Bristol Myers Squibb and Sanofi which co-promote and market Plavix (Clopidogrel Bisulfate) is under fire again. Last time, it was for drug Plavix causing Thrombotic thrombocytopenic purpura (TTP), a typically rare yet very serious and potentially fatal condition where blood clots form in the arteries and block blood flow to organs, including the brain, kidneys, and other vital organs thereby damaging them. Now, after Bristol and Sanofi thought they had stamped out all of the embers regarding bad propensities of their multi-million dollar drug, science and medicine have caught up with legal theories as to why Plavix has historically caused an unreasonably high and unreported increased risk to the African American community. This risk as described below is due to metabolization differences among ethnic groups which is widely known in the scientific community. Plavix essentially raises the risk of heart attacks and strokes amoung African Americans due to an increased risk among people with a particular genetic make up which does not metabolize Plavix as necessary based on standard dosing regimens. What results is a risk of clotting. This risk is prominent in African Americans who have had stent placement to keep arteries open as well as described in detail below.
For some history, in 1997, the following was recognized:
Plavix is associated with a lower metabolization rate in people with the CYP2C19 polymorphism gene trait. CYP2C19 polymorphism has been identified as markedly increased in African American’s as compared to Caucasians and Africans. See The incidence of CYP2C19 polymorphism (most common subtype *2) in African Americans was 25%, which was higher than that reported in Africans or Caucasians. See Goldstein JA, Ishizaki T, Chiba K, et al. Frequencies of the defective CYP2C19 alleles responsible for the mephenytoin poor metabolizer phenotype in various Oriental, Caucasian, Saudi Arabian and American black populations. Pharmacogenetics 1997; 7(1): 59-64.
Accordinly, this race specific connection has been known for over a decade. To our knowledge, there has never been an attempt by Bristol or Sanofi to expressly state that African Americans (”AA community”) are at increased risk of not having plavix metabolize well leading to a risk of thrombosis or clotting. Rather, ironically, they mention Caucasians and Asians in their label but fail to provide any reference to the AA community of patients except for some brief data described below. The label as of the July 17, 2009 (which was when this passing reference to “blacks” was first inserted strangely from a 2001 study – on AAs of seven published studies in 2008 and 2009):
Several polymorphic CYP450 enzymes activate clopidogrel. CYP2C19 is involved in the formation of both the active metabolite and the 2-oxo-clopidogrel intermediate metabolite. Clopidogrel active metabolite pharmacokinetics and antiplatelet effects, as measured by ex vivo platelet aggregation assays, differ according to CYP2C19 genotype. The CYP2C19*1 allele corresponds to fully functional metabolism while the CYP2C19*2 and CYP2C19*3 alleles correspond to reduced metabolism. The CYP2C19*2 and CYP2C19*3 alleles account for 85% of reduced function alleles in whites and 99% in Asians. Other alleles associated with reduced metabolism include CYP2C19*4, *5, *6, *7, and *8, but these are less frequent in the general population. Published frequencies for the common CYP2C19 phenotypes and genotypes are listed in the table below.
Table 1 – CYP2C19 Phenotype and Genotype Frequency
Frequency (%)*
White (n=1356)
Black (n=966)
Chinese (n=573)
Extensive metabolism: CYP2C19*1/*1
74
66
38
Intermediate metabolism: CYP2C19*1/*2 or *1/*3
26
29
50
Poor metabolism: CYP2C19*2/*2, *2/*3 or *3/*3
2
4
14
Xie, et al. Annu Rev Pharmacol Toxicol 2001; 41: 815-50
To date, the impact of CYP2C19 genotype on the pharmacokinetics of clopidogrel’s active metabolite has been evaluated in 227 subjects from 7 reported studies. Reduced CYP2C19 metabolism in intermediate and poor metabolizers decreased the Cmax and AUC of the active metabolite by 30-50% following 300- or 600 mg loading doses and 75 mg maintenance doses. Lower active metabolite exposure results in less platelet inhibition or higher residual platelet reactivity. To date, diminished antiplatelet responses to clopidogrel have been described for intermediate and poor metabolizers in 21 reported studies involving 4,520 subjects. The relative difference in antiplatelet response between genotype groups varies across studies depending on the method used to evaluate response, but is typically greater than 30%.
The association between CYP2C19 genotype and clopidogrel treatment outcome was evaluated in 2 post-hoc clinical trial analyses (substudies of CLARITY-TIMI 281 [n=465] and TRITON-TIMI 382 [n=1,477]) and 5 cohort studies (total n=6,489). In CLARITY-TIMI 28 and one of the cohort studies (n=765; Trenk3), cardiovascular event rates did not differ significantly by genotype. In TRITON-TIMI 38 and 3 of the cohort studies (n= 3,516; Collet,4 Sibbing,5 Giusti6), patients with an impaired metabolizer status (intermediate and poor combined) had a higher rate of cardiovascular events (death, myocardial infarction, and stroke) or stent thrombosis compared to extensive metabolizers. In the fifth cohort study (n=2,208; Simon7), the increased event rate was observed only in poor metabolizers.
Pharmacogenetic testing can identify genotypes associated with variability in CYP2C19 activity.
There may be genetic variants of other CYP450 enzymes with effects on the ability to form clopidogrel’s active metabolite.
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1 Mega JL, Thakuria JV, Cannon CP, Sabatine MS. Sequence variations in CYP metabolism genes and cardiovascular outcomes following treatment with clopidogrel: insights from the CLARITY-TIMI 28 genomic study. 2008; ACC Meeting Abstract
2 Mega et al. Cytochrome P-450 polymorphisms and response to clopidogrel. N Engl J Med 2009; 360:354-62
3 Trenk et al. 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 2008; 51, 20: 1952
4 Collet JP et al. Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. The Lancet 2009; 373: 309-317
5 Sibbing D et al. Cytochrome P450 2C19 loss-of-function polymorphism and stent thrombosis following percutaneous coronary intervention. Eur Heart J 2009:1-7
6 Giusti et al. Relation of cytochrome P450 2C19 loss-of-function polymorphism to occurrence of drug-eluting coronary stent thrombosis. Am J Cardiol 2009; 103:806–811
7 Simon et al. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 2009; 360(4):363-75
So, the above is what the Plavix label reflects. No one can suggest that this properly put anyone much less physicians and AA patients on notice of this 25% increase risk.
Here is a very recent publication which restates what has been known know and should have been both recognized and acted upon re: AA’s from:
Expert Opin Drug Metab Toxicol. 2010 Feb 18. Relation of CYP2C19 loss-of-function polymorphism to the occurrence of stent thrombosis. Giusti B, Gori AM, Marcucci R, Abbate R. Researcher in Clinical Pathology, University of Florence and SOD Atherothrombotic Diseases, Department of Medical and Surgical Critical Care, AOU Careggi, Viale Morgagni 85, 50134 Florence, Italy +390557949420 ; +390557949418 ;
Importance of the field: Major adverse cardiovascular events including stent thrombosis associated with residual platelet reactivity on antiplatelet treatment in high risk vascular patients is a hot issue that needs a strong effort to be solved. Dual antiplatelet therapy with clopidogrel and aspirin prevents ischemic events and improves outcomes following acute coronary syndromes and percutaneous coronary intervention. However, adverse cardiovascular events occur in these patients, and several studies have shown that patients who suffer cardiovascular complications have high post-treatment platelet reactivity despite antiplatelet treatment. Clopidogrel requires conversion to active metabolite by CYP isoenzymes. Recently, CYP2C19*2 polymorphism (G681A nucleotide substitution) has been shown to be associated with decreased metabolisation of clopidogrel, poor antiaggregant effect and increased adverse cardiovascular events. Areas covered in this review: This review summarises the principal studies contributing to establish the relationship between CYP2C19*2 polymorphism and adverse outcomes in high risk patients on clopidogrel treatment. Take home message: Prospective studies are urgently needed to determine the clinical impact of a score that takes into account individual characteristics of patients – CYP2C19*2 genotypes, residual platelet reactivity, drug-drug interaction, as well as traditional and procedural risk factors – for the identification of the therapeutic strategy that provides the best benefit for the single subject.
The Plavix label was slow i.e. 8 years from Xie report to include any reference to the genetic predisposition of certain people having metabolization issues with clopidogrel the label should more adequately warn African American. More recently, this was reported in literature re: use in conjunction with Stents which raises this issue within that context, however, we believe that any African American who suffered a thrombotic even while on Plavix has a legal claim.
We stand poised to represent and litigate any such claims against the manufacturers of Plavix. For a free consultation, please call toll free 877-810-4808 or visit us at: www.awkolaw.com.
