Direct factor Xa inhibitors

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Direct factor Xa inhibitor
Drug class
Class identifiers
Synonyms Direct Xa inhibitor, novel oral anticoagulant
UseTreat and prevent venous thromboembolism
Mechanism of action Inhibit fibrin formation in the final common pathway of the coagulation cascade
Chemical class Direct factor Xa inhibitors [1]
Legal status
In Wikidata

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 (AF). [2] [3]

Contents

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. [4] [5] [6] 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. [2] [3] [7]

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]

Adverse effects

Side effects may include bleeding, most commonly from the nose, gastrointestinal tract (GI) or genitourinary system. [2] 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. [2] Other side effects may include stomach upset, dizziness, anemia or increased blood levels of liver enzymes. [2]

Overdose

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]

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. [2] The blood thinning effects can be reduced if used at the same time as rifampicin and phenytoin, and increased with fluconazole. [2] [11] Compared to warfarin they have fewer interactions with other medications. [8]

Pharmacology

Mechanism of action

Coagulation in vivo, shows final common pathway and where factor Xa acts Coagulation in vivo.png
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]

History

Antistasin, the first discovered naturally occurring direct Xa inhibitor PDB 1skz EBI.jpg
Antistasin, the first discovered naturally occurring direct Xa inhibitor
Rivaroxaban, the first synthetic direct Xa inhibitor marketed as a drug Rivaroxaban structure.svg
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. [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]

Brand names

Brands include rivaroxaban (brand name Xarelto) from Bayer, apixaban (Eliquis) from Bristol-Myers Squibb, [3] edoxaban (Lixiana) from Daiichi, [20] and betrixaban (Bevyxxa) from Portola Pharmaceuticals. [21]

Discontinued xabans

Xabans that never reached the market include darexaban (YM150) from Astellas, [22] [23] otamixaban from Sanofi, [24] letaxaban (TAK-442) from Takeda, [25] and eribaxaban (PD0348292) from Pfizer. [26]

Related Research Articles

<span class="mw-page-title-main">Anticoagulant</span> Class of drugs

An anticoagulant, commonly known as a blood thinner, is a chemical substance that prevents or reduces coagulation of blood, prolonging the clotting time. Some of them occur naturally in blood-eating animals such as leeches and mosquitoes, where they help keep the bite area unclotted long enough for the animal to obtain some blood.

<span class="mw-page-title-main">Venous thrombosis</span> Blood clot (thrombus) that forms within a vein

Venous thrombosis is the blockage of a vein caused by a thrombus. A common form of venous thrombosis is deep vein thrombosis (DVT), when a blood clot forms in the deep veins. If a thrombus breaks off (embolizes) and flows to the lungs to lodge there, it becomes a pulmonary embolism (PE), a blood clot in the lungs. The conditions of DVT only, DVT with PE, and PE only, are all captured by the term venous thromboembolism (VTE).

<span class="mw-page-title-main">Warfarin</span> Medication

Warfarin is an anticoagulant used as a medication under several brand names including Coumadin. While the drug is described as a "blood thinner", it does not reduce viscosity but rather inhibits coagulation. Accordingly, it is commonly used to prevent blood clots in the circulatory system such as deep vein thrombosis and pulmonary embolism, and to protect against stroke in people who have atrial fibrillation, valvular heart disease, or artificial heart valves. Less commonly, it is used following ST-segment elevation myocardial infarction and orthopedic surgery. It is usually taken by mouth, but may also be administered intravenously.

<span class="mw-page-title-main">Prothrombin time</span> Assay for evaluating the extrinsic pathway & common pathway of coagulation

The prothrombin time (PT) – along with its derived measures of prothrombin ratio (PR) and international normalized ratio (INR) – is an assay for evaluating the extrinsic pathway and common pathway of coagulation. This blood test is also called protime INR and PT/INR. They are used to determine the clotting tendency of blood, in such things as the measure of warfarin dosage, liver damage, and vitamin K status. PT measures the following coagulation factors: I (fibrinogen), II (prothrombin), V (proaccelerin), VII (proconvertin), and X.

<span class="mw-page-title-main">Rivaroxaban</span> Anticoagulant drug

Rivaroxaban, sold under the brand name Xarelto among others, is an anticoagulant medication used to treat and prevent blood clots. Specifically it is used to treat deep vein thrombosis and pulmonary emboli and prevent blood clots in atrial fibrillation and following hip or knee surgery. It is taken by mouth.

<span class="mw-page-title-main">Phenprocoumon</span> Drug

Phenprocoumon is a long-acting blood thinner drug to be taken by mouth, and a derivative of coumarin. It acts as a vitamin K antagonist and inhibits blood clotting (coagulation) by blocking synthesis of coagulation factors II, VII, IX and X. It is used for the prophylaxis and treatment of thromboembolic disorders such as heart attacks and pulmonary (lung) embolism. The most common adverse effect is bleeding. The drug interacts with a large number of other medications, including aspirin and St John's Wort. It is the standard coumarin used in Germany, Austria, and other European countries.

<span class="mw-page-title-main">Dabigatran</span> Anticoagulant medication

Dabigatran, sold under the brand name Pradaxa among others, is an anticoagulant used to treat and prevent blood clots and to prevent stroke in people with atrial fibrillation. Specifically it is used to prevent blood clots following hip or knee replacement and in those with a history of prior clots. It is used as an alternative to warfarin and does not require monitoring by blood tests. In a meta analysis of 7 different studies, there was no benefit of dabigatran over warfarin in preventing ischemic stroke; however, dabigatran were associated with a lower hazard for intracranial bleeding compared with warfarin, but also had a higher risk of gastrointestinal bleeding relative to warfarin. It is taken by mouth.

Direct thrombin inhibitors (DTIs) are a class of medication that act as anticoagulants by directly inhibiting the enzyme thrombin. Some are in clinical use, while others are undergoing clinical development. Several members of the class are expected to replace heparin and warfarin in various clinical scenarios.

Hypercoagulability in pregnancy is the propensity of pregnant women to develop thrombosis. Pregnancy itself is a factor of hypercoagulability, as a physiologically adaptive mechanism to prevent post partum bleeding. However, when combined with an additional underlying hypercoagulable states, the risk of thrombosis or embolism may become substantial.

<span class="mw-page-title-main">Idraparinux</span> Chemical compound

Idraparinux sodium is an anticoagulant medication in development by Sanofi-Aventis.

<span class="mw-page-title-main">Vitamin K antagonist</span>

Vitamin K antagonists (VKA) are a group of substances that reduce blood clotting by reducing the action of vitamin K. The term "vitamin K antagonist" is technically a misnomer, as the drugs do not directly antagonize the action of vitamin K in the pharmacological sense, but rather the recycling of vitamin K. Vitamin K antagonists (VKAs) have been the mainstay of anticoagulation therapy for more than 50 years.

The management of atrial fibrillation (AF) is focused on preventing temporary circulatory instability, stroke and other ischemic events. Control of heart rate and rhythm are principally used to achieve the former, while anticoagulation may be employed to decrease the risk of stroke. Within the context of stroke, the discipline may be referred to as stroke prevention in atrial fibrillation (SPAF). In emergencies, when circulatory collapse is imminent due to uncontrolled rapid heart rate, immediate cardioversion may be indicated.

<span class="mw-page-title-main">Edoxaban</span> Anticoagulant drug

Edoxaban, sold under the brand name Lixiana among others, is an anticoagulant medication and a direct factor Xa inhibitor. It is taken by mouth.

<span class="mw-page-title-main">Betrixaban</span> Chemical compound

Betrixaban is an oral anticoagulant drug which acts as a direct factor Xa inhibitor. Betrixaban is FDA approved for venous thrombosis prevention in adults hospitalized for an acute illness who are at risk for thromboembolic complications. Compared to other directly acting oral anticoagulants betrixaban has relatively low renal excretion and is not metabolized by CYP3A4.

<span class="mw-page-title-main">Apixaban</span> Anticoagulant medication

Apixaban, sold under the brand name Eliquis, is an anticoagulant medication used to treat and prevent blood clots and to prevent stroke in people with nonvalvular atrial fibrillation through directly inhibiting factor xa. Specifically, it is used to prevent blood clots following hip or knee replacement and in those with a history of prior clots. It is used as an alternative to warfarin and does not require monitoring by blood tests or dietary restrictions. It is taken by mouth.

<span class="mw-page-title-main">Darexaban</span> Chemical compound

Darexaban (YM150) is a direct inhibitor of factor Xa created by Astellas Pharma. It is an experimental drug that acts as an anticoagulant and antithrombotic to prevent venous thromboembolism after a major orthopaedic surgery, stroke in patients with atrial fibrillation and possibly ischemic events in acute coronary syndrome. It is used in form of the maleate. The development of darexaban was discontinued in September 2011.

Direct thrombin inhibitors (DTIs) are a class of anticoagulant drugs that can be used to prevent and treat embolisms and blood clots caused by various diseases. They inhibit thrombin, a serine protease which affects the coagulation cascade in many ways. DTIs have undergone rapid development since the 90's. With technological advances in genetic engineering the production of recombinant hirudin was made possible which opened the door to this new group of drugs. Before the use of DTIs the therapy and prophylaxis for anticoagulation had stayed the same for over 50 years with the use of heparin derivatives and warfarin which have some well known disadvantages. DTIs are still under development, but the research focus has shifted towards factor Xa inhibitors, or even dual thrombin and fXa inhibitors that have a broader mechanism of action by both inhibiting factor IIa (thrombin) and Xa. A recent review of patents and literature on thrombin inhibitors has demonstrated that the development of allosteric and multi-mechanism inhibitors might lead the way to a safer anticoagulant.

The SAMe-TT2R2 score is a clinical prediction rule to predict the quality of vitamin K antagonist anticoagulation therapy as measured by time in therapeutic INR range (TTR) (VKA e.g. warfarin). It has been suggested that it can aid in the medical decision making between VKAs and new oral anticoagulant/non-VKA oral anticoagulant (NOAC e.g. dabigatran, rivaroxaban, apixaban or edoxaban) in patients with atrial fibrillation (AF). This score can be used with patients with ≥1 additional stroke risk factors using the CHA2DS2-VASc score, where oral anticoagulation is recommended or should be considered.

HAS-BLED is a scoring system developed to assess 1-year risk of major bleeding in people taking anticoagulants for atrial fibrillation (AF). It was developed in 2010 with data from 3,978 people in the Euro Heart Survey. Major bleeding is defined as being intracranial bleedings, hospitalization, hemoglobin decrease > 2 g/dL, and/or transfusion.

Four drugs from the class of direct Xa inhibitors are marketed worldwide. Rivaroxaban (Xarelto) was the first approved FXa inhibitor to become commercially available in Europe and Canada in 2008. The second one was apixaban (Eliquis), approved in Europe in 2011 and in the United States in 2012. The third one edoxaban was approved in Japan in 2011 and in Europe and the US in 2015. Betrixaban (Bevyxxa) was approved in the US in 2017.

References

  1. ↑ "WHOCC – ATC/DDD Index". whocc.no. Archived from the original on 4 April 2021. Retrieved 4 April 2021.
  2. 1 2 3 4 5 6 7 8 9 10 11 Hitchings, Andrew; Lonsdale, Dagan; Burrage, Daniel; Baker, Emma (2019). The Top 100 Drugs: Clinical Pharmacology and Practical Prescribing (2nd ed.). Elsevier. pp. 118–119. ISBN   978-0-7020-7442-4.
  3. 1 2 3 4 Mary Lou Turgeon (29 June 2020). Clinical Hematology: Theory & Procedures, Enhanced Edition. Jones & Bartlett Learning. pp. 575–577. ISBN   978-1-284-29449-1.
  4. ↑ "List of Factor Xa inhibitors". Drugs.com. Archived from the original on 4 April 2021. Retrieved 4 April 2021.
  5. 1 2 BNF (80 ed.). London: BMJ Group and the Pharmaceutical Press. September 2020 – March 2021. pp. 133–139. ISBN   978-0-85711-369-6.
  6. 1 2 American Society of Hematology (2008). "Antithrombotic Therapy - Hematology.org". hematology.org. Archived from the original on 8 April 2021. Retrieved 8 April 2021.
  7. ↑ Chen, Ashley; Stecker, Eric; Warden, Bruce A. (7 July 2020). "Direct Oral Anticoagulant Use: A Practical Guide to Common Clinical Challenges". Journal of the American Heart Association . 9 (13): e017559. doi:10.1161/JAHA.120.017559. PMC   7670541 . PMID   32538234.
  8. 1 2 3 Kiser, Kathryn (2017). Oral Anticoagulation Therapy: Cases and Clinical Correlation. Springer. p. 11. ISBN   9783319546438.
  9. ↑ Portola Pharmaceuticals, Inc. "U.S. FDA Approves Portola Pharmaceuticals' Andexxa, First and Only Antidote for the Reversal of Factor Xa Inhibitors". GlobeNewswire News Room. Retrieved 5 April 2021.
  10. ↑ BNF (80 ed.). London: BMJ Group and the Pharmaceutical Press. September 2020 – March 2021. p. 128. ISBN   978-0-85711-369-6.
  11. ↑ Vranckx, Pascal; Valgimigli, Marco; Heidbuchel, Hein (7 March 2018). "The Significance of Drug—Drug and Drug—Food Interactions of Oral Anticoagulation". Arrhythmia & Electrophysiology Review. 7 (1): 55–61. doi:10.15420/aer.2017.50.1. ISSN   2050-3369. PMC   5889806 . PMID   29636974.
  12. 1 2 Haberfeld H, ed. (2020). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag. Xarelto 20 mg Filmtabletten; Eliquis 5 mg Filmtabletten; Lixiana 60 mg Filmtabletten.
  13. ↑ 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. PMID   25472710.
  14. ↑ Franchini, Massimo; Liumbruno, Giancarlo M.; Bonfanti, Carlo; Lippi, Giuseppe (March 2016). "The evolution of anticoagulant therapy". Blood Transfusion. 14 (2): 175–184. doi:10.2450/2015.0096-15. ISSN   1723-2007. PMC   4781787 . PMID   26710352.
  15. ↑ Spellman, GG Jr.; Nossel, HL (1971). "Anticoagulant activity of dog hookworm". Am J Physiol. 222 (4): 922–27. doi:10.1152/ajplegacy.1971.220.4.922. PMID   5102508.
  16. ↑ Holt, G. D.; Krivan, H. C.; Gasic, G. J.; Ginsburg, V. (1989). "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". The Journal of Biological Chemistry. 264 (21): 12138–40. doi: 10.1016/S0021-9258(18)63831-1 . PMID   2745433.
  17. ↑ "P15358 antistasin". Uniprot. Retrieved 11 April 2014.
  18. ↑ Mousa, Shaker A. (2004). Anticoagulants, Antiplatelets, and Thrombolytics. Humana Press. pp. 96–99. ISBN   978-1-59259-658-4.
  19. ↑ Bauer, K. A. (6 December 2013). "Pros and cons of new oral anticoagulants". Hematology. 2013 (1): 464–70. doi: 10.1182/asheducation-2013.1.464 . PMID   24319220.
  20. ↑ Turpie, AG (January 2008). "New oral anticoagulants in atrial fibrillation". European Heart Journal. 29 (2): 155–65. doi: 10.1093/eurheartj/ehm575 . PMID   18096568.
  21. ↑ 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. PMID   19071881. S2CID   35948814.
  22. ↑ Grogan, Kevin (29 September 2011). "Astellas pulls the plug on darexaban". Pharmatimes. Retrieved 11 April 2014.
  23. ↑ "Astellas Pharma Inc. Discontinues Development of Darexaban (YM150),an Oral Direct Factor Xa Inhibitor". Astellas Pharma. 28 September 2011.
  24. ↑ "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.
  25. ↑ Dwyer J, Walsh C (May 2013). "First Time European Approval for Xarelto in ACS". Decision Resources. Archived from the original on 19 July 2014.
  26. ↑ "Eribaxaban". AdisInsight. 14 March 2021.
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