Review
Suboptimal response to clopidogrel: A genetic risk factor for recurrent ischaemic stroke

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Abstract

Anti-platelet agents (APA) are widely used in the secondary prevention of ischaemic stroke but about 30% of patients derive suboptimal platelet inhibition from APA. An underlying cause for suboptimal platelet inhibition is varying response to clopidogrel, which is linked to polymorphisms in the CYP2C19 gene responsible for the metabolism and activation of clopidogrel. CYP2C19 polymorphism influences clinical outcomes in patients with coronary artery disease, particularly among those treated with percutaneous transluminal coronary artery stenting. Randomized controlled trials have shown that high doses of clopidogrel can overcome suboptimal platelet response in carriers of the CYP2C192 allele. The United States Food and Drug Administration has issued a boxed warning advising clinicians to consider genotyping patients prior to prescribing clopidogrel. There are ongoing studies investigating the clinical utility of genotyping to inform management decisions in stroke prevention.

Introduction

Stroke is Australia’s second most common cause of death after coronary heart disease and a leading cause of disability.1 In 2011, Australians suffered an estimated 60 000 new and recurrent strokes, equivalent to one stroke every 10 minutes.1 Stroke costs Australia an estimated $2.14 billion per year.1 Australia’s ageing population will see the incidence and burden of disease caused by stroke continue to increase annually. In recent years studies have highlighted the importance of suboptimal response to clopidogrel and increased risk of major cardiovascular events.2 It follows that suboptimal response to clopidogrel places patients with ischaemic stroke at increased risk of recurrent events, given the common underlying pathophysiology between cardiovascular and cerebrovascular ischaemia. This review aims to highlight the current understanding of variable response to clopidogrel and its implications for stroke prevention.

Section snippets

Anti-platelets and ischaemic stroke

Anti-platelet agents (APA) have proven benefits in secondary prevention of ischaemic stroke.3 Acetylsalicylic acid is the traditional first line agent in prevention of ischaemic stroke with a 22% reduction in the odds of a recurrent stroke.3 Clopidogrel first came to the fore as an alternative APA in stroke prevention following landmark trials in the late 1990s.4 The Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) trial demonstrated an 8.7% reduction in relative risk

Recurrent stroke: a possible expression of suboptimal platelet inhibition

Despite widespread use of APA, the rate of recurrent stroke remains a significant concern at approximately 6–9% per year after a first-ever stroke.7 Studies investigating acetylsalicylic acid resistance in the ischaemic stroke population have shown the incidence of acetylsalicylic acid resistance to be up to 30%.8 Acetylsalicylic acid resistance increases the risk of adverse vascular events among patients with stable cardiovascular and cerebrovascular disease (hazard ratio [HR] 4.1 95%

Clopidogrel metabolism

Clopidogrel is a pro-drug that, once metabolized to its active form, irreversibly inhibits platelet aggregation by blocking the platelet P2Y12 adenosine diphosphate (ADP) receptor (Fig. 1). The pharmacodynamic and pharmacokinetic effect of clopidogrel demonstrates significant interindividual variation.11 A proposed mechanism for this variation is polymorphism of the genes encoding hepatic cytochrome p450 (CYP) isoenzymes. These enzymes catalyse the oxidation of clopidogrel into its active form

Genetics and clopidogrel

Several genetic variations of the CYP2C19 gene have been analyzed and are associated with varying levels of the active clopidogrel metabolite.13 There are numerous alleles of the CYP2C19 gene, labeled according to the accepted star nomenclature ().14 The most widely studied alleles are 1, 2 and 3. The CYP2C191 allele is fully functional, leading to extensive metabolism of clopidogrel into its active form. The alleles CYP2C192 and CYP2C193 are non-functional, which results in reduced

CYP2C19 polymorphisms in different racial groups

The CYP2C192 and CYP2C193 alleles account for the majority of reduced-function alleles, occurring in 85% of people of Caucasian descent and 99% of Asian descent who are carriers of a loss-of-function allele.16 Conversely the CYP2C1917 allele is associated with increased metabolism of clopidogrel and thus increased platelet inhibition, potentially causing increased risk of bleeding, but this, has not been shown in large randomized trials.[14], [17]

Overall approximately 30% of Caucasians, 50%

Clinical significance of CYP2C19 polymorphism in ischaemic stroke

The United States Food and Drug Administration (FDA) issued a “boxed warning” for clopidogrel in March 2010. The FDA advised clinicians to be aware that the effect of clopidogrel is reduced among patients with reduced-function CYP2C19 alleles, and that tests are available to determine the CYP2C19 genotype.16 This announcement was based on results from a study of 40 healthy individuals randomised to treatment with 300 mg followed by 75 mg daily, and 600 mg followed by 150 mg daily for 5 days, in a

Alternative maintenance dosing

Mega et al. published a recent study showing that higher doses of clopidogrel can overcome suboptimal platelet inhibition.23 The randomized double blind controlled trial published late in 2011 included 333 genotyped patients with stable cardiovascular disease taking an acetylsalicylic acid and varying daily maintenance doses of clopidogrel (75 mg, 150 mg, 225 mg and 300 mg).23 Patients heterozygous for the CYP2C192 allele taking an increased maintenance dose of clopidogrel at ⩾225 mg or greater

Inhibitors of CYP2C19 and clopidogrel efficacy

Inhibitors of the CYP2C19 isoenzyme are a potential cause of suboptimal response to clopidogrel through reducing the metabolism and bioavailability of metabolites required for platelet inhibition. Several drugs have been implicated in the inhibition of the CYP2C19 isoenzyme including statins27 and calcium channel blockers;28 however, proton pump inhibitors (PPI), in particular omeprazole, have been most strongly implicated. The effect of PPI on clopidogrel efficacy has been widely studied over

Conclusion

There is increasing concern, supported by recent literature, that a significant proportion of patients demonstrate suboptimal response to clopidogrel which is strongly predicted by polymorphisms in the CYP2C19 allele. The clinical sequelae of suboptimal response to clopidogrel is more pronounced in patients treated with endovascular procedures. High dose clopidogrel appears to overcome suboptimal platelet inhibition but has not definitively demonstrated improved clinical outcomes. Genetic

Conflicts of interest/disclosures

The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication.

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