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The promise of oral direct Factor Xa inhibition
Rivaroxaban most advanced Factor Xa inhibitor, with promising results from the RECORD trials recently annouced.
The coagulation mechanism is centrally involved in the formation of both arterial and venous thrombi, and the development of molecules that inhibit its function is a major strategy for the design of new antithrombotic drugs. Until recently, pharmacologic prophylaxis of venous thromboembolism was based on three types of anticoagulants: vitamin K antagonists (eg, warfarin), unfractionated heparin and low–molecular-weight heparins.
Although these antithrombotic agents are multitargeted, new antithrombotic drugs have been developed that are selective for one specific coagulation factor. The vitamin K antagonists, the only oral anticoagulants currently approved for use, have a number of limitations; these are shown along with their respective consequences in Table 1. An “improved” oral anticoagulant that is at least as effective as warfarin in preventing thrombus formation and at least as safe with respect to bleeding risk would be highly desirable. The desired properties of such an agent are shown in Table 2.
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Factor Xa is an attractive target for the design of new anticoagulants as the enzyme is positioned at the start of the common pathway of coagulation. As the amount of serine protease is amplified at each step of the cascade, it was hypothesized that selective inhibition of coagulation factors above thrombin might be a highly effective antithrombotic strategy. Furthermore by not inhibiting thrombin activity directly, such agents might allow traces of thrombin to escape neutralization, thereby facilitating hemostasis and leading to a favorable safety profile with respect to bleeding.
Fondaparinux (Arixtra, Glaxo-SmithKline), a parenteral anticoagulant administered subcutaneously, was the first selective Factor Xa inhibitor to receive FDA approval for the prevention and treatment of venous thromboembolism. It is a synthetic pentasaccharide of 1,728 daltons, which rapidly binds to antithrombin in the blood. Fondaparinux induces a critical conformational change in antithrombin that increases its inhibitory activity against Factor Xa by a factor of about 300. In patients undergoing total hip or knee replacement or hip fracture surgery, fondaparinux demonstrated superior efficacy to enoxaparin in preventing VTE. It showed similar efficacy and safety to low–molecular-weight heparin therapy for the prophylaxis of VTE in general surgical patients and in the initial treatment of symptomatic deep venous thrombosis or pulmonary embolism.
Table 1: Limitations of Vitamin K Antagonists |
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Rivaroxaban
Data from clinical studies using fondaparinux clearly demonstrated that selective inhibition of Factor Xa is an effective approach to the prevention and treatment of VTE. This has given considerable impetus to developing oral agents that selectivelyinhibit Factor Xa to prevent and treat patients with thrombosis.
These agents, however, inhibit Factor Xa within the assembled prothrombinase complex as well as free Factor Xa, whereas fondaparinux is only able to inhibit the pool of free Factor Xa in the blood.
Oral direct Factor Xa inhibitors that are in clinical development include rivaroxaban (Bayer Healthcare), apixaban (Bristol-Myers Squibb), YM150 (Astellas), DU-176b (Daiichi), LY517717 (Lilly) and PRT054021 (Portola). Rivaroxaban is most advanced in clinical development, and phase-3 trials employing this agent for the prophylaxis of VTE following major orthopedic surgery recently became available. The remainder of the discussion will focus on these data.
Rivaroxaban (Bay 59-7939) is a nonpeptidic, orally bioavailable small molecule that directly inhibits Factor Xa. It has a rapid onset of action and a half-life of five to nine hours. The ODIXa-KNEE and ODIXA-HIP were phase-2 multicenter, parallel group, double blind, dose-ranging studies in patients undergoing total hip and total knee replacement, respectively.
Table 2: Characteristics of an Improved Oral Anticoagulant |
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The researchers investigated a 12-fold dose range of rivaroxaban (total daily dose 5 mg to 60 mg) given twice daily in patients undergoing total hip and total knee replacement. An additional phase-2 study in patients undergoing total hip replacement investigated an eightfold dose range of rivaroxaban given once daily. Total rivaroxaban daily doses of 5 mg to
20 mg had similar safety and efficacy to enoxaparin for the prevention of VTE following major orthopedic surgery. A dose of 10 mg administered once daily starting six hours after surgery is the dose undergoing evaluation in the phase-3 RECORD program, which includes two double blind studies in total hip replacement and two in total knee replacement.
The RECORD trials
The results of three of the RECORD trials were presented at the 49th American Society of Hematology Annual Meeting in Atlanta in December 2007. In the RECORD 1 and 2 trials the researchers studied patients undergoing total hip arthroplasty and compared therapy with rivaroxaban 10 mg daily with enoxaparin 40 mg subcutaneously daily for 5 weeks.
The primary efficacy endpoint, a composite of distal DVT, major VTE and all-cause mortality, occurred in 1.1% in the rivaroxaban group and 3.7% in the enoxaparin group (P,.001); the incidence of major VTE (proximal DVT, non-fatal pulmonary embolism and VTE-related death) was 0.2% in the rivaroxaban group and 2% in the enoxaparin group (P,.001).
In the RECORD 2 trial, patients received either rivaroxaban 10 mg daily for five weeks or enoxaparin 40 mg subcutaneously daily for 10 to 14 days followed by placebo. The primary efficacy endpoint occurred in 9.3% in the placebo group and 2% in the rivaroxaban group (79% relative risk reduction). The incidence of major VTE was 5.1% in the placebo group and 0.6% in the rivaroxaban group (88% relative risk reduction).
Data from the RECORD 3 trial demonstrated that a rivaroxaban dose of 10 mg administered once daily starting six to eight hours postoperatively for 10 to 14 days was more effective than the 40-mg enoxaparin regimen in VTE prophylaxis following total knee replacement (P,.001). The primary efficacy endpoint occurred in 9.6% of the rivaroxaban group and 18.9% of the enoxaparin group. Significant reductions were also shown for the endpoints of major VTE as well as symptomatic VTE in patients receiving rivaroxaban.
The incidence of major and nonmajor bleeding events was similar between the two comparator groups in each of the three trials. The available data from the RECORD trials also indicate that rivaroxaban is not associated with significant elevations in liver function tests. The results of the RECORD 4 trial, which is evaluating rivaroxaban vs. the North American regimen of enoxaparin (30 mg every 12h postoperatively) following total knee replacement, have yet to be reported. Phase-2 trials of rivaroxaban for the treatment of symptomatic DVT and pulmonary embolism and stroke prevention in atrial fibrillation are ongoing.
During the next year, we will likely see phase-3 trial results of other targeted oral Factor Xa inhibitors in the prophylaxis of VTE following major orthopedic surgery. At the present time, rivaroxaban does not appear to have toxicities that will preclude regulatory agency approval for the prevention of VTE following total major orthopedic surgery. New drugs such as rivaroxaban hold great promise as an oral alternative to warfarin for the many clinical settings in which long-term anticoagulation is required.
Kenneth Bauer, MD, is Professor of Medicine, Harvard Medical School and a HemOnc Today Editorial Board member.