Fast track — ArticlesCytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study
Introduction
Acute and chronic clopidogrel treatment in combination with aspirin can prevent recurrent ischaemic events after an acute coronary syndrome or a percutaneous coronary intervention.1 However, many patients on dual antiplatelet therapy still have thrombotic events. Attention has recently focused on the wide variability between individuals of response to clopidogrel,2 with poor inhibition of the platelet P2Y12 receptor in some patients.3 Persistent high platelet reactivity with clopidogrel treatment has also been associated with more frequent adverse events,4, 5 whereas a higher dose of clopidogrel or more potent drugs can help overcome such poor response and improve clinical outcome.6, 7, 8, 9, 10
High platelet reactivity with clopidogrel could be due to various reasons including polymorphism in the gene encoding the cytochrome P450 2C19 enzyme (CYP2C19), which contributes to the variability of platelet response to clopidogrel. Clopidogrel is a prodrug that has to be converted into an active metabolite that selectively and irreversibly binds to the P2Y12 platelet membrane receptor.11, 12, 13 CYP2C19 is a key enzyme in this activation process,14, 15, 16 and the presence of the loss-of-function CYP2C19 681G>A polymorphism (also called *2) is associated with reduced clopidogrel responsiveness in healthy people and in patients with coronary artery disease.17, 18, 19, 20, 21 However, the direct relation with adverse clinical outcome has not been shown.21
Myocardial infarction in patients younger than 45 years is a rare but serious thrombotic event, which is often treated by percutaneous coronary intervention and stenting and needs optimum and extended antiplatelet therapy. We assessed the effect of the CYP2C19*2 loss-of-function polymorphism in a cohort of young (<45 years) patients who survived a first myocardial infarction and were treated chronically with clopidogrel.
With consideration of the early and extended treatment with clopidogrel for secondary prevention of these patients, we decided to assess the effect of CYP2C19*2 polymorphism on their long-term prognosis during clopidogrel exposure. Only patients who were exposed to clopidogrel were assessed in this pharmacogenetic investigation.
Section snippets
Study design and eligibility
Between April 1, 1996, and April 1, 2008, 378 consecutive patients aged less than 45 years and who survived a myocardial infarction were enrolled in the ongoing AFIJI (Appraisal of risk Factors in young Ischemic patients Justifying aggressive Intervention) multicentre registry, which was dedicated to the management of premature coronary artery disease, including risk factors and genetic profiling. This programme was designed in 1996 to identify classic and unusual risk factors, as well as
Results
Of the 378 patients who entered the secondary prevention programme, 119 were not treated by clopidogrel because premature coronary artery disease had occurred before clopidogrel was made available in 1999 (figure 1). Thus we analysed 259 patients who were all treated by clopidogrel.
Most patients were white men with a high prevalence of familial history of coronary artery disease (table 1). Around half of patients were still actively smoking 3 months after the qualifying event (table 1). Other
Discussion
Results from our study have shown that CYP2C19*2 polymorphism greatly affects clinical outcome in a population of young patients with myocardial infarction on extended clopidogrel treatment with a long follow-up. This novel finding of a strong independent relation between CYP2C19*2 and recurrent coronary events is consistent in a subset analysis, with both acute and long-term effects, of stent-related and stent-independent coronary events.
The active metabolite of clopidogrel, which irreversibly
References (43)
- et al.
Variability in individual responsiveness to clopidogrel clinical implications, management, and future perspectives
J Am Coll Cardiol
(2007) - et al.
Impact of platelet reactivity after clopidogrel administration on drug-eluting stent thrombosis
J Am Coll Cardiol
(2007) - et al.
Impact of the degree of peri-interventional platelet inhibition after loading with clopidogrel on early clinical outcome of elective coronary stent placement
J Am Coll Cardiol
(2006) - et al.
A randomized comparison of high clopidogrel loading doses in patients with non-ST-segment elevation acute coronary syndromes: the ALBION (Assessment of the Best Loading Dose of Clopidogrel to Blunt Platelet Activation, Inflammation and Ongoing Necrosis) Trial
J Am Coll Cardiol
(2006) - et al.
Benefit of a 600-mg loading dose of clopidogrel on platelet reactivity and clinical outcomes in patients with non-ST-segment elevation acute coronary syndrome undergoing coronary stenting
J Am Coll Cardiol
(2006) - et al.
Meta-analysis appraising high clopidogrel loading in patients undergoing percutaneous coronary intervention
Am J Cardiol
(2007) - et al.
Adjusted clopidogrel loading dose to platelet reactivity measure decrease the rate of major adverse cardiovascular events in patients with clopidogrel resistance: a multi centric randomized, prospective study
J Am Coll Cardiol
(2008) - et al.
P2Y(12), a new platelet ADP receptor, target of clopidogrel
Biochem Biophys Res Commun
(2001) - et al.
Common polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel
J Thromb Haemost
(2007) - et al.
Influence of CYP2C19 and CYP3A4 gene polymorphisms on clopidogrel responsiveness in healthy subjects
J Thromb Haemost
(2007)
Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects
Blood
Effect of cytochrome P450 polymorphisms on platelet reactivity after treatment with clopidogrel in acute coronary syndrome
Am J Cardiol
Cytochrome P450 2C19 681G>A polymorphism and high on-clopidogrel platelet reactivity associated with adverse 1-year clinical outcome of elective percutaneous coronary intervention with drug-eluting or bare-metal stents
J Am Coll Cardiol
Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin: the randomized, double-blind OCLA (Omeprazole CLopidogrel Aspirin) Study
J Am Coll Cardiol
Impact of platelet reactivity on cardiovascular outcomes in patients with type 2 diabetes mellitus and coronary artery disease
J Am Coll Cardiol
Increased risk in patients with high platelet aggregation receiving chronic clopidogrel therapy undergoing percutaneous coronary intervention: is the current antiplatelet therapy adequate?
J Am Coll Cardiol
AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update: endorsed by the National Heart, Lung, and Blood Institute
Circulation
Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity
Circulation
Prasugrel versus clopidogrel in patients with acute coronary syndromes
N Engl J Med
Identification of the platelet ADP receptor targeted by antithrombotic drugs
Nature
Identification and biological activity of the active metabolite of clopidogrel
Thromb Haemost
Cited by (857)
Pharmacogenomics testing: An overview
2023, Pharmacogenomics: from Discovery to Clinical ImplementationPharmacogenomics in cardiovascular diseases
2023, Pharmacogenomics: from Discovery to Clinical ImplementationPharmacogenetics: a comprehensive review of genes, genetics, genomics, and epigenetics
2023, Substance Use and Addiction Research: Methodology, Mechanisms, and TherapeuticsCangrelor in STEMI as a bridge to CABG- a mini-case series
2022, American Heart Journal Plus: Cardiology Research and Practice