Limits...
New compounds in the management of venous thromboembolism after orthopedic surgery: focus on rivaroxaban.

Borris LC - Vasc Health Risk Manag (2008)

Bottom Line: The results of the phase III studies showed a significantly better antithrombotic efficacy of rivaroxaban compared with enoxaparin both in the short term (10-14 days) in TKA patients and long term (35 +/- 4 days) in THA patients with a comparable safety.Liver enzyme elevation was seen in patients treated with rivaroxaban, but there was no indication of an increased risk of liver toxicity compared with enoxaparin.In conclusion, rivaroxaban is a potent and safe new compound for antithrombotic prophylaxis in orthopedic surgery.

View Article: PubMed Central - PubMed

Affiliation: Department of Orthopaedic Surgery, Aarhus University Hospital, Aarhus, Denmark. lborr@as.aaa.dk

ABSTRACT
Rivaroxaban (Xarelto) is a member of a new class of oral, direct (antithrombin-independent) factor Xa inhibitors, which restrict thrombin generation both in vitro and in vivo. After oral administration the absorption is near 100%, the bioavailability is near 80%, and the elimination half-life is 5-9 hours with mixed excretion via the renal and fecal/biliary routes. The pharmacokinetics of rivaroxaban are predictable and consistent with a rapid onset of antithrombotic action within 2 hours after administration. Phase II clinical studies have been carried out in patients undergoing total hip arthroplasty (THA) or total knee arthroplasty (TKA) and a dose of 10 mg once daily for thromboprophylaxis was selected for further clinical development. The results of the phase III studies showed a significantly better antithrombotic efficacy of rivaroxaban compared with enoxaparin both in the short term (10-14 days) in TKA patients and long term (35 +/- 4 days) in THA patients with a comparable safety. Symptomatic thromboembolic events were also significantly reduced with rivaroxaban. Liver enzyme elevation was seen in patients treated with rivaroxaban, but there was no indication of an increased risk of liver toxicity compared with enoxaparin. In conclusion, rivaroxaban is a potent and safe new compound for antithrombotic prophylaxis in orthopedic surgery.

Show MeSH

Related in: MedlinePlus

Schematic represention of the coagulation cascade with indication of mechanism of action of direct FXa inhibitors. Reproduced with permission from Bayer HealthCare.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2597756&req=5

f1-vhrm-4-0855: Schematic represention of the coagulation cascade with indication of mechanism of action of direct FXa inhibitors. Reproduced with permission from Bayer HealthCare.

Mentions: Activation of factor X to FXa initiates the conversion of prothrombin to thrombin which leads to conversion of fibrinogen to fibrin and eventually clot formation (Figure 1). An invasive operative procedure cannot be performed without tissue damage resulting in release of tissue factor (TF). Orthopedic surgery due to surgical damage to bone is especially prone to TF release because bone marrow is rich in TF (Dahl et al 1995). In conjunction with factor VIIa, TF activates FXa directly (the extrinsic pathway) or via propagation of the tenase complex (factor VIIIa + factor IXa) on an activated platelet membrane (the intrinsic pathway) (Mann et al 2003). The prothrombinase complex is then formed on the platelet surface and incorporation of FXa into this complex increases the rate of thrombin generation tremendously. The thrombingenerating efficacy of the prothrombinase complex is much more pronounced than that of free FXa (Mann et al 1998; Rauch and Nemerson 2000; Mann et al 2003a). Thus, FXa is the pivotal point in the coagulation cascade because it can be activated both by the extrinsic and the intrinsic pathways; furthermore the only function of FXa in the coagulation process is to promote coagulation and to amplify the events. Thus, it has been estimated that one molecule of FXa catalyzes the formation of ~1000 thrombin molecules (Mann et al 2003b). In the design of new antithrombotic drugs it therefore seems attractive to target the mode of action towards inhibition of FXa. Unfractionated heparin (UFH) and LMWH are indirect FXa inhibitors because they inhibit FXa by potentiation of the natural inhibitory action of antithrombin (AT) that is an endogeneous plasma protein. In addition especially UFH also has an inhibitory action on several other coagulation factors among which factor IIa is the most important. Fondaparinux is a synthetic pentasaccharide with the same mode of action as UFH and LMWH, but in contrast to those it acts solely by the antithrombin-mediated inhibition of FXa (Samama and Gerotziafas 2003). On the contrary, direct FXa inhibitors, including rivaroxaban, do not need AT to exert their inhibitory action on FXa, because they are able to bind directly to the active site of FXa, thereby preventing interaction with its substrates. As a consequence the direct FXa inhibitors are able to inhibit both free FXa and FXa bound in the prothrombinase complex (Perzborn 2005) (Figure 1).


New compounds in the management of venous thromboembolism after orthopedic surgery: focus on rivaroxaban.

Borris LC - Vasc Health Risk Manag (2008)

Schematic represention of the coagulation cascade with indication of mechanism of action of direct FXa inhibitors. Reproduced with permission from Bayer HealthCare.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2597756&req=5

f1-vhrm-4-0855: Schematic represention of the coagulation cascade with indication of mechanism of action of direct FXa inhibitors. Reproduced with permission from Bayer HealthCare.
Mentions: Activation of factor X to FXa initiates the conversion of prothrombin to thrombin which leads to conversion of fibrinogen to fibrin and eventually clot formation (Figure 1). An invasive operative procedure cannot be performed without tissue damage resulting in release of tissue factor (TF). Orthopedic surgery due to surgical damage to bone is especially prone to TF release because bone marrow is rich in TF (Dahl et al 1995). In conjunction with factor VIIa, TF activates FXa directly (the extrinsic pathway) or via propagation of the tenase complex (factor VIIIa + factor IXa) on an activated platelet membrane (the intrinsic pathway) (Mann et al 2003). The prothrombinase complex is then formed on the platelet surface and incorporation of FXa into this complex increases the rate of thrombin generation tremendously. The thrombingenerating efficacy of the prothrombinase complex is much more pronounced than that of free FXa (Mann et al 1998; Rauch and Nemerson 2000; Mann et al 2003a). Thus, FXa is the pivotal point in the coagulation cascade because it can be activated both by the extrinsic and the intrinsic pathways; furthermore the only function of FXa in the coagulation process is to promote coagulation and to amplify the events. Thus, it has been estimated that one molecule of FXa catalyzes the formation of ~1000 thrombin molecules (Mann et al 2003b). In the design of new antithrombotic drugs it therefore seems attractive to target the mode of action towards inhibition of FXa. Unfractionated heparin (UFH) and LMWH are indirect FXa inhibitors because they inhibit FXa by potentiation of the natural inhibitory action of antithrombin (AT) that is an endogeneous plasma protein. In addition especially UFH also has an inhibitory action on several other coagulation factors among which factor IIa is the most important. Fondaparinux is a synthetic pentasaccharide with the same mode of action as UFH and LMWH, but in contrast to those it acts solely by the antithrombin-mediated inhibition of FXa (Samama and Gerotziafas 2003). On the contrary, direct FXa inhibitors, including rivaroxaban, do not need AT to exert their inhibitory action on FXa, because they are able to bind directly to the active site of FXa, thereby preventing interaction with its substrates. As a consequence the direct FXa inhibitors are able to inhibit both free FXa and FXa bound in the prothrombinase complex (Perzborn 2005) (Figure 1).

Bottom Line: The results of the phase III studies showed a significantly better antithrombotic efficacy of rivaroxaban compared with enoxaparin both in the short term (10-14 days) in TKA patients and long term (35 +/- 4 days) in THA patients with a comparable safety.Liver enzyme elevation was seen in patients treated with rivaroxaban, but there was no indication of an increased risk of liver toxicity compared with enoxaparin.In conclusion, rivaroxaban is a potent and safe new compound for antithrombotic prophylaxis in orthopedic surgery.

View Article: PubMed Central - PubMed

Affiliation: Department of Orthopaedic Surgery, Aarhus University Hospital, Aarhus, Denmark. lborr@as.aaa.dk

ABSTRACT
Rivaroxaban (Xarelto) is a member of a new class of oral, direct (antithrombin-independent) factor Xa inhibitors, which restrict thrombin generation both in vitro and in vivo. After oral administration the absorption is near 100%, the bioavailability is near 80%, and the elimination half-life is 5-9 hours with mixed excretion via the renal and fecal/biliary routes. The pharmacokinetics of rivaroxaban are predictable and consistent with a rapid onset of antithrombotic action within 2 hours after administration. Phase II clinical studies have been carried out in patients undergoing total hip arthroplasty (THA) or total knee arthroplasty (TKA) and a dose of 10 mg once daily for thromboprophylaxis was selected for further clinical development. The results of the phase III studies showed a significantly better antithrombotic efficacy of rivaroxaban compared with enoxaparin both in the short term (10-14 days) in TKA patients and long term (35 +/- 4 days) in THA patients with a comparable safety. Symptomatic thromboembolic events were also significantly reduced with rivaroxaban. Liver enzyme elevation was seen in patients treated with rivaroxaban, but there was no indication of an increased risk of liver toxicity compared with enoxaparin. In conclusion, rivaroxaban is a potent and safe new compound for antithrombotic prophylaxis in orthopedic surgery.

Show MeSH
Related in: MedlinePlus