee replacement during perioperative prophylaxis [1–7 d after surgery], whereas SC enoxaparin 40 mg/d is associated with a bleeding rate of 2% for hip replacement during the perioperative period and SC enoxaparin 30 mg every 12 h is associated with a bleeding rate of 1% for knee replacement surgery).^4,5 The RECORD 4 investigators, in commenting on these studies, suggested that because major bleeding did not include bleeding leading to treatment cessation or surgical site bleeding events unless they were fatal or required reoperation, the reported bleedings rates may have been lower than usual.²⁶

No evidence of significant liver toxicity emerged from these 2 RECORD studies, as demonstrated by comparable rates of elevated alanine aminotransferase levels in both treatment groups.^23,24 The slightly higher number of adverse cardiovascular outcomes experienced by patients treated with rivaroxaban (during the follow-up period) in the RECORD 2 trial raised concerns about rebound activation of coagulation. To exclude the possibility of this phenomenon, additional data are needed from ongoing clinical trials.

In the second set of RECORD trials (RECORD 3 and 4), patients undergoing TKR were randomized to receive oral rivaroxaban 10 mg once/d (initiated 6–8 h after wound closure) or SC enoxaparin for 10 to 14 days.^25,26 The FDA-approved dosing of enoxaparin for VTE prophylaxis in TKR is 30 mg twice/d, not the 40 mg once-daily dose used in the RECORD 3 study. The enoxaparin group in RECORD 4 received the FDA-approved dosing regimen. The RECORD 3 and 4 patient populations consisted of more women than men (~65%), older patients (mean age, 64–68 y), and heavier patients (mean body weight, 81–85 kg). RECORD 4 featured a more ethnically diverse patient population than observed in the RECORD 3 study, as Asians, Hispanics, and African Americans accounted for one-third of the RECORD 4 study population.

Compared with enoxaparin, the rivaroxaban group in the RECORD 3 study exhibited a significantly lower risk of experiencing the primary outcome (9.6% vs 18.9%; relative risk reduction, 49%; 95% CI, 35%–61%; P<.001). RECORD 4 investigators also observed a statistically significant reduction in the risk for VTE with rivaroxaban compared with enoxaparin (6.9% vs 10.1%; relative risk reduction, 31%; 95% CI, 8%–49%; P=.016). No significant differences in major bleeding rates and increases in alanine aminotransferase levels were observed between treatment groups in RECORD 3 and 4.^25,26 In RECORD 3, the primary end point difference was driven strictly by differences in rates of distal DVT incidence (absolute risk difference, –7.3%; 95% CI, –10.4% to –4.3%). There was a trend in favor of rivaroxaban for pulmonary embolism rates (absolute risk difference, –0.5%; 95% CI, –1.2% to 0; P=.06).

ADVERSE EVENTS

Because of its pharmacologic mechanism of action, the use of rivaroxaban may be associated with an increased risk of bleeding from any tissue or organ, as reflected by the warning of posthemorrhagic anemia issued by the EU manufacturer.¹⁹ Moreover, the same risk for developing epidural or spinal hematoma after epidural or spinal anesthesia that applies to LMWH and fondaparinux is listed as a major warning in the EU rivaroxaban prescribing information. Safety data from the RECORD clinical trial program demonstrated comparable rates of major bleeding in rivaroxaban- and enoxaparin-treated patients undergoing THR and TKR.^19,23–26 Other commonly reported (1%–10%) adverse events observed in rivaroxaban recipients from the RECORD clinical trial program database include elevated liver transaminase levels, anemia, nausea, and postprocedural hemorrhage.¹⁹

Of note, the unexpected hepatotoxic effect of the oral thrombin inhibitor ximelagatran that led to its withdrawal from the European market has resulted in a heightened scrutiny of this adverse event for rivaroxaban and other oral anticoagulants in development.²⁷ In the RECORD clinical trials, the incidence of elevated alanine aminotransferase levels after 10 to 39 days of exposure to rivaroxaban did not exceed the incidence observed with enoxaparin. However, long-term data on the hepatotoxic effects of rivaroxaban will not become available until the completion of ongoing phase 3 clinical trials on the safety and efficacy of this agent for stroke prevention in AF and for secondary prevention of ACS.¹¹

The cardiotoxicity profile of rivaroxaban represents another unresolved issue that requires further study. In RECORD 2, the concern about rebound activation of coagulation emerged, given the slight excess in the number of adverse cardiovascular outcomes after treatment cessation.²⁴ However, the rebound phenomenon has also been observed in patients with unstable angina after stopping treatment with argatroban (thrombin inhibitor), dalteparin (LMWH), and unfractionated heparin.²⁷

DRUG INTERACTIONS

In a study of healthy participants, coadministration of rivaroxaban 15 mg and naproxen 500 mg did not affect the pharmacodynamics and pharmacokinetics of rivaroxaban in a clinically relevant manner.²⁸ Furthermore, phase 2 clinical studies demonstrated that nonsteroidal anti-inflammatory drug (NSAID)-treated patients receiving rivaroxaban did not experience excessive bleeding.¹⁹ Similarly, a 2-way crossover study in healthy men demonstrated that aspirin did not alter the effects of rivaroxaban on factor Xa activity or clotting tests, and rivaroxaban did not influence the antiplatelet effects of aspirin.²⁹ Kubitza et al³⁰ also demonstrated a lack of interaction between rivaroxaban and digoxin in a phase 1 study.

DOSING AND ADMINISTRATION

The current EU-approved dose of rivaroxaban for VTE prophylaxis is 10 mg once/d in tablet form (starting 6–8 h after surgery in hemodynamically stable patients) for 10 to 14 days in patients undergoing TKR and for up to 35 days in patients undergoing THR.^11,19 The specific dose that will be marketed if FDA approval is granted has not been established, but given the results of the RECORD trials, the same dosing regimens will likely apply to US patients undergoing THR and TKR.^23–26

Because preclinical trials demonstrated a >2-fold increase in rivaroxaban plasma exposure in patients with severe renal impairment (CrCl, 15–29 mL/min), caution should be exercised in patients with more advanced chronic kidney disease. The EU prescribing information recommends avoiding the use of rivaroxaban in patients with severe renal impairment (CrCl <15 mL/min), given the lack of safety data from clinical trials.¹⁹ Patients with severe hepatic impairment were excluded from clinical trials, so there are no known data in this patient population.^23–26 Rivaroxaban is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk, whereas in patients with cirrhosis with moderate hepatic impairment (Child-Pugh B), rivaroxaban plasma exposure has been demonstrated to be increased 2.6-fold relative to healthy matched controls.¹⁹

Ongoing phase 3 trials of rivaroxaban are using the following dosing regimens: for DVT or PE, 15 mg twice/d for 3 weeks, followed by 20 mg once/d for 3 to 12 months; for VTE prophylaxis in medically ill, hospitalized patients, 10 mg once/d for 31 to 39 days; for stroke prevention in patients with AF, 20 mg once/d (15 mg once/d for patients with moderately impaired renal function); and for secondary prevention of ACS, 2.5 mg to 5 mg twice/d.¹¹

Ms Nunokawa and Ms Wong are PharmD candidates at University of the Pacific School of Pharmacy, Stockton, California. Dr Song is an associate professor of pharmacy practice, University of the Pacific School of Pharmacy, and regional coordinator, San Jose Clinical Experience Program, and SCVH&HS PGY1 pharmacy residency coordinator, Department of Pharmacy Services, Santa Clara Valley Medical Center, San Jose, California.

Disclosure Information: The authors report no financial disclosures as related to products discussed in this article.

In each issue, the "Focus on" feature reviews a newly approved or investigational drug of interest to pharmacy and therapeutics committee members. The column is coordinated by Robert A. Quercia, MS, RPh, clinical manager and director of Drug Information, Department of Pharmacy Services, Hartford Hospital, Hartford, Conn, and adjunct associate professor, University of Connecticut School of Pharmacy, Storrs, Conn; and by Craig I. Coleman, PharmD, assistant professor of pharmacy practice, University of Connecticut School of Pharmacy, and director, Pharmacoeconomics and Outcomes Studies Group, Hartford Hospital.

EDITORS' NOTE: The clinical information provided in "Focus on" articles is as current as possible. Due to regularly emerging data on developmental or newly approved drug therapies, articles include information published or presented and available to the author up until the time of the manuscript submission.

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