Rivaroxaban

Rivaroxaban

Clinical data
Pregnancy category	??
Routes of administration	oral
Legal status
Legal status	??
Pharmacokinetic data
Elimination half-life	5.7-9.2
Identifiers
IUPAC name 5-chloro-N-[[2-oxo-3-[4-(3-oxomorpholin-4-yl) phenyl]oxazolidin-5-yl]methyl] thiophene-2-carboxamide
CAS Number	366789-02-8
PubChem CID	6433119
E number	{{#property:P628}}
ECHA InfoCard	{{#property:P2566}}
Chemical and physical data
Formula	C19H18ClN3O5S
Molar mass	435.882

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Clinical Trials
Ongoing Trials on Rivaroxaban at Clinical Trials.gov Trial results on Rivaroxaban Clinical Trials on Rivaroxaban at Google
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US National Guidelines Clearinghouse on Rivaroxaban NICE Guidance on Rivaroxaban NHS PRODIGY Guidance FDA on Rivaroxaban CDC on Rivaroxaban
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

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Overview

Rivaroxaban (BAY 59-7939) is an oral anticoagulant under development by Bayer; it will be marketed as Xarelto. It acts by inhibiting the active form of coagulation factor X (factor Xa).

Development

Rivaroxaban is an oxazolidinone derivative optimised for binding with factor Xa. If marketed, it will be a joint product by Bayer and Ortho-McNeil Pharmaceutical.

Uses

Expected

Due to the decreased need for monitoring, rivaroxaban is likely to be used to replace warfarin for a number of indications, such as atrial fibrillation.

Trial results

In phase IIb trials it was effective in reducing thromboembolic complications (deep vein thrombosis and pulmonary embolism) after orthopedic surgery and it is under investigation for the treatment of DVT and PE and for anticoagulation in atrial fibrillation. Advantages are the oral administration (a benefit over low molecular weight heparins, which require subcutaneous injections) and no need for monitoring (an advantage over warfarin). In studies, dosages of 2.5-10 mg once or twice daily were used.

On July 8, 2007, Bayer sponsored Phase 3 clinical trial data showing once-daily rivaroxaban achieved superior efficacy in the prevention of venous thromboembolism (VTE) in patients undergoing knee replacement surgery in comparison with enoxaparin, a LMWH.

RECORD 1

RECORD 1 is an acronym for the Regulation of Coagulation in major Orthopaedic surgery reducing the Risk of DVT and PE (RECORD1). RECORD1 was an international, randomized, double-blind, double-dummy Phase-3 trial evaluating the efficacy and safety of oral rivaroxaban versus enoxaparin for thromboprophylaxis following total hip replacement. The trial randomized a total of 4,541 patients to either enoxaparin 40 mg once daily (beginning the evening before surgery and restarting 6 to 8 hours after surgery) or rivaroxaban 10 mg (initiated 6 to 8 hours after surgery and then once a day thereafter). Both drugs were continued for 5 weeks after total hip replacement.

The primary efficacy endpoint in RECORD 1 was the composite of any deep vein thrombosis (DVT), nonfatal pulmonary embolism (PE), and all-cause mortality. The incidence of the primary endpoint was 1.1% with rivaroxaban compared with 3.7% with enoxaparin (RRR 70%, p <.001). Likewise, the incidence of the secondary endpoint (major venous thromboembolism and symptomatic VTE) was reduced from 2% with enoxaparin to 0.2% with rivaroxaban (RRR 88%, p <.001).

Despite these differences in efficacy, there was no excess in the trial's main efficacy endpoint, the rates of major bleeding: the rate of major bleeding associated with Rivaroxaban was 0.27% which did not differ from that of enoxaparin at 0.09% (p =.178). The incidence of non-major bleeding was identical for both drugs (5.8%). There was no hepatotoxicity associated with rivaroxaban administration.

Data from the RECORD 2 (total hip relacement) and RECORD 3 (total knee replacement) studies were also presented at the 49th Annual Meeting of the American Society of Hematology.

Highlights from RECORD 2 and 3 are as follows:

• RECORD 2 (n=2,509), which demonstrated a 79% RRR (p<0.001) in total VTE when compared with enoxaparin, again with an 88% RRR (p<0.001) in major VTE
• RECORD 3 (n=2,531), which demonstrated a 49% RRR (p<0.001) in total VTE when compared with enoxaparin, and a 62% RRR (p=0.016) in major VTE
• Major bleeding rates were similar for both drugs (≤0.6%) and differences were not statistically significant
• No routine blood monitoring was required in the Phase III RECORD program at the 10mg dose, based on the Phase II data and pharmacokinetic profile

RECORD 2

The RECORD2 study evaluated the safety and efficacy of rivaroxaban compared with enoxaparin and placebo. The duration of thromboprophylaxis in patients undergoing total hip replacement was 35+/-4 days (extended prophylaxis) for rivaroxaban or 10–14 days for those receiving enoxaparin, followed by placebo. The primary and secondary endpoints were the same as for RECORD1 with a 79% RRR (p<0.001) in total VTE and an 88% RRR (p<0.001) in major VTE for patients treated with rivaroxaban compared with those treated with enoxaparin. Rivaroxaban demonstrated a similar rate of major bleeding compared to enoxaparin (0.1% and 0.1%, respectively, p=0.980), despite the greater treatment duration with rivaroxaban in this study.

RECORD 3

The RECORD3 trial compared the safety and efficacy of rivaroxaban with enoxaparin in patients undergoing total knee replacement surgery. Enoxaparin was initiated 12 hours before surgery, and rivaroxaban was initiated 6–8 hours after surgery; both treatments were continued for 10–14 days. Primary and secondary endpoints were the same as for RECORD1 and there was a 49% RRR (p<0.001) in total VTE and a 62% RRR (p=0.016) in major VTE for patients treated with rivaroxaban compared with those treated with enoxaparin. Rivaroxaban demonstrated similar rates of major bleeding to enoxaparin (0.6% and 0.5%, respectively, p=0.774).

Copies of the abstracts may be viewed online at the ASH website: [www.hematology.org/meetings/abstracts.cfm]

A key secondary endpoint of the study measuring the reduction of symptomatic VTE, also showed clinically meaningful results in favor of rivaroxaban. For this endpoint, the trials showed an RRR of 45% (p=0.222) in RECORD1, an 80% RRR (p=0.004) in RECORD2 and a 66% RRR (p=0.005) in RECORD3, compared to the standard regimen.

RECORD 4

RECORD 4 was a pivotal Phase III clinical trial which demonstrated that rivaroxaban, an oral, once-daily, investigational anticoagulant medication, was superior in preventing venous blood clots in patients who underwent total knee replacement (TKR) surgery. The head-to-head study compared rivaroxaban with the U.S.-approved dosing regimen for enoxaparin, the current standard of care. Data from the RECORD4 clinical trial were first presented at the annual meeting of the European Federation of National Associations of Orthopaedics & Traumatology (EFORT). In RECORD4, among patients undergoing total knee replacement, rivaroxaban (10mg once-daily) was associated with a statistically significant 31% relative risk reduction (RRR) in total venous thromboembolism (VTE) events compared to enoxaparin (30mg twice-daily) (6.9% and 10.1%, respectively, p =0.012). In RECORD 4, VTE was defined as the composite of all deep vein thrombosis, non-fatal pulmonary embolism and all-cause mortality.

RECORD4 compared rivaroxaban to enoxaparin for the prevention of VTE following TKR surgery in 3,148 patients. Rivaroxaban (10mg once-daily) was orally administered 6-8 hours post surgery, compared to enoxaparin (30mg twice-daily), which was initiated by subcutaneous injection 12-24 hours post surgery. The study achieved its primary endpoint, demonstrating a 31% RRR in total VTE for patients treated with rivaroxaban, compared to those treated with enoxaparin (6.9% and 10.1%, respectively; p = 0.012). The rate of major bleeding, the main safety endpoint, was numerically greater in rivaroxaban-treated patients, yet rates were low in both treatment groups (0.7% in rivaroxaban-treated patients and 0.3% in enoxaparin-treated patients). This difference between treatment groups was not statistically significant (p=0.110). Major VTE (composite of proximal deep vein thrombosis, non-fatal pulmonary embolism and VTE-related death) and symptomatic VTE, secondary efficacy endpoints, occurred less frequently with rivaroxaban, but the differences did not reach statistical significance.

RECORD4 is the first RECORD trial to evaluate rivaroxaban against enoxaparin 30mg twice-daily, which is the Food and Drug Administration (FDA)-approved dosing regimen for enoxaparin in knee replacement surgery. The RECORD1, 2 and 3 studies compared rivaroxaban against enoxaparin dosed once-daily at 40mg. The full RECORD data set will be used to support the new drug application for rivaroxaban to the FDA, which is planned for submission in the third quarter 2008.

Related drugs

Ximelagatran, a direct thrombin inhibitor, was not marketed further due to its potential side-effects; the related compound dabigatran is undergoing studies. Together with rivaroxaban, the related factor Xa-inhibitor apixaban (Bristol-Myers-Squibb) and LY517717 (Lilly) are under development as non-monitored antithrombotic drugs.

External links

• Xarelto.com (presently redirects to Bayer's main page)

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