Clinical trial NCT05869591: DOAC in Patients with Child a or B Liver Cirrhosis
Official title: Pharmacokinetics and Pharmacodynamics Assessment of Apixaban and Edoxaban in Patients with Child a or B Liver Cirrhosis
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Liver Cirrhosis
Keywords: Cirrhosis
DOAC
Thrombin generation
Anticoagulation
Lead sponsor: Centre Hospitalier Universitaire Vaudois
Sponsor class: OTHER
First posted: 2023-05-22
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

Brief summary: The goal of this clinical trial is to investigate pharmacokinetics and pharmacodynamics of direct oral anticoagulant drugs (DOAC), specifically apixaban and edoxaban, in patients with Child A or B liver cirrhosis (LC). The primary objective of this study is to verify the ability of apixaban and edoxaban to decrease in vivo thrombin generation in LC patients.

Participants will be randomly assigned to either apixaban (Eliquis®) or edoxaban (Lixiana®) at a therapeutic dosage for 7 consecutive days.

The results of this investigation will contribute to designing a prospective multicentre interventional study to investigate the efficacy of DOAC to improve clinical outcomes in patients with LC

Detailed description: Patients with liver cirrhosis (LC) have a higher risk to develop venous thromboembolism (VTE), in particular portal vein thrombosis (PVT) and the risk is increased with advanced liver disease. Some studies have shown that anticoagulant therapy in patients with LC and PVT could improve their prognosis by reducing liver decompensation, variceal bleeding, encephalopathy, and portal hypertension complications. Direct oral anticoagulant drugs (DOAC) seem to be as effective and safe as traditional anticoagulant drugs \[vitamin K antagonists (VKA) and low molecular weight heparins (LMWH)\]. Moreover, some studies showed lower bleeding rate and more recanalization of PVT with DOAC than traditional anticoagulant drugs. However, physicians are still reluctant to anticoagulate this population. This is well illustrated by the lower rate of adequate prophylaxis during in-hospital treatment in LC compared to other patients. This is probably due to two reasons. First, the fear of inducing bleeding in patients with increased INR and persistent thrombocytopenia, although it has been shown that the VTE risk is independent of INR and thrombocytopenia. Second, there is still a large knowledge gap on the effects of the various anticoagulant drugs and on the best anticoagulant molecule to employ in this population. Indeed, both VKA and LMWH present several disadvantages in LC patients. VKA are not recommended because of unreliable INR (already increased at baseline) and the risk of pseudo-therapeutic INR values. As for LMWH, a non-negligible increase of bleeding complications has been observed in LC patients. It has been demonstrated that patients with LC exhibit a lower anti-Xa activity when treated with LMWH compared to other patients and that after spiking their plasma with a given amount of LMWH, the measured anti-Xa activity was lower than in plasma from healthy controls. Of note, the anti-Xa activity was corrected after supplementation of antithrombin. In case of anti-Xa monitoring, this could lead to LMWH overdosing. In fact, despite a lower anti-Xa activity, the anticoagulant effect of LMWH seems to be increased in LC patients when assessed by thrombin generation, possibly because of antithrombin-independent antithrombotic actions of LMWH. Therefore, also LMWH are not ideal for LC patients. Nevertheless, both VKA and LMWH are the anticoagulant most frequently administrated to patients with LC, possibly also because of limited data about DOAC. In fact, patients with advanced liver disease or "hepatic coagulopathies" have been excluded from clinical trials investigating DOAC.

DOAC (apixaban, rivaroxaban, edoxaban, and dabigatran) represent an alternative to VKA and LMWH with specific advantages, particularly the oral intake and a direct action on coagulation factors. Different studies showed similar to lower bleeding rates in cirrhotic patients on DOAC compared to cirrhotic patients treated with warfarin or heparins. This suggests that DOAC are possibly a safe and effective alternative to VKA and LMWH. However, before performing large randomised controlled trials, the effect of specific DOAC in LC should be further studied, to select the ideal molecule.

Eligibility criteria: Inclusion Criteria:

* Age 18 years or older
* Patient with previously diagnosed liver cirrhosis Child A or B
* Written informed consent

Exclusion Criteria:

* Pregnancy
* Oesophageal varices with grade superior to 1 or with red signs
* Active ulcer disease of the gastrointestinal tract
* History of haemorrhagic stroke
* Severe uncontrolled hypertension
* Recent brain, spinal or ophthalmic surgery
* Kidney function inadequate for DOAC treatment
* Concomitant treatment with anti-platelet drugs
* Concomitant treatment with anticoagulant drugs (VKA, LMWH, DOAC)
* Any contraindications for DOAC administration
* Inability to give informed consent

Primary outcomes:
measure: Changes from thrombin generation parameters before and after apixaban (Eliquis®) intake
timeFrame: At day 1 and day 3 before DOAC intake and 2 hours after intake. At day 8, 24 hours after last pill intake.
measure: Changes from thrombin generation parameters before and after edoxaban (Lixiana®) intake
timeFrame: At day 1 and day 3 before DOAC intake and 2 hours after intake. At day 8, 24 hours after last pill intake.
measure: Changes from peak and trough levels of apixaban (Eliquis ®)
timeFrame: At day 1, at peak level (2 hours after intake). At day 3, at steady state (before intake) and at peak level (2 hours after intake). A day 8 at residual concentration (24 hours after last pill intake). At day 9, 48 hours after last intake.
measure: Changes from peak and trough levels of edoxaban (Lixiana ®)
timeFrame: At day 1, at peak level (2 hours after intake). At day 3, at steady state (before intake) and at peak level (2 hours after intake). A day 8 at residual concentration (24 hours after last pill intake). At day 9, 48 hours after last intake.
Secondary outcomes:
measure: Changes from Thrombin-antithrombin complex (TAT) concentration before and after intake of apixaban (Eliquis®) for one week in patients with Child A or B liver cirrhosis.
timeFrame: At day 1 and day 3 before DOAC intake and 2 hours after intake. At day 8, 24 hours after last DOAC pill intake.
measure: Changes from Thrombin-antithrombin complex (TAT) concentration before and after intake of edoxaban (Lixiana ®) for one week in patients with Child A or B liver cirrhosis.
timeFrame: At day 1 and day 3 before DOAC intake and 2 hours after intake. At day 8, 24 hours after last DOAC pill intake.
measure: Changes from prothrombin activation fragments 1+2 (F1+2) concentration before and after intake of apixaban (Eliquis®) for one week in patients with Child A or B liver cirrhosis.
timeFrame: At day 1 and day 3 before DOAC intake and 2 hours after intake. At day 8, 24 hours after last DOAC pill intake.
measure: Changes from prothrombin activation fragments 1+2 (F1+2) concentration before and after intake of edoxaban (Lixiana®) for one week in patients with Child A or B liver cirrhosis.
timeFrame: At day 1 and day 3 before DOAC intake and 2 hours after intake. At day 8, 24 hours after last DOAC pill intake.
measure: Changes from D-dimers concentration before and after intake of apixaban (Eliquis®) for one week in patients with Child A or B liver cirrhosis.
timeFrame: At day 1 and day 3 before DOAC intake and 2 hours after intake. At day 8, 24 hours after last DOAC pill intake.
measure: Changes from D-dimers concentration before and after intake of edoxaban (Lixiana®) for one week in patients with Child A or B liver cirrhosis.
timeFrame: At day 1 and day 3 before DOAC intake and 2 hours after intake. At day 8, 24 hours after last DOAC pill intake.
measure: Safety analysis with the identification of specific AEs and SAEs
timeFrame: From day 1 to day 14.
Other outcomes:
Locations:
city: Lausanne
country: Switzerland
facility: Centre Hospitalier Universitaire Vaudois (CHUV)
state: Vaud
Study officials:
affiliation: CHUV
name: Lorenzo Alberio, Prof Dr. med
role: PRINCIPAL_INVESTIGATOR
References: