Rivaroxaban

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.

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:

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.

ATLAS ACS-TIMI 46
ATLAS was a phase II, multicenter, double-blind, placebo controlled, dose-escalation study, that demonstrated that among patients with acute coronary syndromes, the use of oral rivaroxaban therapy was associated with a reduction in rates of major adverse events as well as with a dose-dependent increase in rates of clinically significant bleeding. Two candidate doses were associated with a reduction in the risk of death, MI and stroke, and these two low doses will now be studied in a large event driven phase III trial (ATLAS ACS II-TIMI 51). The results were first presented at the 2008 American Heart Association Scientific Sessions in New Orleans, Louisiana and published in The Lancet.

3491 ACS patients treated with either aspirin alone (Stratum 1 n=761) or aspirin plus clopidogrel (Stratum 2 n=2730) at investigator discretion were randomized 1:1:1 to receive either placebo, rivaroxaban once daily, or rivaroxaban twice daily. Total daily doses of oral rivaroxaban were the same whether taken once or twice daily; aspirin alone patients were administered either 5, 10 or 20 mg whereas patients treated with aspirin plus clopidogrel received either 5, 10, 15 or 20mg of the study drug.

Compared to placebo, treatment with oral rivaroxaban was associated with a risk of clinically significant bleeding (TIMI major, TIMI minor or requiring medical attention) that increased in a dose-dependent fashion. Among patients receiving a total dose of 5mg daily, the hazard ratio was 2.21 (95% CI: 1.25 – 3.91), which increased to 3.35 (95% CI: 2.31 – 4.87), 3.60 (95% CI: 2.31 – 4.87) and 5.06 (95% CI: 3.45 – 7.42) among patients receiving total daily doses of 10, 15 and 20 mg respectively (p<0.0001). Treatment with the study drug was associated with a trend toward the reduction of rates of the pre-specified primary efficacy endpoint (death, myocardial infarction, stroke or severe recurrent ischemia requiring revascularization from 7.0% (79/116) for placebo to 5.6% (126/2331) for rivaroxaban, with a hazard ratio (HR) of 0.79 (95%CI: 0.60 – 1.05, p=0.10). The reduction of secondary efficacy endpoint of death, myocaridal infarction or stroke reached significance (5.5% [62/1160] among patients receiving placebo versus 3.9% [87/2331] among patients receiving rivaroxaban, HR = 0.65, 95%CI: 0.50 – 0.96, p=0.027).

The results of this phase II study suggest oral rivaroxaban may reduce major adverse ischemic events among ACS patients with risks of clinically significant bleeding increasing in a dose-dependent manner. Investigators are currently involved in a large event driven phase III (ATLAS II ACS-TIMI 51) study of two candidate low doses.

====ATLAS ACS 2-TIMI 51 ====

Study Design
ATLAS ACS 2-TIMI 51 was a randomized, double-blind, placebo controlled phase 3 trial to evaluate the efficacy and safety of Rivaroxaban twice-daily at doses of 2.5 mg and 5 mg as adjunctive therapy in subjects with acute coronary syndrome.

Study Population

 * Inclusion criteria - Patients ≥18 years of age presenting with symptoms suggestive of an acute coronary syndrome (STEMI, NSTEMI, or unstable angina) were included. Additionally, patients < 55 years with history of diabetes mellitus or a previous myocardial infarction in addition to the index event were also included.
 * Exclusion criteria - Patients with platelet count of < 90,000 / cubic millimeter, a hemoglobin < 10 g / dl, or a creatinine clearance < 30 ml/min, clinically significant git bleeding within 12 months before randomization, previous intracranial hemorrhage or increased bleeding risks were excluded. Also, patients who had a history of previous ischemic stroke or transient ischemic attack and were on dual therapy with both aspirin and thienopyridine were excluded.
 * Sample size - 15,526 patients at 766 sites in 44 countries.

Intervention
Randomization was stratified on the basis of planned use of a thienopyridine. Random assignment of patients to twice-daily administration of either 2.5 mg or 5.0 mg of rivaroxaban or placebo in 1:1:1 fashion. This was in addition to standard medical therapy i.e. low-dose aspirin and thienopyridine (either clopidogrel or ticlopidine on physician's discretion)

Study duration
November 2008 through September 2011

Follow up duration
31 months

Follow-up schedule
4 weeks, 12 weeks, and thereafter every 12 weeks after randomization.

End points

 * Primary efficacy end points - Composite of cardiovascular death, myocardial infarction, or stroke (ischemic, hemorrhagic, or stroke of uncertain cause).
 * Secondary efficacy end points - All causes death, myocardial infarction, or stroke.
 * Primary safety end points - TIMI major bleeding not related to coronary-artery bypass grafting (CABG).
 * All efficacy and safety endpoints were adjudicated by a blinded adjudicator.

Efficacy

 * The primary efficacy endpoint of CV death, MI and stroke was reduced when added to standard therapy for both rivaroxaban doses combined, and for the 2.5 and 5.0 mg BID doses separately when compared with placebo. The incidence rates were 8.9% and 10.7%, for rivaroxaban and placebo respectively (hazard ratio, 0.84; 95% confidence interval [CI], 0.74 to 0.96; P=0.008). CV and all cause death were reduced for both rivaroxaban doses combined, and for the 2.5 mg BID dose in both mITT and ITT analyse.
 * The secondary composite efficacy end point of death from any cause, myocardial infarction, or stroke, was also reduced when compared with placebo. The incidence rates of these composite endpoints were 9.2% and 11.0%, for rivaroxaban and placebo respectively (hazard ratio, 0.84; 95% CI, 0.74 to 0.95; P=0.006).

Safety

 * There was a dose dependent increase in bleeding associated with rivaroxaban.
 * Although ICH was increased with rivaroxaban, there was no excess risk of fatal ICH or fatal bleeding associated with rivaroxaban compared to placebo.
 * No evidence of drug induced liver injury or rebound (post-treatment) ischemic events

Related drugs
Ximelagatran, a direct thrombin inhibitor, was not marketed further due to its potential side-effects (hepatotoxicity ); 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.

Slides
For the ATLAS ACS-TIMI 46 slides presented at AHA 2008, please click [[Media:Atlas_aha_2008_final_version.ppt‎|here]]