MOLECULAR BASIS OF RESISTANCE TO ANTI-PLATELET AGENTS

Cleveland Clinic Lerner Com-Cwru, Cleveland OH

Investigators

Linked publications & trials

Abstract

Aspirin and the thienopyridine clopidogrel have become the mainstay of anti-platelet therapy for[unreadable] prevention of complications of atherosclerotic vascular disease. In recent years, we and others have[unreadable] demonstrated that a significant minority of patients do not achieve the anticipated level of inhibition of[unreadable] platelet aggregation to either aspirin or clopidogrel. Despite several studies that have characterized aspirin[unreadable] and clopidogrel resistance in terms of their natural history and propensity for adverse clinical events, the[unreadable] genomic or proteomic basis for this phenomenon has not yet been defined. Based on preliminary data[unreadable] generated by our group and others, we hypothesize that specific genomic variations account for the[unreadable] marked heterogeneity in response to anti-platelet agents. The principal goal of this project will be to[unreadable] assess whether genotype or platelet phenotype is more predictive of response to antiplatelet therapy and[unreadable] clinical outcome. In Aim 1, we will utilize a haplotype map of the P2RY12 ADP receptor gene to evaluate[unreadable] the significance of genetic heterogeneity with respect to clinical evidence of resistance to clopidogrel in[unreadable] 5000 patients from the CHARISMA trial. In Aim 2, we plan to validate our observation of an association of[unreadable] the P2RY1 C/T893 single nucleotide polymorphism (SNP) with aspirin resistance. We will also assess[unreadable] other SNPs that may be linked to aspirin resistance using a candidate gene and platelet transcriptome[unreadable] approach. In Aim 3, using a prospectively enrolled cohort of patients (n=500) undergoing coronary[unreadable] intervention treated with aspirin + clopidogrel, we will determine whether the genomic abnormalities[unreadable] associated with aspirin and/or clopidogrel resistance identified in Aims 1 and 2 are associated with adverse[unreadable] peri-procedural and one year outcomes. We will further evaluate whether specific phenotypes are important[unreadable] in determining response to clopidogrel and aspirin therapy. At 30 days, patients with suboptimal[unreadable] functional aspirin or clopidogrel effect will have drug doses increased for 30 days and followed to 60 days[unreadable] post-procedure for serial measurement of platelet function. The significance of this project on the practice[unreadable] of medicine is particularly critical. More than 20 million individuals in the US take aspirin for prophylaxis of[unreadable] heart attack, stroke and death. Clopidogrel is prescribed yearly in >2 million patients in the US. Currently,[unreadable] there is no way to individually adjust the dose of anti-platelet therapy according to the genomic profile or[unreadable] functional platelet assay. The results of this project will illuminate the specific pathways to make dose and[unreadable] agent selection individualized and promote rational use of anti-platelet agents in the future.