Study of direct oral anticoagulants (medications that help prevent blood clots) in lung transplant patients

ISRCTN	ISRCTN10003031
DOI	https://doi.org/10.1186/ISRCTN10003031
ClinicalTrials.gov (NCT)	Nil known
Clinical Trials Information System (CTIS)	Nil known
Protocol serial number	MH 001
Sponsor	CHU UCL Namur
Funder	Fonds De La Recherche Scientifique - FNRS

Submission date: 27/11/2023
Registration date: 11/07/2024
Last edited: 11/07/2024

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Haematological Disorders

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Record updated in last year

Plain English summary of protocol

Background and study aims.
Direct oral anticoagulants (DOAC) have transformed the landscape of oral anticoagulant therapy for almost a decade. They are increasingly used in clinical practice, mainly for stroke prevention in atrial fibrillation and the treatment of venous thrombosis.
Venous thrombosis is a common complication after lung transplantation and 25% of lung transplant patients also develop atrial flutter or fibrillation. Oral anticoagulation is therefore often necessary in these patients.
DOAC pharmacology may be affected by physiological changes that occur after lung transplantation, and they are subject to some interactions with drugs given to prevent rejection, which have been little studied. This raises questions about the optimal management of anticoagulant therapy in lung transplant patients, which we are regularly facing in our clinical practice.
The main objective of the study will be to describe the pharmacology of DOAC in lung transplant patients. A secondary objective will be to evaluate clinical outcomes (bleeding and thrombosis) during a 12-months follow-up. Taken together, these data will answer the question: “How best can we safely use DOAC in lung transplant patients?”.

Who can participate?
Any adult lung transplant patient taking a direct oral anticoagulant (apixaban, dabigatran etexilate, edoxaban, or rivaroxaban) for (i) the treatment and secondary prevention of VTE or (ii) stroke prevention in NVAF may participate. However, they must be able to come to the CHU UCL Namur for 24 hours to have the necessary blood samples taken.

What does the study involve?
This study involves taking several blood samples over 24 hours to establish the pharmacological profile of DOACs in lung transplant recipients.

What are the possible benefits and risks of participating?
This is an observational study with no direct benefit to participants. Improved knowledge of the pharmacology of DOAC in lung transplant patients will help to improve their use in this population in the future.
The potential harm to participants is no different from that of a conventional blood collection (e.g., hematoma or transient pain at the puncture site).

Where is the study run from?
CHU UCL Namur in Belgium.

When is the study starting and how long is it expected to run for?
August 2021 to November 2025.

Who is funding the study?
Fonds de la Recherche Scientifique - FNRS (Belgium).

Who is the main contact?
Dr Michael Hardy, michael.hardy@uclouvain.be

Contact information

Dr Michael Hardy
Public, Scientific, Principal investigator

CHU UCL Namur, Service d'Anesthésiologie
Avenue Docteur G. Thérasse, 1
5530 - Yvoir - Belgium
Yvoir
5530
Belgium

ORCID ID	0000-0001-6701-9417
Phone	+32 81 42 39 13
Email	michael.hardy@uclouvain.be

Study information

Primary study design	Observational
Study design	Single-centre prospective observational cohort study with a 12-month follow-up period.
Secondary study design	Cohort study
Study type	Participant information sheet
Scientific title	Pharmacokinetics and pharmacodynamics of direct oral anticoagulants in lung transplant patients: a prospective study
Study acronym	ATRAP
Study objectives	The main objective of the study is to describe the pharmacokinetic and pharmacodynamic profile of direct oral anticoagulants (DOAC) in lung transplant patients. A secondary objective is to evaluate clinical outcomes (bleeding and thromboembolic events) during follow-up. Taken together, these data will answer the question: "How best can we safely use DOAC in lung transplant patients?".
Ethics approval(s)	Approved 01/03/2022, Ethics Committee of the CHU UCL Namur (Avenue Docteur G. Thérasse, 1, Yvoir, 5530, Belgium; +32 81 42 21 11; comite.ethique.g@chuuclnamur.uclouvain.be), ref: B0392022000001
Health condition(s) or problem(s) studied	Direct oral anticoagulant use in lung transplant patients
Intervention	Pharmacokinetic study Apixaban, edoxaban and rivaroxaban plasma levels will be estimated using a calibrated chromogenic anti-Xa assay, the STA®-Liquid anti-Xa (Diagnostica Stago, Asnière, France). Dabigatran plasma levels will be estimated with an ecarin-based assay (STA®-ECA II, Diagnostica Stago). Pharmacodynamic study: Thrombin generation will be assessed using the ST Genesia analyser and STGDrugScreen® and STGThromboScreen® reagent (Diagnostica Stago®, Asnière, France). Thrombin generation at time 0 will also be measured withThromboScreen® reagent after DOAC removal using the DOAC-Stop® system (Haematex, Sydney, Australia) to assess the thrombin generation underlying DOAC. Pharmacogenetic study: The single nucleotide polymorphism (SNP) CYP3A5*3 (rs776746), known to influence tacrolimus dose requirement, will be screened.
Intervention type	Other
Primary outcome measure(s)	Pharmacokinetic study: Concentration-time data will be analyzed using non-compartmental PK to derive PK parameters. DOAC concentrations will be measured in the morning just before DOAC intake (T0), then 1, 2, 3, 4, 6 and 8 hours after DOAC intake. Whenever possible, DOAC concentrations will also be measured the next morning just before DOAC intake (T24) to assess inter-individual variability. Apixaban, edoxaban and rivaroxaban plasma concentrations will be estimated using a calibrated chromogenic anti-Xa assay, the STA®-Liquid anti-Xa (Diagnostica Stago, Asnière, France), using dedicated calibrators from Stago. Dabigatran plasma levels will be estimated with an ecarin-based assay (STA®-ECA II, Diagnostica Stago). 1. Peak concentration (Cmax) 2. Time to reach peak concentration (Tmax) 3. Area under the concentration curve (AUC) extrapolated to infinity 4. The terminal elimination half-life 5. The apparent volume of distribution (Vd/F) 6. The apparent clearance (CL/F). Pharmacodynamic study: Thrombin generation will be measured at through (just before DOAC intake) and at peak (3 hours after DOAC intake) on the ST-Genesia system with STG-DrugScreen and STG-ThromboScreen reagent and the following parameters will be evaluated: 1. Lag time 2. Peak height 3. Time to peak 4. Endogenous thrombin potential (ETP) 5. Velocity index
Key secondary outcome measure(s)	Clinical outcomes during the 12-month follow-up period (or until the end of the study, depending on which comes first) measured using patient records: 1. Any documented thromboembolic event 2. Any documented bleeding event
Completion date	02/11/2025

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Upper age limit	99 Years
Sex	All
Target sample size at registration	15
Key inclusion criteria	1. ≥ 18 years old; 2. Medical history of lung transplant; 3. DOAC prescription (apixaban, dabigatran etexilate, edoxaban or rivaroxaban) for (i) the treatment and secondary prevention of VTE or (ii) stroke prevention in NVAF. 4. DOAC taken for at least three days. 5. Both inpatients and outpatients are considered for inclusion.
Key exclusion criteria	Patient hospitalized in intensive care unit at inclusion.
Date of first enrolment	02/11/2022
Date of final enrolment	02/11/2024

Locations

Countries of recruitment

Belgium

Study participating centre

CHU UCL Namur

Avenue Docteur G Thérasse, 1
Yvoir
5530
Belgium

Results and Publications

Individual participant data (IPD) Intention to share	Yes
IPD sharing plan summary	Stored in publicly available repository
IPD sharing plan	Storing in a publicly available repository.

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Participant information sheet	Participant information sheet	11/11/2025	11/11/2025	No	Yes

Editorial Notes

11/01/2024: Trial's existence confirmed by Ethics Committee of the CHU UCL Namur