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MINI-FOCUS ISSUE: PLATELET INHIBITIONState-of-the-Art Paper

Clopidogrel and Proton Pump InhibitorsInfluence of Pharmacological Interactions on Clinical Outcomesand Mechanistic Explanations

Udaya S. Tantry, PHD,* Dean J. Kereiakes, MD,† Paul A. Gurbel, MD*

Baltimore, Maryland; and Cincinnati, Ohio

Dual antiplatelet therapy with aspirin and clopidogrel is associated with a significant reduction in vas-

cular ischemic events; however, gastrointestinal bleeding events are a major concern in high-risk and

older patients. Clinical practice guidelines recommend combination therapy with proton pump inhibi-

tors (PPI) and dual antiplatelet therapy to attenuate gastrointestinal bleeding risk. In addition, high on-

treatment platelet reactivity has been associated with recurrent ischemic events. Whether or not the

pharmacological interaction between clopidogrel and PPI, which results in diminished antiplatelet ef-

fect, adversely influences clinical efficacy is highly controversial and the subject of debate. Based on

largely anecdotal post-hoc analyses, the U.S. Federal Drug Administration’s and European Medicines

Agency’s recommendations discourage PPI use (particularly omeprazole) in patients treated with clopi-

dogrel. However, many American College of Cardiology/American Heart Association/Society for Cardio-

vascular Angiography and Interventions experts do not support change in clinical practice guidelines

recommendations without adequately powered, prospective, randomized clinical trial data. (J Am Coll

Cardiol Intv 2011;4:365–80) © 2011 by the American College of Cardiology Foundation

Iltwcaa

The clinical efficacy of dual antiplatelet therapy(DAPT) combining aspirin with clopidogrel for pre-venting recurrent cardiovascular ischemic events hasbeen demonstrated in a wide range of patients andhas been incorporated into clinical practice guidelines(1). However, the recurrence of ischemic events�10%) and their association with high on-treatmentlatelet reactivity (HPR) in response to adenosineiphosphate (ADP) remain important concerns (2).

From the *Sinai Center for Thrombosis Research, Sinai Hospital ofBaltimore, Baltimore, Maryland; and †Christ Hospital, Heart andVascular Center/The Lindner Research Center at The Christ Hospital,Cincinnati, Ohio. Dr. Tantry has reported that he has no relationshipsto disclose. Dr. Kereiakes has received research grants from AbbottVascular, Amylin Pharmaceuticals, Cordis/Johnson & Johnson, BostonScientific, and Daiichi Sankyo, Inc.; has received consulting fees andhonoraria from Abbott Vascular, Boston Scientific, Eli Lilly and Co.,Medpace, and REVA Medical Inc.; and is on the Speakers’ Bureau forEli Lilly & Co. Dr. Gurbel has received research grants from AstraZen-eca, Boston Scientific, Medtronic, Porotola, Pozen, and Sanofi-Aventis;and he has received consulting fees and honoraria from AstraZeneca,Haemoscope, Porotola/Novartis, Pozen, Sanofi-Aventis, Bayer, Eli Lillyand Co., Daiichi Sankyo, and Schering-Plough/Merck.

Manuscript received November 19, 2010; revised manuscript receivedDecember 14, 2010, accepted December 26, 2010.

n addition, the cardioprotective property of pro-onged aspirin therapy is associated with gastrointes-inal complications including ulceration and bleeding,hich have been attributed to topical mucosal injury

aused by inhibition of prostaglandin and to systemicntiplatelet effects owing to inhibition of thrombox-ne A2 production (3). Prostaglandins are responsible

for increased mucosal blood flow, proliferation ofgastric epithelial cells, and stimulation of mucus andbicarbonate secretion. Therefore, inhibition of pros-taglandin synthesis by aspirin reduces the gastricmucosa protection and makes it susceptible to gastriculcer formation caused by endogenous acid, pepsin,and bile salts (3). Furthermore, inhibition of plateletaggregation as well as growth factor release fromplatelets at the site of vascular injury attenuates gastrichealing and increased susceptibility to gastrointestinalbleeding (GIB) (4). Small bowel mucosal abnormal-ities have been demonstrated following 100 mg aspi-rin daily for 2 weeks as have upper gastrointestinalendoscopic abnormalities after DAPT for 3 months(5,6). A meta-analysis of 14 randomized trials involv-

ing �57,000 patients demonstrated a 2-fold increase

r1spFqd(Rvd

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in major GIB in patients treated with aspirin compared withpatients treated with placebo. Although no relationship be-tween aspirin dose and major bleeding risk was observed in thismeta-analysis, other studies have demonstrated a dose-dependent effect of aspirin on GIB (7,8).

Unlike aspirin, clopidogrel does not directly cause gastricinjury, but its antiplatelet effects may impair healing ofexisting gastric erosions and may exacerbate GI complica-tions associated with the concomitant administration ofaspirin and nonsteroidal anti-inflammatory drugs, or in thesetting of Helicobacter pylori infection. For example, aspirin

325 mg daily (but not clopi-dogrel 75 mg daily) for 8 dayscaused direct effects on GI mu-cosa in healthy volunteers (9). Inthe CAPRIE (Clopidogrel Ver-sus Aspirin in Patients at Risk ofIschaemic Events) trial (10), as-pirin monotherapy was associ-ated with an increase in majorGIB (risk ratio [RR]: 1.45; 95%confidence interval [CI]: 1.00 to2.10) when compared withclopidogrel monotherapy. In theCURE (Clopidogrel in UnstableAngina to Prevent RecurrentEvents) trial, aspirin mono-therapy was associated with lessfrequent major GIB when com-pared with aspirin � clopidogrel(RR: 0.56; 95% CI: 0.39 to 0.80)and in the MATCH (Manage-ment of Atherothrombosis WithClopidogrel in High-Risk Pa-tients) trial, clopidogrel mono-therapy was associated with lessfrequent major GIB than clopi-dogrel � aspirin was (RR: 0.34;95% CI: 0.23 to 0.51) (11,12).In a Danish case control study,more GIB complications wereobserved in patients treated witheither low dose aspirin (odds

atio [OR]: 1.8; 95% CI: 1.5 to 2.1), or clopidogrel (OR:.1; 95% CI: 0.6 to 2.1) when compared with age- andex-matched controls. The greatest risk of GIB occurred inatients receiving DAPT (OR: 7.4, 95% CI: 3.5 to 15) (13).inally, a correlation between major bleeding with subse-uent myocardial infarction (MI), stroke, and death at 30ays was demonstrated in both the CURRENT/OASIS-7Clopidogrel Optimal Loading Dose Usage to Reduceecurrent EveNTs/Optimal Antiplatelet Strategy for Inter-

entionS) and CURE trials (14). In the CHARISMA (Clopi-

Abbreviationsand Acronyms

ADP � adenosinediphosphate

ATPase � adenosinetriphosphatase

CL-AM � clopidogrel activemetabolite

DAPT � dual antiplatelettherapy

FDA � U.S. Food and DrugAdministration

GI � gastrointestinal

GIB � gastrointestinalbleeding

HPR � high on-treatmentplatelet reactivity

LD � loading dose

MACE � major adversecardiac event(s)

MD � maintenance dose

MI � myocardial infarction

PCI � percutaneouscoronary intervention

PPI � proton pump inhibitors

SNPs � single nucleotidepolymorphism

VASP-PRI � vasodilatorstimulated phosphoprotein–platelet reactivity index

ogrel for High Atherothrombotic Risk and Ischemic Stabi-

lization, Management, and Avoidance) trial (15), moderatebleeding was associated with all-cause mortality (hazard ratio[HR]: 2.55; 95% CI: 1.71 to 3.80; p � 0.0001), MI (HR: 2.92;95% CI: 2.04 to 4.18; p � 0.0001), and stroke (HR: 4.20; 95%CI: 3.05 to 5.77; p � 0.0001). It should be noted that patientswho experience GIB are frequently older and have morecomorbidities.

The Rationale for Combining PPIs WithAntiplatelet Therapy

The prior observations provide a rationale for concomitantadministration of proton pump inhibitors (PPI) in patientstreated with either aspirin alone or DAPT, particularlythose at greatest risk for GIB complications (16–19). Forexample, the addition of a PPI (omeprazole, lansoprazole,pantoprazole, rabeprazole, or esomeprazole) to either aspi-rin or thienopyridine therapy reduced the incidence of GIBcompared with either agent administered without a PPI(RR: 0.32 and 0.19, respectively) (16). Histories of pepticulcer disease or cardiogenic shock were independent predic-tors of GIB in patients treated with DAPT. Importantly,PPI therapy administered concomitantly with DAPT oraspirin can significantly reduce GIB (17). For example,clopidogrel monotherapy (no PPI) was associated with ahigher incidence of recurrent ulcer bleeding than combinedaspirin plus esomeprazole treatment (8.6% vs. 0.7%, 95%CI: 3.4 to 12.4%) in patients who were H. pylori negativewith a history of GI bleeding on low dose aspirin therapy(18). These multiple observations suggest that the additionof PPI as a gastroprotective agent in patients treated witheither aspirin or DAPT can mitigate the potential for GIB.

A clinical expert consensus document states that PPIshould be added to oral antiplatelet therapy in cardiovascu-lar disease patients to reduce the risk of GIB (3). Clopi-dogrel and PPIs are among the most widely prescribedmedications with worldwide sales of U.S. $8.6 and $26.5billion, respectively, in 2008 (20). Furthermore, the fre-quency of coadministration (thienopyridine with any PPI)was 31% in the CREDO (Clopidogrel for Reduction ofEvents During Observation) (21), 33% in the TRITON–TIMI 38 (Trial to Assess Improvement in TherapeuticOutcomes by Optimizing Platelet Inhibition With Prasug-rel–Thrombolysis In Myocardial Infarction 38) (22), 54% inthe PLATO (Platelet Inhibition and Patient Outcomes)(clopidogrel arm) trials, and 64% in the Veterans Affairsretrospective analysis study. Among these studies, omepra-zole was the predominant PPI and accounted for 60% and37% of PPI use in the VA and TRITON–TIMI 38 studies,respectively (21–23). Based on the apparent high frequency ofcoadministration, any pharmacokinetic/pharmacodynamic in-teraction of the long-term regimens between PPIs and thien-opyridines that could influence clinical efficacy and/or safety

must be carefully evaluated. In this regard, guidelines of the

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U.S. Food and Drug Administration (FDA), European Med-icines Agency, and American College of Cardiology/AmericanHeart Association have provided conflicting recommen-dations regarding the concomitant use of PPI and clopi-dogrel (3,24 –28) (Table 1). Thus, it is appropriate andtimely to review available pharmacokinetic and pharmaco-dynamic as well as clinical information regarding interac-tions between these medication classes.

Clopidogrel Metabolism, SNPs,and Clinical Outcomes

Most absorbed clopidogrel (�85%) is hydrolyzed by hepaticcarboxylesterase to an inactive carboxylic acid metabolite,SR26334, and the remaining �15% is converted to an activethiol metabolite by hepatic cytochromes (CYP) in a 2-stepprocess (Fig. 1) (29). The parent compound is usuallyundetectable in plasma at 2 h after oral administration. The

Table 1. Guidelines, Recommendations, and Policy Statements Regarding

ACCF/ACG/AHA 2008 expert consensus document (3)

“Recommendation: The use of low-dose ASA for cardioprophylaxis is associated wreduce the risk of bleeding. For patients at risk of adverse events, gastroprotectio

The risk of UGIE increases with ASA dose escalation; thus, for the chronic phase o

“Recommendation: Substitution of clopidogrel for ASA is not a recommended strathe combination of ASA plus PPI.”

ACC and AHA (2007) guidelines for the management of patients with unstable angin

“In UA/NSTEMI patients with a history of gastrointestinal bleeding, when ASA andrecurrent gastrointestinal bleeding (e.g., proton-pump inhibitors) should be prescr

“Clopidogrel 75 mg daily (preferred) or ticlopidine (in the absence of contraindicacontraindicated or not tolerated because of hypersensitivity or gastrointestinal intof Evidence: A).”

U.S. FDA update to clopidogrel labeling (25)

”The concomitant use of omeprazole and clopidogrel should be avoided becauserisk for heart attacks or strokes, who are given clopidogrel to prevent blood clots,omeprazole or the OTC form (Prilosec OTC).

� Separating the dose of clopidogrel and omeprazole in time will not reduce this

� At this time, FDA does not have sufficient information about drug interactionsrecommendations about their coadministration. Healthcare professionals and patie

European Medicines Agency public statement on possible interaction between clopi

“Taking all the data into account, the Agency’s Committee for Medicinal Productsrecommended that the product information for all clopidogrel-containing medicinmedicines unless absolutely necessary. Accordingly, the marketing authorization happlications to amend the product information.

Furthermore, CHMP recommended that further information is needed in relation toimplications of genetic variation which results in a small proportion of individualsactive form, regardless of interactions with other medicines.”

International Consensus Upper Gastrointestinal Bleeding Conference Group. Internatupper gastrointestinal bleeding (27)

“In patients with previous ulcer bleeding who require cardiovascular prophylaxis,combined with a PPI” and “Patients with upper GIB who require secondary cardioprophylaxis outweigh gastrointestinal risks (usually within 7 days); ASA plus PPI th

2009 focused updates: ACC/AHA guidelines for the management of patients with STFoundation/American Heart Association Task Force on Practice Guidelines (28).

“The writing committee concluded that additional data, notably randomized trialrecommendation can be made about the use of dual antiplatelet therapy with PP

ACC � American College of Cardiology; ACCF � American College of Cardiology Foundation; ACG

FDA � Food and Drug Administration; GIB � gastrointestinal bleeding; NSTEMI � non–ST-segme

angina; UA/NSTEMI � unstable angina/non–ST-segment elevation myocardial infarction; UGIE � upper ga

thiophene ring is first oxidized to 2-oxo-clopidogrel and toan active metabolite (CL-AM), R-130964, in the secondstep. This highly unstable CL-AM binds covalently andspecifically to the platelet ADP-binding site in the P2Y12

receptor when platelets pass through the hepatic circulation.Recent studies indicate that the CYP2C19, CYP1A2,CYP2B6 isoenzymes are responsible for the first step,whereas CYP2C19, CYP2C9, CYP2B6, and CYP3A4 areresponsible for the second step. As noted, CYP2C19 con-tributes substantially to both steps, whereas CYP3A4 con-tributes substantially to the second step (30).

Multiple lines of evidence suggest that variable andinsufficient CL-AM generation following clopidogrel ad-ministration are the primary explanations for clopidogrelresponse variability and nonresponsiveness, respectively.Variable levels of CL-AM generation may be explained bymultiple genetic, environmental, and clinical factors. In

se in Patients Treated With Oral Antiplatelet Therapy

- to 4-fold increase in UGIE risk. Enteric-coated or buffered preparations do notld be prescribed.

py, doses �81 mg should not be routinely prescribed.”

o reduce the risk of recurrent ulcer bleeding in high-risk patients and is inferior to

–ST-segment elevation myocardial infarction (24)

ogrel are administered alone or in combination, drugs to minimize the risk ofoncomitantly (Classic Journal, Level of evidence: B).”

should be given to patients recovering from UA/NSTEMI when ASA ise (but with gastroprotective agents such as proton-pump inhibitors) (CLASS, Level

effect on clopidogrel’s active metabolite levels and anticlotting activity. Patients atot get the full protective anticlotting effect if they also take prescription

interaction.

en clopidogrel and PPIs other than omeprazole and esomeprazole to make specificould consider all treatment options carefully before beginning therapy.”

and proton-pump inhibitors (26)

man Use (CHMP) and its Pharmacovigilance Working Party (PhVWP) haveuld be amended to discourage concomitant use of PPI and clopidogrel-containingfor the clopidogrel-containing medicines will shortly be submitting variation

ibition of clopidogrel metabolism by other medicines, and in relation to thelled “CYP2C19 poor metabolizers”) being unable to fully convert clopidogrel to its

onsensus recommendations on the management of patients with nonvariceal

ld be recognized that clopidogrel alone has a higher risk for rebleeding than ASAr prophylaxis should start receiving ASA again as soon as cardiovascularis preferred over clopidogrel alone to reduce bleeding.”

ion myocardial infarction: a report of the American College of Cardiology

at have been peer reviewed and published, are needed before an officiale setting of ACS.”

rican College of Gastroenterology; AHA � American Heart Association; ASA � acetylsalicylic acid;

tion myocardial infarction; OTC � over the counter; PPI � proton pump inhibitor; UA � unstable

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addition, intestinal p-glycoprotein transporter and its inhib-itors (including omeprazole) may play a role in clopidogrelabsorption (31). Moreover, a relationship between thep-glycoprotein gene polymorphisms and the occurrence ofadverse ischemic events has been demonstrated in patientstreated with dual antiplatelet therapy (32–34).

Functional variability in hepatic P450 isoenzyme activityowing to single nucleotide polymorphisms (SNPs), drug-drug interactions, and other factors may affect clopidogrelmetabolism and its clinical efficacy. A diminished pharma-codynamic response to clopidogrel has been observed withcoadministration of PPIs, lipophilic statins, calcium channelblockers, and warfarin that are metabolized by theCYP2C19, CYP3A4, and CYP2C9 isoenzymes, respectively(35–38). Moreover, cigarette smoking and coadministrationof Saint John’s wort or rifampin are known to augment theantiplatelet response to clopidogrel through activation ofCYP1A2 and CYP3A4, respectively (36,39,40). The clinicalconsequences of these pharmacodynamic interactions remaincontroversial. Furthermore, increased body mass index, diabe-tes mellitus (particularly in the contexts of elevated serumfibrinogen, poor glucose control, or diminished renal function)and the extent of existing coronary disease may be associatedwith increased baseline platelet reactivity and a diminished

Figure 1. Clopidogrel Metabolism and Sites of Drug-Drug Interactions and

Clopidogrel response variability is a pharmacokinetic problem primarily influenmetabolite. Clopidogrel absorption may be affected by polymorphism of the Adrug-drug interactions (DDIs), single nucleotide polymorphisms (SNPs), and otfrom Bonello et al. (2).

antiplatelet response to clopidogrel (41–43). w

Recent studies have evaluated the relationship betweensingle SNPs of the gene encoding CYP2C19 isoenzymeswith clopidogrel response variability and clinical outcomes(44–48). It remains uncertain whether other factors asso-ciated with a diminished clopidogrel response may beadditive to SNPs in further reducing the antiplatelet effectof clopidogrel and thus, potentially, its clinical efficacy inreducing ischemic events. Of at least 25 SNPs for the geneencoding the CYP2C19 isoenzyme (49), the most frequentand widely analyzed include *2, which has been associatedwith a complete absence of 2C19 activity (allele frequency�15% in Caucasians and African Americans and �30% inAsians) and *17, which has been associated with increasedexpression and enzyme function (allele frequency �15% inCaucasians and African Americans and �4% in Asians).The *3, *4, *5, and *8 variants are less frequently observedloss of function alleles (50).

Based on ADP-induced platelet aggregation measure-ment to reflect clopidogrel responsiveness in the GWAS(Genome Wide Association Study), Shuldiner et al. (45)identified a 13-SNP cluster (within a flanking CYP2C18-2C19-2C9-2C8 cluster of 1.5 megabases on 10q24) out of�400,000 SNPs that was associated with 70% of clopi-dogrel response (p � 10�7) and from which CYP2C19*2

ic Polymorphisms

y cytochrome P450 (CYP) isoenzyme activity in the generation of the activegene. The activity of the hepatic cytochrome isoenzymes are influenced bytors such as smoking and caffeine consumption. Modified, with permission,

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associated signal. In the same study, carriers of theCYP2C19*2 genotype who had undergone percutaneouscoronary intervention (PCI) experienced higher cardiovas-cular event rates than noncarriers did (HR: 2.42; p � 0.02)(45). In healthy volunteers, a 32.4% relative reduction (p �0.001) in plasma CL-AM and a 25% relative reduction inmean platelet aggregation (p � 0.001) was observed incarriers of at least 1 CYP2C19 reduced-function allelecompared with noncarriers (46). Numerous studies havecorrelated adverse clinical outcomes with CYP2C19*2 carrierstatus (44–48,50–53). Among patients with acute coronarysyndromes who had PCI and were treated with clopidogrelin the TRITON–TIMI 38 trial, carriers of a 2C19 reduced-function allele had an increase in primary endpoint events(cardiovascular death, nonfatal MI, or nonfatal stroke) (HR:1.53; p � 0.04) and stent thrombosis (HR: 3.09; p � 0.02)compared with noncarriers (46). Similarly, compared with2C19 wild-type homozygotes, 2C19*2 carriers were dem-onstrated to have an increased incidence of stent thrombosisto 30 days (HR: 3.81; p � 0.007) (15). These investigatorsalso demonstrated that 2C19*17 allele carriers had lowerlevels of ADP-induced platelet aggregation (p � 0.039) andhigher bleeding risk during clopidogrel treatment comparedwith wild-type carriers (p � 0.01) (51). Meta-analyses byboth Hulot et al. (52) and Mega et al. (53) have demon-strated that carriers of the 2C19*2 allele, when comparedwith noncarriers, have an increased risk for major adversecardiac events (MACE) including death and stent throm-bosis, and risk was independent of baseline cardiovascularrisk. In the Hulot et al. (52) meta-analyses, an increased riskfor MACE and mortality was also observed in PPI users (vs.nonusers) particularly those with high baseline cardiovascu-lar risk. Conversely, in the recently published geneticsubstudies of the CHARISMA (54), CURE (55), andACTIVE A (Effect of Clopidogrel Added to Aspirin inPatients With Atrial Fibrillation) (55) trials, there was noassociation of CYP2C19*2 allele with adverse clinical out-comes in clopidogrel-treated subjects. Potential explana-tions for these apparent discrepant observations include thelower use of PCI with stenting in the CURE trial (14.5%)as well as the relatively lower-risk populations enrolled intothe ACTIVE A and CHARISMA trials (nonacute coro-nary syndrome, non-PCI/stenting) (56).

Thienopyridines may inhibit CYP isoenzymes as demon-strated in in vitro studies using human liver microsomes andrecombinantly expressed P450 isoforms. Both clopidogreland ticlopidine were associated with time- and con-centration-dependent inhibition of CYP2B6 and to a lesserextent, CYP2C19 (57). A weak inhibitory effect of 2-oxo-clopidogrel, prasugrel, and R-95913 (active metabolite ofprasugrel) was also observed (58). Inhibition of CYP2C19activity by ticlopidine was directly proportional to the levelof baseline activity and, thus, was most evident in normal

(*1/*1) metabolizers. Repeated ticlopidine dosing was asso- C

ciated with an increase in omeprazole concentrations inrapid metabolizers but not in the poor metabolizers (59,60).The influence of clopidogrel on CYP2C19-dependentomeprazole metabolism was evaluated in healthy volunteerswho received either placebo or clopidogrel (300-mg load, 75mg/day for 3 days) coadministered with omeprazole (40mg/day). A significant increase (mean 30%) in plasmaomeprazole and a significant decrease (mean 24%) in plasma5-hydroxyomeprazole were observed in rapid metabolizers(*1/*1 allele) but not in poor metabolizers (*2/*2 allele) (61).This study demonstrated that clopidogrel inhibitedCYP2C19-mediated hydroxylation of omeprazole in rapidmetabolizers but had no effect on CYP3A4-catalyzed sul-foxylation of omeprazole. Thus, omeprazole metabolismmay be shifted to CYP3A4 in poor (CYP2C19) metabo-lizers or in the presence of a CYP2C19 inhibitor such asclopidogrel (61).

PPIs

Mechanism of action and metabolism. Proton pump inhib-tors are benzimidazole-derivative prodrugs whose absorp-ion from the bowel is influenced by the p-glycoproteinransporter. The H�/K�-adenosine triphosphataseATPase) present in the canalicular membrane of gastricarietal cells secretes hydrochloric acid and a proton isxchanged for potassium with ATP breakdown. Followingbsorption, PPIs undergo activation and the activated cycliculfonamide covalently binds to the extracytoplasmic cys-eine residues of H�/K�-ATPase and irreversibly inhibits�/K�-ATPase pump activity/gastric secretion. Because

f the short plasma half-life (1 to 2 h) of PPIs andontinuous activation of inactive pumps, up to 3 days areequired to achieve maximum acid suppression by PPIs (62).lthough all PPIs are highly effective in inhibiting gastric

cid secretion, pharmacokinetic and pharmacodynamic dif-erences may influence clinical effectiveness as well as theotential for drug-drug interactions (62). Although theioavailability of pantoprazole, lansoprazole, and rabepra-ole are similar, plasma concentrations of omeprazole in-rease 1.5- to 2-fold and of esomeprazole 3-fold following 5ays of therapy compared with day 1 (63).

Effects of PPIs on CYP-isoenzyme activity and drug-druginteractions. All PPIs, except for rabeprazole, are exten-ively metabolized by and competitively inhibit CYP2C19nd CYP3A4 (60). Lansoprazole and omeprazole appear toe the strongest (Ki � 0.4 to 1.5 �mol/l and 2 to 6 �mol/l,

respectively), whereas pantoprazole is the weakest inhibitor(Ki � 14 to 69 �mol/l) of CYP2C19. The observation ofignificant interaction between PPIs and other CYP2C19

etabolized drugs such as diazepam, phenytoin,-warfarin, and clopidogrel is not surprising in that �70%f all therapeutic drugs are metabolized by CYP3A4 and

YP2C219 isoenzymes (62) (Fig. 2). Moreover, a significant

fs

such a

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association between omeprazole metabolism and CYP2C19genotype (metabolizer status, loss or gain of function alleles)exists (62,64).

The CYP2C19*2 reduced function allele is associated withpoor metabolism of omeprazole and other drugs such asdiazepam and phenytoin (65). In addition, other CYP-isoenzymes such as CYP3A4 may become more important inCYP2C19*2 poor metabolizers or in the presence of potentCYP2C19 inhibitors such as clopidogrel (61,65). Interest-ingly, the coadministration of drugs with high affinity forCYP3A4 (ketoconazole or clarithromycin) inhibits omepra-zole metabolism and is associated with increased plasmaomeprazole concentrations in poor as well as extensiveCYP2C19 metabolizers. Conversely, coadministration ofginkgo biloba or St John’s wort (CYP2C19 inducers) en-hances the metabolism of omeprazole (62). Rabeprazole,which is mainly metabolized through nonenzymatic reduc-tion to a thioether compound, has the least inhibitory effecton CYP isoenzyme activities (62). A recent meta-analysissuggests that the efficacy of omeprazole but not rabeprazolein the treatment of H. pylori infection depends on CYP2C19gene polymorphism and metabolizer status (66). In addi-tion, in vitro studies demonstrated that PPIs could inhibitthe p-glycoprotein mediated efflux of digoxin (67). Finally,

Figure 2. Omeprazole Metabolism, Mechanism of Action, and Sites of Drug

After absorption, omeprazole undergoes activation (protonation) and the activpump activity/gastric secretion. Omeprazole is extensively metabolized by andpathway involves its conversion by CYP2C19 to inactive 5-hydroxyomeprazolesecond step. However, omeprazole first metabolized by CYP3A4 to omeprazoleallele carriers or subjects treated with drugs that are mainly metabolized by 2C19

both CYP2C19 and p-glycoprotein genetic polymorphisms p

may influence drug-drug interactions and the pharmacoki-netic/pharmacodynamic properties of PPIs, which in turnmay influence clinical outcomes related to gastric acidsuppression and/or H. pylori eradication (66–68).

Drug-Drug Interactions BetweenClopidogrel and PPIs

Pharmacokinetic and pharmacodynamic interactions. Mul-tiple pharmacodynamic studies have demonstrated the in-fluence of PPI treatment (particularly omeprazole) on clopi-dogrel antiplatelet effects (35,62,69–80) (Table 2). In adouble-blind, randomized controlled study, PCI patientstreated with aspirin (75 mg/day) and clopidogrel (300-mgloading dose [LD] � 75-mg/day maintenance dose [MD])were randomly assigned to receive either omeprazole (20mg/day) or placebo for 7 days. Omeprazole reduced clopi-dogrel antiplatelet effect (vasodilator stimulated phospho-protein–platelet reactivity index [VASP-PRI]: 39.8% pla-cebo vs. 51.4% omeprazole, p � 0.0001) at 7 days but noton day 1. Moreover, the prevalence of a poor clopidogrelresponse (defined by a VASP-PRI �50%) was higherollowing omeprazole than placebo (60.9% vs. 26.7%, re-pectively, p � 0.0001) (35). Similarly, in a randomized

Interactions and Genetic Polymorphisms

yclic sulfonamide irreversibly inhibits H�/K�–adenosine triphosphataseetitively inhibits CYP2C19 and CYP3A4. The major omeprazole metabolismmetabolized to inactive omeprazole hydroxy sulfonate by CYP3A4 in theate and further to omeprazole hydroxy sulfonate in the 2C19 loss-of-functions clopidogrel, diazepam, and phenytoin. Abbreviations as in Figure 1.

-Drug

ated ccompthat issulfon

harmacodynamic study involving 20 healthy volunteers,

MdP

cprPcc

ccjf(s(MiliaolciiVtcbagnCcoioe(ps

otcftP

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coadministration of clopidogrel (600-mg LD � 75-mg/dayD for 14 days) with omeprazole (20 mg/day) resulted in

ecreased platelet inhibition (measured by the VerifyNow2Y12 assay) at day 14 (p � 0.048) but not at 1 or 7 days

(70). In a post hoc subgroup analysis of the PRINCIPLE–TIMI 44 (The Prasugrel in Comparison to Clopidogrel forInhibition of Platelet Activation and Aggregation–Thrombolysis In Myocardial Infarction 44) trial, coadmin-istration of PPI with clopidogrel reduced platelet inhibitionat 2, 6, and 18 to 24 h after 600-mg clopidogrel LD with atrend toward reduction in platelet inhibition following150-mg/day MD for 15 days compared with clopidogrelmonotherapy. Prasugrel-mediated platelet inhibition wasalso reduced both acutely and at 15 days by PPI coadmin-istration compared with prasugrel alone and the proportionsof nonresponders (defined by �29% inhibition of 20 �mol/lADP-induced aggregation) to both clopidogrel and prasu-grel were increased by PPI coadministration (71).

A differential response between various PPI and clopi-dogrel has been suggested. For example, using the Multi-plate analyzer (Multiplate, Munich, Germany), Sibbing etal. (72) observed that patients coadministered omepra-zole, but not pantoprazole or esomeprazole, had higherresidual platelet aggregation while on clopidogrel therapy(p � 0.001). In addition, the prevalence of a poor clopi-dogrel response (defined as an arbitrary unit [AU] � min�456) was higher in patients treated with omeprazole (33%vs. 19% without, p � 0.008). However, other factors such asdiabetes, body mass index, renal insufficiency, and smoking(in addition to omeprazole treatment) were independentpredictors of antiplatelet response to clopidogrel treatment(72). In a crossover study involving healthy volunteerstreated with single doses of either clopidogrel (300 mg) orprasugrel (60 mg), the coadministration of lansoprazole didnot alter platelet inhibition by prasugrel, but a trend towardreduction in clopidogrel-mediated platelet inhibition wasobserved that was most pronounced in clopidogrel respond-ers (74). Other studies have suggested that the PPI-clopidogrel interaction to reduce clopidogrel-mediatedplatelet inhibition is less evident following pantoprazole orrabeprazole than omeprazole (64,75). Furthermore,CYP2C19 metabolizer status may significantly influence themagnitude of PPI-clopidogrel interaction. For example, areduction in antiplatelet effect of clopidogrel effect wasobserved in rapid metabolizers (genotype *1/*1) adminis-tered either omeprazole (p � 0.015) or rabeprazole(p � 0.035) but not in decreased metabolizers (*2 or *3 allelearriers). Nevertheless, clopidogrel-induced inhibition oflatelet aggregation remained lower in decreased versusapid metabolizers irrespective of concomitant or spacedPI administration (p � 0.0001), and there were nolopidogrel poor responders among the rapid metabolizer

ohort (64).

Finally, 4 randomized, placebo-controlled, crossoveromparison studies involving 282 healthy volunteers wereonducted to analyze the PPI-clopidogrel interaction. Sub-ects received either omeprazole (80-mg/day delayed-releaseormulation) or pantoprazole (80 mg/day) and clopidogrel300-mg LD � 150-mg/day MD) was administered eitherynchronously (with PPI) or separately (76). A synchronouswith omeprazole) clopidogrel 600-mg LD � 150-mg/day

D was also assessed. Unchanged plasma clopidogrel levelsncreased (19% at day 2, 37% to 51% at day 5) and CL-AMevels decreased (45% to 55% at day 2, 40% to 54% at day 5)rrespective of clopidogrel LD or the timing of omeprazoledministration. This observation argues against the presencef a drug-drug interaction at the p-glycoprotein transporterevel or related to gastric pH effects. During omeprazoleoadministration, platelet aggregation (5 �mol/l ADP)ncreased by 11% to 16% on day 1 and 6% to 8% on day 5n concert with a decrease in CL-AM levels. Similarly,ASP-PRI increased on days 1 (17% to 20%) and 5 (19%

o 27%) of omeprazole treatment. During pantoprazoleoadministration, CL-AM decreased (14% to 20%) whereasoth platelet aggregation and VASP-PRI increased by 4.3%nd 3.9% to 5.1%, respectively. These observations sug-est: 1) the PPI-clopidogrel interaction is more promi-ent for omeprazole than pantoprazole; 2) a reduction inL-AM level is the primary explanation for the PPI-

lopidogrel interaction; and 3) staggering the time coursef clopidogrel-omeprazole dosing does not influence thenteraction. However, these studies were performed with-ut aspirin coadministration (which has dose-dependentffects on platelet function) and the dose of omeprazole80 mg/day omeprazole for 5 days before clopidogrel orlacebo dosing) was 2 to 4 times that commonly pre-cribed clinically (76).

However, in a study of healthy volunteers administeredmeprazole (40-mg/day delayed-release formulation) ei-her concomitantly or staggered by 8 to 12 h withlopidogrel (600-mg LD and 75-mg/day MD), no dif-erence in clopidogrel-induced antiplatelet effect (lightransmittance aggregometry, VASP-PRI, VerifyNow2Y12) was observed following the loading dose or at 1 week

of maintenance therapy (77). Either synchronous or spacingomeprazole coadministration strategies resulted in higherVASP-PRI levels compared with clopidogrel monotherapy.Finally, the pharmacodynamic interaction between clopi-dogrel (300-mg LD � 75-mg/day MD) and PA32540, anovel combination drug (325 mg enteric-coated aspirin �40 mg immediate-release omeprazole) was evaluated inhealthy volunteers using both synchronous as well as stag-gered (12 h apart) dosing regimens. In this study, staggeredclopidogrel and PA32540 administration was associatedwith a greater clopidogrel-induced antiplatelet effect (re-duced drug-drug interaction) compared with synchro-

nous administration (78). Variations in CYP2C19 genotype,

Table 2. Pharmacodynamic Studies Demonstrating the Relation of Clopidogrel Antiplatelet Response With PPI Use

First Author (Ref. #) Patients (n) Treatment Method Results Comments

Gilard et al. (35)Randomized, double-blind,

placebo controlled study

Elective PCI (124) OMZ 20 mg (n � 64) orplacebo (n � 60); CLP300-mg LD � 75-mg MD,ASA 75 mg MD for 7 days

VASP-PRIDay 1Day 7

Day 1 � 83.9 � 4.6% vs.83.2 � 5.6%; p � NSDay 7 � 51.4 � 16.4% vs. 39.8 � 15.4%;

p � 0.001 �50% PRI � 60.9% vs. 26.7%;p � 0.001

Randomized studyOmeprazole effect was observed

on day 7, more nonresponders

Gilard et al. (69)Observational study

High risk coronaryangiography (105)

ASA; clopidogrel, PPI VASP-PRI�48 h after antiplatelettherapy

Mann-Whitney U test—no difference for statins, ACEI, ANG IIantagonists and beta blockers—with (n � 24) and without PPI (n � 81)PRI � 61.4 � 23.2% vs. 49.5 � 16.3%;p � 0.007

Observational study

Yun et al. (70)Crossover study

Healthy volunteers (n � 20) 75 mg/day CLP or placebofor 14 days followed by75 mg/day CLP or 20 mgOMZ for 14 days

VerifyNow P2Y12 assay 1 and 7 days—no change14 days PRU: OMZ, 281.3 � 54 vs.

240 � 72.2, p � 0.04814 days % inhibition: OMZ 22.7 � 29.9 vs.

35.1 � 18.7, p � 0.014

O’Donoghue et al. (71)Post-hoc, nonrandomized subgroupanalysis of PRINCIPLE–TIMI 44 study

Planned PCI (201) 600 mg/150 mg CLP(n � 22) � PPI vs. CLP alone

(n � 71) 60 mg/10 mgPRS � PPI (n � 25) vs.PRS alone (n � 77)

IPA 20 �mol/l ADP LTA CLP � PPI: significantly decreased IPA at 2, 6,2–24 h and 15 days;p � 0.003, 0.02, 0.03, and 0.06,respectively)

No information on PPI; PPIpatients were not randomized;study was not powered todetect the difference in IPA

0.5, 2, 6, 20–24 h and 15 days.Nonresponders (�20% IPA)at 6 h and 15 days

Nonresponders: 6 h: 50% vs. 18.2%p � 0.009 and 15 days: 50% vs. 7.9%,p � 0.012 PRS � PPI: significantlydecreased IPA at 0.5, 6, and 15 days;p � 0.009, 0.054, and 0.01 respectively) 6 h:0% vs. 0% p � NS and 15 days: 10% vs.0%, p � 0.025)

Sibbing et al. (72)Cross-sectional observational study

Controlled PCI (n � 1,000) Pts on median 7 months75-mg/day CLP treatment

No PPI � 732, PNT � 158,OMZ � 64, ESM � 74

At hospital admissionMultiplate analyzer: 6.4 �mol/l

ADP-induced AU � minNonresponders � upper

quintile (456 AU � min)

No PPI � 220 AU � minOMZ � 295.5AU � min (p � 0.001)

Nonresponders: OMZ � 32.8% vs. 19.1(p � 0.008)

PNT � 226 AU � min (p � 0.69)ESM � 209.0 AU � min (p � 0.88)

Zuren et al. (73)Observational study

CAD PCI (n � 1,425) �1 week PPI use before60-mg CLP LD OMZ � 36,PNT � 108, ESM � 280

20 �mol/l ADP � LTA � 20 hafter LD

No PPI vs. PPI; 40 � 16.6 vs. 41.1 � 17.4p � 0.005

Similar effect with all PPIs, PPI,age, BMI, ACEI are associatedwith HPR (�49%)

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which may have influenced the clopidogrel-omeprazoleinteraction, were not assessed in these later studies.

Coadministration of PPI WithClopidogrel and Clinical Outcomes

Multiple epidemiological studies have suggested that theconcomitant administration of PPI with clopidogrel may beassociated with adverse clinical events (71,79–89) (Table 3).For example, the potential interaction between clopidogreland PPIs was evaluated by a case-control study of patientswho filled prescriptions for clopidogrel within 3 days ofhospital discharge following acute MI. After extensivemultivariate adjustment, the concurrent use of PPIs withclopidogrel was associated with an increased incidence ofrecurrent MI to 90 days (adjusted odds ratio [AOR]: 1.27)(80). However, the lack of data on patient compliance withantiplatelet therapy as well as the inability to account forethnicity and CYP2C19 gene polymorphisms limits thereliability of this observation (81).

In a retrospective analysis of patients receiving clopi-dogrel after hospital discharge for acute coronary syndrome,multivariate analysis identified coadministration of PPI andclopidogrel therapy (vs. clopidogrel monotherapy) to beassociated with an increased risk for death or rehospitaliza-tion (AOR: 1.25) as well as hospitalization for recurrentacute coronary syndrome or revascularization (AOR: 1.86and 1.49, respectively) (82). In the clopidogrel MedcoOutcomes study of clopidogrel-treated patients followingcoronary stenting, MACE to 1 year was increased by 50% inpatients receiving concomitant PPI therapy compared withthose who were not (83). This relative risk persistedfollowing statistical adjustment for baseline differences inage, sex, and comorbidities. Moreover, the effect of PPI wasmore pronounced (AOR: 1.86) among patients with ahistory of cardiovascular events before stenting. Althoughthe risk associated with PPI among clopidogrel-treatedpatients persisted regardless of PPI type (omeprazole, es-omeprazole, pantoprazole, and lansoprazole), no risk wasapparent (PPI vs. no PPI) in the absence of concomitantclopidogrel therapy. Conversely, in a retrospective analysisof the CREDO trial, primary endpoint events at 28 days(death, MI, and urgent target vessel revascularization) and 1year (death, MI, and stroke) were increased in patientsreceiving PPIs at study baseline, regardless of their subse-quent randomized clopidogrel (vs. placebo) treatment allo-cation (84). Treatment with clopidogrel reduced cardiovas-cular events through 1 year to a similar degree whether ornot patients were receiving concomitant PPI. No influenceof PPI on clopidogrel clinical efficacy was observed (p �.69 for interaction of PPI and randomized treatment).inally, in a Danish nationwide cohort study of patientsospitalized for MI, an �30% increase in risk for cardio-

vascular death or rehospitalization for MI or stroke wasT S C A IP p V

Table 3. Studies Demonstrating the Influence of Coadministration of PPI on Clinical Efficacy of Clopidogrel Treatment

First Author (Ref. #) Patients (n) Treatment End point Results Comments

O’Donoghue et al. (71)Post-hoc, nonrandomizedsubgroup of TRITON–TIMI 38study

ACS-planned PCI (n � 13,608) PRS: 60-mg LD � 10-mg MD CLP:300-mg LD � 75-mg MD

PPI � 33.3% pts, PNT � 1,844,OMZ � 1,675, ESM � 613,LNZ � 441, RBR � 66

Pts with and without reducedfunction 2C19 allele

1-year composite of CVdeath, nonfatal MI, ornonfatal stroke (adjustedfor 28 variables)

Adjusted HRCLP � 0.94, 95% CI: 0.80–1.11PRS � 1.00, 95% CI: 0.84–1.20.

No effect of individual PPI.Reduced function allele CLP pts

without and with PPI 10.2%vs. 13% HR: 0.76. Reducedfunction allele PRS ptswithout and with PPI 7.4% vs.9.9% HR � 0.81.

PPI use determined at the time ofrandomization and at follow-uppoints.

Pezalla et al. (79)Retrospective cohort

�65-year-old pts treated withCLP

No PPI (n � 4,800), low PPI exposure(n � 712), high PPI exposure(n � 3,345)

1-year MI No PPI � 1.38%, Data corrected only for comorbidities

Low PPI � 3.08%, High PPI �

5.03%; p � 0.005

Juurlink et al. (80)Nested-control study

�65-year-old UA pts treatedwith CLP following MI

(n � 13,636)

PPI vs. no PPI, 734 (PPI � 194) ptsreadmitted for MI, controls � 2,057(PPI � 424)

90-days and 1-year acute MI Current use of PPI, OR: 1.27 Data adjusted for demographicvariables, concomitantmedications, and comorbidity.

CYP2C19 metabolized PPIs:OR � 1.40. PNT (Non-CYP2C19 metabolized):OR: 1.02

Ho et al. (82)VA hospital databaseretrospective study

ACS pts taking CLP(n � 8,205)

63.9% � prescribed PPI at discharge36.1% � no PPI

Death or RH Adjusted or for death or RH PPIvs. no PPI: 1.25, RH � 1.86,revascularization � 1.49,death � 0.91.

Risk of confounding variables atbaseline were adjusted foranalysis.

OMZ (59.7%) � 1.24,RBR (2.9%) � 2.83

Each 10% increase in the time takingCLP � PPI was associated withhigher risk for death orrevascularization (OR � 1.07)

Kreutz et al. (83)Retrospective (Medco) study

Previous PCI (n � 16,690) Pts never made PPI prescription over1-year post-stenting (n � 9,862)Pts with PPI (6,828)

1-year MACEhospitalization CV death for

stroke/TIA, ACS, orcoronaryrevascularization.

MACE � 17.9%, vs. 25.1%HR � 1.51; 95% CI: 1.39–1.64,

p � 0.0001. HR for OMZ �

1.39, ESM � 1.57, PNT �

1.61, LNS � 1.39

No increased risk of PPI in patientsnot treated with CLP comparedwith no PPI. (20.8% no PPI vs. PPI24.8%; HR � 1.19; 95% CI: � 0.84–1.70)

Dunn et al. (84)Retrospective cohort of CREDOrandomized trial

Undergoing or high likelihoodof PCI (n � 1,053)

CLP � ASA for 4 weeks vs. 1 year.PPI � CLP � 176 vs. CLP � 877PPI � 190 vs. no PPI � 873

1-year death, MI, or stroke CLP � PPI vs. CLP; OR: 1.63,p � 0.043

PPI vs. no PPI; OR � 1.55,p � 0.035

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Table 3. Continued

First Author (Ref. #) Patients (n) Treatment End point Results Comments

Kwok et al. (86)Meta-analysis

23 studies(n � 93,278)

CLP � PPI MACE � 19 studiesMI � 17 studies

No risk association in propensity-matched or randomized trials.

Observational studies adjusted forconfounders. MACE, OR � 1.44,p � 0.0001, Mortality � 1.04

Substantial heterogeneity.Overall, CLP and PPI use may be

associated with adverse CV eventsand MI, but no effect on mortality.

Siller-Matula et al. (87)Meta-analysis

Randomized trials(TRITON–TIMI 38,COGENT, CREDO)

CLP � PPI MACE, MI, death MACE: RCT: OR � 1.08, p � 0.60Non-RCT: OR � 1.33, p � 0.0004MI: RCT: OR � 0.98, p � 0.79 Non-RCT:

OR � 1.27, p � 0.07 Death: RCT:OR � 68, p � 0.04 Non-RCT:OR � 0.95, p � 0.30

Investigators conclude that higher rateof comorbidities in pts with CLP �

PPI might be major cause forobserved worse clinical outcomerather than effect of PPI.

Rassen et al. (88)Retrospective cohort

�65 years old, PCI, orhospitalized for ACS(n � 18,565)

CLP � PPI 6-month MI or death Propensity score adjusted ratio for deathor MI � 1.22, death � 1.20,revascularization � 0.97.

Demonstrated only a modest effect(risk unlikely to exceed �20%).

Bhatt et al. (89)Double-blind randomized

AMI, UA pts undergoingstenting

(n � 3,267)

CLP � OMZ delayed-releasecombination product)

CLP � placebo

Primary:GI events

Secondary: CV death, nonfatalMI, CABG, or PCI or stroke

OMZ has fewer GI eventsHR � 0.55, p � 0.007)

No difference inCV events (HR � 1.02).

Combination drug properties unknown.Premature termination. No completefollow-up. Low risk of confoundingvariables owing to specific inclusionand exclusion criteria.

ACS � acute coronary syndrome; CABG � coronary artery bypass grafting; COGENT � Clopidogrel and the Optimization of Gastrointestinal Events; CREDO � Clopidogrel for Reduction of Events During Observation; CV � cardiovascular; GI � gastrointestinal; HR � hazard

ratio; MACE � major adverse cardiac events; MI � myocardial infarction; OR � odds ratio; RCT � randomized clinical trial; RH � rehospitalization; RBR � rabeprazole; TIA � transient ischemic attack; TRITON–TIMI 38 � Trial to Assess Improvement in Therapeutic Outcomes

by Optimizing Platelet Inhibition With Prasugrel; other abbreviations as in Tables 1 and 2.

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observed in patients treated with PPI and clopidogrelcompared with clopidogrel alone (85). However, a similarrisk was also observed with PPI in patients not receivingconcomitant clopidogrel and was attributed to unmeasuredcofounders. No interaction was demonstrated between PPIand clopidogrel.

Discrepancy in the reported clinical relevance of a poten-tial PPI-clopidogrel interaction may in part be explained byrecent meta-analyses (86,87) that support the concept thatthe presence and magnitude of relative hazard related to PPIin clopidogrel-treated patients depends on study type andmethod of analysis. The relative risk ratio for adverseoutcomes related to PPI progressively diminishes fromcrude raw data to statistically adjusted observational studiesand finally to propensity score adjusted analyses or random-ized trials. These studies conclude that evidence for ameaningful clopidogrel-PPI interaction on cardiovascularoutcomes is inconsistent and that no definite evidence existsfor an effect on mortality. This premise finds support in aretrospective population-based study of elderly PCI patientsthat concluded that the relative risk attributable to PPIfailed to meet conventional thresholds for statistical signif-icance and did not exceed 20% (88).

Although concern regarding concomitant PPI-thieno-pyridine administration persists and has been heightened bya FDA communication, this concern has not been substan-tiated to date by adequately powered, large-scale random-ized trials with clinical endpoints. In the recently reportedCOGENT (Clopidogrel and the Optimization of Gastro-intestinal Events) trial, 3,873 clopidogrel-treated patientswere randomized to receive either CGT-2168 (combinationof 75 mg clopidogrel � 20 mg omeprazole) or 75 mgclopidogrel in conjunction with aspirin therapy followingPCI (89). The primary endpoint (6 months upper gastro-intestinal events) was reduced in the CGT-2168 cohort(1.1% vs. 2.9% clopidogrel alone). Furthermore, uppergastrointestinal bleeding was reduced in CGT-2168 treatedpatients (0.2% vs. 1.2% clopidogrel alone) and the secondaryoutcome measures of all cardiovascular events (compositeoccurrence of cardiovascular death, nonfatal MI, coronaryartery bypass graft, PCI, or ischemic stroke), MI, and therequirement for revascularization procedures were similarbetween randomized treatment groups. The investigatorsconcluded that no clinically relevant adverse interactionbetween clopidogrel and PPI treatment was evident (89).Multiple potential limitations to the COGENT studyshould be acknowledged including premature study termi-nation (planned enrollment 5,000 patients), low cardiovas-cular event rates (4.9% CGT-2168, 5.7% clopidogrel) andthe lack of either platelet function data (CGT-2168 plusaspirin vs. clopidogrel plus aspirin) or genotyping in the

study population (94% white).

Potential Mechanisms ofClopidogrel-Omeprazole Interaction

Preliminary in vitro studies suggest intestinal p-glycoproteinto be the first site of a potential drug-drug interaction (Fig. 3).Although both omeprazole and clopidogrel are known toinfluence p-glycoprotein function, a recent study indicatedthat omeprazole (80 mg/day) does not have any effect onclopidogrel absorption. In addition, evidence that plasmaunchanged clopidogrel levels are not lower during PPIadministration argue against a significant effect of gastricpH on absorption (77).

The major site of interaction appears to involve hepaticCYP P450 isoenzymes where both clopidogrel and PPIs(particularly omeprazole) are extensively metabolized byCYP2C19 and CYP3A4 (Fig. 3). In vitro studies indicatethat clopidogrel and PPIs inhibit each other’s metabolismexcept in poor metabolizers (CYP2C19*2 homozygotes). Inhealthy volunteers, omeprazole (80 mg/day) was associatedwith a decrease in CL-AM levels and an increase inVASP-PRI irrespective of clopidogrel dose or time oftreatment. The coadministration of omeprazole (20 to 40mg/day) with clopidogrel resulted in a moderate (�20%)decrease in clopidogrel-induced platelet inhibition. Thisinteraction was more pronounced following 7 to 14 days oftherapy (vs. 1 day) and translated into a significant increasein the prevalence of clopidogrel nonresponders with HPR.The subsequent reduction in clopidogrel-mediated plateletinhibition by PPIs may influence clinical outcomes byshifting more patients into the category of HPR (3). Insupport of this hypothesis is the observation that therelationship between platelet inhibition and the occurrenceof ischemic events is nonlinear (sigmoid) so that relativelysmall changes in platelet inhibition may be associated withmore frequent ischemic events in patients who have bor-derline HPR (90). Moreover, most pharmacokinetic/pharmacodynamic studies have involved a short duration(up to 14 days) of observation whereas clinical outcomestudies that have evaluated the PPI-clopidogrel interactionspan much longer periods (�1 year). Indeed, the pharma-cokinetic/dynamic interaction following long-term coad-ministration is not known.

Alternative Treatment Strategies

In the context that all PPIs are equally effective in gastricacid suppression with appropriate dosing and that thepharmacokinetic-pharmacodynamic interaction with clopi-dogrel is in large part mediated by hepatic CYP P450isoenzymes (CYP2C19 and CYP3A4), either pantoprazole(least dependent on CYP metabolism) or rabeprazole (non-CYP metabolized) may be alternatives for omeprazole.Another option may be to increase the MD of clopidogrel

during long-term therapy although the efficacy of dose

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escalation to overcome clopidogrel response variability hasnot been established. Moreover, in the PRINCIPLETIMI-44 study, a significant pharmacodynamic interactionbetween clopidogrel 150 mg daily and omeprazole has beendemonstrated (71). In addition, prasugrel is associated withgreater active metabolite levels (compared with clopidogrel)and has been shown to overcome clopidogrel nonrespon-siveness, but may be associated with increased bleeding risk.A fourth proposed alternative was to separate the timing ofclopidogrel and omeprazole administration. As the plasmahalf-lives of both clopidogrel and omeprazole are short (1 to2 h), the potential for drug-drug competition at CYP2C19level might be reduced by this strategy. Although the resultsof 4 recent studies that evaluated the effect of synchronousversus staggered coadministration have provoked contro-versy (76–78), it would appear that the relative “benefit” ofa staggered dose regimen is at best small and may depend onPPI (especially omeprazole) dose.

A fifth option might involve the nonthienopyridine,ticagrelor, which does not require metabolic conversion byhepatic CYP P450 isoenzymes to exert its antiplatelet effect.The antiplatelet effect of ticagrelor is not influenced by CYPgenetic polymorphisms (91) and clinically significant drug-drug interactions have not been reported (FDA) (92).

The use of histamine receptor antagonists and/or antacidsmay also be considered. The safety and clinical efficacy of

Figure 3. Potential Mechanisms of Drug-Drug Interaction Between Clopido

Based on pharmacogenomics, pharmacokinetics, and pharmacodynamics data,and clopidogrel are intestinal ABCB1 transporter and hepatic 2C19 isoenzymes

H2-receptor antagonist therapy was demonstrated in the

FAMOUS (Famotidine for the Prevention of Peptic Ulcersin Users of Low-Dose Aspirin) trial (93). Finally, in theupdated 2010 American College of Cardiology Foundation/American College of Gastroenterology/American HeartAssociation expert consensus document, PPIs are regardedas appropriate therapy for patients with multiple risk factorsfor gastrointestinal bleeding who require antiplatelet ther-apy, and routine use is not recommended in patients atlower risk of upper GIB (94).

Conclusions

Various studies have demonstrated a pharmacokinetic/pharmacodynamic interaction between PPIs (particularlyomeprazole) and thienopyridines (particularly clopidogrel).Although several observational studies have suggested thatthis interaction may attenuate clopidogrel’s therapeutic ef-ficacy and may be associated with increased adverse clinicaloutcomes, interpretation of these post hoc, nonrandomizedanalyses is confounded by covariate imbalance and statisticalbias. After multivariate regression and propensity scoreadjustment, the clinical relevance of a clopidogrel-PPIinteraction appears limited (86,87), and no difference incardiovascular outcomes was observed between clopidogrelalone versus clopidogrel plus omeprazole (CGT-2168) in asingle, prematurely terminated randomized clinical trial

nd Omeprazole

ssumed that the major pathways of interaction between omeprazoleeviations as in Figure 1.

grel a

is it a

(89). Based on the lack of definitive data regarding a

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clinically relevant interaction between these drugs, it is notappropriate at this time to recommend termination of PPIcoadministration (including omeprazole) in clopidogrel-treated patients or to suggest alternative therapeutic strate-gies. Administration of PPIs (with or without concomitantclopidogrel treatment) should be guided by the individualpatient’s risk for GIB. In rare situations where significantconcern exists for both GIB and thrombotic complications(e.g., patient with history of GIB who experiences stentthrombosis), an assessment of on-treatment (PPI plusclopidogrel) platelet reactivity may be warranted. A recentexpert consensus document has defined HPR as it corre-lates with MACE or stent thrombosis using availabletechniques including light transmittance aggregometry,the VerifyNow and Multiplate analyzer point-of-careassays, and VASP-PRI (2). Definitive recommendationsawait the performance and analysis of adequately pow-ered, prospective randomized clinical trials involvingpharmacodynamic assessments.

Reprint requests and correspondence: Dr. Paul A. Gurbel, SinaiCenter for Thrombosis Research, Cardiac Catheterization Labo-ratory, 2401 West Belvedere Avenue, Baltimore, Maryland 21215.E-mail: pgurbel@lifebridgehealth.org.

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Key Words: bleeding � clopidogrel � cytochromes � drug-rug interactions � omeprazole � platelet reactivity � proton

pump inhibitors � single nucleotide polymorphisms.