The overall goal of this proposal is to measure platelet function, genotypes, and circulating protein biomarkers in subjects enrolled in a clinical trial of prolonged dual antiplatelet therapy (aspirin and a thienopyridine) after percutaneous coronary intervention (PCI) and correlate these measures with clinical outcomes, including death, myocardial infarction, stroke, stent thrombosis, and bleeding, in order to improve our ability to risk stratify patients and tailor antiplatelet therapy.
In Aim 1, thienopyridine-induced platelet inhibition will be quantified using an assay that specifically assesses an intermediate downstream to activation of the P2Y12 ADP receptor (the target of thienopyridines). The degree of platelet inhibition will be correlated with the risk of ischemic and bleeding outcomes. A target range of platelet reactivity will be defined to balance these competing risks and maximize net clinical benefit for patients and then validated.
In Aim 2, subjects will be genotyped for polymorphisms in genes involved in thienopyridine metabolism. The association between genetic variants and the degree of platelet inhibition and clinical events in response to thienopyridine efficacy will be examined. In addition, the association between concomitant use of medications that inhibit or require CYP450 metabolism and the degree of platelet inhibition and risk of clinical outcomes with thienopyridine therapy will be examined.
In Aim 3, circulating biomarkers of platelet activation and thrombosis will be measured and their association with the incidence of cardiovascular outcomes examined. In addition, the ability of those biomarkers to identify patients who derive greater benefit from prolonged dual antiplatelet therapy will be investigated.
Approximately 1 million percutaneous coronary interventions are performed annually in the United States alone, yet there remains a critical evidence gap in terms of how long patients should be on potent antiplatelet therapy after the procedure. In the context of a clinical trial testing the benefit of prolonged antiplatelet therapy, we plan to measure platelet function, genotypes, and protein biomarkers in order to improve our ability to risk stratify patients and tailor antiplatelet therapy.
| Mega, J L; Stitziel, N O; Smith, J G et al. (2015) Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials. Lancet 385:2264-2271 |
