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What are the available clinical data and continuing concerns regarding rivaroxaban (Xarelto®)?
Introduction
Rivaroxaban (Xarelto®; Johnson & Johnson) is an investigational oral direct factor Xa inhibitor, which could be the first new oral anticoagulant in the United States since the approval of warfarin (Coumadin) in 1954.1,2 The drug is currently available in Europe and Canada. Rivaroxaban exerts its anticoagulant effect by competitively inhibiting free and clot-bound factor Xa, which is the coagulation factor at the convergence of the intrinsic and extrinsic pathways of the coagulation cascade.1 The approval of oral rivaroxaban may offer several advantages over therapy with warfarin. Warfarin therapy can result in numerous drug and/or dietary interactions, be influenced by individual genetic factors, and has a narrow therapeutic index resulting in frequent monitoring and dosage adjustments.
Clinical Data
On March 20, 2009, the Cardiovascular and Renal Drugs Advisory Committee of the Food and Drug Administration (FDA) recommended approval of rivaroxiban for the prophylaxis of venous thromboembolic events (VTEs) in patients undergoing hip and knee replacement surgery by a 15 to 2 vote.2 This recommendation was based primarily on results from the 4 phase III RECORD (Regulation of Coagulation in Orthopedic Surgery to Prevent Deep Vein Thrombosis and Pulmonary Embolism) trials, which cumulatively involved over 12,500 patients. The major results of these trials are summarized in table 1. Overall, rivaroxaban was found to exhibit superior efficacy to the comparator, enoxaparin, with a similar bleeding risk profile in patients scheduled for elective total hip or knee arthroplasty.3-6
Table 1. Phase III clinical trial summaries involving rivaroxaban – RECORD 1 through 4.3-6
Citation |
Design/
Duration |
Population |
Interventions |
Primary and secondary endpoints |
Outcomes and conclusions |
Eriksson et al 2008
(RECORD 1) |
MC, DB, DD, RCT
Duration of therapy: 35 days (range: 31 to 39 days) |
N = 4541 adults scheduled for elective total hip arthroplasty |
Rivaroxaban 10 mg PO once daily (n = 2266)
Enoxaparin 40 mg SC once daily (n = 2275)
Enrollees were administered a placebo injection or tablet dependent upon randomization.
Rivaroxaban was initiated after surgery, while enoxaparin was initiated the evening prior to surgery. |
Primary: composite of DVT, nonfatal PE, or death from any cause at 36 days (range: 30 to 42 days)
Secondary: major VTE occurrence
Main safety outcome: incidence of major bleeding from the first dose until up to 2 days after the last dose of study medication |
The composite primary outcome occurred in 18 (1.1%) of 1595 patients receiving rivaroxaban and 58 (3.7%) of 1558 patients administered enoxaparin in the modified ITT analysis (weighted risk reduction: 2.6%; 95% CI: 1.5 to 3.7; p<0.001).
Major VTE occurred in 4 (0.2%) of 1686 patients in the rivaroxaban group and 33 (2%) of 1678 patients in the enoxaparin group in the modified ITT analysis (weighted risk reduction: 1.7%; 95% CI: 1.0 to 2.5; p<0.001).
The incidence of major bleeding was similar between the groups: 0.3% rivaroxaban vs. 0.1% enoxaparin (p=0.18).
Rivaroxaban was shown to be more effective than enoxaparin for extended thromboprophylaxis in hip arthroplasty with a similar safety profile. |
Kakkar et al 2008
(RECORD 2) |
MC, DB, DD, RCT
Duration of therapy: 31 to 39 days for rivaroxaban and 10 to 14 days for enoxaparin |
N = 2509 adults scheduled for elective total hip arthroplasty |
Rivaroxaban 10 mg PO once daily (n = 1252)
Enoxaparin 40 mg SC once daily (n = 1257)
Placebo injections were given to patients in the rivaroxaban group for 10 to 14 days starting 12 hours before surgery and placebo tablets were given to patients in the enoxaparin group for 31 to 39 days starting 6 to 8 hours after wound closure. |
Primary: composite of DVT, nonfatal PE, or all-cause mortality up to day 30 to 42
Secondary: major VTE occurrence
Main safety outcome: incidence of major bleeding from the first dose until up to 2 days after the last dose of study medication |
Primary outcome occurrence in modified ITT population: 2% rivaroxaban vs. 9.3% enoxaparin (absolute risk reduction: 7.3%, 95% CI: 5.2 to 9.4; p<0.0001).
Major VTE occurrence in modified ITT population: 0.6% rivaroxaban vs. 5.1% enoxaparin (absolute risk reduction: 4.5%, 95% CI: 3 to 6; p<0.0001).
Any on-treatment bleeding occurred in 81 (6.6%) of 1228 patients receiving rivaroxaban and 68 (5.5%) of 1229 enoxaparin-treated patients (p=0.25).
One patient in each group experienced major bleeding.
Extended duration rivaroxaban was significantly more effective than short-term enoxaparin therapy with regard to prevention of VTE. |
Lassen et al 2008
(RECORD 3) |
MC, DB, DD, RCT
Duration of therapy: at least 10 days up to 14 days |
N = 2531 adults scheduled for total knee arthroplasty |
Rivaroxaban 10 mg PO once daily (n = 1254)
Enoxaparin 40 mg SC once daily (n = 1277)
Enrollees were administered a placebo injection or tablet dependent upon randomization.
Rivaroxaban was initiated after surgery while enoxaparin was initiated the evening prior to surgery. |
Primary: composite of DVT, nonfatal PE, or death from any cause within 13 to 17 days after surgery
Secondary: major VTE occurrence
Main safety outcome: incidence of major bleeding from the first dose until up to 2 days after the last dose of study medication
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The composite primary outcome occurred in 9.6% of patients receiving rivaroxaban vs. 18.9% of enoxaparin-treated patients (weighted absolute risk reduction: 9.2%; 95% CI: 5.9 to 12.4; p<0.001).
Significantly less major VTE events occurred in the rivaroxaban group (1% vs. 2.6%; weighted absolute risk reduction: 1.6%; 95% CI: 0.4 to 2.8; p=0.01).
Major bleeding was reported in 7 (0.6%) of 1220 rivaroxiban-treated patients vs. 6 (0.5%) of 1239 enoxaparin-treated patients (weighted absolute risk increase: 0.1%; p=0.77). Fatal bleeding episodes did not occur in either group.
Rivaroxaban was more effective than enoxaparin with regard to thromboprophylaxis after total knee arthroplasty with similar bleeding rates. |
Turpie et al 2009
(RECORD 4) |
MC, DB, DD, RCT
Duration of therapy: at least 10 days up to 14 days |
N = 3148 adults scheduled for total knee arthroplasty |
Rivaroxaban 10 mg PO once daily (n = 1584)
Enoxaparin 30 mg SC twice daily (n = 1564)
Enrollees were administered a placebo injection or tablet dependent upon randomization.
Rivaroxaban was initiated 6 to 8 hours after surgery while enoxaparin was started 12 to 24 hours after surgery. |
Primary: composite of DVT, nonfatal PE, or death from any cause up to day 17 after surgery
Secondary: major VTE occurrence
Main safety outcome: incidence of major bleeding from the first dose until up to 2 days after the last dose of study medication
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The occurrence of the primary outcome for the modified ITT population was significantly reduced with rivaroxaban as compared to enoxaparin (6.9% vs. 10.1%; absolute risk difference:
-3.19%; 95% CI: -5.67 to
-0.71; p=0.0118).
Major VTE occurrence was similar between the groups in the modified ITT population (1.2% rivaroxaban vs. 2% enoxaparin; absolute risk difference: -0.8; 95% CI:
-1.82 to 0.22; p=0.1237).
Major bleeding was also similar between the groups (0.7% rivaroxaban vs. 0.3% enoxaparin; p=0.1096).
Rivaroxaban was superior to enoxaparin for the prevention of VTE after knee arthroplasty with a similar bleeding risk. |
MC = multicenter; DB = double-blind; DD = double-dummy; RCT = randomized controlled trial; PO = oral; SC = subcutaneous; DVT = deep vein thrombosis; PE = pulmonary embolism; VTE = venous thromboembolic event; ITT = intention-to-treat; CI = confidence interval.
Concerns
At the subcommittee hearing on rivaroxaban, multiple concerns were discussed by the members including RECORD design issues, bleeding risks, hepatotoxicity potential, and dosage debates.2 The main design concern of the RECORD trials involved the use of venography to determine the most prevalent component of the primary endpoint (i.e., deep vein thrombosis). One of the subcommittee members (Dr. Sanjay Kaul of Cedars-Sinai Medical Center in Los Angeles, CA) found the use of venography to be of questionable value as this procedure is not often performed in clinical practice to determine the occurrence of a venous thrombosis. With regard to bleeding risks, Dr. Kaul noted that: “Even if you pool the [RECORD] data and focus the analysis only on symptomatic VTEs and balance that benefit with major bleeding risks—including bleeding at surgical sites—the numbers needed to treat [NNT] and the numbers needed to harm [NNH] were pretty close to each other. If the analysis is focused on major bleeds and surgical bleeds, the NNT is 454 and the NNH is 303; it's a wash.”
The potential for hepatotoxicity with rivaroxaban remains an important safety concern as another oral direct thrombin inhibitor, ximelagatran, which was approved in Europe, was eventually removed from that market due to hepatotoxicity.2 In data collected to date with rivaroxaban, 1 hepatic-related death has been reported with 6 additional cases in which there may have been a potential toxic effect of rivaroxaban on the liver. Johnson & Johnson submitted data on these patients explaining that the 1 fatality was more than likely due to hepatitis B while the hepatotoxic effects observed in the 6 other patients were likely associated with “some other explanation” than a direct injurious effect of rivaroxaban.
The dosage debate centered on the merits of having the company manufacture a 5 mg dose of rivaroxaban that could be administered to certain subgroups of patients (i.e., patients > 75 years of age or those with moderate renal impairment) who may be at a greater risk of adverse events with the proposed daily dose of 10 mg.2 At the end of this debate, 5 members voted yes to this proposal, 9 voted no, and 3 abstained. Those who voted against the 5 mg dose noted that there was currently no efficacy data for the dose and that the availability of a lower dose may tempt prescribers to use rivaroxiban for longer periods of time and for off-label indications. Subcommittee members who supported the proposal for a 5 mg dose observed that the availability of such a dose may be favorable in the orthopedic setting where surgeons are “notoriously reluctant” to administer anticoagulants because of bleeding risks.
Summary
Rivaroxaban is an investigational oral direct factor Xa inhibitor, which if approved by the FDA, would represent the first oral anticoagulant approved in the United States in over 50 years. Four phase III trials (RECORD 1 to 4) showed rivaroxaban to have superior efficacy to enoxaparin, with a similar bleeding risk, in patients undergoing elective total hip or knee arthroplasty. However, concerns remain regarding this agent including trial design and safety issues such as the potential for hepatotoxicity and bleeding risks. Although Johnson & Johnson is currently hoping for the FDA to approve rivaroxaban for prophylaxis of VTEs after hip or knee surgery, clinical trials are ongoing for other indications, including: secondary prevention and long-term treatment of patients with DVT/PE (pulmonary embolism, EINSTEIN), hospitalized medically ill patients (MAGELLAN), stroke prevention in atrial fibrillation (ROCKET-AF and J-ROCKET-AF), and secondary prevention of cardiovascular events after an acute coronary syndrome (ATLAS).2
References
- Abrams PJ, Emerson CR. Rivaroxaban: a novel, oral, direct factor Xa inhibitor. Pharmacotherapy. 2009;29(2):167-181.
- Heartwire. Rivaroxaban recommended for approval by FDA advisory panel. http://www.theheart.org/article/949571.do. Accessed May 27, 2009.
- Eriksson BI, Borris LC, Friedman RJ, for the RECORD1 Study Group. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008;358(26):2765-2775.
- Kakkar AK, Brenner B, Dahl OE, for the RECORD2 investigators. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomized controlled trial. Lancet. 2008;372(9632):31-39.
- Lassen MR, Ageno W, Borris LC, for the RECORD3 investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008;358(26):2776-2786.
- Turpie AGG, Lassen MR, Davidson BL, for the RECORD4 investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomized trial. Lancet. 2009;373(9676):1673-1680.
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