Clinical trial NCT04874428: Direct Oral Anticoagulants (Rivaroxaban and Apixaban) in Patients With Liver Cirrhosis
Official title: Pharmacokinetics and Pharmacodynamics of Single Doses of Rivaroxaban and Apixaban in Patients With Compensated Liver Cirrhosis
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Liver Cirrhosis
Keywords: Rivaroxaban
Apixaban
Factor Xa Inhibitors
Antithrombins
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Anticoagulants
Pharmacokinetics
Pharmacodynamics
Thromboembolism
Venous Thromboembolism
Embolism and Thrombosis
Vascular Diseases
Cardiovascular Diseases
Liver Cirrhosis
Liver Diseases
Lead sponsor: Insel Gruppe AG, University Hospital Bern
Sponsor class: OTHER
Collaborators: name: Centre Hospitalier Universitaire Vaudois
First posted: 2021-05-05
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: The aim of this study is to investigate the pharmacokinetic and pharmacodynamic parameters of rivaroxaban and apixaban in patients with compensated liver cirrhosis (Child-Pugh class A and B).

The enrolled participants receive a prophylactic single oral dose of either rivaroxaban (10 mg) or apixaban (2.5 mg) at around 8 a.m. on the day of the trial. Blood samples are taken 0.5 hours pre-dose and 1, 2, 3, 4, 6, 8, 12 hours post-dose.

A follow-up telephone call is performed 5 days after the study intervention to collect safety data.

Detailed description: Background:

Cirrhosis is an increasing cause of morbidity and mortality in more developed countries, being the 14th most common cause of death worldwide but fourth in central Europe. Patients with liver cirrhosis frequently require anticoagulation and the main indication for anticoagulation in cirrhotic patients is portal vein thrombosis.

The most studied and used anticoagulants for patients with liver cirrhosis so far have been low molecular weight heparins (LMWH) and warfarin (vitamin K antagonist, VKA). LMWH are safe and effective in cirrhotic patients, reduce the risk of portal vein thrombosis and liver decompensation and improve liver function and Child-Pugh score as well as overall survival. On the other side, VKA treatment is challenging in patients with liver disease as warfarin has high plasma protein binding (\~99%) and is predominantly eliminated by the liver through a cytochrome P450-dependent metabolism, and INR at baseline is often elevated. Thus, the dose of warfarin and the target International Normalized Ratio (INR) are not well defined in this population. Both of them, LMWH and VKA, have some important drawbacks. On one hand, the LMWH require a daily subcutaneous injection. On the other hand, the orally ingested VKA need monitoring of the INR value. The measurement of the INR value in patients with liver cirrhosis is inadequate to guide anticoagulation as the INR value is altered in association with liver cirrhosis.

Because of the enumerated reasons above, it might be desirable to use direct oral anticoagulants (DOAC) in patients with liver cirrhosis. DOAC do not need routine INR monitoring and can be taken orally at a fixed dose and hence do not need injection. Furthermore, DOAC have a quicker onset of action than Warfarin and show a lower risk of bleeding.

The DOAC rivaroxaban and apixaban are approved for the prevention of venous thromboembolic events in patients who have undergone elective hip or knee replacement surgery, for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) and to prevent recurrent DVT and PE. Furthermore, they are approved for the prevention of stroke and systemic embolism in case of non-valvular atrial fibrillation. It is important to note that DOAC are already used off label in cirrhotic patients with Child Pugh class A and B. DOAC are not recommended for cirrhotic patients with Child Pugh class C.

However, the scientific evidence for the use of DOAC in cirrhotic patients is scarce as most randomized trials studying DOAC have excluded patients with remarkable liver disease and cirrhosis. Therefore, only limited data exists about the efficacy and safety of DOAC in this specific population. Nevertheless, some studies about the use of DOAC in cirrhotic patients yet exist. As it stands now, studies say it is reasonable to consider DOAC as an alternative in patients with compensated liver cirrhosis. According to them, DOAC appear to be as safe and efficacious as traditional anticoagulants in patients with compensated cirrhosis, provided that liver function is within Child-Pugh stages A or B. However, randomized trials are necessary to investigate the safety and efficacy of DOAC in more detail, especially to establish future guidelines of their use in cirrhosis.

The concerns about the use of DOAC in cirrhotic patients arise due to multiple reasons. One important point is that patients with liver cirrhosis show haemostatic alterations, which affect pro- and anticoagulant state. Affected from the haemostatic alterations are primary haemostasis, coagulation and fibrinolysis. The primary haemostasis undergoes both, prothrombotic (increased von Willebrand factor) and prohaemorrhagic (thrombocytopenia and in vitro thrombocytopathy) changes and possibly results in a rebalanced primary haemostasis. The coagulation shifts to a rather procoagulant state. The reduced activity of coagulation factors is counterbalanced by an increase in factor VIII, decrease of natural anticoagulants, complex changes in circulating microparticles, cell-free DNA and neutrophil extracellular traps. Concerning fibrinolysis, it is not yet clear whether the changes shift fibrinolysis or not. In summary, the changes overall result in a rather prothrombotic state. Another reason for concerns is, that DOAC are metabolized via the liver to various degrees. The two drugs that will be investigated in this trial, rivaroxaban and apixaban, are partially metabolized via cytochrome P450. Considering this, pharmacokinetics and pharmacodynamics of these DOAC can change according to the stage of liver cirrhosis. This could possibly lead to a shift in the risk/benefit ratio of DOAC for cirrhotic patients.

Until now, there exists no randomized trial comparing the safety and efficacy of DOAC versus traditional anticoagulants. Furthermore, as can be seen above, cirrhotic patients were excluded from most randomized trials investigating DOAC. This phase 1 clinical trial offers the opportunity to investigate pharmacokinetics and pharmacodynamics of DOAC in cirrhotic patients. The results of this trial might help to design larger trials in this specific patient population with the final goal of safe and efficient use of rivaroxaban and apixaban in patients with compensated liver cirrhosis.

Eligibility criteria: Inclusion Criteria:

* Age 18 years or older
* Patient with previously diagnosed liver cirrhosis (Child-Pugh score grade A and B).
* Written informed consent

Exclusion Criteria:

* Positive pregnancy test (only for women in childbearing age with intact uterus), pregnancy or nursing women
* Intake of prophylactic or therapeutic oral anticoagulant (phenprocoumon, acenocoumarol, dabigatran etc.) 2 weeks prior to inclusion in the study
* Application of parenteral anticoagulant, e.g. unfractionated heparin, low molecular weight heparins, heparin derivatives (fondaparinux etc.) 1 week prior to inclusion in the study
* Pharmacologic platelet inhibition within 2 weeks prior to inclusion in the study
* Known coagulation disorders (e.g. von Willebrand's disease, hemophilia)
* Active, clinically significant bleeding
* Congenital or acquired bleeding disorder
* High risk of bleeding (e.g. active ulcerative gastrointestinal disease)
* Uncontrolled severe hypertension
* Vascular retinopathy
* Acute infection
* Acute bacterial endocarditis
* Severe anemia (haemoglobin ≤100 g/L)
* Hereditary galactose intolerance, Lapp lactase deficiency, glucose-galactose malabsorption
* Severe liver dysfunction (Child-Pugh Score grade C)
* Hepatic encephalopathy ≥ grade 3
* Severe renal impairment with a creatinine clearance (GFR) of \<30 ml/min
* Known intolerance to the study medications rivaroxaban and/or apixaban
* Concomitant treatment with a strong CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, lopinavir, ritonavir, indinavir).
* Concomitant treatment with a P-glycoprotein inhibitor and a weak or moderate CYP3A4 inhibitor (e.g., erythromycin, azithromycin, diltiazem, verapamil, quinidine, ranolazine, dronedarone, amiodarone, felodipine).
* Concomitant treatment with a P-glycoprotein inducer and a strong CYP3A4 inducer (e.g., carbamazepine, phenytoin, rifampicin).
* Wash-out period of less than two weeks prior to the application of study drug in case of prior treatment with a strong CYP3A4 inhibitor or a P-glycoprotein inhibitor and weak or moderate CYP3A4 inhibitor or with a P-glycoprotein inducer or strong CYP3A4 inducer.

Primary outcomes:
measure: Area under the plasma concentration-time curve (AUC) of rivaroxaban
timeFrame: Up to 12 hours
measure: Maximum plasma concentration (Cmax) of rivaroxaban
timeFrame: Up to 12 hours
measure: Time to maximum plasma concentration (tmax) of rivaroxaban
timeFrame: Up to 12 hours
measure: Terminal half-life (t1/2) of rivaroxaban
timeFrame: Up to 12 hours
measure: Trough plasma concentration (Cmin) at 24 hours post application of rivaroxaban (imputed)
timeFrame: 0.5 hours pre-dose
measure: AUC of apixaban
timeFrame: Up to 12 hours
measure: Cmax of apixaban
timeFrame: Up to 12 hours
measure: tmax of apixaban
timeFrame: Up to 12 hours
measure: t1/2 of apixaban
timeFrame: Up to 12 hours
measure: Cmin at 24 hours post application of apixaban (imputed)
timeFrame: 0.5 hours pre-dose
Secondary outcomes:
measure: Cmax of prothrombin fragment (F1+2) after administration of rivaroxaban
timeFrame: Up to 12 hours
measure: tmax of F1+2 after administration of rivaroxaban
timeFrame: Up to 12 hours
measure: Cmax of thrombin-antithrombin-complexes (TAT) after administration of rivaroxaban
timeFrame: Up to 12 hours
measure: tmax of TAT after administration of rivaroxaban
timeFrame: Up to 12 hours
measure: Cmax of D-dimers (DD) after administration of rivaroxaban
timeFrame: Up to 12 hours
measure: tmax of DD after administration of rivaroxaban
timeFrame: Up to 12 hours
measure: Cmax of F1+2 after administration of apixaban
timeFrame: Up to 12 hours
measure: tmax of F1+2 after administration of apixaban
timeFrame: Up to 12 hours
measure: Cmax of TAT after administration of apixaban
timeFrame: Up to 12 hours
measure: tmax of TAT after administration of apixaban
timeFrame: Up to 12 hours
measure: Cmax of DD after administration of apixaban
timeFrame: Up to 12 hours
measure: tmax of DD after administration of apixaban
timeFrame: Up to 12 hours
Other outcomes:
Locations:
city: Berne
country: Switzerland
facility: Department of Visceral Surgery and Medicine, University Hospital Inselspital, Berne
Study officials:
affiliation: Insel Gruppe AG, University Hospital Bern
name: Dr. med. Guido Stirnimann
role: PRINCIPAL_INVESTIGATOR
References:
citation: Tsochatzis EA, Bosch J, Burroughs AK. Liver cirrhosis. Lancet. 2014 May 17;383(9930):1749-61. doi: 10.1016/S0140-6736(14)60121-5. Epub 2014 Jan 28.
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citation: Turco L, de Raucourt E, Valla DC, Villa E. Anticoagulation in the cirrhotic patient. JHEP Rep. 2019 Jul 16;1(3):227-239. doi: 10.1016/j.jhepr.2019.02.006. eCollection 2019 Sep.
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