DOAC in Chinese Patients With Atrial Fibrillation (DOAC-REAL)
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|ClinicalTrials.gov Identifier: NCT05378035|
Recruitment Status : Recruiting
First Posted : May 17, 2022
Last Update Posted : October 13, 2022
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Direct oral anticoagulants (DOACs) have emerged as safe and efficacious ischemic stroke prophylaxis for non-valvular atrial fibrillation (NVAF). All four DOACs - apixaban, dabigatran, edoxaban, and rivaroxaban - were shown to reduce the risk of major bleeding compared to warfarin. The predictable pharmacokinetic profiles of DOACs also favour their use over warfarin. Together with increasing AF incidence due to population ageing, increased AF detection, and territory-wide reimbursement schemes, DOAC prescriptions have been surging worldwide. In Hong Kong, more than 78,354 patients received DOAC from January 2009 through April 2021 according to the Hospital Authority registry.
The more liberal use of DOACs has led to new issues that require a thorough understanding of ethnic-specific DOAC pharmacokinetic profiles. For instance, 12- 15% of anticoagulated patients annually required interventional procedures that involve temporary discontinuation of DOAC for 48 hours or more. Although guideline-based periprocedural DOAC interruption resulted in a low 30-day thromboembolism rate of 0.16% - 0.6% in a Caucasian cohort, same measures for elective colonoscopies in a local population-based study resulted in a 30-day periprocedural thromboembolism rate of up to 2.2%. Although these studies cannot be compared directly, the remarkable interethnic discrepancy between the two cohorts warrants further pharmacokinetic and pharmacogenomic studies. More importantly, quantifying residual DOAC levels during the interruption periods may imply on duration of periprocedural DOAC interruption, length of hospital-stay, and the risk of thromboembolic and bleeding complications.
Mapping inter- and intra-individual variations in DOAC levels may also impact on the management of ischemic stroke among DOAC recipients. Epidemiological studies have shown alarmingly up to 13% of acute ischemic stroke patients were on anticoagulation prior to stroke onset with increasing number of DOAC. These patients received low rates of recanalization therapy due to apprehension of bleeding complications, thus compromised survival and neurological recovery. A prospective study that reveals Asian-specific DOAC pharmacokinetic profiles may inform cross-disciplinary, territory-wide periprocedural care and acute stroke intervention strategy for the rapidly expanding DOAC population.
|Condition or disease||Intervention/treatment|
|Atrial Fibrillation Stroke Stroke, Acute Brain Diseases Major Adverse Cardiovascular Event Arterial Thromboembolism Venous Thromboembolism||Diagnostic Test: Blood Tests|
|Study Type :||Observational|
|Estimated Enrollment :||427 participants|
|Official Title:||Direct Oral Anticoagulant Levels in Chinese Patients With Atrial Fibrillation - A Real- World Pharmacokinetic Study|
|Actual Study Start Date :||September 28, 2022|
|Estimated Primary Completion Date :||September 27, 2027|
|Estimated Study Completion Date :||December 31, 2027|
We shall recruit the DOAC recipients that meet the following inclusion criteria:
Diagnostic Test: Blood Tests
Eligible subjects will receive additional blood tests for determination of DOAC levels and pharmacogenomic studies. Participants shall undergo DOAC level testing at peak, trough, 24, and 48 hours after discontinuation of DOAC for elective medical procedures. We shall also record their baseline demographics, clinical assessments, medical comorbidities, blood parameters, and concurrent medications. We shall minimize the blood taking by combining DOAC levels and blood tests essential for routine medical consultation and pre-procedural workup. Blood taking will only be performed by clinicians or phlebotomists who are experienced in the procedure.
- Specific coagulation assays [ Time Frame: December, 2024 ]Edoxaban is measured with the Technochrome anti-Xa kit (technoclone). Dabigatran level will be determined by HemosIL Direct Thrombin Inhibitor (DTI) Assay, a modified dilute thrombin time test performed on citrated patient plasma. Citrated patient plasma is diluted in pooled normal plasma (DTI Plasma Diluent - supplied as part of the assay) to reduce interferences from pre-analytical variables. A fixed concentration of reconstituted bovine thrombin is then added to the diluted patient sample, activating the coagulation cascade and converting fibrinogen into fibrin. The presence of Dabigatran in patient samples will have an inhibitory effect on the procoagulant activity of the exogenous thrombin added to the patient sample. The associated clotting time in seconds is measured on the ACL TOP® Hemostasis Testing Systems.
- Liquid chromatography-mass spectrometry [ Time Frame: December, 2024 ]The method will be developed and validated with respect to the assay precision, accuracy, specificity, linearity, sensitivity, extraction recovery matrix effect and stability of analyte. Briefly, DOAC in plasma samples will be extracted using protein precipitation, liquid-liquid extraction or solid-phase extraction prior to LC-MS/MS analysis. Calibration standards and quality control samples will be prepared by spiking known amount of DOAC in drug-free plasma, and will be processed in the same manner as patient's samples from the same run. A calibration curve of each DOAC will be constructed using the chromatographic peak area ratio (analyte/internal standard) obtained from the calibration standards, and the concentrations of DOAC in patient's sample will be quantified based on the linear regression model obtained from the calibration curve.
- Pharmacogenomics [ Time Frame: December, 2024 ]The genotypes of subjects will be determined by DNA microarray. Genomic DNA will be isolated from peripheral blood samples by the DNeasy blood & tissue kit (QIAGEN, Germany). The isolated DNA will be subject to library preparation and Infinium beadchip (Illumina) analysis according to the manufacturer's instructions (Illumina, USA). The beadchips will be scanned using an Illumina iScan System. To optimize the identification of related genotypes (e.g., single-nucleotide polymorphisms), the Infinium Global Diversity Array with Enhanced Pharmacogenomics (PGx) Content-8 v1.0 will be used.
Biospecimen Retention: Samples With DNA
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|Ages Eligible for Study:||18 Years to 80 Years (Adult, Older Adult)|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
|Sampling Method:||Probability Sample|
- Chinese nonvalvular atrial fibrillation (NVAF) patients on apixaban, dabigatran, edoxaban, or rivaroxaban for 6 months or more.
- Patients aged 18-80 years old.
- Patients who are able to provide an informed consent.
- Patients who are indicated for elective medical procedures that require interruption of direct oral anticoagulants (DOAC) for 48 hours.
- Patients who developed thromboembolism (e.g. ischemic stroke, ischemic bowel, etc.) or major systemic bleeding (e.g. intracerebral haemorrhage, gastrointestinal bleeding) during DOAC usage.
- Patients with creatinine clearance by Cockroft-Gault formula ≤ 30 mL/min.
- Patients with inappropriate DOAC dosages with respect to age, body weight, and creatinine clearance.
- Patients who receive DOAC with indications other than NVAF, such as history of mitral stenosis, metallic heart valve, thrombophilia, venous thromboembolism, etc.
- Patients with conditions that alter haemostasis besides DOAC use, such as essential thrombocytosis, hepatic congestion, hepatic failure with coagulopathy, etc.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05378035
|Contact: Bonaventure Yiu Ming IP, MB ChBfirstname.lastname@example.org|
|Contact: Thomas Wai Hong LEUNG, MB ChBemail@example.com|
|Chinese University of Hong Kong||Recruiting|
|Hong Kong, Hong Kong|
|Contact: Bonaventure Yiu Ming IP, MB ChB 852-28902002 firstname.lastname@example.org|
|Principal Investigator:||Bonaventure Yiu Ming IP, MB ChB||Chinese University of Hong Kong|
|Responsible Party:||Dr. IP Yiu Ming Bonaventure, Assistant Professor, Chinese University of Hong Kong|
|Other Study ID Numbers:||
|First Posted:||May 17, 2022 Key Record Dates|
|Last Update Posted:||October 13, 2022|
|Last Verified:||October 2022|
|Individual Participant Data (IPD) Sharing Statement:|
|Plan to Share IPD:||No|
|Studies a U.S. FDA-regulated Drug Product:||No|
|Studies a U.S. FDA-regulated Device Product:||No|
Central Nervous System Diseases
Nervous System Diseases
Embolism and Thrombosis