2013-08-012024-05-18https://scholars.lib.ntu.edu.tw/handle/123456789/704815Background: Heart diseases and cerebrovascular diseases remain the 2nd and 3rd mortality causes in Taiwan and lead to 15,675 and 10,134 deaths in 2010, respectively. Anti-platelet therapy is the standard treatment for patients with acute coronary syndrome (ACS) and ischemic stroke. However, anti-platelet therapy has become the major cause of peptic ulcer bleeding (PUB). Clopidogrel is a prodrug activated in the liver by CYP2C19 isoenzymes. Higher rate of subsequent cardiovascular events were found in patients with an acute myocardial infarction carrying CYP2C19 loss-of-function alleles than those not carrying. Certain PPIs further attenuate the antiplatelet effect of clopidogrel by competitively inhibition of CYP2C19. Previous studies: The drug-drug interaction between clopidogrel and PPIs is especially important because of the higher prevalence of poor metabolizers (PMs) of CYP2C19*2 in Taiwan. We found 12.7% Taiwanese were PMs, which was significantly higher that the prevalence in the Caucasian. In our recent published nationwide cohort study, we found concomitant use of clopidogrel and H2RA or PPI in ACS patients increases the risk of rehospitalization and mortality. Specific Aims: This study has three specific aims: 1. Using National Health Insurance Research Database to construct a “Thrombotic-Plus- Bleeding Risk Calculator” and validate it in clinical patients 2. Conduct nested case-controls studies to examine the roles of CYP2C19 phenotypes in PPI-clopidogrel interaction 3. Conduct randomized Clinical Trials to examine how CYP2C19 genotypes impact on metabolism of clopidogrel and PPIs Method: Study I: “Bleeding-Plus-thrombotic Risk Calculator” pro-type construction and validation 1. We will use Taiwan’s National Health Research Institute Database (NHIRD) to develop a “Thrombotic-Plus-Bleeding Risk Calculator” pro-type to estimate thrombotic and UGIB risks for patients who will receive anti-platelet therapy. 2. This calculator pro-type will be validated based on clinical patients in Prince of Wales’ Hospital, Hong Kong, to examine its external validity. The pro-type will be modified according to the validation results. Study II: Examine the roles of CYP2C19 phenotypes in PPI-clopidogrel interaction 1. We will conduct hospital-based nested case-control studies to examine the roles of CYP2C19 phenotypes in the risk of thrombotic and UGIB events in ACS and ischemic stroke patients. 2. The roles of CYP2C19 phenotypes in PPI-clopidogrel interaction will be further examined in ACS and ischemic stroke patients. 3. The roles of CYP2C19 phenotypes in the risk of thrombotic and UGIB events and in the PPI-clopidogrel interaction will be added to the “Thrombotic-Plus-Bleeding Risk Calculator” pro-type. Study III: Randomized Clinical Trials to examine how CYP2C19 genotypes impact on metabolism of clopidogrel and PPIs 1. We will conduct hospital-based randomized clinical trials to examine how CYP2C19 genotypes impact on metabolism of clopidogrel with concurrent use of PPI. 2. We will measure the anti-platelet activity of clopidogrel and serum level of PPIs in ACS and ischemic stroke patients with different CYP2C19 genotypes who take clopidogrel and PPIs concurrently. 3. We will further investigate whether the antiplatelet activity of clopidogrel and serum level of PPIs altered by co-administration of PPIs and clopidogrel. Anticipated Results and Significances: 1. This study will be helpful to develop a “Thrombotic-Plus-Bleeding Risk Calculator” to estimate thrombotic and UGIB risks for individual patient who will receive anti-platelet therapy. This calculator will help physicians to communicate with their patients. 2. This study will contribute to determine whether ACS or ischemic stroke patients with different CYP2C19 genotypes have varied thrombotic and UGIB events risks, especially while they are taking PPIs or H2RAs concurrently. 3. This study will be helpful to explore strategies aiming to minimize the negative interaction between PPIs, H2RAs and clopidogrel in ACS or ischemic stroke patients with high thrombotic and UGIB risks.