Role of phenotypic and genetic testing in managing clopidogrel therapy

Abstract

The P2Y12 inhibitors, clopidogrel, prasugrel, and ticagrelor, are administered in fixed doses without laboratory monitoring. Randomized trials in acute coronary syndrome have shown that prasugrel and ticagrelor are more effective than standarddose clopidogrel. Nonetheless, standarddose clopidogrel remains widely used because it causes less bleeding and is less expensive. Patients treated with standarddose clopidogrel have substantial variability in platelet inhibition, which is partly explained by genetic polymorphisms encoding CYP2C19, the hepatic enzyme involved in biotransformation of clopidogrel to its active metabolite. Some advocate tailoring P2Y12 inhibitor therapy according to the results of routine laboratory testing. Although there is good evidence for analytic, biological, and clinical validity of several phenotypic and genotypic biomarkers, the benefit of a management strategy that incorporates routine biomarker testing over standard of care without such testing remains unproven. Appropriately designed, adequately powered trials are needed but face the challenges of feasibility, cost, and the progressive switch from clopidogrel to prasugrel or ticagrelor. (Blood. 2014;124(5):689-699)

Pharmacogenomics in the clinic

“…Examples for which there has been disagreement include testing for warfarin 64 and for clopidogrel 65 , with a common reason for lack of support for genetic testing being the paucity of randomized prospective controlled trials comparing genetically guided testing vs conventional therapy, Also, many professional societies and guideline-generating groups have approached evaluations of pharmacogenomic tests from the standpoint of whether the clinician is obligated to order the genetic test. 49,64–66 However, with inexpensive multi-gene tests becoming increasingly available, the question is shifting from whether to order a genetic test, to how the genetic test results “already” generated can and should be used for prescribing decisions.…”

Influence of CYP2C19 genotype on antiplatelet treatment outcomes after percutaneous coronary intervention in patients with coronary heart disease

“…The association between CYP2C19 gene mutations and cardiovascular MACE rates is debatable, but different studies have selected different patient populations with different risk factors (14,15). The CYP2C19 gene polymorphism is not the only factor affecting the individual response to clopidogrel; age, body mass index, blood lipid levels, combined medication, and clopidogrel doses can also affect the patient's platelet activity (16).…”

Platelet function testing: does a randomized controlled trial settle the debate?

“…First, there is a need to exercise caution, with highly favorable results often observed in early small RCTs. Large and significant reductions in the major adverse cardiac event (MACE) rate by using PFTs to modify therapy were also reported in the initial small cardiology RCTs (n=74–429) 6. Subsequent larger and more robust trials failed to confirm these results.…”

“…The common feature of these early percutaneous coronary intervention (PCI) RCTs was their biomarker enrichment trial design 6. These trials aimed to determine whether intensified treatment is better than standard treatment in poor responders identified using PFTs.…”