Nonresponders to clopidogrel: pharmacokinetics and ... · Clopidogrel pharmacokinetics and pharmacogenomics 3.1 An overview of clopidogrel pharmacokinetics After its absorption in

1. Introduction

2. Methods

3. Clopidogrel pharmacokinetics

and pharmacogenomics

4. Expert opinion

Review

Nonresponders to clopidogrel:pharmacokinetics and interactionsinvolvedMariano A Giorgi†, Guillermo Di Girolamo & Claudio D Gonzalez†Department of Cardiology and Cardiovascular Surgery, FLENI, Buenos Aires, Argentina

Importance of the field: The use of clopidogrel and aspirin has become

standard therapy in patients with acute coronary syndromes and stent

implantation. However, concern arises because about 25% of subjects are

nonresponders to clopidogrel. This nonresponsiveness is associated with a

threefold increase in adverse outcomes. Clopidogrel resistance is multifacto-

rial, but genetic polymorphisms in clopidogrel’s metabolic activation (e.g.,

cytochrome P450 2C19) and drug--drug interactions at this level (e.g., between

proton pump inhibitors (PPIs) and clopidogrel) are both associated with

decreased clopidogrel efficacy. Despite all PPIs being potent inhibitors of

CYP2C19, evidence about their clinical impact is controversial.

Areas covered in this review: Pharmacogenomic and pharmacokinetic aspects

of clopidogrel nonresponsiveness were considered in detail.

What the reader will gain: The reader will gain an exhaustive review of the

current state of the controversial issues regarding genetic polymorphisms

and drug--drug interactions affecting clopidogrel efficacy.

Take home message: It is important to consider clopidogrel resistance in some

patients and establish strategies to handle this problem (e.g., genotyping,

platelet aggregability tests, new antiplatelet drugs). The combined use of

PPIs and clopidogrel is at present regulated by the FDA and EMEA; however,

the risk/benefit balance should be made for each patient individually.

Keywords: clopidogrel, interactions, nonresponders, pharmacogenomic, pharmacokinetic

Expert Opin. Pharmacother. (2010) 11(14):2391-2403

1. Introduction

Since the publication of the results of the CURE [1] and PCI-CURE [2] trials, atrue revolution has come in the management of antiplatelet therapy for acutecoronary syndromes (ACS). These trials provided the initial evidence supportingthe efficacy of dual antiplatelet therapy of aspirin and clopidogrel in reducingmajor cardiovascular events and stent thrombosis in patients with non-ST elevation ACS and for those treated with coronary percutaneous intervention(PCI). Additional research led to the use of dual antiplatelet therapy in patientswith ST-elevation ACS irrespective of the reperfusion strategy adopted [3,4]. Theeffectiveness of combination therapy and its safety was also demonstrated [5],and it became the standard of care for patients with ACS or those submitted tostent implantation [6,7]. However, despite the amount of evidence favoring theuse of clopidogrel, there still remains a variable proportion of patients who suf-fered cardiovascular events under such treatment [8]. In a recent meta-analysis of3960 patients from 15 trials (including randomized or observational prospectivestudies in which clopidogrel activity had been measured by light transmissionaggregometry), Combescure et al. [9] estimated that the presence of clopidogrel

10.1517/14656566.2010.498820 © 2010 Informa UK, Ltd. ISSN 1465-6566 2391All rights reserved: reproduction in whole or in part not permitted

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nonresponse was associated with a threefold increase in therisk of recurrent ischemic events (relative risk (RR) = 3.53;95% CI 2.39 -- 5.20). The mechanism underlying the poorresponse to clopidogrel is still a matter of research anddebate. The categorization of a patient as a nonrespondercase is essentially based on biochemical indicators and teststhat evaluate the extent of platelet inhibition after clopidog-rel treatment. There are many definitions and methods totest clopidogrel response variability [8]. As stated byAngiolillo et al. [10], this variability is multifactorial inessence, comprising genetic (single-nucleotide polymor-phisms in genes related to the drug’s pathway), cellular(expression of receptors for clopidogrel, platelet turnover)and clinical factors (diabetes, chronic renal failure, age,sex). In this review we examine some of these mechanisms.Clopidogrel is a prodrug that needs to be activated to

inhibit platelets. This has led to an large increase in informa-tion related to pharmacokinetic factors implied in clopi-dogrel metabolism and effects in recent years. Therefore,we focus on the pharmacokinetic issues that may affectclopidogrel efficacy.

2. Methods

A Medline search of published papers including pharmacoki-netic, pharmacodynamic and pharmacogenomic informationrelated to clopidogrel andmechanisms for clopidogrel resistancewas done. Terms included in the primary search (up toDecember 2009) were: clopidogrel, proton pump inhibitors,pharmacokinetics and pharmacogenomics. All abstracts werereviewed and selected articles were retrieved. A secondary searchwas carried out from references of articles from the first search.Information from abstracts and presentations at the 2010American College of Cardiology scientific sessions was alsoincluded. Relevant information on these aspects was registeredand compiled.

3. Clopidogrel pharmacokinetics andpharmacogenomics

3.1 An overview of clopidogrel pharmacokineticsAfter its absorption in the intestine, clopidogrel needs to beactivated in the liver. This biotransformation process involvesmany mono-oxigenases of the cytochrome P450 system [11].As shown in Figure 1, the first oxidative reaction involvesCYP1A2, CYP2B6 and CYP2C19 enzymes and leads to theproduction of 2-oxo-clopidogrel, an inactive intermediary.Kazui et al. [12] recently demonstrated that CYP2C19 makesthe key contribution to this oxidative phase. The followingstep is the conversion of 2-oxo-clopidogrel into its active thiolmetabolite (R130964). In this case, the main contributor isCYP3A4, followed by CYP2C19 (Figure 1). According tothese data, any modification in CYP2C19 and, to a lesserextent, in CYP3A4 or 3A5 functioning will influence theconversion rate of clopidogrel into its active metabolite.This phenomenon, in which the concentration of the activemetabolite relies on the activity of a single key metabolicpathway, is considered a clear example of the so-called‘high-risk pharmacokinetic profile’ [13] and would haveclinical relevance, as described below.

Interestingly, clopidogrel is a thienopyridine derivativecontaining an asymmetric carbon, which results in theexistence of two enantiomers (R and S), of which theS-enantiomer is the active compound [14-16]. As required bythe International Conference on Harmonisation of TechnicalRequirements for Registration of Pharmaceuticals for HumanUse (ICH) [17], the content of the inactive R-enantiomer mustbe carefully controlled in bulk substance and drug products.Also, according to the ICH guideline on impurities in newdrug products [17], the level of impurities in the productshould be carefully controlled, and the upper level of theseimpurities should be determined and supported by adequatedata in the registration application. In a study comparingthe purity of 18 clopidogrel copies with the original brandedproduct, Gomez et al. [18] found high levels of impuritiesin the copies. More than 60% of the copies containedmore than fourfold the amount of hydrolysis product orR-enantiomer compared with the reference product. Becausethe R-enantiomer is devoid of anti-aggregatory activity [14,19],it makes sense that evaluation of the S-enantiomer should berequired in studies of the bioequivalence of clopidogrel for-mulations. For the same reason, the active metabolite ofclopidogrel should be measured. The impact of these poten-tially confounding factors in these studies is unknown, andthe relevance of this phenomenon in studies addressingnonresponsiveness to clopidogrel should be addressed.

3.2 Pharmacogenomics of clopidogrel nonresponseIt is difficult to assess the prevalence of clopidogrel unrespon-siveness, defined by the lack of the inhibitory effect over pla-telets. However, in a meta-analysis including 4564 patientswith coronary heart disease, Sofi et al. [20] reported a

Article highlights.

. Concern rose about clopidogrel nonresponsiveness.

. Pharmacogenomic and pharmacokinetic mechanismswere identified, especially at the level of clopidogrelactivation mediated by cytochrome P450 2C19.

. There is no supported evidence to handle lack ofclopidogrel efficacy attributed to CYP2C19polymorphisms. Alternatives under researchinclude use of platelet function tests, genotypingand new antiplatelet drugs.

. Proton pump inhibitors (PPIs) interact, in vitro, withclopidogrel. Their influence on adverse cardiovascularoutcomes is still a matter of debate. Despite the use ofPPI and that clopidogrel association was recentlyregulated by the FDA and EMEA, therisk/benefit balance should be considered in eachpatient individually.

This box summarizes key points contained in the article.

Nonresponders to clopidogrel

2392 Expert Opin. Pharmacother. (2010) 11(14)

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frequency of 26.4% of clopidogrel unresponsiveness. Thisauthor reports that, after 1 year of follow-up, residual plateletactivity was associated with a fivefold increase in the risk ofdeath or thrombotic recurrences. These figures are similarto those found by Combescure et al. [9] in their meta-analysis of 3290 patients, in which on average 25% of subjectsrevealed nonresponse to clopidogrel. As mentioned before,one of the key hypotheses to explain this phenomenonresides in the genetically determined modifications in thepharmacokinetic profile of clopidogrel. Because CYP2C19 isinvolved in both reactions that lead to active clopidogrel,it is a key player in drug response variability. In generalterms, loss-of-function variants of CYP2C19 (2C19*2 and2C19*3) account for more than 95% of poor metabolism inclinically relevant medications [21]. Despite it being a contro-versial issue, it is estimated that 2 -- 15% of Caucasians [22],4% of Blacks, and 10 -- 25% of Southeast Asians exhibit thesepoor metabolism variants [23]. The rationale for this line ofresearch is shown in Figure 2. Regarding the influence ofCYP2C19 loss-of-function polymorphisms on clopidogrel

response, Hulot et al. [24] reported that healthy subjects het-erozygous for the 2C19*2 variant had less inhibitory responseto clopidogrel, using two different tests to assess platelet func-tion. The next challenge was to demonstrate the link betweenpolymorphisms and suboptimal platelet inhibition in patientsunder clopidogrel treatment. This hypothesis was tested byGiusti et al. [25] in a sample of 1419 patients with ACS undertreatment with clopidogrel. In this study, carriers of the los-s-of-function allele had more residual platelet activity thanother patients. Carriers of the CYP2C19*2 allele had higherplatelet aggregation levels than noncarriers (p = 0.001). Theseauthors also found that this genotype was an independentpredictor of response variability to clopidogrel.

How much of this variability in response is attributable togenetic polymorphisms of the CYP2C19 is still a difficultquestion to answer. Shuldiner et al. [26] identified somegenetic variants related to ex vivo clopidogrel response(assessed by aggregometry) in 429 apparently healthy Amishpersons. Because genetic polymorphisms are heritable, theinclusion of an Amish community, in which all individuals

CYP 1A2 (35.8%)CYP 2B6 (19.4%)CYP 2C19 (44.9%)

CYP 2B6 (32.9%)CYP 2C9 (6.79%)

CYP 2C19 (20.6%)CYP 3A4 (39.8%)

CYP 3A5 (nr)

Esterases

Clopidogrel 2-oxo clopidogrel

Inactive metabolitesfor elimination

Active form of clopidogrel15% of administered dose

85% of administered dose

100% of administered dose

N

ClS

COO

N

ClS

COO

O

N

Cl

HOOC

HS

OCH3O

Figure 1. Clopidogrel metabolism. The relative contribution to clopidogrel biotransformation by each enzyme is shown

between brackets.CYP: Cytochrome P450.

Giorgi, Di Girolamo & Gonzalez

Expert Opin. Pharmacother. (2010) 11(14) 2393

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are highly related, seems to offer an optimal approach to testthis topic. Performing a genome-wide association study, theseauthors found a cluster of 13 single nucleotide polymor-phisms, near the coding region for CYP2C19, which are asso-ciated with a reduced response to clopidogrel. Amish personshomozygous for CYP2C19*2 (2.1% of the population) hadthe poorest response to clopidogrel. Subjects with 0, 1 and2 copies of this allele had 40.7, 47.1 and 65.4%, respectively,of reduction in ADP-induced platelet aggregation. It was esti-mated that the presence of the CYP2C19*2 genotypeaccounted for 12% of the variability in the clopidogrelresponse. These findings were verified in an independentcohort of patients who underwent programmed percutaneouscoronary intervention (PCI) in whom the presence of theCYP2C19*2 polymorphism was associated with a greaterresidual platelet activity, and, perhaps more important, to anincreased risk of cardiovascular ischemic event or death at1 year of follow-up (hazard ratio (HR) = 2.42, 95% CI1.18 -- 4.99; p = 0.02).A special emphasis should be made on the type of stent

used (bare metal or drug eluting). As drug-eluting stents areprone to thrombosis (and cardiovascular events) in the long-term, guidelines indicate that treatment with aspirin plus clo-pidogrel should be extended to, at least, 1 year [7]. Still, theefficacy of clopidogrel is similar regardless of the type ofstent used. This issue was assessed by Trenk et al. [27] in astudy with 797 patients who underwent programmed PCIwith stent implantation treated with clopidogrel. Theseauthors observed that subjects carrying the loss-of-functionCYP2C19*2 allele exhibited some residual platelet reactivity.After 1 year of follow-up, these patients had a threefoldincrease in the incidence of death and myocardial infarctionindependently of the type of stent implanted.In a different clinical setting, Collet et al. [28] tested the

impact of some polymorphisms in samples from 259 youngpatients (< 45 years old) who had a first myocardial infarction,and were under chronic treatment with clopidogrel (medianclopidogrel exposure 1.07 years; IQR = 0.28 -- 3.0). The over-all prevalence of the loss-of-function CYP2C19*2 genotypewas 15.8% (25% were heterozygous and 3% homozygous).After a median of 3 years of follow up there were more

ischemic events (cardiovascular death, nonfatal myocardialinfarction or urgent revascularization; HR = 3.69, 95% CI1.69 -- 8.05, p = 0.0005) and stent thrombosis (HR = 6.02,95% CI 1.81-20.04; p = 0.0009) in carriers than in noncar-riers. One of the limitations of this study is that it focusedon only one variant of single nucleotide polymorphism. Thestudy by Simon et al. [29] evaluated this problem. Theseauthors studied 2208 patients admitted for acute myocardialinfarction to the French registry FAST-MI. All subjectsreceived clopidogrel and were followed up for 1 year afterthe index event. Samples were tested for single nucleotidepolymorphisms at genes ABCB1 (that modulate clopidogrelabsorption), P2RY12 and ITGB3 (both related to the mecha-nism of action), CYP3A5 and CYP2C19. Two ABCB1polymorphisms were associated with an increased risk ofcardiovascular events (HR = 1.72, 95% CI 1.20 -- 2.47). Aninteresting finding was an elevated event rate (death, nonfatalmyocardial infarction, or stroke) observed in carriers of CYP2C19 loss-of-function polymorphisms *2, *3, *4 and*5 (HR = 1.98, 95% CI 1.10 -- 3.58), especially in those sub-jects homozygous for such polymorphisms. In the subgroupof carriers of such variants who underwent PCI, the outcomewas much worse (HR = 3.58, 95% CI 1.71 -- 7.51). Noassociation was observed with other assessed polymorphisms.

Another study that contributed to the topic was carried outby Mega et al. [30], who investigated the complete pathwaythat goes from CYPs’ genetic polymorphism, through activeclopidogrel levels and platelet function, to their clinical impact.In 162 healthy subjects treated with clopidogrel, they initiallyassessed the association between genetic variants of all CYPsinvolved in clopidogrel metabolism (1A2, 2B6, 2C9, 2C19,and 3A5), plasma levels of active clopidogrel and platelet inhi-bition. An inverse relationship for loss-of-function polymor-phism and active clopidogrel levels was observed forCYP2C19 and, to a much lesser extent, CYP2B6. Accordingto these data, patients were classified as ‘ultrarapid’, ‘extensive’,‘intermediate’ and ‘poor’ metabolizers if they had at least onecopy of the CYP2C19 loss-of-function allele. Therefore, fol-lowing a gradient pattern across the metabolizer type, the loweractivated clopidogrel concentration had the higher residualplatelet reactivity. The second phase of the trial involved the

CYPs involved inclopidogrelmetabolism

‘Wild type’gene

Genepolymorphisms

CYP activity Clopidogrelactivation

Clopidogrelefficacy

(platelet function)

Clopidogreleffectiveness(CV events)

Reduced

Normal

Reduced

Normal

Reduced

Usual

Reduced

Usual

Figure 2. Relationship between genomic polymorphism in clopidogrel biotransformation and its efficacy and effectiveness.CV: Cardiovascular; CYP: Cytochrome P450.



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genotyping of DNA samples from 1477 patients with ACS,participants of the TRITON-TIMI38 [31] trial who wereassigned to clopidogrel. Cardiovascular outcomes were mea-sured in subject carriers and noncarriers of theCYP2C19 loss-of-function variant. At 1.5 years of follow-up, carriers had significantly more ischemic events (deathfrom cardiovascular cause, myocardial infarction or stroke)than noncarriers (HR = 1.53, 95% CI 1.07 -- 2.19). Similarresults were observed for stent thrombosis (HR = 3.09, 95%CI 1.19 -- 8.00).

As mentioned before, the other CYPs involved in clopidog-rel activation are CYP3A4 and CYP3A5. CYP3A4, 3A5accounts for ~ 50% of the CYP3A system activity in theliver [32]. Evidence regarding the influence of CYP3A singlenucleotide polymorphisms over clopidogrel efficacy and effec-tiveness is contradictory. Small studies have revealed a linkbetween clopidogrel, loss-of-function polymorphisms, resid-ual platelet activation and cardiovascular events. In a two-phase study, Suh et al. [33] selected 32 healthy subjects andgenotyped them for CYP3A5. After treatment with clopidog-rel they compared platelet aggregation in carriers and noncar-riers of the loss-of function allele CYP3A5*3. It was foundthat carriers had more impaired platelet function than noncar-riers. In a second phase, 348 patients submitted for PCI andstent implantation, who had been treated with clopidogrel,were genotyped for those variants. After a 6-month follow-up period it was observed that carriers had a lower cardiovas-cular events rate (cardiovascular death, myocardial infarction,nonhemorrhagic stroke) compared with noncarriers. How-ever, these results are inconsistent, and other authors did notreach similar conclusions [24,30,34]. Regarding CYP3A4 poly-morphisms, studying 82 patients under clopidogrel, Angio-lillo et al. [35] observed that carriers of the IVS10+12G>Apolymorphism displayed a higher platelet reactivity than non-carriers. Again, these findings are inconsistent and other pub-lications suggested different results [25,34]. Therefore, theevidence that supports the influence of CYP3A4/5 polymor-phisms on clopidogrel pharmacokinetics or pharmacodynam-ics is inconclusive. The information is also controversial forthe rest of the CYPs variants involved in clopidogrelmetabolism [36].

In summary, the available evidence supports someCYP2C19 polymorphisms on clopidogrel efficacy and effec-tiveness. As it can be easily understood, the translation ofsuch information into the clinical setting is difficult to practice.As it was pointed out by Storey [37], in an acute setting (e.g., ina case of an ST-evation ACS), genotyping of patients in orderto adjust therapy (in a yet undefined way) is not an option,mainly because any delay in reperfusion therapy would repre-sent a reduction in myocardial salvage and survival. Despitethe recent availability of ‘point-of-care’ devices to assess plateletfunction, in patients with ST-segment elevation myocardialinfarction they are not a valid alternative because it wouldbe necessary to wait 6 -- 12 h from the administration ofclopidogrel to evaluate its response. However, in patients with

non-ST-elevation ACS in nonurgent condition, these devicescould be an option to genotyping [20]. Finally, there are anincreasing number of new drugs available as alternatives to clo-pidogrel for such patients. By contrast, for patients to be sub-mitted to a programmed PCI, it could be useful to knowbeforehand its loss-of-function polymorphism carrier condi-tion. But, even in these cases, more research is also requiredto assess the effectiveness of such approach.

3.3 Pharmacokinetic drug--drug interactions and

clopidogrelBecause the CYP450 system accounts for at least 50% of themetabolism of the most common drugs used in practice [21],it is logical to expect that drugs metabolized through thispathway are susceptible to drug--drug interactions. In somecases the problem relies on the coadministration of drugsthat compete for the same metabolic pathway. For many yearsit was believed that the main CYP involved in clopidogrelactivation was CYP3A4/5. Therefore, it was considered neces-sary to explore if cotreatment with drugs such as those listedin Table 1 [38] could affect clopidogrel activation. Accordingto these data, Lau et al. [39] investigated the effect of the coad-ministration of clopidogrel and atorvastatin (a drug thatcould probably compete with clopidogrel at the level ofCYP3A4 metabolism) on their pharmacokinetics. This studyalso has clinical relevance because this combination representsa very frequently used association as most of the patients whohave coronary artery disease also exhibit hypercholesterolemia.In a sample of 44 patients submitted to PCI and stent place-ment, the authors treated 19 patients with clopidogrel alone,9 with clopidogrel and pravastatin (a statin devoid of CYPmetabolism) and 16 with clopidogrel and atorvastatin. Plate-let aggregation was higher in the atorvastatin plus clopidogrelgroup. No differences were found between clopidogrel aloneand clopidogrel plus pravastatin. Also, it was observed adose-dependent pattern in residual platelet reactivity aftertesting for different doses of atorvastatin. Despite the internalconsistency of this study and the concern that it provoked inthe medical community, many other studies have refutedsuch findings. To investigate the potential clinical impact ofthis interaction, a post hoc analysis of the CREDO trial (clopi-dogrel for the reduction of events during observation), whichrandomized 2116 patients who underwent PCI to clopidogrelpretreatment followed by 1 year’s treatment or no pretreat-ment and 1 month’s treatment, was carried out. A total of1001 patients received CYP3A4 metabolized statins (atorvas-tatin, simvastatin, lovastatin and cerivastatin). There were nodifferences in clinical end points (death, myocardial infarctionor stroke) after 1 year of follow-up [40]. Finally, in onestudy that prospectively included a cohort of 1001 patientssubmitted for cardiac catheterization, Hochholzer et al. [41]

observed no among-treatment effect when clopidogrel iscombined with different statins metabolized by CYP3A4(atorvastatin, fluvastatin, simvastatin and lovastatin) overresidual platelet reactivity.



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In recent years drug interactions involving CYP2C19 havereceived a lot of attention. As shown in Table 1, many drugscommonly used in clinical practice are metabolized by thisCYP member. However, the most remarkable drug--druginteraction with clopidogrel is the one that involves protonpump inhibitors (PPIs). The frequency of the use of PPIs inpractice is increasing over time, but the impact of their inter-action with clopidogrel is still a subject for debate. Because theuse of clopidogrel and aspirin in combination was associatedwith an increased risk of gastrointestinal bleeding [42], theuse of PPIs became more and more frequent in order to pre-vent this complication, especially in patients treated for longperiods of time. In 2008, the American College of CardiologyFoundations, the American Heart Association and the Amer-ican College of Gastroenterology published an expert consen-sus document addressing the reduction of gastrointestinalrisks associated with the use of antiplatelets [43]. In thatdocument the use of PPIs in patients under dual antiplatelettherapy (aspirin plus clopidogrel) is clearly recommended.In a recently published retrospective cohort study using datafrom 8205 patients who were treated with clopidogrel afterdischarge for ACS, it was observed that 63.9% of subjectswere also prescribed with a PPI [44]. As shown in Table 1, allof the available PPIs inhibit CYP2C19 to a certain degreeand, consequently, they could probably affect clopidogrel per-formance. However, at least in vitro, not all PPIs inhibitCYP2C19 activity to the same extent, as Li et al. reported [45].In this study, the maximal inhibition in the CYP2C19 medi-ated by S-Mephenytoin and 4¢hydroxilation was observedwith omeprazole (Figure 3). On the other hand, pantoprazoleseemed to affect CYP to a lesser extent. A critical issue for

practice is that omeprazole is an over-the-counter drug inmany countries and the magnitude of the epidemiologicalimpact is difficult to assess.

The first clue that gave support to this hypothesis was astudy by Gilard et al. [46], who observed higher levels of resid-ual platelet reactivity in 105 patients treated with clopidogrelplus omeprazole. The same group validated their findings in arandomized, double-blind, placebo-controlled trial including124 patients treated with clopidogrel, who underwent stentimplantation and were assigned to omeprazole or placebo [47].After 7 days of treatment, platelet reactivity was significantlyhigher in the omeprazole group. In the same way, O’Donog-hue et al. [48] studied 99 patients from the PRINCIPLE-TIMI 44 trial (prasugrel in comparison to clopidogrel forinhibition of platelet activation and aggregation; TIMI44).These authors observed that patients who underwent treat-ment with a PPI had significantly lower platelet inhibitionthan those not receiving such drugs.

To evaluate the clinical impact of this drug--drug interac-tion, Juurlink et al. [49] did a retrospective, population-based,nested case-control study. Using a database of Ontario resi-dents they identified 13,636 patients, aged > 66 years, whowere prescribed with clopidogrel after acute myocardialinfarction. Cases were defined as patients who died or suffereda recurrent myocardial infarction 90 days after discharge.Controls were selected from the same population but hadnot been readmitted for acute myocardial infarction. Basedon prescription records, the authors defined the exposure toPPIs in the population. After several analyses it was concludedthat the use of PPIs in addition to clopidogrel was associatedwith recurrence in myocardial infarction at 3 months after theindex event (odds ratio (OR) = 1.27, 95% CI 1.03 -- 1.57).The use of pantoprazole was not associated with reinfarctionin the short-term (OR = 1.02, 95% CI 0.70 -- 1.47), butthe use of other PPIs seemed to be involved in such an inter-action (OR = 1.40, 95% CI 1.10 -- 1.77). Similar findingswere also published by Ho et al. [44], who analyzed prescrip-tion data from 8205 patients with ACS receiving clopidogrelin a retrospective cohort study. Two-thirds of patients werealso prescribed with PPIs at discharge. With the aim of assess-ing these drug--drug interactions, a nested case-control studywas performed. In the multivariable analysis, it was observedthat PPI use was associated with an increased risk of deathor readmission due to ACS (OR = 1.25, 95% CI1.11 -- 1.41) compared with non-users after a medianfollow-up of 521 days. Analyzing only the cohort of patientsprescribed with PPI and clopidogrel (n = 5244), it wasobserved that those who discontinued PPIs for a periodof > 14 days had a significantly lower event rate than for sub-jects who continued on PPI therapy (OR = 1.27, 95% CI1.10 -- 1.46). These findings indicate that the addition of aPPI may attenuate the effectiveness of clopidogrel. Becausethe use of a PPI could be a marker of comorbidity and, there-fore, act as a conditioning factor of adverse outcomes, theinvestigators adjusted the analysis according to the history of

Table 1. Selected substrates, inhibitors and inducers of

cytochrome P450 3A4 and 2C19.

Substrates Inhibitors Inducers

3A4 DiltiazemNifedipinAlprazolamAtorvastatinSimvastatinClarithromycinLosartanSildenafil

DiltiazemKetoconazoleIndinavirItrakonazoleClarithromycinGrapefruit juice

RifampinPhenytoinCarbamazepineEfavirenz

2C19 DiazepamCarisoprodolClopidogrelImipramineLansoprazoleOmeprazoleRabeprazoleEsomeprazolePantoprazoleWarfarinPropranolol

CimetidineFluconazoleFluoxetineEfavirenzLansoprazoleOmeprazoleRabeprazoleEsomeprazolePantoprazoleTiclopidine

BarbituratesPhenytoinRifampin

From [21] and [38].



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gastrointestinal bleeding. They observed that, independentlyof previous gastrointestinal bleeding history, the associa-tion between PPI use and worst clinical outcome stillremained significant.

Nevertheless, there are many authors that describe no clin-ical impact of the cotreatment of clopidogrel and PPIs.Neutral results were observed by Siller-Matula et al. [50] in anonrandomized trial (authors do not declare how the inter-vention was assigned) of 300 subjects treated with clopidogrelfor PCI, with no differences in platelet aggregation betweensubjects treated with clopidogrel alone or plus pantoprazole,or esomeprazole. This could be evidence favoring a differen-tial inhibitory effect on CYP2C19 with distinct PPIs.O’Donoghue et al. [48] analyzed the data from 6795 patientsallocated to clopidogrel in the TRITON-TIMI 38 trial. Inthis study, 4529 patients (33%) also received a PPI at thetime of randomization. The investigators found no associa-tion between the use of PPIs and clopidogrel at randomiza-tion and the occurrence of cardiovascular death, myocardialinfarction or stroke (HR = 0.94, 95% CI 0.80 -- 1.11) [48] dur-ing the follow-up period. Similar results were recentlyreported by Ray et al. [51] in a retrospective database analysisof 20,596 patients with ACS (13,003 with clopidogrelalone and 7593 with clopidogrel plus a PPI). There was noassociation between PPI use and fatal or nonfatal myocardialinfarction, sudden cardiac death, stroke or cardiovasculardeath (HR = 0.99, 95% CI 0.82 -- 1.19) after a 1-yearfollow-up period.

There is a state of debate across the medical communitybecause of the contradictory evidence on this issue. Fromthe regulatory perspective, a recent warning delivered by theEMEA [52] and the FDA [53] shows the importance assignedby the authorities to this topic. In May 2009, the EMEArecognized that some PPIs could affect clopidogrel activation

and recommended some modifications in clopidogrel label-ing to advise doctors and patients and to discourage theuse of this association unless absolutely necessary [52]. InNovember 2009, the FDA recommended that the concomi-tant use of omeprazole or esomeprazole with clopidogrel beavoided [53]. Box 1 summarizes the FDA recommendationson this topic.

Despite the recommendations provided by the diff-erent regulatory authorities, it is relevant to the scientificcommunity to understand in a more comprehensive waythis complex interaction. In the editorial accompanyingO’Donoghue et al. ’s article [48], Sibbing and Kastrati [54] pre-sented the problem as a matter of fact or fiction. According tothem, it must be highlighted that clinical evidence comesfrom very different sets of patients. On the one side we havepopulation-based studies, which give information from unse-lected populations with higher prevalence of clinical factorsassociated with less clopidogrel response (i.e., chronic renaldisease, diabetes mellitus, BMI). On the other hand,O’Donoghue et al. [48] analyzed subjects from a randomized,controlled trial who are certainly healthier than those fromnonselected populations. It should be noticed that in thisstudy 40.7% of recruited subjects using PPI were on panto-prazole. The results of the COGENT trial also support thelack of interaction. Presented at the Late Breaking ClinicalTrials Sessions during the Transcatheter Cardiovascular Ther-apeutics 2009 meeting, Bhatt’s [55] study randomized patientswith ACS or stent implantation to clopidogrel alone or a tab-let with a fixed-dose combination of clopidogrel 75 mg andomeprazole 20 mg. Although the study was interrupted withalmost 70% of the calculated sample of 5000 subjects, itwas observed that the risk of cardiovascular events wassimilar in both arms of the study with a conclusive benefiton gastrointestinal events favoring the association of a PPI.

CYP2C19inhibitionconstant

Reaction

CYP2C19inhibition

1. Lansoprazole

2. Omeprazole

3. Esomeprazole

4. Rabeprazole

5. Pantoprazole

Omeprazole Esomeprazole Lansoprazole Pantoprazole

6.2 ± 0.8 mM

2.4 ± 0.05 mM 7.9 ± 0.5 mM

8.6 ± 1.0 mM

0.74 ± 0.09 mM

0.45 ± 0.07 mM

15.3 ± 1.1 mM

69.4 ± 9.2 mM

Rabeprazole

18.8 ± 1.3 mM

21.3 ± 2.8 mMS-Mephenytoin

4¢hydroxilation

+

–

Figure 3. Inhibitory constants for CYP2C19 S-Mephenytoin and 4¢hydroxilation using different proton pump inhibitors in

human liver microsomes.From [45].



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The lack of any clinically relevant interaction between PPIsand clopidogrel was also seen in the abovementioned studyby Ray et al. [51]. However, it is important to highlight that,in the later study, 62% of the patients with a PPI were onpantoprazole. This fact should have been taken into accountat the time to interpret the conclusions of the evidenceshowed. In the accompanying editorial of Grinswold et al.[56], it was concluded that, despite the consistency of themethodology used by the authors, the question still remainsundefined. More recently, during the 2010 American Collegeof Cardiology scientific sessions, Harjai et al. [57] reported in aretrospective population-based registry of patients submittedfor PCI that there was no association between PPI use (28%of patients included in the registry) and myocardial infarction,target vessel revascularization or stroke at 5-year follow-up.These authors also did a propensity-adjusted multivariableanalysis to assess interaction in the subset of patients takingomeprazole or esomeprazole which represented 12% of theoriginal cohort. Surprisingly, there was a lower incidence ofcardiovascular events in the group treated with PPI comparedwith non-PPI subjects (3.9 vs 6.1%, respectively). Regardingthis study, it is important to underline that, although theuse of propensity scores is a consistent way to handle unbal-anced groups in observational studies [58], the reduced sizeof the analyzed sample implies a clear limitation to rulingout PPI and clopidogrel interaction.Another relevant question regarding the potential interac-

tion between clopidogrel and PPI is about the timing ofdrug administration. Some experts have suggested that

the lessened clopidogrel efficacy attributed to PPI coadmin-istration could be overcome by separating both pills by 12 h.This strategy has no supporting evidence and, as wasstated by Depta and Bhatt [59], is contradictory to someex vivo data.

In summary, there is evidence provided from basic andclinical studies that supports the hypotheses that not all PPIsequally affect clopidogrel efficacy and effectiveness. Thesestudies would indicate that pantoprazole probably has leasteffect on clopidogrel and also point out that the presence ofcomorbidities potentially related to ‘platelet resistance’could potentiate the adverse impact of PPIs in generalon clopidogrel-treated patients. Perhaps, as we suggestedin Figure 4, in patients similar to those included in random-ized, controlled trials, with less prevalence of conditionsrelated to clopidogrel resistance (e.g., less age, body massindex and chronic renal failure), the addition of a PPI to clo-pidogrel does not imply any change in clinical outcome. Inthe same way, in patients more representative of generalnonselected populations (like those analyzed in registries),this drug--drug interaction could really lead to an adversecardiovascular outcome.

4. Expert opinion

Regarding the pharmacogenomic evidence presented, theinfluence of some selected polymorphisms on clopidogrelactivation is well established. In particular, the role ofCYP2C19 loss-of-function alleles was highlighted as clinicallyrelevant. A consequence of this were the modifications to clo-pidogrel labeling in May 2009 (an FDA request), addinginformation on this topic [60]. However, there is no acceptedway to handle this phenomenon in clinical practice. Withrespect to relevant pharmacokinetic interactions, a key issuesurrounds the debate on the concomitant use of PPIs and clo-pidogrel. An explanation for the contradictory results of stud-ies on this topic could be related to the type of PPI evaluated(pantoprazole seems to be the ‘safest’ in view of its lack ofrelevant interaction with the CYP family) and the type ofpopulation on which the combination of drugs were tested(‘real-life’ patients in the population-based studies vs ‘selected’patients from the randomized, controlled studies). Despite theongoing debate in the medical community, regulatory author-ities have declared that the use of omeprazole or esomeprazoleshould be avoided in these patients, and that other PPIsshould be used after a risk/benefit analysis.

Because many patients will still be treated with clopido-grel and would need concomitant protection to reducethe risk of gastrointestinal bleeding, it is important for treat-ing physicians to have more information on this topic.The use of statistics to solve problems in processing datafrom observational studies should be complemented withrational design in retrospective studies. However, in recentyears many new antiplatelet compounds have arisen asalternatives to clopidogrel. The approval of prasugrel, a new

Box 1. FDA recommendation for the use of

concomitant medication in clopidogrel-treated

subjects.

Information supports avoidancePPIsOmeprazoleEsomeprazoleOther drugsCimetidineFluconazoleKetoconazoleEtravirineFelbamateFluoxetineFluvoxamineVoriconazoleThere is no evidence of interactionRanitidineFamotidineNizatidineThere is no evidence to give a recommendationBalance risk/benefit in each patientPantoprazoleRabeprazole

From [53].



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P2Y12 inhibitor, was the first step on this pathway. This drug,which is hydrolyzed by esterases and activated in the liver byCYPs 3A4, 2B6, and to a lesser extent by 2C9 and 2C19,would not have clinically significant drug--drug interac-tions [61,62] and demonstrates a reduction in the rate ofcardiovascular death, nonfatal myocardial infarction ornonfatal stroke in patients with ACS [33]. The other moleculethat is about to obtain FDA approval is ticagrelor, a non-thienopyridine reversible and direct antagonist of P2Y12receptor which requires no metabolic activation and hasrecently demonstrated reduction in cardiovascular death,myocardial infarction or stroke without a rise in bleedingrate at 1-year follow-up [63].

Nevertheless, more information on efficacy and safetyof these alternatives will be required to make a more appro-priate and balanced comparative analysis with regards to thewell-established clopidogrel-based antiplatelet therapies.

Acknowledgement

We thank S Waldman for her kind help in the final revisionof the manuscript.

Declaration of interest

The authors state no conflict of interest and have received nopayment in preparation of this manuscript.

‘Real life’patients

(more diabetes,renal failure, age)

Randomized-controlled trial

patients

(less diabetes,renal failure, age)Clopidogrel resistance

PPIs

Ad

vers

e ca

rdio

vasc

ula

rev

ents

Figure 4. Suggested conceptual framework for clopidogrel and proton pump inhibitor (PPI) interaction. The disparities

observed between information from clinical trials and registries could be related to the population included in each type of

study. In a randomized controlled trial-like population the addition of PPI seemed to produce no modification on clopidogrel

effectiveness. The opposite was observed in registries with fewer selected subjects. In each case, the presence of comorbid

conditions that modulate platelet responsiveness could be the explanation for this phenomenon.



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32895609en.pdf [Last accessed

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Professionals/ucm190787

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premature interruption, gives

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AffiliationMariano A Giorgi†1,2 MD,

Guillermo Di Girolamo3,4 MD PhD &

Claudio D Gonzalez2,5 MD†Author for correspondence1Department of Cardiology &

Cardiovascular Surgery,

FLENI,

Montaneses 2325 (1428),

Buenos Aires, Argentina

E-mail: [email protected] of Pharmacology,

School of Medicine,

Universidad Austral,

Juan Domingo Peron 1500 (B1664INZ),

Pilar, Buenos Aires, Argentina3Department of Pharmacology,

School of Medicine,

Universidad de Buenos Aires,

Paraguay 2155 Piso 16 (C1121ABG),

Buenos Aires, Argentina4Department of Physiological,

Biochemistry & Pharmacological Sciences,

School of Medicine,

Universidad Favaloro,

Solıs 453 (C1078AAI),

Buenos Aires, Argentina5Department of Pharmacology,

School of Medicine,

Instituto Universitario CEMIC,

Av. Galvan 4102 (C1431FWO),

Buenos Aires, Argentina



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