Genetic determinations of variable responsiveness to clopidogrel and implications for neurointerventional procedures

Endovascular intervention is emerging as a substitute for open surgical procedures for the treatment of cerebrovascular disease. However, up to 9% of patients undergoing neurointerventional procedures develop thromboembolic complications. Strategies to reduce periprocedural thromboembolic events are dominated by the use of dual antiplatelet therapy (DAT) which has been validated based on studies of peripheral vascular and coronary intervention. Of note, DAT decreases adverse vascular outcomes by 75-80% in patients undergoing percutaneous coronary intervention (PCI). It follows that similar treatment effects would be observed in neurointerventional populations. However, a growing body of evidence demonstrates that a subgroup of patients respond suboptimally to DAT, and in particular to clopidogrel (termed clopidogrel hyporesponders). These patients may be at an increased risk of thromboembolic complications such as in-stent thrombosis following neurointerventional procedures. Previous studies report 5-30% suboptimal response to clopidogrel in the cardiovascular population, while a higher prevalence is seen in populations undergoing neurointerventional procedures, i.e. as much as 66%. Knowledge of the mechanism leading to clopidogrel hyporesponsiveness is accumulating. A number of genetic polymorphisms, in particular CYP 2C19*2, have been associated with clopidogrel hyporesponsiveness and clinical outcomes. In addition, there are significant differences in the prevalence of CYP 2C19*2 across racial groups. Approximately 50% of Asians and 25% of Caucasians harbor the CYP 2C19*2 allele. While no prospective randomized trials currently exist to demonstrate improved clinical outcomes with genotype-based treatment for carriers of the CYP 2C19*2 polymorphism, a number of studies show that an increased dose of clopidogrel improves platelet inhibition in hyporesponders. The aim of the review is to examine the current understanding of the genetic basis of clopidogrel hyporesponsiveness in patients undergoing neurointerventional procedures and to explore current efforts using genotype and phenotype testing as well as alternative strategies to overcome the clopidogrel hyporesponsiveness.