Direct factor Xa inhibitors (xabans) are
anticoagulant
An anticoagulant, commonly known as a blood thinner, is a chemical substance that prevents or reduces the coagulation of blood, prolonging the clotting time. Some occur naturally in blood-eating animals, such as leeches and mosquitoes, which ...
s (blood thinning drugs), used to both treat and prevent
blood clots in veins, and prevent stroke and embolism in people with
atrial fibrillation
Atrial fibrillation (AF, AFib or A-fib) is an Heart arrhythmia, abnormal heart rhythm (arrhythmia) characterized by fibrillation, rapid and irregular beating of the Atrium (heart), atrial chambers of the heart. It often begins as short periods ...
(AF).
Medical use
Direct factor Xa inhibitors include
rivaroxaban
Rivaroxaban, sold under the brand name Xarelto among others, is an anticoagulant medication (blood thinner) used to treat and reduce the risk of blood clots. Specifically it is used to treat deep vein thrombosis and pulmonary emboli and prev ...
,
apixaban
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. It is used as an al ...
and
edoxaban
Edoxaban, sold under the brand name Lixiana among others, is an anticoagulant medication and a direct factor Xa inhibitor. It is taken by mouth.
Compared with warfarin, it has fewer drug interactions, and does not require regular assessment ...
, and are types of
direct oral anticoagulant
An anticoagulant, commonly known as a blood thinner, is a chemical substance that prevents or reduces the coagulation of blood, prolonging the clotting time. Some occur naturally in blood-eating animals, such as leeches and mosquitoes, which he ...
(DOAC), which are
blood thinning drugs, one of the classes of
antithrombotic
An antithrombotic agent is a drug that reduces the formation of blood clots ( thrombi).http://cancerweb.ncl.ac.uk/cgi-bin/omd?antithrombotic Antithrombotics can be used therapeutically for prevention ( primary prevention, secondary prevention) or ...
drugs.
They are commonly prescribed to treat and prevent
blood clots in veins, prevent stroke and
embolism
An embolism is the lodging of an embolus, a blockage-causing piece of material, inside a blood vessel. The embolus may be a blood clot (thrombus), a fat globule (fat embolism), a bubble of air or other gas (air embolism, gas embolism), amniotic ...
in people with non-valvular
atrial fibrillation
Atrial fibrillation (AF, AFib or A-fib) is an Heart arrhythmia, abnormal heart rhythm (arrhythmia) characterized by fibrillation, rapid and irregular beating of the Atrium (heart), atrial chambers of the heart. It often begins as short periods ...
(AF) who have other risk factors, and prevent blood clots after routine
knee
In humans and other primates, the knee joins the thigh with the leg and consists of two joints: one between the femur and tibia (tibiofemoral joint), and one between the femur and patella (patellofemoral joint). It is the largest joint in the hu ...
and
hip replacement
Hip replacement is a surgery, surgical procedure in which the hip joint is replaced by a prosthetic implant (medicine), implant, that is, a hip prosthesis. Hip replacement surgery can be performed as a total replacement or a hemi/semi(half) repl ...
surgery.
Direct factor Xa inhibitors can be considered as an alternative to
warfarin
Warfarin, sold under the brand name Coumadin among others. It is used as an anticoagulant, anticoagulant medication. It is commonly used to prevent deep vein thrombosis and pulmonary embolism, and to protect against stroke in people who ha ...
, particularly if a person is on several other medications that interact with warfarin, or if attending medical appointments and laboratory monitoring becomes difficult.
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
Valvular heart disease is any cardiovascular disease process involving one or more of the four valves of the heart (the aortic and mitral valves on the left side of heart and the pulmonic and tricuspid valves on the right side of heart). The ...
, state of
kidney function
Assessment of kidney function occurs in different ways, using the presence of symptoms and medical sign, signs, as well as measurements using urine tests, blood tests, and medical imaging.
Renal physiology, Functions of a healthy kidney include ...
, the
risk of stroke and the
risk of bleeding.
[
]
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.
Adverse effects
Side effects may include bleeding
Bleeding, hemorrhage, haemorrhage or blood loss, is blood escaping from the circulatory system from damaged blood vessels. Bleeding can occur internally, or externally either through a natural opening such as the mouth, nose, ear, urethr ...
, most commonly from the nose
A nose is a sensory organ and respiratory structure in vertebrates. It consists of a nasal cavity inside the head, and an external nose on the face. The external nose houses the nostrils, or nares, a pair of tubes providing airflow through the ...
, gastrointestinal tract
The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the Digestion, digestive system that leads from the mouth to the anus. The tract is the largest of the body's systems, after the cardiovascula ...
(GI) or genitourinary system
The genitourinary system, or urogenital system, are the sex organs of the reproductive system and the organs of the urinary system. These are grouped together because of their proximity to each other, their common embryological origin and the u ...
. Compared to the risk of bleeding with warfarin
Warfarin, sold under the brand name Coumadin among others. It is used as an anticoagulant, anticoagulant medication. It is commonly used to prevent deep vein thrombosis and pulmonary embolism, and to protect against stroke in people who ha ...
use, direct factor Xa inhibitors have a higher risk of GI bleeding, but lower risk of bleeding in the brain. Other side effects may include stomach upset, dizziness
Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to Balance disorder, disequilibrium or a non-specific feeling, such as giddiness or foolishness.
Dizziness is a ...
, anemia
Anemia (also spelt anaemia in British English) is a blood disorder in which the blood has a reduced ability to carry oxygen. This can be due to a lower than normal number of red blood cells, a reduction in the amount of hemoglobin availabl ...
or increased blood levels of liver enzymes.
Overdose
A specialist may request a quantitative factor Xa assay in a situation of overdose. Andexanet alfa
Andexanet alfa, sold under the brand name Andexxa among others, is an antidote for the medications rivaroxaban and apixaban, when reversal of anticoagulation is needed due to uncontrolled bleeding. It has not been found to be useful for oth ...
, a specific antidote
An antidote is a substance that can counteract a form of poisoning. The term ultimately derives from the Greek term φάρμακον ἀντίδοτον ''(pharmakon antidoton)'', "(medicine) given as a remedy". An older term in English which is ...
to reverse the anticoagulant activity of direct Xa inhibitors in the event of major bleeding, was approved by the FDA
The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...
in 2018. It is also available in the UK.
Drug interactions
The risk of bleeding is increased if used at the same time as other blood thinning drugs such as nonsteroidal anti-inflammatory drug
Non-steroidal anti-inflammatory drugs (NSAID) are members of a Indication (medicine), therapeutic drug class which Analgesic, reduces pain, Anti-inflammatory, decreases inflammation, Antipyretic, decreases fever, and Antithrombotic, prevents bl ...
s, antiplatelet drugs and heparin
Heparin, also known as unfractionated heparin (UFH), is a medication and naturally occurring glycosaminoglycan. Heparin is a blood anticoagulant that increases the activity of antithrombin. It is used in the treatment of myocardial infarction, ...
. The blood thinning effects can be reduced if used at the same time as rifampicin
Rifampicin, also known as rifampin, is an ansamycin antibiotic used to treat several types of bacterial infections, including tuberculosis (TB), ''Mycobacterium avium'' complex, leprosy, and Legionnaires' disease. It is almost always used tog ...
and phenytoin
Phenytoin (PHT), sold under the brand name Dilantin among others, is an anticonvulsant, anti-seizure medication. It is useful for the prevention of tonic-clonic seizures (also known as grand mal seizures) and focal seizures, but not absence se ...
, and increased with fluconazole
Fluconazole is an antifungal medication used for a number of fungal infections. These include candidiasis, blastomycosis, coccidioidomycosis, cryptococcosis, histoplasmosis, dermatophytosis, and tinea versicolor. It is also used to pr ...
. Compared to warfarin
Warfarin, sold under the brand name Coumadin among others. It is used as an anticoagulant, anticoagulant medication. It is commonly used to prevent deep vein thrombosis and pulmonary embolism, and to protect against stroke in people who ha ...
they have fewer interactions with other medications.[
]
Pharmacology
Mechanism of action
Direct factor Xa inhibitors block the enzyme called factor Xa
Coagulation factor X (), or Stuart factor, is an enzyme of the coagulation cascade, encoded in humans by ''F10'' gene. It is a serine endopeptidase (protease group S1, PA clan). Factor X is synthesized in the liver and requires vitamin K for ...
, preventing the conversion of prothrombin
Prothrombin (coagulation factor II) is encoded in the human by the F2-gene. It is proteolytically cleaved during the clotting process by the prothrombinase enzyme complex to form thrombin.
Thrombin (Factor IIa) (, fibrose, thrombase, throm ...
to thrombin
Prothrombin (coagulation factor II) is encoded in the human by the F2-gene. It is proteolytically cleaved during the clotting process by the prothrombinase enzyme complex to form thrombin.
Thrombin (Factor IIa) (, fibrose, thrombase, throm ...
in the final common pathway of clot formation in veins and the heart.
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
Phenprocoumon (marketed under the brand names Marcoumar, Marcumar and Falithrom) is a long-acting anticoagulant to be taken by mouth, and a coumarin derivative. It acts as a vitamin K antagonist and inhibits blood clotting (coagulation) by blocki ...
are often paused up to a week before surgery, and low-molecular-weight heparin
Low-molecular-weight heparin (LMWH) is a class of anticoagulant medications. They are used in the prevention of blood clots and, in the treatment of venous thromboembolism (deep vein thrombosis and pulmonary embolism), and the treatment of myocar ...
s are used to "bridge" the therapy gap, typically for several weeks.
Also in contrast to warfarin and phenprocoumon, direct factor Xa inhibitors do not require frequent monitoring of the prothrombin time
The prothrombin time (PT) – along with its derived measures of prothrombin ratio (PR) and international normalized ratio (INR) – is an assay for evaluating the Coagulation#Extrinsic pathway, extrinsic pathway and Coagulation#Common pathway, ...
(also called the ''INR'') and dose adjustments.
History
Prior to the introduction of direct factor Xa inhibitors, vitamin K antagonists
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 t ...
such as warfarin were the only oral anticoagulants for over 60 years, and together with heparin
Heparin, also known as unfractionated heparin (UFH), is a medication and naturally occurring glycosaminoglycan. Heparin is a blood anticoagulant that increases the activity of antithrombin. It is used in the treatment of myocardial infarction, ...
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
Low-molecular-weight heparin (LMWH) is a class of anticoagulant medications. They are used in the prevention of Thrombosis prevention, blood clots and, in the treatment of venous thromboembolism (deep vein thrombosis and pulmonary embolism), and ...
(LMWH) and the ability of self-injecting subcutaneously at home. Biotechnology developments then paved way for the first successful synthetic anticoagulants including hirudin
Hirudin is a naturally occurring peptide in the salivary glands of blood-sucking leeches (such as ''Hirudo medicinalis'') that has a blood anticoagulant property. This is essential for the leeches' habit of feeding on blood, since it keeps a h ...
. The monitoring of warfarin and keeping the international normalized ratio
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 c ...
(INR) between 2.0 and 3.0, along with avoiding over and under treatment, has driven a search for an alternative.
A naturally occurring inhibitor of factor Xa was reported in 1971 by Spellman et al. from the dog hookworm. In 1987, Tuszynski et al. discovered antistasin, which was isolated from the extracts of the Mexican leech, '' Haementeria officinalis''. Later, another naturally occurring inhibitor, tick anticoagulant peptide (TAP) was isolated from the extract of tick ''Ornithodoros moubata
''Ornithodoros moubata'', commonly known as the African hut tampan or the eyeless tampan, is a species of tick in the family Argasidae. It is an ectoparasite and vector of relapsing fever in humans, and African swine fever in pigs.
Description
S ...
''. 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.
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.[
]
Brand names
Brands include rivaroxaban
Rivaroxaban, sold under the brand name Xarelto among others, is an anticoagulant medication (blood thinner) used to treat and reduce the risk of blood clots. Specifically it is used to treat deep vein thrombosis and pulmonary emboli and prev ...
(brand name Xarelto) from Bayer
Bayer AG (English: , commonly pronounced ; ) is a German multinational pharmaceutical and biotechnology company and is one of the largest pharmaceutical companies and biomedical companies in the world. Headquartered in Leverkusen, Bayer' ...
, apixaban
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. It is used as an al ...
(Eliquis) from Bristol-Myers Squibb
The Bristol-Myers Squibb Company, doing business as Bristol Myers Squibb (BMS), is an American multinational pharmaceutical company. Headquartered in Princeton, New Jersey, BMS is one of the world's largest pharmaceutical companies and consist ...
, edoxaban
Edoxaban, sold under the brand name Lixiana among others, is an anticoagulant medication and a direct factor Xa inhibitor. It is taken by mouth.
Compared with warfarin, it has fewer drug interactions, and does not require regular assessment ...
(Lixiana) from Daiichi, and betrixaban
Betrixaban (trade name Bevyxxa) is an oral anticoagulant drug which acts as a direct factor Xa inhibitor. Betrixaban is Food and Drug Administration, FDA approved for venous thrombosis prevention in adults hospitalized for an Acute (medicine), ac ...
(Bevyxxa) from Portola Pharmaceuticals
Portola Pharmaceuticals is an American clinical stage biotechnology company that researches, develops, and commercializes drugs. The company focuses primarily on drugs used in the treatment of thrombosis and hematological malignancies. Founded ...
.
Discontinued xabans
Xabans that never reached the market include darexaban
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 wi ...
(YM150) from Astellas, otamixaban from Sanofi
Sanofi S.A. is a French Multinational corporation, multinational pharmaceutical and healthcare company headquartered in Paris, France. The corporation was established in 1973 and merged with Synthélabo in 1999 to form Sanofi-Synthélabo. In 200 ...
, letaxaban (TAK-442) from