Genetic polymorphisms and response to clopidogrel and risk of cardiovascular events

Across the whole spectrum of acute coronary syndromes and in patients undergoing PCI and stenting, dual anti-platelet therapy with aspirin and clopidogrel is the current recognised standard of care. However, significant variation in response to clopidogrel is observed between patients, with those with lesser degrees of platelet inhibition being at higher risk of adverse cardiovascular events.  Two studies in the New England Journal of Medicine investigate the possible reasons for this.

The first study tested the association between functional genetic variants in CYP genes, plasma concentrations of the active drug metabolite and platelet inhibition in response to clopidogrel in 162 healthy controls. Subsequently, they evaluated the association between these genetic variants and cardiovascular outcomes in 1477 patients with acute coronary syndromes who were treated with clopidogrel in the Trial to Assess Improvement in Therapeutic Outcomes by Optimising Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMI 38). The primary efficacy outcome was a composite of death from cardiovascular causes, myocardial infarction or stroke. An important pre-specified secondary outcome was definite or probable stent thrombosis as defined by the Academic Research Consortium. In healthy individuals treated with clopidogrel, carriers of at least one reduced function CYP2C19 allele (30% of the study population) had a relative reduction of 32.4% in plasma exposure to the active metabolite of clopidogrel when compared to non-carriers (p < 0.001). Carriers demonstrated an absolute reduction in maximal platelet aggregation in response to clopidogrel that was 9% less than that see with non-carriers (p < 0.001). In the TRITON-TIMI 38 population, in those treated with clopidogrel, carriers had a relative increase of 53% in the composite primary efficacy outcome as compared with non-carriers (12.1% vs 8%, HR for carriers 1.53, 95% CI 1.07-2.19, p = 0.01). An increase by a factor of 3 times was observed for risk of stent thrombosis (2.6% vs 0.8%, HR 3.09, 95%CI 1.19-8.0, p = 0.02).

The results from this study provide strong evidence that CYP genetic variation leads to reduced exposure to the active drug metabolite of clopidogrel, less platelet inhibition and decreased protection from recurrent ischaemic events. Common polymorphisms in the CYP2C19 gene are seen in 30% of whites, 40% of blacks and >55% of East Asians resulting in decreased pharmacokinetic and pharmacodynamic responses to clopidogrel in approximately 1/4 to 1/3 of individuals. In patients with ACS treated with clopidogrel, there was a greater then 50% increase in the risk of the primary outcome and a 3 fold increase in the risk of stent thrombosis.

The second study evaluated the relationship between known polymorphisms of relevant genes and clinical outcome after myocardial infarction in patients receiving clopidogrel. The polymorphisms of genes involved in clopidogrel absorption (ABCB1), metabolic activation (CYP3A5 and CYP2C19), and biological activity (P2RY12 and ITGB3) were assessed against death or ischaemic events during the first year of follow-up of the French Registry of Acute ST elevation and Non-ST elevation Myocardial Infarction (FAST-MI). 2208 patients were enrolled and assessed for the previously mentioned allelic variants to risk of death from any cause, non-fatal stroke, or myocardial infarction during 1 year follow-up. 225patients died and 94 suffered a non-fatal MI or stroke. None of the selected single nucleotide polymorphisms (SNPs) in CYP3A5, P2RY12, or ITGB3 were associated with risk of adverse outcome. Patients homozygous for the variant of ABCB1 were observed to have a higher rate of cardiovascular events at 1 year than their wild-type counterparts (15.5% vs 10.7%, HR 1.72, 95% CI 1.20-2.47). Patients who were homozygous for CYP2C19 loss of function alleles also had a higher event rate compared to wild-type (21.5% vs 13.3%, HR 1.98, 95% CI 1.10-3.58). 1535 patients underwent percutaneous coronary intervention during admission and the rate of cardiovascular events in patients homozygous for CYP2C19 was 3.58 times that seen with wild-type (95% CI 1.71-7.51).

Previously there has been some concern that there may be reduced antiplatelet activity of clopidogrel in patients prescribed omeprazole a CYP2C19 inhibitor. This was not observed in this study and is an important finding as there is a high frequency of co-prescription of anti-platelet agents and proton pump inhibitors. This study was observational in design and therefore does not allow discernment of cause and effect relationships. It is therefore possible that both ABCB1 and CYP2C19 may have an effect on atherothrombosis directly rather than modulating platelet response to clopidogrel.

Both these studies further expand the understanding of the pharmacogenetics of clopidogrel and the advent of newer anti-platelet therapies such as prasugrel will provide possible alternatives for patients not achieving an appropriate anti-platelet response with current therapies.

·      Mega JL, Close SL, Wiviott SD et al. Cytochrome P-450 Polymorphisms and Response to Clopidogrel. N Engl J Med 2009;360 (online-early)

·      Simon T, Verstuyft C, Mary-Krause M et al. Genetic Determinants of Response to Clopidogrel and Cardiovascular Events. N Engl J Med 2009;360 (online-early)