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Clopidogrel Resistance: Effect on Outcomes, Genetic Causes, How to Test for it, & What to do About it

Henry I. Bussey, Pharm.D., FCCP, FAHA
December, 2008

While uncertainty continues in several aspects of how to evaluate and manage patients with clopidogrel resistance, several publications appeared this month that address these issues and provide interesting new insight.

Three studies reported a strong correlation between genetic causes of clopidogrel resistance and cardiac events.^1-3 A commentary accompanying one of the 3 reports suggested that platelet function tests might be preferred over genotyping and that newer antiplatelet agents may offer some advantages in this area.⁴ Finally, the complex issues of which antiplatelet tests to use and how to adjust therapy based on the results are discussed in several articles in the December 2008 issue of the Journal of the American College of Cardiology - Intervention.⁵

Only the 3 studies reporting the correlation in clinical outcomes are highlighted below; the reader is referred to the commentary and the issue of JACC - Intervention listed below for a more thorough discussion on the controversies that those publications address.

Study by Mega, et al.¹

• Among 1477 patients with acute coronary syndrome (ACS), 21% had at least 1 CYP2C19*2 allele that results in reduced conversion of clopidogrel to its active metabolite and, therefore, less platelet inhibition.
  
  
• Patients with the CYP2C19*2 allele had a 53% relative increase in the composite of death from cardiovascular causes + myocardial infarction (MI) + stroke (12.1% vs. 8.0%, p=0.01)
  
  
• There was a 3-fold increase in stent thrombosis (2.6% vs. 0.8%, p=0.02) among those with the CYP2C19*2 polymorphism
  
  
• CYP2C19*2 accounted for 95% of the reduced function alleles and previously had been reported to occur in 30% of whites, 40% of blacks, and 55% of east Asians

Study by Simone, et al. ²

• 2208 Acute MI patients were studied from a French registry
  
  
• Those with 2 variant alleles of ABCBI (a gene that modulates absorption of clopidogrel) had a higher cardiovascular event rate at 1 yr (15.5% vs. 10.7%, hazard ratio of 1.72, CI 1.2 - 2.47)
  
  
• Those with 2 "loss of function" alleles (*2, *3, *4, *5) of the CYP2C19 had almost a 2-fold increase (hazard ratio 1.98) in cardiovascular events (21.5% vs 13.3%)
  
  
• Among 1535 who received percutaneous coronary intervention, cardiovascular events were 3.58 fold higher in those with 2 "loss of function" alleles in CYP2C19.

Study by Collet, et al.³

• 259 young (< 45 yo) post-MI patients, 186 non-carriers and 73 carriers of CYP2C19*2.
  
  
• Primary events (death, MI, urgent revascularization during clopidogrel treatment): 11 events in 186 non-carriers vs. 15 events in 73 carriers (hazard ratio 3.69 p=0.0005)
  
  
• Secondary events = stent thrombosis: 8 in non-carriers vs. 4 in carriers (hazard ratio 6.02, p=0.0009).

Although the 3 studies provide impressive evidence of an association between these genetic markers, clopidogrel resistance, and an increase in cardiovascular event rates; there are a number of questions that remain. Is the association actually cause-and-effect? The mechanism of reduced conversion of clopidogrel to its active metabolite certainly supports a cause-and-effect relationship; but it is possible that other factors may be involved as well. Should we be performing genetic testing to identify individuals with these genetic polymorphisms or would it be better to rely on studies of platelet inhibition? If we are to rely on a test of platelet inhibition (as Storey suggests⁴), which platelet function test should we use. What options are there for mitigating the effect of such clopidogrel resistance? These questions and others are discussed in the commentary by Storey⁴ and in the Dec. 2008 issue of JACC - Intervention.⁵

References

1. Mega JL, Close SL, Wiviott SD, et al. Cytochrome P-450 Polymorphisms and Response to Clopidogrel http://content.nejm.org/cgi/content/full/NEJMoa0809171 This article (10.1056/NEJMoa0809171) was published at NEJM.org on December 22, 2008. It will appear in the January 22 issue of the Journal.
   
   
2. Simon T, Verstuyft C, Mary-Krause M, et al. Genetic Determinants of Response to Clopidogrel and Cardiovascular Events. (French Registry study): http://content.nejm.org/cgi/content/full/NEJMoa0808227 This article (10.1056/NEJMoa0808227) was published at NEJM.org on December 22, 2008. It will appear in the January 22 issue of the Journal.
   
   
3. Collet J-P, Hulot J-S, Pena A, et al. Cytochrome P 450 2C19 Polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. http://www.thelancet.com/journals/lancet/
   article/PIIS0140-6736(08)61845-0/fulltext The Lancet, Early Online Publication, 23 December 2008. doi:10.1016/S0140-6736(08)61845-0
   
   
4. Storey RF. Clopidogrel in acute coronary syndrome: to genotype or not? The Lancet published online Dec. 23, 2008 DOI:10.1016/S0140-6736(08)61846-2
   
   
5. Aleil B et al. Cuisset T et al. Gladding P et al. J Am Coll Cardiol Intv 2008 (Dec. 18); 1: 631-638, 649-653, 612-627.) These articles are discussed and reference links provided by heartwire at: http://www.theheart.org/viewArticle.do?
   primaryKey=930009&nl_id=tho23dec08

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