Direct factor Xa inhibitors can be considered as an alternative to warfarin, particularly if a person is on several other medications that interact with warfarin, or if attending medical appointments and laboratory monitoring becomes difficult.[8] Factors considered before deciding on whether warfarin or a DOAC or which direct factor Xa inhibitor is used, include: the presence or absence of valvular heart disease, state of kidney function, the risk of stroke and the risk of bleeding.[8]
Contraindications
Direct Xa inhibitors are contraindicated in people who are actively bleeding or who are at high risk of bleeding. The effects on a fetus or neonate are unknown, hence these drugs are not prescribed in pregnancy or breast feeding mothers.[2]
A specialist may request a quantitative factor Xa assay in a situation of overdose.[2]Andexanet alfa, a specific antidote to reverse the anticoagulant activity of direct Xa inhibitors in the event of major bleeding, was approved by the FDA in 2018.[9] It is also available in the UK.[10]
Coagulation in vivo, shows final common pathway and where factor Xa acts
Direct factor Xa inhibitors block the enzyme called factor Xa, preventing the conversion of prothrombin to thrombin in the final common pathway of clot formation in veins and the heart.[2]
Pharmacokinetics
They have a rapid onset and offset of action. This means it is often possible to pause them 12 to 48 hours before surgery and resume them shortly after the surgery. By contrast, warfarin and phenprocoumon are often paused up to a week before surgery, and low-molecular-weight heparins are used to "bridge" the therapy gap, typically for several weeks.[12][13]
Also in contrast to warfarin and phenprocoumon, direct factor Xa inhibitors do not require frequent monitoring of the prothrombin time (also called the INR) and dose adjustments.[12]
Antistasin, the first discovered naturally occurring direct Xa inhibitorRivaroxaban, the first synthetic direct Xa inhibitor marketed as a drug
Prior to the introduction of direct factor Xa inhibitors, vitamin K antagonists such as warfarin were the only oral anticoagulants for over 60 years, and together with heparin have been the main blood thinners in use. People admitted to hospital requiring blood thinning were started on an infusion of heparin infusion, which thinned blood immediately, and were then discharged from the hospital after almost a week on warfarin, which takes time to work. The ability to have a shorter stay in hospital came with the advent of low molecular weight heparin (LMWH) and the ability of self-injecting subcutaneously at home. Biotechnology developments then paved way for the first successful synthetic anticoagulants including hirudin.[6] The monitoring of warfarin and keeping the international normalized ratio (INR) between 2.0 and 3.0, along with avoiding over and under treatment, has driven a search for an alternative.[3][14]
A naturally occurring inhibitor of factor Xa was reported in 1971 by Spellman et al. from the dog hookworm.[15] In 1987, Tuszynski et al. discovered antistasin, which was isolated from the extracts of the Mexican leech, Haementeria officinalis.[16][17] Later, another naturally occurring inhibitor, tick anticoagulant peptide (TAP) was isolated from the extract of tick Ornithodoros moubata.[18] Trials subsequently demonstrated efficacy and safety against warfarin for stroke prevention in AF and against LMWH for treatment and prevention of VTE including in people undergoing hip or knee replacement.[19]
Society and culture
Economics
The cost of direct Xa inhibitors can reach more than 50 times that of warfarin, although this difference may be offset by lower monitoring costs.[2][5]
^Douketis, J. D.; Healey, J. S.; Brueckmann, M.; Eikelboom, J. W.; Ezekowitz, M. D.; Fraessdorf, M.; Noack, H.; Oldgren, J.; Reilly, P.; Spyropoulos, A. C.; Wallentin, L.; Connolly, S. J. (2015). "Perioperative bridging anticoagulation during dabigatran or warfarin interruption among patients who had an elective surgery or procedure. Substudy of the RE-LY trial". Thrombosis and Haemostasis. 113 (3): 625–32. doi:10.1160/TH14-04-0305. PMID25472710.
^Eriksson BI, Quinlan DJ, Weitz JI (2009). "Comparative pharmacodynamics and pharmacokinetics of oral direct thrombin and factor xa inhibitors in development". Clinical Pharmacokinetics. 48 (1): 1–22. doi:10.2165/0003088-200948010-00001. PMID19071881. S2CID35948814.
^"AstraZeneca, Sanofi Cut Programs". Chemical & Engineering News. American Chemical Society. 91 (23): 17. 10 June 2013. Sanofi is ending development on two compounds, the anticancer compound iniparib and the anticoagulant otamixaban, both of which flunked Phase III studies.
