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

Study Overview
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Brief Summary
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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.

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

Conditions
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Novel Oral Anticoagulants, NOACs, Rivaroxaban, Apixaban, Edoxaban, Dabigatran, Ticagrelor, Pharmacodynamics, Pharmacogenomics, RNA Profile, Bleeding, Biomarker

Intervention / Treatment
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* 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


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Novel oral anticoagulants cohort<br> | Genetic: Detection of genotype and RNA profile in platelet and white blood cell<br>* Detection of genotype by next generation sequencing Detection of RNA profile in platelet and white blood cell by RNA sequencing<br>Other: Indicators test related to coagulation function<br>* 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.<br>|
| Ticagrelor cohort<br> | Genetic: Detection of genotype and RNA profile in platelet and white blood cell<br>* Detection of genotype by next generation sequencing Detection of RNA profile in platelet and white blood cell by RNA sequencing<br>Other: Indicators test related to platelet function<br>* 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.<br>|

What is the study measuring?
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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. |