CYP2C19 Genotype Prevalence and Association With Recurrent Myocardial Infarction in British–South Asians Treated With Clopidogrel

Background Cytochrome P450 family 2 subfamily C member 19 (CYP2C19) is a hepatic enzyme involved in the metabolism of clopidogrel from a prodrug to its active metabolite. Prior studies of genetic polymorphisms in CYP2C19 and their relationship with clinical efficacy have not included South Asian populations. Objectives The objective of this study was to assess prevalence of common CYP2C19 genotype polymorphisms in a British–South Asian population and correlate these with recurrent myocardial infarction risk in participants prescribed clopidogrel. Methods The Genes & Health cohort of British Bangladeshi and Pakistani ancestry participants were studied. CYP2C19 diplotypes were assessed using array data. Multivariable logistic regression was used to test for association between genetically inferred CYP2C19 metabolizer status and recurrent myocardial infarction, controlling for known cardiovascular disease risk factors, percutaneous coronary intervention, age, sex, and population stratification. Results Genes & Health cohort participants (N = 44,396) have a high prevalence (57%) of intermediate or poor CYP2C19 metabolizers, with at least 1 loss-of-function CYP2C19 allele. The prevalence of poor metabolizers carrying 2 CYP2C19 loss-of-function alleles is 13%, which is higher than that in previously studied European (2.4%) and Central/South Asian populations (8.2%). Sixty-nine percent of the cohort who were diagnosed with an acute myocardial infarction were prescribed clopidogrel. Poor metabolizers were significantly more likely to have a recurrent myocardial infarction (OR: 3.1; P = 0.019). Conclusions A pharmacogenomic-driven approach to clopidogrel prescribing has the potential to impact significantly on clinical management and outcomes in individuals of Bangladeshi and Pakistani ancestry.

P harmacogenomics (PGx) explores how genetic variants contribute to interindividual variation in medication response.
Cytochrome P450 family 2 subfamily C member 19 (CYP2C19) is a hepatic enzyme crucial to the 2-stage sequential oxidation of clopidogrel (inactive prodrug) to the active metabolite. 1 The CYP2C19 gene that codes for the enzyme is highly polymorphic.Three key single nucleotide polymorphisms (SNPs) are referred to as *2, *3, and *17. 2 The *2 (c.681G>A) and *3 (c.636G>A) SNPs both results in an early stop codon and, therefore, a truncated and nonfunctional protein (loss of function [LOF]). 3The *17 SNP (c.-806C>T) is a transition in the promoter region that increases enzyme expression and activity, thereby conferring gain of function leading to increase active metabolite. 3Pharmacokinetic studies have demonstrated lower active metabolite concentrations leading to decreased platelet response to clopidogrel in poor metabolizers (PMs) and intermediate metabolizers (IMs); the inverse is true of rapid and ultrarapid metabolizers, in a dose-dependent fashion. 4,5PMs and IMs have been linked with higher risk of secondary cardiovascular events on clopidogrel, while some studies have suggested rapid or ultrarapid metabolizers may have a higher risk of bleeding. 4,6Although there are known to be substantial trans ancestry differences in the prevalence of validated PGx SNPs *2, *3, and *17, many ethnic subgroups have not been investigated to date in resources with clinical outcome data.
Clopidogrel is an P2Y12-inhibiting antiplatelet medication licensed to treat acute coronary syndrome (ACS), stroke, and peripheral vascular disease. 7though the European Cardiology Society and national guidelines have advocated the use of non-CYP2C19-dependent P2Y12 antagonist (ticagrelor and prasugrel) over clopidogrel in ACS owing to clinical trials showing superior efficacy, clopidogrel remains widely used. 8,9This may be due to concerns about the higher bleed risk, lower tolerability, and increased cost of ticagrelor and prasugrel as compared with clopidogrel.Clopidogrel is also the only antiplatelet agent to have a Class I indication in patients with stable coronary artery disease undergoing stent implantation and is recommended in those with a contraindication to ticagrelor or prasugrel or those taking an oral anticoagulant. 9gulatory bodies and PGx consortia have given disparate guidance.The U.S. Food and Drug Administration recommends considering an alternate drug in PMs, while the European Medicines Agency merely discourages the co-use of CYP2C19 inhibiting drugs with clopidogrel. 7,10The Clinical Pharmacogenetics Implementation Consortium (CPIC) recommends an alternate therapy in IMs or PMs generally, but classifies PMs and those who have percutaneous coronary intervention (PCI) as populations at higher risk of treatment failure. 3The Dutch Pharmacogenetics Working Group recommends an alternate drug for PMs in those undergoing PCI and an alternate drug or increased dose of clopidogrel for IMs undergoing PCI. 11ere is currently no routine implementation of CYP2C19 testing in clinical care in the United Kingdom's (UK) National Health Service (NHS), but this is likely to change as the National Institute for Health and Care Excellence recommends testing in the context of ischemic stroke. 12uth Asian populations represents almost 25% of the world's population and 9% of the United Kingdom. 13,14The UK-South Asian ancestry population is disproportionately affected by cardiometabolic disease and multimorbidity and suffer from a shortened life expectancy as compared with regional averages. 15,16Some of this can be attributed to disproportionate rates of socioeconomic deprivation. 13In addition, this population has been underrepresented in both clinical trial cohorts and genetics study cohorts historically.The objectives of this study were to assess CYP2C19 genotypes in a British-South Asian ancestry cohort and to correlate inferred metabolizer phenotypes with recurrent myocardial infarction (MI) events in participants prescribed clopidogrel.September 2014.The methods of data collection for the G&H resource have been previously described. 13 summary, >44,000 volunteers were recruited, donated saliva for DNA extraction, and gave consent to link to their electronic health records.Participants were genotyped on the Illumina GSAMD-24v3-0-EA chip, and imputation was undertaken using the TOPMED-r2 data set. 17The Genome Research Consortium human build 38 was used.1.There was not substantial missingness.The population was not in HWE for the *2 and *17 alleles, likely due to previously reported relatedness (random mating is an assumption of HWE). 13However, the 3 SNPs used did not deviate from HWE in the subpopulation studied for clinical outcomes (those that had an MI and were treated with clopidogrel) (Supplemental Table 1).SNPs were extracted from the data set using PLINK 2.0. 18,19The *2 allele was defined as c.681G>A, rs4244285 (chr10:94781859).The *3 allele was defined as c.636G>A, rs4986893 (chr10:94780653).The *17 allele was defined as (c.-806C>T), rs12248560 (chr10:94761900).Subsequent analysis was done using Rstudio. 20y participant with 1 LOF SNP (either *2 or *3) was designated as an intermediate CYP2C19 metabolizer.Medication data were obtained by linkage with primary care data.We limited our analyses to participants who had medication data available from participating CCGs (84.4% of the initial cohort).Participants diagnosed with an acute MI who had been prescribed 75 mg clopidogrel in primary care were assessed for recurrent MI events.Smoking status was defined in primary care records by using SNOMED codes to distinguish never-smokers from those who had ever smoked (all codes are listed in Supplemental Table 2).Participants were classed as ever having smoked if they had a code in any of the smoking or ex-smoking categories and never having smoked if they did not have any codes associated with smoking or ex-smoking and had a code of never or currently not smoking.PCI with stent insertion was defined by ICD 10 code Z955, "presence of coronary angioplasty implant and graft" in Barts Health NHS Trust data.This was a cross-sectional analysis.Multivariable logistic regression was performed to look for association of CYP2C19 diplotypes with recurrent MI in those who had been prescribed clopidogrel by the GP in the

Magavern et al
CYP2C19 Genotype and Association With Recurrent MI in British-South Asians Treated With Clopidogrel secondary prevention dose (75 mg).Four levels were used for the CYP2C19 inferred metabolizer type variable: PM, IM, and ultrarapid metabolizers, with normal and rapid metabolizers as the reference group.Sex, age at enrollment, and known cardiovascular disease comorbidities (diabetes mellitus, hypertension, dyslipidemia, obesity, chronic kidney disease, having ever smoked) were included as covariates.As the published literature suggests higher risk of in-stent thrombosis in PMs or IMs on clopidogrel, and a lower percentage of those who had stents were prescribed clopidogrel, PCI with stent insertion was also included as a covariate. 24There were 14 participants in the acute MI group, which included 1 participant in the recurrent MI group, for whom no PCI data were available.These participants were removed for logistic regression incorporating PCI data.The participant in the recurrent MI group who was excluded from this analysis due to the missing data was a normal CYP2C19 metabolizer.
The 39 participants with recurrent MIs who had been prescribed clopidogrel were unrelated as assessed by the G&H curated KING analysis. 25Multicollinearity was assessed using the variance inflation factor of the car package in Rstudio. 26nsitivity analysis was undertaken using the principal component analysis inferred ethnicity curated by G&H.20 G&H curated principal components were included as covariates in a second logistic regression to control for population stratification.The G&H team have prior published data underpinning these variables, which they have made available to all researchers. 17 A further analysis was undertaken in which CYP2C19 LOF diplotypes were parametrized to a continuous variable where the unit was LOF alleles, 0 for none, 1 for one (IM), 2 for two (PM).Multivariable logistic regression analysis was then performed as above, controlled for age, sex, cardiovascular disease risk factors (smoking, diabetes mellitus, hypertension, obesity, dyslipidemia, chronic kidney disease), percutaneous coronary intervention, and 20 principal components.The 11 ultrarapid metabolizers were excluded from this analysis as outliers.This was undertaken to elucidate the impact of LOF alleles more clearly in absence of the ultrarapid diplotype which is an outlier in the trend of interaction between metabolizer type and clinical outcome.percent of participants were PMs, with 2 LOF alleles, while 44% were IMs, with 1 LOF allele (Figure 1).Furthermore, 2.7% of participants were ultrarapid metabolizers, homozygous for the *17 allele.Figure 1 illustrates that normal CYP2C19 metabolizers then represent only 25% of this population.This is a concern because it diverges from representation of SNP prevalence in largely European ancestry landmark clinical trials on PGx.[29][30][31] P r e v a l e n c e o f c l o p i d o g r e l p r e s c r i p t i o n s i n t h e a c u t e M I c o h o r t .Medication data were available for those participants with linked primary care records (participating CCGs), which represented 84.4% of the acute MI cohort.We only included participants with prescribing data in our analysis.As antiplatelet choice post-MI is led by tertiary centers there is not expected to be any bias based on CCG linkage.The percentage of those who had an acute MI who were prescribed clopidogrel was 69.3% (Figure 2).For the subgroup who had a stent inserted, it was lower at 44.2%.Of those 697 participants who had an acute MI and were prescribed clopidogrel by their GP, 39 of them had recurrent MIs (5.6%) (Figure 2).Characteristics of the cohort with acute MI are noted in Table 2.Those with recurrent MIs were older and more likely to have PCI.metabolizers (OR: 10, 95% CI: 1.9-47, P ¼ 0.003), and recurrent MI.IM status was not significantly associated with recurrent MI (P ¼ 0.36) (Table 3).Reclassification of *2/*17 or *3/*17 from intermediate to normal metabolizers for sensitivity analysis did not change results.Apart from CYP2C19 diplotype, increased age at recruitment was the only other factor found to be significantly associated with a recurrent MI event in the cohort prescribed clopidogrel (Table 3).Diagnosis of obesity, hypertension, dyslipidemia, diabetes mellitus, chronic kidney disease, or ever-smoking status were not significantly independently associated with recurrent MI risk in the cohort prescribed clopidogrel (though prevalence of all known risk factors was high).Multicollinearity was not found to be present.Sensitivity analyses to correct for the genetically determined subancestry group (British-Bangladeshi and British-Pakistani) did not alter the findings.Twenty principal components curated by G&H were controlled for to ensure our results were not biased by population stratification (Table 3).Table 4 shows the number of patients in the acute MI and recurrent MI cohort stratified by metabolizer status.There is a decrease in risk of recurrent MI on a gradient from PM to rapid metabolizer.There was an unexpected rise in risk in the ultrarapid metabolizer group, but there were only 11 participants in this group, as compared with 90-301 participants in the other metabolizer groups.
As the primary interest for clinical implementation is CYP2C19 LOF variants contributing to clopidogrel resistance, the 11 ultrarapid metabolizers were excluded and LOF diplotypes changed to a continuous variable where the unit was LOF allele (0, 1, or 2).This was undertaken to elucidate the impact of LOF alleles more clearly in absence of the ultrarapid diplotype which is an outlier in the trend of interaction between metabolizer type and clinical outcome (Table 4).The results show an OR of 1.95 (95% CI: 1.16-3.29 [P ¼ 0.011]) per LOF allele (Table 5).

DISCUSSION
People of diverse ancestry have different population prevalence of PGx SNPs, leading to different response to the same therapeutic agent between populations.A prospective PGx approach to prescribing, in which genotype is checked prior to medication prescription, is not standard of care at present.The case for implementation therefore must be proved as an improvement on current standards.Thus, the assumption is that we are at equipoise at baseline without implementation of PGx.a Not specified.

FIGURE 2 Linking Medication Data With Clinical Outcomes
Primary care prescribing data was available for 84.4% of G&H participants diagnosed with an acute myocardial infarction (MI).69% of these participants were prescribed clopidogrel.One potential explanation for the continued prevalence of clopidogrel use is cost.In the United Kingdom, for example, the cost of 1 month of ticagrelor is 54.60 GBP as compared with clopidogrel, 1.24 GBP. 41,42Prasugrel is now off patent and therefore cheaper than ticagrelor, yet still more expensive than clopidogrel (cheapest available 10.14 GBP per month). 43In the United Kingdom, these cost differences are born by the NHS.In the global context, patients may have significant economic constraints relevant to decision-making if they are self-paying.
These factors underscore the relevance of continued attention to clopidogrel PGx.P < 0.001). 46The difference in risk of recurrent MI alone was significant but of a magnitude just over 1% (5.8% vs 6.9%, P ¼ 0.005). 46A large Canadian cohort study found no difference in the efficacy of clopidogrel vs ticagrelor for secondary prevention but did not look at ethnic composition of the cohort. 40 Cause specific mortality data may also have refined our model, as a composite endpoint of recurrent MI or cardiovascular death could be considered, but these data were not available.
Furthermore, we did not consider coprescriptions that may cause drug-drug interactions or phenoconversion (ie, CYP2C19 inhibiting medication taken by a normal metabolizer which may convert them to an IM).This was due to our lack of timeline data and relatively small cohort.Comorbidities may also cause phenoconversion, for example diabetes is known to be associated with decreased CYP2C19 function. 48 did not have data to assess adverse events which may lead to clopidogrel discontinuation, for example significant gastrointestinal or intracranial bleed.However, the lack of the above data would be expected to mask any existing association between genotype and outcomes, meaning that our analysis would underrepresent rather than overrepresent a signal.

CONCLUSIONS
This study shows high rates of genetically determined THE GENES & HEALTH COHORT.The Genes & Health (G&H) resource was accessed after approval by the G&H Access Review Committee.G&H is a UK cohort study, including those of Bangladeshi and Pakistani ancestry. 13G&H operates under ethical approval, 14/LO/1240, from London South East NRES Committee of the Health Research Authority, dated 16 A B B R E V I A T I O N S A N D A C R O N Y M S ACS = acute coronary syndrome CPIC = Clinical Pharmacogenetics Implementation Consortium G&H = Genes & Health IM = intermediate metabolizer LOF = loss-of-function MI = myocardial infarction PCI = percutaneous coronary intervention PGx = pharmacogenomics PM = poor metabolizers SNP = single nucleotide polymorphism The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors' institutions and Food and Drug Administration guidelines, including patient consent where appropriate.For more information, visit the Author Center.Manuscript received March 3, 2023; revised manuscript received July 4, 2023, accepted July 17, 2023.

Any participant with 2 LOF
SNPs was characterized as a PM.Any participant with 1 *17 allele (in absence of a *2 or *3 allele) was designated a rapid metabolizer, and those with 2 *17 alleles were designated as ultrarapid metabolizers.The prevalence of these genotypes, diplotypes, and corresponding phenotypes were then compared with published population prevalence data provided by CPIC and with those represented in major recent randomized control trials (RCTs) evaluating PGx implementation.LINKING CYP2C19 PREDICTED PHENOTYPES WITH RECURRENT MYOCARDIAL INFARCTION IN PARTICIPANTS WHO HAD AN ACUTE MI AND WERE PRESCRIBED CLOPIDOGREL.Curated data sets from G&H were used for clinical phenotypes including acute MI (International Classification of Diseases [ICD]-10 code I21), subsequent MI (ICD-10 I22), Diabetes (DM) (E10; type 1 diabetes mellitus, E11; type 2 diabetes mellitus, E13; other specified diabetes mellitus, E14; unspecified diabetes mellitus), dyslipidemia (ICD-10 code E78), obesity (ICD-10 code E66), chronic kidney disease (ICD-10 code N18), and hypertension (ICD-10 code I10).These phenotypes were defined using ICD-10 codes, SNOMED codes, and Office of Population Censuses and Surveys codes from linkage with electronic health records, including Barts Health, NHS digital, Bradford teaching hospitals, and primary care clinical commissioning groups (CCGs).Participating CCGs included Barking, Havering and Redbridge, Tower Hamlets, Waltham Forest, and Newham.The methodology used to generate these curated phenotypes is based on UK Biobank methodology and described in prior publications; the code is available on the G&H website. 21-23ICD-10 codes were identified in Barts Health NHS trust secondary care data, Bradford Teaching Hospitals NHS Trust, and NHS Digital hospital episode and mortality statistics.Primary care and secondary care SNOMED codes were then mapped to the ICD-10 code lists to capture the first recording of the code (1:1 mapping).
STATISTICAL METHODS.Fisher's Exact Test was used to compare baseline characteristics of participants who had a recurrent MI with those who did not, in the index acute MI population.T-test was used to compare means of continuous variables.
RESULTSCHARACTERIZATION OF CYP2C19 GENOTYPES IN G&H COHORT.The *2 SNP was very common in the G&H cohort (N ¼ 44,396), with 56% of the population having at least 1 copy present.The *3 allele was less common, with 1.2% having at least 1 copy.In addition, 27.6% of the cohort had at least 1 copy of the *17 increased function allele.C Y P 2 C 1 9 d i p l o t y p e s a n d i n f e r r e d m e t a b o l i z e r p h e n o t y p e s .PMs or IMs, carrying at least 1 LOF allele (*2 or *3), comprised 57% of the cohort.Thirteen L i n k i n g C Y P 2 C 1 9 p h e n o t y p e s w i t h c l i n i c a l o u t c o m e s : r e c u r r e n t M I i n c o h o r t p r e s c r i b e d c l o p i d o g r e l .Multivariable logistic regression controlling for age, sex, cardiovascular comorbidities, smoking, and stent insertion showed a significant relationship between poor CYP2C19 metabolizers (OR: 3.1, 95% CI: 1.2-8.1,P ¼ 0.019) and ultrarapid CYP2C19

CYP2C19
Genotype and Association With Recurrent MI in British-South Asians Treated With Clopidogrel assumption as burden of prescribing without prospective genotype is not equally bourn by diverse ethnic groups.One of the underlying causes is that medications have historically been trialed in Caucasian ethnicity populations.The regulatory approval outcome studies of clopidogrel in ACS did not include representative participation from communities at higher risk of inefficacy based on genetic data7,[32][33][34][35][36][37][38]

CYP2C19
Genotype and Association With Recurrent MI in British-South Asians Treated With Clopidogrel (Central Illustration).It combines this with new data showing higher than expected PM and IM prevalence in this British-South Asian cohort.Considering these results, caution should be used in extrapolating results from trials of European populations to diverse global populations, as conclusions may not be valid.Our results highlight risks inherent in prescribing medications to populations that vary widely from those including in studies used for licensure and postmarketing surveillance.When comparing safety and efficacy of clopidogrel to non-CYP2C19-dependent antiplatelet agents the ethnic composition of the cohort is likely to have an impact.Indeed, differences in data comparing efficacy of clopidogrel to ticagrelor may well be due to differences in ethnic representation.The PLATO trial, which included 6% Asian participants in the clopidogrel arm found a lower risk of the primary MACE endpoint in the ticagrelor group (in 9.8% of patients vs 11.7% at 12 months; HR: 0.84; 95% CI: 0.77-0.92;

3 CYP2C19
CENTRAL ILLUSTRATION The G&H South-Asian Ancestry Population Has a High Prevalence of CYP2C19 LOF Alleles, Leading to Poor Activation of Clopidogrel and Linked With a Gradient of Increased Risk of Recurrent Myocardial Infarction With Increased LOF Burden Magavern EF, et al.JACC Adv.2023;2(7):100573.Due to the small number of ultra-rapid metabolizers present in the acute MI cohort, they were excluded from the graph showing recurrent MI risk.GOF ¼ gain of function; IM ¼ intermediate metabolizer; LOF ¼ loss of function; MI ¼ myocardial infarction; NM ¼ normal metabolizer; PM ¼ poor metabolizer; RM ¼ rapid metabolizer; UM ¼ ultra-rapid metabolizer.Magavern et al J A C C : A D V A N C E S , V O L . 2 , N O .7 , 2 0 2 Genotype and Association With Recurrent MI in British-South Asians Treated With Clopidogrel S E P T E M B E R 2 0 2 3 : 1 0 0 5 7 3

CYP2C19
impaired clopidogrel activation in a large South Asian ancestry population with high risk of cardiovascular disease.Poor CYP2C19 activation of clopidogrel was correlated with an increased risk of recurrent MI.This "real-world" data show that clopidogrel is frequently prescribed and this appears to be particularly detrimental in individuals of South Asian ancestry due to the high proportion of PMs.Therefore, a pharmacogenomic-driven approach to antiplatelet prescribing has the potential to improve clinical management of MI and outcomes in individuals of Bangladeshi and Pakistani ancestry.High-quality health economic studies have shown that this approach is affordable.In absence of a PGx approach, prescribing non-CYP2C19-dependent antiplatelet agents is likely to have a disproportionate benefit in this British-Bangladeshi and British-Pakistani population.This study illustrates how socioeconomic deprivation, ethnic differences in pharmacogenes, and poor representation in research studies can intersect to compound ill health in an already disadvantaged subpopulation.Further analysis of such effects in clinical medicine are needed.ACKNOWLEDGMENTS The authors thank Social Action for Health, Centre of The Cell, members of our Community Advisory Group, and staff who have recruited and collected data from volunteers.They thank the NIHR National Biosample Centre (UK Biocentre), the Social Genetic & Developmental Psychiatry Centre (King's College London), Wellcome Sanger Institute, and Broad Institute for sample processing, genotyping, sequencing and variant annotation.They thank Barts Health NHS Trust, NHS Clinical Commissioning Groups (City and Hackney, Waltham Forest, Tower Hamlets, Newham, Redbridge, Havering, Barking and Dagenham), East London NHS Foundation Trust, Bradford Teaching Hospitals NHS Foundation Trust, Public Health England (especially David Wyllie), Discovery Data Service/Endeavour Health Charitable Trust (especially David Stables), NHS Digital -for GDPR-compliant data sharing backed by individual written informed consent.Most of all the authors J A C C : A D V A N C E S , V O L . 2 , N O .7 Genotype and Association With Recurrent MI in British-South Asians Treated With Clopidogrel thank all of the volunteers participating in Genes & Health.

TABLE 1
[27][28][29][30][31]eographic and Trial Cohorts[27][28][29][30][31] 30,31The Clinical Pharmacogenetics International Consortium (CPIC) considers a large number of *alleles, while we only considered only the 3 mostvalidated variants for clinical impact (*2 and *3 together account for 99% of all LOF in Asian populations).Each row value is rounded to the nearest whole number.The bold values are the sum of all participants with a *2 or *3 LOF allele.G&H cohort N ¼ 44,396.CPIC CYP2C19 allele frequency estimates are based on Systematic Review of PubMed Indexed Publications; N ¼ 7,100 for Central/South Asian and N ¼ 71,782 for European.

TABLE 2
Comparison of Cardiovascular Risk Factors and Outcomes in the Genes & Health Cohort Who Had Acute MI and Were Prescribed Clopidogrel aValues are % (n) or mean AE SD. a P < 0.05.MI ¼ myocardial infarction.

TABLE 3
Recurrent MI in Cohort Prescribed Clopidogrel a Multivariable logistic regression analysis was used and controlled for age, sex, cardiovascular disease risk factors (smoking, diabetes mellitus, hypertension, obesity, dyslipidemia, chronic kidney disease) and percutaneous coronary intervention.The bottom values in each row are the principal component adjusted analysis results.a P < 0.05.confirm or disprove this hypothesis with the data available.The risk of clopidogrel intolerance and discontinuation in *17/*17 ultrarapid metabolizers has not been adequately assessed in clinical studies; future RCTs should genotype for *17 and assess for discontinuation rates and compliance in this subgroup as well as bleed-related adverse events.The number of patients who were ultrarapid metabolizers

TABLE 4
Ischemic Events in those Prescribed Clopidogrel Stratified by CYP2C19Values are n or %. 90 participants were poor metabolizers (2 LOF alleles), 301 participants were intermediate metabolizers (1 LOF allele), 199 participants were normal metabolizers (no LOF or GOF alleles), and 96 participants were rapid metabolizers (1 GOF allele).There were very few participants in the ultrarapid metabolizer group (2 GOF alleles), N ¼ 11.The percentage of participants in each metabolizer group to experience a recurrent MI is shown in bold.

TABLE 5
Risk of Recurrent MI in Cohort Prescribed ClopidogrelMultivariable logistic regression analysis was used and controlled for age, sex, cardiovascular disease risk factors (smoking, diabetes mellitus, hypertension, obesity, dyslipidemia, chronic kidney disease) and percutaneous coronary intervention, as well as 20 principal components.CYP2C19 LOF diplotypes were parametrized to a continuous variable where the unit was LOF alleles, 0 for none, 1 for one (intermediate metabolizer), 2 for two (poor metabolizer).Ultrarapid metabolizers were excluded.