Factor xa inhibitors

Factor Xa inhibitors are drugs from the anticoagulant group. They inhibit factor Xa, which is important for hemostasis. In a narrower sense, the term Factor Xa inhibitors is used to describe the new, direct Factor Xa inhibitors (DOAK = direct oral coagulants). These belong to the so-called "new oral anticoagulants" (NOAK).

These are orally administered, antithrombotic agents whose action is based on the inhibition of blood coagulation factor Xa, which plays a central role in the blood coagulation cascade. Compared with heparins , direct Factor Xa inhibitors offer the advantage of oral application. They do not normally require dose adjustment or continuous monitoring of coagulation parameters as is the case with vitamin K antagonists.

The most common possible ADRs include bleeding in various organs. These can be potentially severe and even life-threatening.

Antidotes are now available.

Group of anticoagulants whose point of attack is the activated factor Xa. These are:

• Raviroxaban (Xarelto®)
• Apixaban (Eliquis®)
• Edoxaban (Lixiana®)
• Otamixaban
• Betrixaban

The use of direct oral anticoagulants (DOAKs) for the treatment of patients with venous thromboembolism (VTE) or for the treatment of patients with non-valvular atrial fibrillation is now standard practice (Ruff CT et al. 2014). The substances have a lower risk of cerebral haemorrhage, but depending on the substance and study, a higher risk of gastrointestinal haemorrhage than vitamin K antagonists (Ruff CT et al. 2014).

DOAKs achieve a rapid onset of action and peak 1-3 hours after ingestion. DOAKs have a very short plasma elimination half-life compared to VKA (Masahir I et al. 2016; Schwarb H et al. 2016). Therefore, discontinuation of the substance is probably sufficient to stop bleeding for most bleeding events (Heidbuchel A et al 2013). All currently available DOAKs are partially eliminated via the kidney. Note: Patients with heavy bleeding often have chronic renal failure with delayed DOAK clearance (Willet CK et al (2017).

Laboratory controls: The biological effect of the Factor Xa inhibitors in coagulation diagnostics is noticeable by a reduction of the Quick value. A prolongation of the PTT may also occur, but the effect is less pronounced. Overall, however, the coagulation parameters mentioned are not suitable for controlling the therapy. The effective level of Factor Xa inhibitors can be determined via the anti-Factor Xa activity. However, this is not a true determination of the concentration of the substance concerned (Gressenberger P 2019).

For DOAKs, the risk of bleeding remains the most significant ADR.

Antagonizing the anticoagulant effect can save lives in potentially life-threatening hemorrhages.

Andexanet-alfa (antidote for rivaroxaban (Xarelto®) and Apixaban (Eliquis®): The recombinant substance Andexanet-alfa is a modified recombinant Factor Xa that has no coagulation factor Xa activity. It acts as a binding trap for Xa inhibitors by binding to them and by complexing them to cancel the anticoagulant effect. The antidote was approved in the USA in May 2018 (AndexXa®). Andexanet alfa is able to cancel the effect of the Factor Xa inhibitors rivaroxaban (Xarelto®) and apixaban (Eliquis®) in an emergency. This provides an antidote for the Factor Xa inhibitors. The study is based on data from two Phase III studies (ANNEXA-R and ANNEXA-A) in which the safety and efficacy of reversing the effects of rivaroxaban and apixaban were tested in healthy volunteers.

A further substance (ciraparantag) is currently in development.

For further side effects and interactions, see below Rivaroxaban and Apixaban

Procedure in case of bleeding complications: If bleeding occurs under anticoagulation with a DOAK, it is necessary to find out which substance was taken. If possible, the exact time of the last intake and the exact dosage should also be evaluated. Together with the kidney and liver function parameters, it can be estimated whether the drug level will rise or fall. With normal kidney and liver function, normal hemostasis can be expected 12-24 hours after the last DOAK intake. It is also important to identify the exact source of bleeding, and mechanical or surgical measures may be necessary or helpful. In any case, anticoagulation should be interrupted in case of bleeding complications. The interruption of anticoagulation is mandatory in the case of life-threatening bleeding. After the administration of an antidote in the context of bleeding complications, a detailed risk-benefit evaluation must of course be followed by the reintroduction of anticoagulation, since the indication for this remains and otherwise vascular endpoints are threatened. The substitution of blood preserves should be considered depending on the hemoglobin value in the laboratory and clinical picture (Gressenberger P 2019)

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