Should new oral anticoagulants replace low-molecular-weight heparin for thromboprophylaxis in orthopaedic surgery?

Abstract

Current anticoagulant provision is dominated by parenteral low-molecular-weight heparin and oral vitamin K antagonists (VKAs), which indirectly inhibit several steps of the coagulation pathway. Two unmet needs for anticoagulation are safety and ease of use. Safety relates primarily to the incidence of major bleeding, which remains the key concern of orthopaedic surgeons and anaesthetists, over and above any efficacy advantage, and convenience of use, which centres on oral administration replacing the need for injections or monitoring platelets or coagulation with VKA. Recent research efforts towards identifying small-molecule inhibitors of coagulation enzymes as novel therapies for thrombotic disorders have been particularly successful in developing orally available molecules to directly inhibit the key proteases, factors IIa and Xa. Of the new oral anticoagulants in development, dabigatran etexilate (BIBR 1048) and rivaroxaban (BAY 59-7939), which inhibit factors IIa and Xa, respectively, are the most advanced and were approved in Europe in 2008. Based on the available data, we can conclude that dabigatran etexilate is non-inferior to enoxaparin in terms of efficacy and safety, and two different doses (220 and 150 mg/day) have now been approved. The 150 mg/day dose is intended for elderly patients and those with moderate renal impairment, which allows clinicians to decrease the risk of bleeding in the increasing number of fragile patients undergoing major orthopaedic surgery. In conclusion, rivaroxaban is superior in efficacy to enoxaparin, even with the US enoxaparin dosing regimen (30 mg b.i.d.), without significant differences in safety.

Oral fondaparinux: use of lipid nanocapsules as nanocarriers and in vivo pharmacokinetic study

“…32 Due to its safety/efficacy profile, Fp should be an ideal agent for home therapy. 30,[32][33][34] Until nowadays, it is not clear even if dabigatran and/or rivaroxaban, are more effective than Fp due to the lack of studies comparing them. 31 On the basis of the above mentioned considerations, it was sought, in this study, to combine the advantages of LNCs as oral delivery systems with the benefit of the presence of acquired positive charge on their surfaces, to both associate the anionic hydrophilic macromolecule Fp and to increase electrostatic interactions with the intestinal mucosa.…”

Looking at the proteases from a simple perspective

“…Interestingly, DTs reduce thrombin activity more effectively than UFH and LMWH (Heras et al, 1989;Badimon et al, 1991;Eikelboom, 2003), and they do not rely on a vitamin K mechanism for activity, so dietary ingestion of green leafy vegetables does not alter their effect (Weitz and Bates, 2003;Eriksson and Dahl, 2004). Because they do not bind to plasma proteins and are not inactivated by heparinases, DTIs produce a more predictable anticoagulant response than UFH (Heras et al, 1989;Badimon et al, 1991;Eikelboom, 2003) and seem to be safe and efficacious (Rosencher et al, 2009;Mismett and Laporte 2009;Baines et al, 2009).…”

“…In addition, it should be orally available, inexpensive, reversible, and not requiring monitoring. Rational drug design has already resulted in synthetic compounds that present a closer profile of the ideal agent (Stü rzebecher et al, 1997;Petitou et al, 1997;Huntington and Baglin, 2003;Gabriel et al, 2009) and several oral and intravenous anticoagulants are currently under development (Sagi et al, 2003;Becker, 2005;Verghese et al, 2009;Valerie, 2009;Rosencher et al, 2009;Mismetti1 and Laporte, 2009).…”

“…Recent literature described new oral direct thrombin inhibitors such as dabigatran etexilate, which is the prodrug of dabigatran, the active compound binds reversibly to thrombin with high affinity and specificity (Rosencher et al, 2009;Mismett and Laporte 2009) and Rivaroxaban, which would probably be the first oral anticoagulant drug direct inhibitor of factor Xa (FXa) available (Baines et al, 2009). The pharmacokinetic of these new anticoagulants include rapid absorption, with high bioavailability and plasma protein binding and half-life ranging from 2-8 h. These new anticoagulants seem to have practical advantages, safety and efficacy.…”

A Systems Pharmacology Model for Predicting Effects of Factor Xa Inhibitors in Healthy Subjects: Assessment of Pharmacokinetics and Binding Kinetics

“…The simulation of drug concentration after multiple doses (5, 10, 20, and 30 mg twice daily) was conducted based on this PK model. Plasma protein binding of rivaroxaban was assumed to be 93% (i.e., within the reported range of 92–95% in man) 23. In the pharmacodynamic study, healthy white male subjects, 20–45 years of age, were assigned to receive rivaroxaban (n = 8 per dose regimen) orally and the dosing regimens were 5, 10, 20, and 30 mg twice daily.…”