Imapct of bioMarkers on Pharmacodynamics and Bleeding Risk of Direct Oral AntiCoagulants and Ticagrelor Study II

Imapct of bioMarkers on Pharmacodynamics and Bleeding Risk of Direct Oral AntiCoagulants and Ticagrelor Study II (IMPACT 2)

Individual differences in drug efficacy and adverse reactions are common in the clinical application of drugs. Individual differences are caused by many factors, among which genetic factors account for more than 20%. Novel oral anticoagulant drugs (NOACs, including rivaroxaban, apixaban, edoxaban, dabigatran, etc.) and novel antiplatelet drug ticagrelor have the advantages of convenient use and no need for monitoring. But novel oral antithrombotic drugs also increase the risk of bleeding, and there is currently a lack of effective antagonists when antithrombosis is excessive or emergency surgery is required. At present, there are few studies on the causes of individual differences in novel antithrombotic drugs, and there is a lack of predictable biomarkers or drug genotypes, especially in China. Therefore, on the basis of previous studies on NOACs and ticagrelor individualized medication cohorts, this study plans to establish a validation cohort for novel antithrombotic drugs bleeding related biomarkers, conduct multi-omics testing and long-term follow-up, and explore markers related to pharmacodynamics of antithrombotic drugs, adverse bleeding reactions and clinical outcomes.

Study Overview

• Status: Not yet recruiting
• Conditions: Bleeding; Pharmacodynamics; Apixaban; Pharmacogenomics; Biomarker; Ticagrelor; Rivaroxaban; Novel Oral Anticoagulants; NOACs; Dabigatran; Edoxaban; RNA Profile
• Intervention / Treatment: Genetic: Detection of genotype and RNA profile in platelet and white blood cell; Other: Indicators test related to coagulation function; Other: Indicators test related to platelet function

• Study Type: Observational
• Enrollment (Anticipated): 2000

Contacts and Locations

• Study Contact: Name: Qian Xiang, Dr.; Phone Number: +86-18610260623; Email: xiangqz@pkufh.com

Study Locations

• China
  • Anhui
    • Hefei, Anhui, China
      • Anhui Provincial Hospital#The First Affiliated Hospital Of USTC#
      • Contact: Zhaoyi Yang, PhD; Phone Number: 800 +86551-62283379; Email: young2382@163.com
  • Beijing
    • Beijing, Beijing, China
      • Peking University First Hospital
      • Contact: Qian Xiang, PhD; Phone Number: +86-18610260623; Email: xiangqz@pkufh.com
  • Chongqing
    • Chongqing, Chongqing, China
      • The Second Affiliated Hospital of Chongqing Medical University
  • Henan
    • Zhengzhou, Henan, China
      • The 7th People's Hospital of Zhengzhou
      • Contact: Dongdong Yuan, MS; Phone Number: +86371-89905878; Email: 44676878@qq.com
  • Shanghai
    • Shanghai, Shanghai, China
      • Zhongshan Hospital Fudan University
      • Contact: Xiaoyu Li; Phone Number: 5062 +8621-64041990; Email: li.xiaoye@zs-hospital.sh.cn
    • Shanghai, Shanghai, China
      • Renji Hospital, School of Medicine, Shanghai Jiao Tong University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Chinese Patients taking NOACs or ticagrelor#In accordance with anticoagulation indications of NOACs or with diagnosis of acute coronary syndrome (ACS)# received NOACs or ticagrelor in a month and intend to take NOACs or ticagrelor, or have received NOACs or ticagrelor for more than one week continuously#1000 patients for each cohort (NOACs or ticagrelor).

Description

Inclusion Criteria:

(I) Chinese Patients taking NOACs

• In accordance with anticoagulation indications of NOACs, include prevention of thrombosis in non valvular atrial fibrillation, prevention and treatment of deep vein thrombosis / pulmonary embolism and prevention of thrombosis after knee / hip replacement;
• More than 18 years of age, male or female;
• Never received NOACs in a month and intend to take NOACs or have received NOACs for more than one week continuously;
• sign informed consent.

(II) Chinese Patients taking ticagrelor

• With diagnosis of acute coronary syndrome (ACS), included unstable angina, non ST segment elevation myocardial infarction and ST segment elevation myocardial infarction;
• More than 18 years of age, male or female;
• Never received ticagrelor in a month and intend to take ticagrelor or have received ticagrelor for more than one week continuously#
• sign informed consent.

Exclusion Criteria:

• With history of immunodeficiency disease, including positive HIV index;
• Positive Hepatitis B surface antigen (HBsAg) and HCV index;
• Combined therapy of CYP3A4 strong inhibitors and P-gp inhibitors (e.g., systemic pyrrole antifungal agents such as ketoconazole, itraconazole, voriconazole and posaconazole; human immunodeficiency virus (HIV) - protease inhibitors such as ritonavir), CYP3A4 strong inducers and P-gp inducers (e.g., rifampicin, phenytoin, phenobarbital, carbamazepine, St. John's Wort, etc.) in 14 days before treatment with NOACs;
• Severe liver dysfunction and abnormal renal function;
• Include contraindications of antithrombosis, such as hypersensitivity, active bleeding, moderate or severe liver disease, previous history of intracranial hemorrhage, gastrointestinal hemorrhage in the past 6 months and major operation within 30 days.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Novel oral anticoagulants cohort	Genetic: Detection of genotype and RNA profile in platelet and white blood cell; Detection of genotype by next generation sequencing Detection of RNA profile in platelet and white blood cell by RNA sequencing; Other: Indicators test related to coagulation function; Indicators test including prothrombin time (PT), activated partial thrombin time (APTT), thrombin time (TT), diluted TT (dTT), snake vein enzyme coagulation time (ECT), anti-XA or IIa activity, etc.
Ticagrelor cohort	Genetic: Detection of genotype and RNA profile in platelet and white blood cell; Detection of genotype by next generation sequencing Detection of RNA profile in platelet and white blood cell by RNA sequencing; Other: Indicators test related to platelet function; Indicators test related to platelet function. Platelet reactivity was measured by VASP. Platelet aggregation rate was measured by turbidimetric method. Platelet and fibrinolytic function were measured by thrombologram, etc.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of new bleeding events	During the observation time, record the incidence of new bleeding events after NOACs(rivaroxaban, apixaban, edoxaban, dabigatran) or ticagrelor administration by telephone and out-patient clinic, including subcutaneous bleeding, gingival bleeding, gastrointestinal bleeding, intracranial hemorrhage, etc.	Within 1 month after enrollment
Incidence of new bleeding events	During the observation time, record the incidence of new 'bleeding events after NOACs(rivaroxaban, apixaban, edoxaban, dabigatran) or ticagrelor administration by telephone and out-patient clinic, including subcutaneous bleeding, gingival bleeding, gastrointestinal bleeding, intracranial hemorrhage, etc.	From 1 month to 6 months after enrollment
Incidence of new bleeding events	During the observation time, record the incidence of new bleeding events after NOACs(rivaroxaban, apixaban, edoxaban, dabigatran) or ticagrelor administration by telephone and out-patient clinic, including subcutaneous bleeding, gingival bleeding, gastrointestinal bleeding, intracranial hemorrhage, etc.	From 6 months to 1 year after enrollment
Incidence of new bleeding events	During the observation time, record the incidence of new bleeding events after NOACs(rivaroxaban, apixaban, edoxaban, dabigatran) or ticagrelor administration by telephone and out-patient clinic, including subcutaneous bleeding, gingival bleeding, gastrointestinal bleeding, intracranial hemorrhage, etc.	From 1 year to 2 years after enrollment
Incidence of new major cardiovascular events and all-cause death	During the observation time, record the new incidence of major cardiovascular events (MACEs) and all-cause death after NOACs(rivaroxaban, apixaban, edoxaban, dabigatran) or ticagrelor administration by telephone and out-patient clinic. MACEs including cardiac death, myocardial infarction (MI), stroke or transient cerebral thrombus (TIA), ischemic-driven coronary revascularization(PCI, CABG, thrombolysis, etc.), etc.	Within 1 month after enrollment
Incidence of new major cardiovascular events and all-cause death	During the observation time, record the new incidence of major cardiovascular events (MACEs) and all-cause death after NOACs(rivaroxaban, apixaban, edoxaban, dabigatran) or ticagrelor administration by telephone and out-patient clinic. MACEs including cardiac death, myocardial infarction (MI), stroke or transient cerebral thrombus (TIA), ischemic-driven coronary revascularization(PCI, CABG, thrombolysis, etc.), etc.	From 1 month to 6 months after enrollment
Incidence of new major cardiovascular events and all-cause death	During the observation time, record the new incidence of major cardiovascular events (MACEs) and all-cause death after NOACs(rivaroxaban, apixaban, edoxaban, dabigatran) or ticagrelor administration by telephone and out-patient clinic. MACEs including cardiac death, myocardial infarction (MI), stroke or transient cerebral thrombus (TIA), ischemic-driven coronary revascularization(PCI, CABG, thrombolysis, etc.), etc.	From 6 months to 1 year after enrollment
Incidence of new major cardiovascular events and all-cause death	During the observation time, record the new incidence of major cardiovascular events (MACEs) and all-cause death after NOACs(rivaroxaban, apixaban, edoxaban, dabigatran) or ticagrelor administration by telephone and out-patient clinic. MACEs including cardiac death, myocardial infarction (MI), stroke or transient cerebral thrombus (TIA), ischemic-driven coronary revascularization(PCI, CABG, thrombolysis, etc.), etc.	From 1 year to 2 years after enrollment
Incidence of new thromboembolic events	During the observation time, record the incidence of new thromboembolic events after NOACs(rivaroxaban, apixaban, edoxaban, dabigatran) or ticagrelor administration by telephone and out-patient clinic, including stroke or TIA, systemic embolism (SE), deep vein thrombosis (DVT), pulmonary embolism, left auricular thrombus, stent thrombosis, stent stenosis and stent endothelial hyperplasiastent, etc.	Within 1 month after enrollment
Incidence of new thromboembolic events	During the observation time, record the incidence of new thromboembolic events after NOACs(rivaroxaban, apixaban, edoxaban, dabigatran) or ticagrelor administration by telephone and out-patient clinic, including stroke or TIA, systemic embolism (SE), deep vein thrombosis (DVT), pulmonary embolism, left auricular thrombus, stent thrombosis, stent stenosis and stent endothelial hyperplasiastent, etc.	From 1 month to 6 months after enrollment
Incidence of new thromboembolic events	During the observation time, record the incidence of new thromboembolic events after NOACs(rivaroxaban, apixaban, edoxaban, dabigatran) or ticagrelor administration by telephone and out-patient clinic, including stroke or TIA, systemic embolism (SE), deep vein thrombosis (DVT), pulmonary embolism, left auricular thrombus, stent thrombosis, stent stenosis and stent endothelial hyperplasiastent, etc.	From 6 months to 1 year after enrollment
Incidence of new thromboembolic events	During the observation time, record the incidence of new thromboembolic events after NOACs(rivaroxaban, apixaban, edoxaban, dabigatran) or ticagrelor administration by telephone and out-patient clinic, including stroke or TIA, systemic embolism (SE), deep vein thrombosis (DVT), pulmonary embolism, left auricular thrombus, stent thrombosis, stent stenosis and stent endothelial hyperplasiastent, etc.	From 1 year to 2 years after enrollment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Genotype detected by next generation sequencing	Collect blood specimen before NOACs administration, then detect genotype of NOACs by next generation sequencing.	Through study completion, collection only once
Expression level of RNA in platelet and white blood cell	Before and after NOACs or ticagrelor administration, detect the expression level of RNA in platelet and white blood cell .	NOACs: Once each before administration, before and after administration at stable concentration (at least 48h for rivaroxaban, 72h for apixaban or edoxaban). Ticagrelor: Once before administration and once after stable concentration (at least 48h).
Anticoagulantion activity evaluation (for NOACs only)	Before and after NOACs administration, record anti-factor Xa activity(for rivaroxaban, apixaban, edoxaban) or anti-factor IIa activity (for dabigatran only) detected by blood coagulation tests.	Once each before administration, before and after administration at stable concentration (at least 48h for rivaroxaban, 72h for apixaban or edoxaban) .
Platelet reactivity evaluation (for Ticagrelor only)	Before and after ticagrelor administration, record PRI detected by one or more following methods: 1)LTA; 2)VASP ELISA test; 3)TEG.	Once before administration and once after stable concentration.

Collaborators and Investigators

• Sponsor: Peking University First Hospital

Study record dates

Study Major Dates

• Study Start (Anticipated): March 1, 2023
• Primary Completion (Anticipated): December 1, 2026
• Study Completion (Anticipated): December 1, 2027

Study Registration Dates

• First Submitted: February 16, 2023
• First Submitted That Met QC Criteria: March 1, 2023
• First Posted (Estimate): March 10, 2023

Study Record Updates

• Last Update Posted (Estimate): March 10, 2023
• Last Update Submitted That Met QC Criteria: March 1, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Hemorrhage
• Other Study ID Numbers: 2022CR67

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No