Author Storey RF.
Title Clopidogrel in acute coronary syndrome: to genotype or not?
Full source Lancet 2009;373:276-8
Text
ADP has an important role in platelet activation.1 The molecule can be released by damaged cells but a major source is platelet dense granules, from which it is released on platelet activation.2 ADP initiates platelet activation via the P2Y1 receptor, while binding of ADP to the P2Y12 receptor amplifies this response such that sustained ADP-induced platelet aggregation depends on continuing activation of the P2Y12 receptor. P2Y12 also has an important role in amplifying the responses to other agonists-ADP is released from platelet dense granules regardless of the activating stimulus, be that thrombin, collagen, thromboxane A2, or other agonists. Then, subsequent binding of ADP to the P2Y12 receptor not only amplifies the aggregation response but also augments other important platelet responses, including granule secretion and platelet procoagulant activity (figure). Consequently, P2Y12 has a major role in arterial thrombosis and the accompanying inflammatory response, and pharmacological targeting of this receptor has become an important strategy in cardiovascular disease.2


Platelet activation mechanisms and site of action of aspirin and of P2Y12 and GPIIb/IIIa receptor antagonists
Platelet activation via multiple pathways leads to dense granule secretion of ADP which binds to P2Y1 and P2Y12 receptors; latter has powerful role in amplification of platelet activation and numerous responses associated with such activation. “Exploding stars” are reactions to activation: platelet procoagulant changes in surface membrane for thrombin generation; platelet shape change; endothelial activation by sCD40L; and outside-in signalling via aIIb ß3. Light-green ovals=platelet receptors. TxA2=thromboxane A2. 5HT=serotonin. ßTG=ß thromboglobulin. PDGF=platelet-derived growth factor. RANTES=regulated on activation, normal T-cell expressed and secreted (a protein). PF4=platelet factor 4. TGF ß=transforming growth factor ß. PSGL-1=P-selectin glycoprotein ligand-1. aIIb ß3=platelet integrin. sCD40L=soluble human CD40 ligand. NO=nitric oxide. GP=glycoprotein. Adapted from reference 2.

Clopidogrel is converted in the liver to an active metabolite that irreversibly blocks binding of ADP to the P2Y12 receptor.3 The drug's action therefore depends on generation of sufficient levels of active metabolite to achieve a degree of blockade of the P2Y12 receptor that substantially reduces the extent of P2Y12-mediated amplification of platelet activation. Conversion to the active metabolite involves several cytochrome P450 (CYP) enzymes,4 and one important influence on clopidogrel's action is that the activity of these CYP enzymes varies considerably between individuals.5 CYP2C19 has an important role in conversion of clopidogrel to its active metabolite and a single nucleotide polymorphism (SNP) in the gene encoding this enzyme, the CYP2C19*2 allele, is associated with inactivation of the enzyme and impaired metabolism of drugs via this pathway. Healthy carriers of CYP2C19*2 have an impaired pharmacodynamic response to clopidogrel,6 and patients with acute coronary syndromes who are treated with clopidogrel and who have a poor pharmacodynamic response have a much higher risk of arterial thrombotic events, such as recurrent myocardial infarction or coronary artery stent-thrombosis, than those who have a good pharmacodynamic response.7
In The Lancet today, Jean-Philippe Collet and co-workers 8 show that carriage of at least one copy of the CYP2C19*2 allele in young survivors of acute myocardial infarction who are treated with clopidogrel is associated with a greatly increased risk of recurrent arterial thrombotic events. The degree of increased risk was remarkable. Because conversion of clopidogrel to its active metabolite can be achieved through several CYP enzymes, there is a degree of redundancy in CYP enzymes and so reduced CYP2C19 activity only moderately shifts the distribution of response to clopidogrel in CYP2C19*2 carriers.9 However, there is growing evidence that there could be a threshold level of platelet reactivity at which the risk of arterial thrombotic events is substantially increased, which might explain why such a shift in population response could have a strong effect on risk of recurrent arterial thrombosis. However, other mechanisms need to be explored and further studies done to determine whether CYP2C19*2 carriage is associated with other genetic determinants of risk. Whether CYP2C1 9 activity has a more important role in the response to clopidogrel in younger individuals compared with the older majority of patients with acute coronary syndrome also needs to be studied.
Collet and co-workers raise the issue of whether genotyping in patients with acute coronary syndrome is appropriate to identify CYP2C19*2 carriers and contribute to risk stratification. Whilst this concept is attractive, there are important issues that temper enthusiasm. First, the results of such an analysis would be unlikely to be available at the time of starting clopidogrel and during the early high-risk phase of an acute coronary syndrome. A more rapid approach would be to do pharmacodynamic testing with an estimation of P2Y12-mediated platelet function, such as ADP-induced platelet aggregation or, perhaps more specifically, a flow cytometric assay of P2Y12-mediated effect on phosphorylation of vasodilator-stimulated phosphoprotein in PGE1-treated platelets. This approach has the potential added benefit of identifying those who are homozygous for the wild-type CYP2C19*1 allele yet still have a poor pharmacodynamic response to clopidogrel, because many other factors can influence this response including age, diabetes, renal failure, and cardiac failure.9 Second, new drugs that target P2Y12 and are in late stages of development, such as prasugrel, ticagrelor (AZD6140), and cangrelor, achieve consistently high levels of receptor inhibition, and potentially provide solutions to the problem of variability in the response to clopidogrel.10 Prasugrel is more resistant to inactivation than clopidogrel and more efficiently converted to its active metabolite, without a detectable effect of CYP2C19 genotype,11 while ticagrelor and cangrelor are reversible P2Y12 antagonists that do not require metabolic activation.12 Although the fascinating observations of Collet and co-workers focus attention on the importance of factors that influence the response to clopidogrel, genotyping of patients with acute coronary syndrome is not necessarily the appropriate solution without further work to validate such an approach.

I have received research grants, consultancy fees, and/or honoraria from AstraZeneca, Eli Lilly, Daiichi Sankyo and The Medicines Company.

References

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