International Journal of Neuroscience, 2013; 123(3): 143–154Copyright © 2013 Informa Healthcare USA, Inc.ISSN: 0020-7454 print / 1543-5245 onlineDOI: 10.3109/00207454.2012.744308

Genetic Polymorphisms and Drug Interactions Leading toClopidogrel Resistance: Why the Asian PopulationRequires Special Attention

Md. Shariful Hasan,1 Hamidon Bin Basri,2 Lim Poh Hin,2 and Johnson Stanslas3

1Neurology Unit, Department of Medicine and Institute of Gerontology, Faculty of Medicine and Health Sciences, UniversityPutra Malaysia, Serdang, Selangor Darul Ehsan, Malaysia2Neurology Unit, Department of Medicine, Faculty of Medicine and Health Sciences, University Putra Malaysia, Serdang,Selangor Darul Ehsan, Malaysia3Pharmacotherapeutics Unit, Department of Medicine, Faculty of Medicine and Health Sciences, University PutraMalaysia, Serdang, Selangor Darul Ehsan, Malaysia

ABSTRACT

Ischemic heart disease and stroke are the two leading causes of death worldwide. Antiplatelet therapy playsthe most significant role in the management of these cardiovascular and cerebrovascular occlusive events toprevent recurrent ischemic attack. Clopidogrel, an antiplatelet drug, is widely prescribed either alone or in com-bination with aspirin as dual antiplatelet therapy for the prevention of vascular occlusive events. The antiplateletresponse to clopidogrel varies widely. Hyporesponders and nonresponders are likely to have adverse cardio-vascular events during follow-up. Some drugs, such as proton pump inhibitors (omeprazole), calcium channelblockers, selective serotonin reuptake inhibitors (nefazadone), coumarin derivatives (phenprocoumon), benzo-diazepines, sulfonylurea, erythromycin, and itraconazole, decrease the antiplatelet effect of clopidogrel whenadministered concomitantly. Decreased response to clopidogrel is common among Asians due to genetic poly-morphisms associated with clopidogrel resistance, and it is nearly 70% in some of the Asian communities. Itis necessary to study Asian populations, because there are a large number of Asians throughout the world dueto increased migration. Current guidelines do not make genetic testing or platelet response testing mandatoryprior to clopidogrel prescription. Therefore, it is important for clinicians treating Asian patients to keep in mindthe interindividual variability in response to clopidogrel when prescribing the drug.

KEYWORDS: Asian, clopidogrel resistance, interindividual variability, pharmacogenomics

INTRODUCTION

Cardiovascular and cerebrovascular occlusive events,such as MI and ischemic stroke, are the two leadingcauses of death worldwide. Secondary prevention playsthe most significant role in the management of ischemicheart disease and stroke. As antiplatelet drugs inhibitintravascular thrombosis, they are commonly used toprevent vascular occlusive events. A study on peopleat high risk for vascular events showed that antiplatelet

Received 28 May 2012.

Address correspondence to Md. Shariful Hasan, Neurology Unit, Departmentof Medicine, Faculty of Medicine and Health Sciences, University PutraMalaysia, 43400 UPM Serdang, Selangor Darul Ehsan, Malaysia. E-mail:shariful hsn@yahoo.com or shariful@medic.upm.edu.my

drugs can prevent serious cardiovascular illness by20% and vascular death by 15% [1]. Clopidogrel is anantiplatelet drug and is used along with aspirin as thegold standard therapy for managing patients with CAD.It is used for the secondary prevention of MI, ischemicstroke, and thrombosis prevention after percutaneouscoronary interventions (PCIs). Clopidogrel-inducedplatelet inhibition is at times insufficient. Patientsoften have heterogeneous antiplatelet responses to thedrug [2]. This suggests the possibility of interindivid-ual variability of clopidogrel responses, such as lowresponsiveness (hyporesponsiveness) and resistance(nonresponsiveness). Although these terms are usedinterchangeably in the literature and cause confusion,they are not synonymous [3]. According to the recentconsensus by Bonello et al. [3], low responsiveness

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can be defined as <30% absolute platelet inhibitionduring treatment compared with baseline, whereasclopidogrel resistance is <10% absolute change fromthe baseline (assessed by light transmittance aggregom-etry). High on-treatment platelet reactivity (HTPR)literally means high posttreatment residual plateletactivity and reflects the pharmacodynamic action ofclopidogrel on platelets. As ADP-stimulated plateletaggregation varies from person to person, and no singlereceptor mechanism is responsible for platelet aggre-gation, the response to clopidogrel is best determinedby the presence of posttreatment P2Y12 activity [3,4].The causes of HTPR are the same as the causes oflow clopidogrel response and resistance [5]. To date,the most acceptable and widely used cutoff values forHTPR are as follows: (1) Platelet Reactivity Index(PRI) ≥ 50% by vasodilator-stimulated phosphoproteinphosphorylation (VASP-P); (2) >235–240 P2Y12

Reaction Unit (PRU) by VerifyNow assay; (3) >46%maximal 5-μmol/L ADP-induced aggregation; and (4)>468 arbitrary aggregation units per minute in responseto ADP by multiplate analyzer [3,6–9]. The pharma-cological effect of clopidogrel is multifactorial anddepends on age, gender, genetics, dosing, interactionswith foods and drugs, comorbidities (obesity, diabetes),and patient compliance, etc. [2,10,11]. The details ofall these factors are beyond the scope of this review. Themain focus of this review is to discuss the establishedgenetic polymorphisms responsible for producinginsufficient active clopidogrel metabolites, leading toinadequate clopidogrel responses, and certain drug in-teractions mimicking similar responses. In comparisonwith Western populations, Asian populations have beenless studied for variable clopidogrel responses. There-fore, it is highly necessary to study Asian populations,because there are a large number of Asians throughoutthe world due to increased migration. This prompted usto highlight the clinical importance of clopidogrel resis-tance in Asian populations in this review. However, it isimperative to have a clearer concept on the mechanismof action of clopidogrel to understand the variabilityin clopidogrel response. It is also equally important torealize the clinical significance of it. Hence, prior todiscussing the clopidogrel responses in Asian popula-tions, we will briefly discuss the mechanism of actionof clopidogrel, the mechanism of variable clopidogrelresponse, and their clinical significance.

MECHANISM OF ACTION OFCLOPIDOGREL

Clopidogrel is a second-generation thienopyridine pro-drug. The major portion (85%) of the absorbed clopi-dogrel from the intestine is hydrolyzed by esterases and

converted into an inactive carboxylic acid derivative(Figure 1). The rest (15%) undergoes metabolism byhepatic cytochrome P450 (CYP450) and is convertedinto an intermediate metabolite, 2-oxo-clopidogrel.This intermediate metabolite undergoes further oxida-tion by several isoenzymes, resulting in the formation ofan inactive carboxyl group and a highly unstable activethiol derivative. Up to date, four isomers (H1–H4) ofthe clopidogrel active metabolite have been identified.However, only the H4 isomer has been proven to pos-sess clinically relevant properties of the active clopido-grel metabolite [12].

The active thiol group binds to the ADP receptorP2Y12, present on the platelet cell membrane, via adisulphide bridge to two cysteine residues (cys17 andcys270) in the extracellular domains of the P2Y12 re-ceptor. Thus, it irreversibly inhibits the binding of ADPto P2Y12 for the lifespan of the platelet. The drug alsodecreases platelet–leukocyte aggregate formation andthe expression of the platelet-dependent inflammatorymarkers C-reactive protein, CD62P (P-selectin) andCD40 ligand. It also decreases the rate of thrombinformation [2,4,13].

MECHANISM OF VARIABLE RESPONSETO CLOPIDOGREL

Although the observed interindividual variability in clin-ical response can be due to several reasons, the primarycause is insufficient active metabolite generation dueto genetic polymorphisms associated with reduced in-testinal absorption and enzymatic activation of clopido-grel (pharmacokinetics). Besides single-nucleotide poly-morphisms of the genes coding for hepatic enzymes(CYP450) responsible for metabolic activation of clopi-dogrel, drug–drug interactions also affect the activa-tion process [3]. However, postactivation clopidogrel re-sponses also depend on ADP-P2Y12 receptor interac-tions (pharmacodynamics).

Role of ABCB1 Gene Involvement

Genetic polymorphisms of the ABCB1 gene are knownto restrain the intestinal absorption of clopidogrel.Taubert et al. [14] found that among patients who re-ceived a clopidogrel loading dose prior to elective PCI,the bioavailability of clopidogrel was significantly lessin patients who carried either one copy (CT genotype)or two copies (TT genotype) of the ABCB1 C3435Tsingle-nucleotide polymorphism compared with non-carriers (CC genotype).

In a larger study, researchers assessed the relation-ship between known gene polymorphisms and death orischemic events during a 1-year follow-up period amongFAST-MI (French Registry of Acute ST-Elevation and

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Clopidogrel Resistance in Asian Population 145

FIGURE 1. Mechanism of action of clopidogrel (reproduced with permission from Yinand Miyata) [32].

Non-ST-Elevation MI) patients who were receivingclopidogrel after acute MI (AMI) [15]. At 1 year, thosewith the TT genotype had a higher event rate than thosewith the CC genotype [15.5% vs. 10.7%; adjusted haz-ard ratio, 1.72; 95% confidence interval (CI), 1.20 to2.47]. The highest risk of events was found among pa-tients who had two CYP2C19 loss-of-function allelesand either one or two ABCB1 alleles.

In the PLATO (Platelet Inhibition and Patient Out-comes) trial, researchers found a significantly increasedrate of cardiovascular occlusive events in the patientswith the high-expression ABCB1 polymorphism [16].However, Harmsze et al. [17] did not find any signifi-cant relationship between ABCB1 gene polymorphismsand the risk of stent thrombosis in a patient cohort withstent thrombosis during dual antiplatelet therapy afterPCI and stent implantation.

Effect of CYP2C19 Polymorphism onClopidogrel Metabolism

Clopidogrel is converted into an intermediate metabo-lite in the presence of three hepatic isoenzymes

(CYP1A2, CYP2B6, and CYP2C19) before being con-verted into the active form [13]. In March 2010, theUS Food and Drug Association (FDA) released aboxed warning to warn healthcare professionals thatpatients with the CYP2C19 gene polymorphism haveimpaired ability to convert the drug into its activeform—in them, the effectiveness of clopidogrel may bereduced [18,19].

The genes depicting the cytochrome P450 en-zymes have different alleles. The normal copy with fullCYP2C19 enzymatic activity is the ∗1 (star 1) allele.Carriers of CYP2C19 loss-of-function alleles (∗2 -∗8)are often poor metabolizers [20,21]. The presence ofthe active metabolite of clopidogrel is dependent on thenumber of the reduced functional alleles.

Mega et al. [22] tested the association of CYP genevariants with the plasma concentration of active clopi-dogrel metabolites and clopidogrel-induced plateletinhibition in healthy subjects. They found that 30%of the study population had at least one CYP2C19reduced-function allele and a significantly lower plasmalevel of the active clopidogrel metabolite in this groupcompared with noncarriers. Mega et al. [22] also

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studied the association of this finding with cardio-vascular outcomes in a separate cohort study named“TRITON–TIMI 38” (Trial to Assess Improvement inTherapeutic Outcomes by Optimizing Platelet Inhibi-tion with Prasugrel–Thrombolysis in MI 38). This clin-ical trial revealed that carriers of at least one CYP2C19reduced-function allele had reduced formation of theactive metabolite of clopidogrel as well as reducedclopidogrel-induced platelet inhibition, and it was asso-ciated with adverse cardiovascular outcomes, includingstent thrombosis. A meta-analysis by the same authorhas confirmed this finding [23].

In a randomized control study, 95% of the pa-tients who carried an allele with reduced CYP2C19function had a CYP2C19∗2 allele [22]. Although theCYP2C19∗2 and the CYP2C19∗3 alleles account formost of the nonfunctional alleles, their frequency alsovaries according to ethnicity [19,24–26]. Holmes et al.[25] found that at least one copy of the CYP2C19∗2allele was present in approximately 50% of Chinese,34% of African Americans, 25% of Whites, and 19%of Mexican Americans. The chance of carrying at leastone loss-of-function allele is higher among the Asianpopulation [27].

Interestingly, a recently published systemic reviewand meta-analysis of Bauer et al. [28] and Holmeset al. [29] did not show any significant association be-tween CYP2C19 genotype and cardiovascular events.However, Mega et al. [30] have challenged the reviewof Holmes et al. and highlighted several flaws in themethodology, such as the inclusion of patients withcomparatively less or no benefit from clopidogrel.Moreover, the findings in these two reviews are alsoinconsistent with a previously published meta-analysis[23] and pharmacokinetic, pharmacodynamics, andpharmacogenomics studies [26,30,31]. As the presenceof the CYP2C19 polymorphism is higher in Asian pop-ulations and Asian populations have been less studied,we believe the findings of the insignificant associationbetween the CYP2C19 polymorphism and adversecardiovascular outcomes need to be further evaluatedin a separate meta-analysis in Asian populations only.In support of this, we are currently conducting a studyon clopidogrel resistance in the Malaysian population,composed of Malays, Chinese, and Indians.

Other CYP450 Isoenzymes

Besides CYP2C19, there are other isoenzymes involvedin converting clopidogrel into its active metabolite [13].These are CYP1A2, CYP3A4, CYP3A5, CYP2B6,CYP2C9, and PON1 [32].

A study on acute coronary syndrome (ACS) patientstreated with clopidogrel did not show any association be-tween the carriers of the reduced-function allele of the

three CYP genes (CYP2C9, CYP3A5, and CYP1A2)and the reduction of the pharmacological response toclopidogrel [22]. However, in the same study, carri-ers of the reduced-function CYP2B6 allele had 15.7%lower plasma exposure to the active clopidogrel metabo-lite and had less reduction of platelet aggregation com-pared with noncarriers. In the same study, researchersdid not find any polymorphism of CYP3A4. However,another study assessing clopidogrel response in patientsundergoing coronary artery stent implantation as wellas in healthy volunteers found a correlation betweenCYP3A4 metabolic activity and the interindividual vari-ability in response to clopidogrel. Healthy volunteerswho were coadministered clopidogrel and rifampicin (aCYP3A4 inducer) showed better platelet inhibition thanthose who were administered clopidogrel alone [33].

In separate studies, Brandt et al. [34] and Harm-sze et al. [35] demonstrated that a polymorphism ofCYP2C9 was associated with low exposure to the activeclopidogrel metabolite and higher platelet reactivity.

Paraoxonase-1 (PON1) also takes part in the processof clopidogrel activation. Q192R, the common func-tional variant of PON1, has recently been reported byBouman et al. [36] as a major determinant of clopido-grel response, but this statement has been opposed byLewis et al., which is also consistent with the studies byTrenk et al. and Sibbing et al. [37–39]. This is furthersupported by a recent study conducted by Gong et al.[40]. According to this study, PON1 does not generatethe H4 isomer of the thiol metabolite. That is why poly-morphisms of PON1 are unlikely to affect the pharma-cological action of clopidogrel.

Polymorphisms of the Gene Encoding P2Y12Receptor

Researchers have assessed the genetic variations in thegene encoding the P2Y12 receptor, the site on theplatelet where the clopidogrel metabolite binds. Staritzet al. [41] demonstrated that the H2 haplotype of theP2Y12-ADP receptor gene was associated with platelethyperreactivity and clopidogrel resistance. However,in several studies, there was no significant associationfound between clopidogrel responsiveness and poly-morphisms of the gene encoding the P2Y12 receptor[15,42,43].

Drug Interactions

Several other drugs are also metabolized by the CYP450metabolic pathway. Drug interactions that inhibit orinduce enzymes involved in clopidogrel metabolism canalso result in interindividual differences in clopidogrelresponse.

The cytochrome P450 (CYP) 3A system consistsof the CYP3A4 and CYP3A5 isoenzymes. The net

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metabolism of a drug, which is equally metabolized byboth CYP3A4 and CYP3A5, depends on the sum ofCYP3A4 and CYP3A5 activity [44]. A Korean studyinvestigated the influence of CYP3A5 polymorphismson the drug interaction of clopidogrel [44]. The studywas conducted in two phases. In phase 1, clopidogrelwas administered in healthy volunteers who were pre-treated with itraconazole (a potent CYP3A4 inhibitor).The result showed higher inhibition of platelet aggre-gation (IPA) in the CYP3A5 expressor genotype groupthan the nonexpressor genotype group. In phase 2,patients who had received post-PCI clopidogrel treat-ment were followed up. Within 6 months of the follow-up, atherothrombotic events occurred more frequentlyamong the patients with the nonexpressor genotype thanamong those with the expressor genotype.

A landmark publication revealed that when clopido-grel was coadministered with atorvastatin, its effect oninhibiting platelet aggregation was reduced [45]. The re-searchers concluded that by inhibiting CYP3A4 activity,atorvastatin decreased the conversion of clopidogrel toits active form. Other statins, such as pravastatin, thatare not metabolized by the CYP3A4 pathway are notexpected to alter clopidogrel metabolism. Some studies,however, do not support the claim that combined ther-apy of atorvastatin and clopidogrel reduces the efficacyof clopidogrel [46].

Calcium channel blockers also inhibit CYP3A4activity. Several studies demonstrated that calciumchannel blockers, when coadministered with clopido-grel, decreased the platelet inhibition by clopidogrel byinhibiting CYP3A4 activity [47– 49].

Several other CYP3A4 inhibitors, such as macrolides(erythromycin) and selective serotonin reuptake in-hibitors (nefazadone), also decrease the antiplateletactivity of clopidogrel [49].

Concomitant use of clopidogrel with other drugs thatare also metabolized by CYP3A4, such as coumarinderivatives (phenprocoumon) and benzodiazepines (al-prazolam) also decreases the antiplatelet effect of clopi-dogrel [49–51].

Antidiabetic drugs, such as sulfonylureas, are metab-olized by CYP2C9. They reduce the antiplatelet activityof clopidogrel when coadministered with clopidogrel[10].

Omeprazole, a proton pump inhibitor, is usuallyadded to dual antiplatelet therapy to lower the risk of up-per gastrointestinal complications, such as gastric ero-sion [52]. Omeprazole inhibits the CYP2C19 enzymeand decreases the platelet inhibition by clopidogrel iftaken concomitantly [49,53]. However, this effect isproven for omeprazole but not for pantoprazole, lanso-prazole, or esomeprazole [54,55]. Considering the ex-tensive use of clopidogrel and omeprazole, this drug in-teraction has immense importance. Both the US FDA

and the European Medicines Agency discourage theconcomitant use of omeprazole and clopidogrel [56].

CLINICAL IMPLICATION OF VARIABLECLOPIDOGREL RESPONSE

Although clopidogrel reduces the risk of cardiovascu-lar events after CAD and stenting, the clinical conse-quences of the high variability in clopidogrel efficacycan be serious. Several studies have proven the adverseclinical implications of the interindividual variability inclopidogrel response. In addition to the definite het-erogeneity in clopidogrel response, a significant num-ber of patients show complete nonresponsiveness (re-sistance) to clopidogrel [3,57]. In Western populations,clopidogrel resistance is seen in 5% to 44% of patients,whereas it is nearly 70% in some of the Asian commu-nities [42,55,58–60].

Hyporesponsiveness and nonresponsiveness are asso-ciated with adverse cardiovascular events [3,61]. Huber[13] stated that nearly 20% to 30% of all clopidogrel-treated patients were prone to an increased risk of recur-rent cardiovascular events, and this is due to inadequateclopidogrel response.

Matetzky et al. [59] described an increased risk of re-current atherothrombotic events associated with clopi-dogrel resistance in patients with AMI. Twenty-five per-cent of their study population was resistant to clopido-grel, and the authors described clopidogrel resistance asADP-induced platelet aggregation 103±8% of baseline(assessed by aggregometer).

Geisler et al. [62] also found an increase in the oc-currence of cardiovascular events and death in “clopi-dogrel low-responders” compared to “clopidogrel nor-moresponders” among patients with symptomatic CADtreated with elective PCI. In this study, >70% aggre-gation of platelets after treatment with clopidogrel wastaken as the cutoff value for low response (assessed byChrono-log Lumi aggregometer).

In the PAPI (Pharmacogenomics of Antiplatelet In-tervention) study (2006–2008), Shuldiner et al. [31]found a strong association of the CYP2C19∗2 variantwith increased cardiovascular ischemic events or deathduring 1 year of follow-up in patients who underwentPCI. In this study, the authors did not mention any clearcutoff value for clopidogrel resistance but stated a signif-icant difference in ADP-stimulated platelet aggregationin response to clopidogrel in the carriers of CYP2C19∗2(0.73, SE, 0.12; 95% CI, 0.49–0.97; p < .001)compared with baseline (0.33, SE, 0.13; 95% CI,0.08–0.58; p = .005) [31].

Harmsze et al. [17] also described that carriers of theloss-of-function alleles CYP2C19∗2 and CYP2C9∗3were at increased risk of stent thrombosis after PCI.

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The authors considered the cutoff value for the post-treatment poor response if there was >70% plateletaggregation (assessed by light transmittance aggre-gometry) or PRU value > 235 (assessed by VerifyNowP2Y12 assay) [35].

A recent study on patients with stable cardiovasculardisease showed that a tripling of the daily maintenancedose of clopidogrel in patients with CYP2C19∗2 het-erozygotes achieved the optimal clopidogrel response,similar with the standard dose prescribed in noncarrierpatients, but in the case of CYP2C19∗2 homozygotes,there was no similar response at the same high doses[63].

The HTPR plays a significant role in the pathogen-esis of ischemic vascular events, and it is considered apredictor of major adverse cardiovascular events [5,43].Trenk et al. [64] followed up patients undergoing PCIand found that those who were carrying at least oneCYP2C19∗2 allele were more prone to HTPR. Thiswas associated with a significant increase in incidenceof death and MI.

ASIANS AND CLOPIDOGRELRESISTANCE

Asians have a lower rate of coronary heart disease com-pared to Caucasians, but they have a high rate of strokeincidence [65]. Stroke mortality is also high amongAsian populations. In Malaysia, stroke is the third com-monest cause of mortality, whereas in China, it is theleading cause [66,67]. In Singapore, the prevalence ofstroke among Chinese, Malays, and Indians is similar[68]. Ischemic stroke is the commonest form of stroke.

In the year 2010, NICE (National Institute forHealth and Clinical Excellence), UK, reported thatclopidogrel was the most cost-effective treatment forpatients with ischemic stroke or transient ischemicattacks [69]. Clopidogrel is also widely prescribedacross Asia for secondary prevention of ischemic strokeand ischemic cardiovascular events [70,71]. Althoughthere are several studies in Western populations thathave clearly demonstrated interindividual variability inclopidogrel response, there are scarce comprehensivedata available about the prevalence of clopidogrelnonresponsiveness among Asian populations. A searchusing the PubMed and EMBASE databases revealedthat clopidogrel resistance was as high as 68% to 73%among Chinese Americans who had received coronarystents and 72.5% among Indians with recurrent ACS[55,60]. A recent publication by Kitzmiller et al. [27]also demonstrated that nearly 50% of Asians hadat least one CYP2C19 loss-of-function allele, andthis diminished their response to clopidogrel. A largestudy involving 2146 Korean patients treated with

drug-eluting stent (DES) confirmed this finding [72].At least one CYP2C19∗2 allele was found in 47% ofthe patients. There was a significant increase in MI orstent thrombosis among carriers of this allele.

In the study of pharmacokinetics and pharmacody-namics of clopidogrel in healthy Korean subjects, Kimet al. [73] reported that the CYP2C19 polymorphismwas the possible cause of poor metabolizers, leading toclopidogrel resistance. In this study, IPA (22.9±13.4%,assessed by Chrono-log Lumi-Aggregometer) was takenas the cutoff value for poor metabolizers. In a separatestudy of Korean patients with CAD, the CYP2C19∗3polymorphism was present in nearly 29% of the pa-tients, and it was identified as an independent risk fac-tor of clopidogrel resistance (percent inhibition <20%from baseline, assessed by VerifyNow P2Y12 assay)[74]. Another Korean study in AMI patients revealedthat CYP2C19 loss-of-function variants were associatedwith intermediate metabolizers and poor metabolizers in59% and 19% of the study patients, respectively [75].This was also associated with HTPR. In this study, thecutoff value for HTPR was >59% maximal 20 μmol/LADP-induced aggregation (assessed by light transmit-tance aggregometry). A study by Park et al. [76] in114 Korean patients with ACS who received clopidogreltherapy demonstrated that the interindividual variabilityof platelet inhibition ranged from 0% to 76%; 49% wasclopidogrel resistant. CYP2C19∗2 and CYP2C19∗3 al-leles were more commonly observed in the nonrespon-ders than in the responders. In this study, <20% in-hibition of platelets was taken as the cutoff value fornonresponders (assessed by VerifyNow P2Y12 assay).The CROSS-VERIFY (Clopidogrel Resistance to As-sure Safety After PCI Using VerifyNow) cohort studyrevealed that a genetic polymorphism of CYP3A was as-sociated with HTPR (PRU > 249) and that thromboticevents increased after PCI [77].

A study in Japanese patients who were scheduled forPCI showed that although the rate of clopidogrel non-responders was only 14%, nearly 50% of the patientsstudied were hyporesponders [78]. IPA in nonrespon-ders and hyporesponders was <10% and <30%, re-spectively (assessed by optical aggregometer). AnotherJapanese study in healthy individuals demonstrated that30% of the study subjects had CYP2C19 variants, whichaffected the pharmacokinetics and pharmacodynamicsof clopidogrel, leading to low responsiveness (interme-diate metabolizers and poor metabolizers) to clopidogrel[79]. PRI in intermediate and poor metabolizers was61.5±12.5% and 70.2±10.4%, respectively (assessedby VASP-P analysis). In a separate study on Japanesepatients with CAD, Maeda et al. [80] reported that∼65% of the patients were low responders to clopido-grel, and this was associated with CYP2C19 variants.In this study, clopidogrel response was determined by

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Clopidogrel Resistance in Asian Population 149

residual platelet aggregation, which was 33.1±8.7% inpoor metabolizers (assessed by light transmittance ag-gregometry).

A study by Kumar et al. [81] demonstrated the ex-istence of clopidogrel resistance (2.54%) and semire-sponders (12.7%) among Indian patients with ACS. Inthis study, the cutoff value for clopidogrel resistance was<10% IPA, whereas for semiresponders, it was 10% to29% (assessed by optical aggregometer). Another studyin Indian patients with ACS revealed that ∼20% of thepatients were resistant to clopidogrel and that ∼12% pa-tients were resistant to both clopidogrel and aspirin [82].In the study, researchers defined resistance as ≥70%platelet aggregation in the presence of 10 mM ADP but<70% aggregation with 2 mg/ml collagen (assessed byoptical aggregometer).

In a study among Chinese patients who underwentselective PCI with DESs), clopidogrel resistance wasabout 20%, and it was associated with a higher risk ofstent thrombosis during follow-up [83]. In a separatestudy conducted in 415 CAD patients of Han national-ity, the CYP2C19∗2 gene mutation was associated withan increased risk for recurrence of post-PCI cardiovas-cular events [83,84]. Another study among 1738 Chi-nese patients with CAD receiving clopidogrel therapyshowed a significant association between the presenceof at least one CYP2C19∗2 allele and increased risk ofstent thrombosis at 180 days of follow-up [85]. The risk

was highest among those who had the CYP2C19∗2/∗2genotype.

Prescribing Regulation in Asian Countries

To the best of our knowledge, no specific prescrib-ing regulation for clopidogrel has been adopted byany Asian countries to overcome clopidogrel resistance.Generally, most of the Asian countries follow US FDAguidelines. However, in real clinical practice, irrationalpolypharmacy is common, especially in South Asia [86].Moreover, concurrent use of calcium channel blockers,statins, and antidiabetic medication with clopidogrel isvery common due to the presence of several metabolicrisk factors associated with ischemic vascular diseases.On top of it, omeprazole, a common over-the-counterdrug, is commonly taken for gastritis, and nonspecificdyspepsia further complicates the situation. Althoughcurrent guidelines do not make genetic testing or plateletresponse testing mandatory prior to clopidogrel pre-scription, it is necessary to implement a comprehensiveconsensus on clopidogrel to guide prescribing practices,especially in Asian countries.

DISCUSSION

Clopidogrel is often prescribed in Asian countries forprevention of recurrent stroke and myocardial ischemia

TABLE 1. Summary of genetic polymorphisms associated with metabolism

Genes involved Relevance to clopidogrel action References

1 ABCB1 polymorphism Restrain the intestinal absorption of clopidogrel. TT genotype is athigher risk than CC genotype. However, the role of ABCB1 geneneeds to be further studied because of its ambiguous role inclopidogrel therapy stated in some publications.

[15,16,98]

2 CYP2C19 polymorphism Impaired ability to convert the prodrug into its active form. Carriers ofCYP2C19 loss-of-function alleles (∗2 -∗8) are often poor metabolizers.CYP2C19∗2 allele was present in approximately 50% of Chinese, 34%of African American, 25% of White, and 19% of Mexican Americanpopulation. The chance of carrying at least one loss-of-function alleleis higher among the Asian population.

[21,25,27]

3 CYP2C9 polymorphism Low exposure to active clopidogrel metabolite. High platelet reactivity. [34,35]4 CYP1A2 polymorphism No association with the pharmacokinetic and pharmacodynamic

responses to clopidogrel.[22]

5 CYP3A4 polymorphism CYP3A4 inducer (rifampicin) + clopidogrel showed better plateletinhibition than those who were administered clopidogrel alone.

[33]

6 CYP3A5 polymorphism Atherothrombotic events occur more frequently among patients with thenonexpressor genotype than among those with the expressor genotype.

[44]

7 CYP2B6 polymorphism Carriers of the reduced-function CYP2B6 allele have 15.7% lowerplasma exposure to the active metabolite of clopidogrel and lessreduction of platelet aggregation.

[22]

8 PON1 polymorphism No association with the pharmacokinetic and pharmacodynamicresponses to clopidogrel.

[37–40]

9 Polymorphism of the geneencoding P2Y12receptor

Conflicting study results. Role of the gene encoding P2Y12 receptorneeds to be studied further.

[15,41–43]

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TABLE 2. Summary of drug interactions causing clopidogrel resistance

Drug interaction Relevance to clopidogrel action References

1. Statins Inhibits CYP3A4 activity. Because of conflicting study results, combinedtherapy of atorvastatin and clopidogrel needs to be studied further.

[45,46]

2. Itraconazole Inhibits CYP3A activity and reduces clopidogrel response. [44]3. Calcium channel

blockersInhibits CYP3A4 activity and decreases the platelet inhibition by

clopidogrel.[47,48]

4. Macrolides(erythromycin)

Inhibits CYP3A4 activity and decreases the platelet inhibition byclopidogrel.

[33,49]

5. Selective serotoninreuptake inhibitors(nefazadone)

Inhibits CYP3A4 activity and decreases the platelet inhibition byclopidogrel.

[33,49]

6. Proton pump inhibitors(omeprazole)

Inhibits CYP2C19 activity and decreases the platelet inhibition byclopidogrel. US FDA and European Medicines Agency discourageconcomitant use of omeprazole and clopidogrel.

[53–55]

7. Coumarin derivative(phenprocoumon)

Metabolized by CYP3As and decreases the platelet inhibition byclopidogrel.

[49–51]

8. Benzodiazepines(alprazolam)

Metabolized by CYP3As and decreases the platelet inhibition byclopidogrel.

[49–51]

9. Sulfonylurea Metabolized by CYP2C9 and decreases the platelet inhibition byclopidogrel.

[10]

and in patients undergoing PCI. For cardiovascular is-chemia, both aspirin and clopidogrel are used in com-bination. This combination has a synergistic inhibitoryeffect on platelet aggregation and is more effective thaneither agent alone [87]. Dual platelet therapy could,however, result in greater gastrointestinal complica-tions, such as bleeding [88–90]. Unlike in cardiovas-cular ischemia, either clopidogrel or aspirin is pre-scribed in ischemic stroke. Since several studies denoteincreased ischemic vascular events in hyporespondersand nonresponders, it is imperative to keep in mindthe wide interindividual variability in clopidogrel re-sponse when clopidogrel is prescribed as a monother-apy [83,85,91–93]. Although several factors play impor-tant roles in the mechanism of clopidogrel action, it isevident that the primary cause for inadequate clopido-grel response is the genetic polymorphisms associatedwith the generation of active clopidogrel metabolite. Itis also supported by many studies that presence of theCYP2C19 polymorphism is high in Asian populations.However, it is clinically important to exclude other pos-sible causes of low clopidogrel response, such as the im-pact of age, sex, obesity, diabetes, etc. Otherwise, it maycause a wrong estimation of the clinical risk associatedwith it. That is why genetic screening and platelet func-tion assessment tests should be incorporated with rou-tine laboratory investigations for metabolic risk factorsto understand the overall picture of low clopidogrel re-sponse and resistance.

It is necessary to overcome the inadequate clopido-grel response if clopidogrel is chosen to treat patients,considering its safety and cost-effectiveness. Althoughmodifying the clopidogrel maintenance doses according

to the platelet reactivity is associated with the decreasedrate of major adverse cardiovascular events without in-creasing the bleeding, about 5% of patients remain re-sistant to clopidogrel [3,94]. Moreover, the practicalityof it in the clinical setting and the long-term effect ofthis dose modification strategy are still unclear and needlarge prospective studies for further clarification regard-ing the timing of the platelet reactivity test, dosing, typesof the patient, and clinical outcomes [95,96]. Thereare also studies suggestive of the addition of cilosta-zol or a switch to more potent antiplatelet drugs, suchas prasugrel, ticagrelor, elinogrel, and GP IIb/IIIa in-hibitors, to avoid clopidogrel resistance [3,97]. Consid-ering the facilities in the clinical setting, patient compli-ance, cost, and other factors responsible for inadequateclopidogrel response, treatment with an alternative an-tiplatelet agent would be the better choice than doseadjustment options in the case of low responders andresistance.

CONCLUSION

In summary, both genetic polymorphisms in themetabolic activation of clopidogrel (Table 1) as well asdrug interactions (Table 2) are associated with wideinterindividual variability in the response to clopido-grel. Current guidelines do not mandate genotype test-ing or routine platelet function testing to identify thoseindividuals who are prone to decreased clopidogrelresponses [25]. Since genetic polymorphisms associatedwith decreased clopidogrel response are more common

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among Asians, medical practitioners should considergenotype testing and platelet function tests in Asianpatients aimed for clopidogrel treatment. Care shouldbe taken when prescribing other drugs concomitantly.However, due to a lack of firm evidence of the associ-ation between all the factors responsible for inadequateclopidogrel response, Asian populations need to be fur-ther studied in a large prospective study to establish con-crete associations of genetic polymorphisms, clopidogrelresponse, platelet function assessment, and clinical out-come.

ACKNOWLEDGMENTS

The authors would like to thank Dr. Natasha Das andBlue Pencil Science for providing editing assistance;Dr. Toshiyuki Miyata (Director of National Cerebraland Cardiovascular Center, Research Institute, Fujishi-rodai, Suita, Japan) for reviewing this manuscript; andthe University Putra Malaysia for providing ResearchUniversity Grant Scheme (04-02-12-178RU) to sup-port the study on clopidogrel resistance in the Malaysianpopulation.

Declaration of interest: This work was supportedby the Research University Grant Scheme (04-02-12-178RU) funded by the University Putra Malaysia. Be-side this grant, the authors report no conflicts of interest.

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