{{Short description|Blood thinning drugs}} {{Use dmy dates|date=April 2022}} {{Infobox drug class | Name = Direct factor Xa inhibitor | Image = | Alt = | Caption = | Pronounce = | Synonyms = Direct Xa inhibitor, novel oral anticoagulant <!-- Class identifiers --> | Use = Treat and prevent venous thromboembolism | ATC_prefix = | Mode_of_action = | Mechanism_of_action = Inhibit fibrin formation in the final common pathway of the coagulation cascade | Biological_target = | Chemical_class = Direct factor Xa inhibitors<ref name="WHOCC">{{cite web |title=WHOCC – ATC/DDD Index |url=https://www.whocc.no/atc_ddd_index/?code=B01AF&showdescription=no |website=whocc.no |access-date=4 April 2021 |archive-url=https://web.archive.org/web/20210404064333/https://www.whocc.no/atc_ddd_index/?code=B01AF&showdescription=no |archive-date=4 April 2021}}</ref> <!-- Clinical data --> | Drugs.com = <!-- {{Drugs.com|drug-class|?}} --> | Consumer_Reports = | medicinenet = | rxlist = <!-- External links --> | MeshID = }} '''Direct factor Xa inhibitors''' ('''xabans''') are anticoagulants (blood thinning drugs), used to both treat and prevent blood clots in veins, and prevent stroke and embolism in people with atrial fibrillation.<ref name="Hitchings2019"/><ref name="Turgeon2018"/>
==Medical use== Direct factor Xa inhibitors include rivaroxaban, apixaban and edoxaban, and are types of direct oral anticoagulant (DOAC), which are blood thinning drugs, one of the classes of antithrombotic drugs.<ref name="Drugs.com">{{cite web |title=List of Factor Xa inhibitors |url=https://www.drugs.com/drug-class/factor-xa-inhibitors.html |website=Drugs.com |access-date=4 April 2021 |archive-url=https://web.archive.org/web/20210404072015/https://www.drugs.com/drug-class/factor-xa-inhibitors.html |archive-date=4 April 2021 |language=en}}</ref><ref name=BNF80>{{cite book | title=BNF|date= September 2020 – March 2021|publisher=BMJ Group and the Pharmaceutical Press|isbn=978-0-85711-369-6|edition=80|location=London|pages=133–139}}</ref><ref name="ASH2008">{{cite web |last1=American Society of Hematology |title=Antithrombotic Therapy - Hematology.org |url=https://www.hematology.org/about/history/50-years/antithrombotic-therapy |website=hematology.org |access-date=8 April 2021 |archive-url=https://web.archive.org/web/20210408043026/https://www.hematology.org/about/history/50-years/antithrombotic-therapy |archive-date=8 April 2021 |language=en |year=2008}}</ref> They are commonly prescribed to treat and prevent blood clots in veins, prevent stroke and embolism in people with non-valvular atrial fibrillation (AF) who have other risk factors, and prevent blood clots after routine knee and hip replacement surgery.<ref name="Hitchings2019">{{Cite book|last1=Hitchings|first1=Andrew|url=https://books.google.com/books?id=FPx0DwAAQBAJ|title=The Top 100 Drugs: Clinical Pharmacology and Practical Prescribing|last2=Lonsdale|first2=Dagan|last3=Burrage|first3=Daniel|last4=Baker|first4=Emma|date=2019|publisher=Elsevier|isbn=978-0-7020-7442-4|edition=2nd|pages=118–119|language=en}}</ref><ref name="Turgeon2018">{{cite book|author=Mary Lou Turgeon|title=Clinical Hematology: Theory & Procedures, Enhanced Edition|url=https://books.google.com/books?id=HFzsDwAAQBAJ&pg=PA575|date=29 June 2020|publisher=Jones & Bartlett Learning|isbn=978-1-284-29449-1|pages=575–577}}</ref><ref name="Chen2020">{{cite journal |last1=Chen |first1=Ashley |last2=Stecker |first2=Eric |last3=Warden |first3=Bruce A. |title=Direct Oral Anticoagulant Use: A Practical Guide to Common Clinical Challenges |journal=Journal of the American Heart Association |date=7 July 2020 |volume=9 |issue=13 |article-number=e017559 |doi=10.1161/JAHA.120.017559 |pmid=32538234 |pmc=7670541 }}</ref>
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.<ref name=Kiser2017>{{cite book |last1=Kiser |first1=Kathryn |title=Oral Anticoagulation Therapy: Cases and Clinical Correlation |date=2017 |publisher=Springer |isbn=978-3-319-54643-8 |page=11 |url=https://books.google.com/books?id=byYmDwAAQBAJ&pg=PA11 |language=en}}</ref> 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.<ref name=Kiser2017/>
==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.<ref name="Hitchings2019"/>
==Adverse effects== Side effects may include bleeding, most commonly from the nose, gastrointestinal tract (GI) or genitourinary system.<ref name="Hitchings2019"/> Compared to the risk of bleeding with warfarin use, direct factor Xa inhibitors have a higher risk of GI bleeding, but lower risk of bleeding in the brain.<ref name="Hitchings2019"/> Other side effects may include stomach upset, dizziness, anemia or increased blood levels of liver enzymes.<ref name="Hitchings2019"/>
== Overdose == A specialist may request a quantitative factor Xa assay in a situation of overdose.<ref name="Hitchings2019"/> 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.<ref>{{Cite news |last=((Portola Pharmaceuticals, Inc.)) |first= |title=U.S. FDA Approves Portola Pharmaceuticals' Andexxa, First and Only Antidote for the Reversal of Factor Xa Inhibitors |language=en-US |work=GlobeNewswire News Room |url=https://globenewswire.com/news-release/2018/05/04/1496534/0/en/U-S-FDA-Approves-Portola-Pharmaceuticals-Andexxa-First-and-Only-Antidote-for-the-Reversal-of-Factor-Xa-Inhibitors.html |access-date=5 April 2021}}</ref> It is also available in the UK.<ref name=BNF80Andex>{{cite book | title=BNF|date= September 2020 – March 2021|publisher=BMJ Group and the Pharmaceutical Press|isbn=978-0-85711-369-6|edition=80|location=London|page=128}}</ref>
==Drug interactions== The risk of bleeding is increased if used at the same time as other blood thinning drugs such as nonsteroidal anti-inflammatory drugs, antiplatelet drugs and heparin.<ref name="Hitchings2019"/> The blood thinning effects can be reduced if used at the same time as rifampicin and phenytoin, and increased with fluconazole.<ref name="Hitchings2019"/><ref name="Vranckx2018">{{cite journal |last1=Vranckx |first1=Pascal |last2=Valgimigli |first2=Marco |last3=Heidbuchel |first3=Hein |title=The Significance of Drug—Drug and Drug—Food Interactions of Oral Anticoagulation |journal=Arrhythmia & Electrophysiology Review |date=7 March 2018 |volume=7 |issue=1 |pages=55–61 |doi=10.15420/aer.2017.50.1 |pmid=29636974 |pmc=5889806 |issn=2050-3369}}</ref> Compared to warfarin they have fewer interactions with other medications.<ref name=Kiser2017/>
==Pharmacology== ===Mechanism of action=== class=skin-invert-image|thumb|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.<ref name="Hitchings2019"/>
===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.<ref name="AC" /><ref>{{cite journal|pmid=25472710|year=2015|last1=Douketis|first1=J. D.|last2=Healey|first2=J. S.|last3=Brueckmann|first3=M.|last4=Eikelboom|first4=J. W.|last5=Ezekowitz|first5=M. D.|last6=Fraessdorf|first6=M.|last7=Noack|first7=H.|last8=Oldgren|first8=J.|last9=Reilly|first9=P.|last10=Spyropoulos|first10=A. C.|last11=Wallentin|first11=L.|last12=Connolly|first12=S. J.|title=Perioperative bridging anticoagulation during dabigatran or warfarin interruption among patients who had an elective surgery or procedure. Substudy of the RE-LY trial|journal=Thrombosis and Haemostasis|volume=113|issue=3|pages=625–32|doi=10.1160/TH14-04-0305}}</ref>
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.<ref name="AC">{{cite book|title=Austria-Codex| veditors = Haberfeld H |at=Xarelto 20 mg Filmtabletten; Eliquis 5 mg Filmtabletten; Lixiana 60 mg Filmtabletten|publisher=Österreichischer Apothekerverlag|location=Vienna|year=2020|language=de}}</ref>
==History== {{main|Discovery and development of direct Xa inhibitors}} [[File:PDB 1skz EBI.jpg|class=skin-invert-image|thumb|Antistasin, the first discovered naturally occurring direct Xa inhibitor]] [[File:Rivaroxaban structure.svg|class=skin-invert-image|thumb|Rivaroxaban, 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.<ref name="ASH2008"/> 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.<ref name="Turgeon2018"/><ref name="Franchini2016">{{cite journal |last1=Franchini |first1=Massimo |last2=Liumbruno |first2=Giancarlo M. |last3=Bonfanti |first3=Carlo |last4=Lippi |first4=Giuseppe |title=The evolution of anticoagulant therapy |journal=Blood Transfusion |date=March 2016 |volume=14 |issue=2 |pages=175–184 |doi=10.2450/2015.0096-15 |pmid=26710352 |pmc=4781787 |issn=1723-2007}}</ref>
A naturally occurring inhibitor of factor Xa was reported in 1971 by Spellman et al. from the dog hookworm.<ref name=Spellman>{{cite journal | last1 = Spellman | first1 = GG Jr. | last2 = Nossel | first2 = HL | year = 1971 | title = Anticoagulant activity of dog hookworm | journal = Am J Physiol | volume = 222 | issue = 4| pages = 922–27 | doi = 10.1152/ajplegacy.1971.220.4.922 | pmid = 5102508 }}</ref> In 1987, Tuszynski et al. discovered antistasin, which was isolated from the extracts of the Mexican leech, ''Haementeria officinalis''.<ref>{{cite journal|pmid=2745433|year=1989|last1=Holt|first1=G. D.|last2=Krivan|first2=H. C.|last3=Gasic|first3=G. J.|last4=Ginsburg|first4=V.|title=Antistasin, an inhibitor of coagulation and metastasis, binds to sulfatide (Gal(3-SO4) beta 1-1Cer) and has a sequence homology with other proteins that bind sulfated glycoconjugates|journal=The Journal of Biological Chemistry|volume=264|issue=21|pages=12138–40|doi=10.1016/S0021-9258(18)63831-1|doi-access=free}}</ref><ref name=P15358>{{cite web|title=P15358 antistasin|url=https://www.uniprot.org/uniprot/P15358|publisher=Uniprot|access-date=11 April 2014}}</ref> Later, another naturally occurring inhibitor, tick anticoagulant peptide (TAP) was isolated from the extract of tick ''Ornithodoros moubata''.<ref name="Mousa2004">{{cite book|last= Mousa|first=Shaker A. |title=Anticoagulants, Antiplatelets, and Thrombolytics|url=https://books.google.com/books?id=C-gQ6Ve13i0C&pg=PA96|year=2004|publisher=Humana Press|isbn=978-1-59259-658-4|pages=96–99}}</ref> 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.<ref name="pro's and cons">{{cite journal|last=Bauer|first=K. A.|title=Pros and cons of new oral anticoagulants|journal=Hematology|date=6 December 2013|volume=2013|issue=1|pages=464–70|doi=10.1182/asheducation-2013.1.464|pmid=24319220|doi-access=free}}</ref>
==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.<ref name="Hitchings2019"/><ref name=BNF80/>
===Brand names=== Brands include rivaroxaban (brand name Xarelto) from Bayer, apixaban (Eliquis) from Bristol-Myers Squibb,<ref name="Turgeon2018"/> edoxaban (Lixiana) from Daiichi,<ref>{{cite journal|last=Turpie|first=AG|title=New oral anticoagulants in atrial fibrillation.|journal=European Heart Journal|date=January 2008|volume=29|issue=2|pages=155–65|pmid=18096568|doi=10.1093/eurheartj/ehm575|doi-access=free}}</ref> and betrixaban (Bevyxxa) from Portola Pharmaceuticals.<ref name="pmid19071881">{{cite journal |vauthors=Eriksson BI, Quinlan DJ, Weitz JI |title=Comparative pharmacodynamics and pharmacokinetics of oral direct thrombin and factor xa inhibitors in development |journal=Clinical Pharmacokinetics |volume=48 |issue=1 |pages=1–22 |year=2009 |pmid=19071881 |doi= 10.2165/0003088-200948010-00001|s2cid=35948814 }}</ref>
===Discontinued xabans=== Xabans that never reached the market include darexaban (YM150) from Astellas,<ref>{{cite news|last=Grogan|first=Kevin|title=Astellas pulls the plug on darexaban|url=http://www.pharmatimes.com/Article/11-09-29/Astellas_pulls_the_plug_on_darexaban.aspx|access-date=11 April 2014|newspaper=Pharmatimes|date=29 September 2011|archive-date=13 April 2014|archive-url=https://web.archive.org/web/20140413143135/http://www.pharmatimes.com/Article/11-09-29/Astellas_pulls_the_plug_on_darexaban.aspx}}</ref><ref>{{cite news|url=https://www.astellas.com/en/news/13301|title=Astellas Pharma Inc. Discontinues Development of Darexaban (YM150), an Oral Direct Factor Xa Inhibitor|publisher=Astellas Pharma|date=28 September 2011}}</ref> otamixaban from Sanofi,<ref>{{cite journal | journal = Chemical & Engineering News | publisher = American Chemical Society | date = 10 June 2013 | volume = 91 | number = 23 | page = 17 | title = AstraZeneca, Sanofi Cut Programs | quote = Sanofi is ending development on two compounds, the anticancer compound iniparib and the anticoagulant otamixaban, both of which flunked Phase III studies.}}</ref> letaxaban (TAK-442) from Takeda,<ref>{{cite web | first1 = Joseph | last1 = Dwyer | first2 = Conor | last2 = Walsh | name-list-style = vanc | title = First Time European Approval for Xarelto in ACS | publisher = Decision Resources | date = May 2013 | url = http://decisionresources.com/The-Decision-Resources-Blog/May-2013/European-Approval-for-Xarelto-in-ACS-052913 | archive-url = https://web.archive.org/web/20140719173801/http://decisionresources.com/The-Decision-Resources-Blog/May-2013/European-Approval-for-Xarelto-in-ACS-052913 | archive-date=19 July 2014 }}</ref> and eribaxaban (PD0348292) from Pfizer.<ref>{{cite web|url=https://adisinsight.springer.com/drugs/800024432|title=Eribaxaban|publisher=AdisInsight|date=14 March 2021}}</ref>
==References== {{reflist}}
{{Antithrombotics}}
Category:Anticoagulants Category:Direct Xa inhibitors