DOAC in Chinese Patients With Atrial Fibrillation

NCT05378035 | Recruiting

• 1 other identifier: CREC 2022.333
• Study Type: observational
• Target: 427
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Atrial Fibrillation; Stroke; Stroke, Acute; Brain Diseases; Major Adverse Cardiovascular Event; Arterial Thromboembolism; Venous Thromboembolism

Outcome Measures

Primary Outcomes (3)

• Specific coagulation assays

  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.

  December, 2024

• Liquid chromatography-mass spectrometry

  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.

  December, 2024

• Pharmacogenomics

  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.

  December, 2024

Study Arms (1)

DOAC Recipients

We shall recruit the DOAC recipients that meet the following inclusion criteria: 1. Chinese NVAF patients on apixaban, dabigatran, edoxaban, or rivaroxaban for 6 months or more. 2. Patients aged 18-80 years old. 3. Patients who are able to provide an informed consent. 4. Patients who are indicated for elective medical procedures that require interruption of DOAC for 48 hours, such as colonoscopy, pleural biopsy, cardiac catheterization, digital subtraction angiograph, etc.

Diagnostic Test: Blood Tests

Interventions

Blood Tests DIAGNOSTIC_TEST

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.

DOAC Recipients

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

Chinese nonvalvular atrial fibrillation patients on direct oral anticoagulants.

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Chinese University of Hong Kong: lead

Study Sites (1)

Chinese University of Hong Kong

Hong Kong, Hong Kong

RECRUITING

Biospecimen

Retention: SAMPLES WITH DNA

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.The samples will be kept at -80oC freezer for storage after processed.

MeSH Terms

Conditions

Atrial Fibrillation; Stroke; Brain Diseases; Venous Thromboembolism

Interventions

Hematologic Tests

Condition Hierarchy (Ancestors)

Arrhythmias, Cardiac; Heart Diseases; Cardiovascular Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Cerebrovascular Disorders; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Thromboembolism; Embolism and Thrombosis

Intervention Hierarchy (Ancestors)

Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Investigative Techniques

Study Officials

• Bonaventure Yiu Ming IP, MB ChB

  Chinese University of Hong Kong

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Bonaventure Yiu Ming IP, MB ChB

CONTACT

852-28902002; bonaventureip@cuhk.edu.hk

Thomas Wai Hong LEUNG, MB ChB

CONTACT

852-28902002; drtleung@cuhk.edu.hk

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor

Study Record Dates

• First Submitted: May 12, 2022
• First Posted: May 17, 2022
• Study Start: September 28, 2022
• Primary Completion (Estimated): September 27, 2027
• Study Completion (Estimated): December 31, 2027
• Last Updated: January 29, 2025

Record last verified: 2025-01

Data Sharing

• IPD Sharing: Will not share

Locations

HK (1)