ARTICLES
Drug Interactions
Drug–Drug Interaction Between Clopidogrel and the Proton
Pump Inhibitors
Nicholas B Norgard, Kathryn D Mathews, and Geoffrey C Wall
here is an evolving emphasis on op-
T timizing antiplatelet therapy in the
treatment of vascular disease and in pa-
tients undergoing vascular procedures.
Emerging from this is the concept of a
poor response to clopidogrel or clopido-
grel resistance, defined as failure of the
drug to achieve the expected suppression
of platelet function as measured by vari-
ous laboratory tests. Although not yet
routine, tests of platelet function, such as
platelet aggregation and vasodilator-stimu-
lated phosphoprotein (VASP) phos-
phorylation are used to measure clopido-
grel response and have been shown to be
predictive of cardiovascular events.1-9 The
mechanisms for a poor response to clopi-
dogrel are unclear, although genetic,
metabolic, cellular, and clinical factors
have been proposed. Clopidogrel is a pro-
drug. It is believed that reduced generation
of its active metabolite contributes to poor
clopidogrel responsiveness, due to vari-
abilities in intestinal absorption and the
availability and/or activity of cytochrome
P450 isoenzymes.10 A drug that reduces
the availability of clopidogrel’s active me-
tabolite will lessen clopidogrel-induced
platelet inhibition and represents a poten-
tial interaction with clopidogrel. This is
important because a reduced response to clopidogrel leads to
an increased risk of major adverse cardiac events such as car-
diovascular death, stent thrombosis, recurrent acute coronary
syndrome, and recurrent revascularization.
Author information provided at the end of the text.
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OBJECTIVE: To evaluate the interaction between clopidogrel and proton pump
inhibitors (PPIs).
DATA SOURCES: Literature retrieval was accessed through PubMed (1980–
January 2009), abstracts from 2008 American Heart Association and 2009 Society
of Cardiovascular Angiography and Interventions Scientific Sessions, and media
press releases using the terms clopidogrel, proton pump inhibitors, cytochrome
2C19, genetic cytochrome P450 polymorphisms, and drug interaction. In addition,
reference citations from publications identified in the search were reviewed.
STUDY SELECTION AND DATA EXTRACTION: Relevant original research articles and
review articles were evaluated. Articles were selected if they were published in
English and focused on any of the key words or appeared to have substantial
content addressing the drug interaction.
DATA SYNTHESIS: Recent attention has been placed on a potential interaction
observed between clopidogrel and the widely used PPIs. Preliminary evidence
suggests that omeprazole interacts with clopidogrel, reducing clopidogrel’s
antiplatelet effects as measured by various laboratory tests. Most data indicate that
the interaction involves the competitive inhibition of the CYP2C19 isoenzyme. The
interaction appears to be clinically significant, as several retrospective analyses have
shown an increase in adverse cardiovascular outcomes when PPIs and clopidogrel
are used concomitantly. However, this may not be a class effect.
CONCLUSIONS: Available data suggest that omeprazole is the PPI most likely to
have a significant interaction with clopidogrel. Further studies are needed to
determine that an interaction between the other PPIs and clopidogrel does not
exist. In situations in which both clopidogrel and a PPI are indicated, pantoprazole
should be used since it is the PPI least likely to interact with clopidogrel.
KEY WORDS: clopidogrel, drug interactions, proton pump inhibitors.
Ann Pharmacother 2009;43:xxxx.
Published Online, 26 May 2009, www.theannals.com, DOI 10.1345/aph.1M051
THIS ARTICLE IS APPROVED FOR CONTINUING EDUCATION CREDIT
ACPE UNIVERSAL PROGRAM NUMBER: 407-000-09-xxx-H01-P
Attention has been placed on a potential interaction ob-
served between clopidogrel and the widely used proton
pump inhibitors (PPIs).11 PPIs are commonly used for gas-
trointestinal bleeding prophylaxis in patients receiving an-
tiplatelet therapy. In a 2008 American College of Cardiology/
American College of Gastroenterologists/American Heart
Association (AHA) Clinical Expert Consensus Document,
The Annals of Pharmacotherapy n 2009 July/August, Volume 43 n
NB Norgard et al.
PPIs are recommended for the therapy and prophylaxis of
aspirin-associated gastrointestinal injury, particularly in pa-
tients on dual antiplatelet therapy.12 In addition, the Ameri-
can College of Cardiology/American Heart Association
2007 Unstable Angina/Non–ST-Segment Elevation My-
ocardial Infarction guidelines recommend concomitant PPI
therapy with aspirin and clopidogrel in patients with a his-
tory of gastrointestinal bleeding.13 Consequently, the num-
ber of patients affected by a PPI–clopidogrel interaction
could be substantial. In fact, a combined total of 100 mil-
lion prescriptions are written for both PPIs and clopidogrel
annually.14 However, this does not include all omeprazole
use since, at some strengths, it is available over-the-
counter. It has been hypothesized that PPI use concurrently
with clopidogrel will increase the risk of major adverse
cardiac events.
Mechanism of Interaction
Approximately 15% of an absorbed clopidogrel dose is
converted to an active thiol metabolite (R-130964), mainly
by the hepatic cytochrome P450 isoenzymes.15 The metab-
olism of clopidogrel is a complex process involving a
number of cytochrome P450 isoenzymes in varying de-
grees (Figure 1).16-18 The CYP2C19 isoform is the key en-
zyme in the metabolism of many of the PPIs, which are
also inhibitors of the CYP2C19 isoenzyme in varying de-
grees. This is important because the antiplatelet effects of
clopidogrel rely, to a degree, upon CYP2C19 activity.19-22
This has led to the assumption that some PPIs have the ca-
pability to inhibit metabolic activation of clopidogrel. A
PPI’s ability to inhibit CYP2C19 activity would reduce R-
130964 generation and cause a diminished clopidogrel re-
sponse. However, this mechanism is unproven. In addition
to metabolic inconsistencies, variability of intestinal ab-
sorption is also an important determinant of the wide re-
sponse variability to clopidogrel. PPIs are substrates and
inhibitors of the intestinal efflux transporter P-glycopro-
tein, a key factor for intestinal absorption of clopido-
grel.23,24 Alterations in P-glycoprotein activity could poten-
tially affect plasma concentrations of clopidogrel and
hence the concentration of R-130964. Results from in vitro
studies show that in the presence of different inhibitors of
P-glycoprotein–mediated transport, clopidogrel absorption
is increased.24 In addition, patients found to have a genetic
deficiency in P-glycoprotein had lower P-glycoprotein ac-
tivity and enhanced clopidogrel absorption. As inhibitors
of P-glycoprotein, PPIs would be expected to increase the
bioavailability of clopidogrel and R-130964. However,
there seems to be a lack of correlation between in vivo re-
ports and the predicted effect from in vitro P-glycoprotein
studies. Nevertheless, P-glycoprotein modification repre-
sents another potential mechanism of a clopidogrel–PPI in-
teraction and requires further exploration.
n The Annals of Pharmacotherapy n 2009 July/August, Volume 43
R-130964 is present at very low concentrations in the
plasma and is highly labile.25 The inactive SR26334 me-
tabolite is the major circulating compound in the plasma
and has historically been used as a surrogate to obtain in-
formation on the absorption and elimination of clopido-
grel.26,27 We now have methods to directly measure plas-
ma concentrations of R-130964, which will guide us to a
better understanding of the pharmacokinetics of clopido-
grel.
There is a correlation between plasma concentrations of
R-130964 and pharmacodynamic measurements of clopi-
dogrel response.28 A number of tests are available to mea-
sure the pharmacodynamic response of clopidogrel and
provide estimates of active metabolite generation in
vivo. The active metabolite of clopidogrel irreversibly
binds to the P2Y12 receptor, preventing platelet activa-
tion by adenosine diphosphate (ADP). ADP-induced
platelet aggregation measured by light transmission ag-
gregometry has historically been regarded as the gold
standard for monitoring clopidogrel response. This test
determines the percent of platelet aggregation after the
introduction of a platelet agonist such as ADP. Optimal-
ly, platelet aggregation is measured before and after
clopidogrel administration. A poor response to clopido-
grel is a minimal absolute difference in pre- and post-
clopidogrel aggregation percentages. However, there is
no consensus definition for classifying clopidogrel re-
sponse using this test.
VASP phosphorylation is a test that directly measures
the function of the P2Y12 receptor (the clopidogrel
target).29 Dephosphorylation of VASP occurs following
P2Y12 stimulation. Levels of VASP phosphorylation/de-
phosphorylation thus reflect P2Y12 inhibition/activation.
VASP phosphorylation provides a selective index of
platelet reactivity to clopidogrel (platelet reactivity index
[PRI]) and is not affected by other commonly used platelet
inhibitors such as aspirin. Based on previous studies, pa-
tients are regarded as good responders to clopidogrel if PRI
is less than 50% and poor responders if PRI is greater than
50%.1 While ADP-induced platelet aggregation is consid-
ered the standard, many regard VASP phosphorylation as a
more specific test of clopidogrel response, and its use is be-
coming increasingly common in the research setting.
Evidence of Interaction
PHARMACOLOGIC EVIDENCE
The first evidence to suggest a clopidogrel–PPI interac-
tion was reported in a brief letter to the editor showing an
association between omeprazole treatment and a dimin-
ished biological response to clopidogrel.30 Platelet reactivi-
ty was measured in 105 consecutive patients receiving as-
pirin and clopidogrel after coronary angioplasty. Patients
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using omeprazole had higher mean platelet reactivity, as
measured by VASP phosphorylation, compared with pa-
tients not taking the PPI (mean ± SD 61.4 ± 23.2, n = 24 vs
49.5 ± 16.3, n = 81; p = 0.007). These results led to the de-
velopment of the OCLA (Omeprazole CLopidogrel As-
pirin) study.31 In this study, 140 patients undergoing coronary
stent placement were randomized to receive omeprazole
20 mg daily or placebo for 7 days while on clopidogrel.
Platelet reactivity was the primary endpoint in the study
and was assessed by measuring platelet-phosphorylated
VASP. The mean PRI was similar for both groups at base-
line (83.2% vs 83.9%, respectively) prior to the initiation
of clopidogrel and omeprazole/placebo. However, after 7
days of clopidogrel therapy, the mean PRI was 39.8% in
the placebo group and 51.4% in the omeprazole group (p <
0.0001). In addition, there was also a higher number of
poor clopidogrel responders (PRI >50%) in the omepra-
zole group, thus giving the indication that omeprazole sig-
nificantly decreased the antiplatelet effect of clopidogrel. It
must be taken into account that up to one third of patients
have inadequate responses to clopidogrel whether they are
on a PPI or not. The study may have provided a clearer
picture of the potential interaction if only clopidogrel re-
sponders were included.11 While omeprazole reduced the
effect of clopidogrel shown in platelet function tests, the
clinical impact of this remains unclear. Nevertheless, di-
minished effects in platelet function tests such as VASP
phosphorylation have been shown to be predictive of car-
diovascular events.
Figure 1. Metabolism of clopidogrel. Clopidogrel undergoes a 2-step metabolism and can involve several different cytochrome P450 enzymes.
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Drug–Drug Interaction Between Clopidogrel and the Proton Pump Inhibitors
CLINICAL EVIDENCE
The strongest evidence addressing this drug– drug inter-
action is limited to platelet reactivity studies. Nevertheless,
several retrospective analyses have been done focusing on
the clinical significance of the interaction. To date, 2 large
epidemiologic studies have been published with full results,
while several analyses were presented at the cardiology or-
ganization Scientific Sessions and are available only in ab-
stract form, which limits in-depth analysis of the findings.
In a letter to the editor following the OCLA study, the
insurance company Aetna examined their medical and
pharmacy databases for myocardial infarction (MI) rates in
members receiving clopidogrel with or without concurrent
PPI therapy.32 Based on adherence rates, members were
categorized as no PPI exposure (control), low PPI expo-
sure (<6 mo), or high PPI exposure (>6 mo). Results re-
vealed 1-year acute MI rates of 1.38% in the control group,
3.08% in the low PPI exposure group, and 5.03% in the
high PPI exposure group, with a significant difference (p <
0.05) in MI rates found between the control and high expo-
sure groups. After risk adjustment for comorbidities, these
MI rates became 2.60%, 10.00%, and 11.38%, respective-
ly. In addition, relative risk for acute MI in the high PPI ex-
posure group was 337% greater than in the control group
(p < 0.05), suggesting that PPI use decreased the ability of
clopidogrel to prevent cardiovascular events. These data
are subject to significant limitation, since they were ad-
dressed in a letter to the editor and did not undergo peer re-
view.
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NB Norgard et al.
The Medco Outcomes Study, an abstract presented at
the AHA 2008 Scientific Sessions, analyzed a retrospec-
tive cohort of 14,383 patients who were at least 80% ad-
herent to clopidogrel following stent placement during a 1-
year period.33 Patients who had no preceding cardiovascu-
lar events prior to receiving their stent showed a 32.5%
incidence of major adverse cardiovascular events (hospi-
talization for stroke, MI, angina, or coronary artery bypass
graft) within 1 year of stent placement if they were also on
PPI therapy compared with a 21.2% incidence in patients
not taking PPIs (adjusted OR 1.79; 95% CI 1.62 to 1.97).
However, a more pronounced effect was seen among pa-
tients with a preceding cardiovascular event prior to re-
ceiving their stent (PPI 39.8% vs no PPI 26.2%; adjusted
OR 1.86; 95% CI 1.63 to 2.12).
A similar study, the Clopidogrel Medco Outcomes
Study, was presented at the Society of Cardiovascular An-
giography and Interventions (SCAI) 2009 Scientific Ses-
sions.34 Researchers analyzed integrated data on pharmacy
and medical claims from more than 10 million patients, in-
cluding 16,690 patients taking clopidogrel for a full year
following coronary stenting. Of these patients, 41% also
took a PPI, on average, for more than 9 months of the year.
Over that 12-month period during which patients took
clopidogrel, investigators evaluated the risk of hospitaliza-
tion for major adverse cardiovascular events, which they
defined as a combination of myocardial infarction, unsta-
ble angina, stroke or TIA, urgent target vessel revascular-
ization, or cardiovascular death. The study found that the
risk of major adverse cardiovascular events was raised
from 17.9% to 25.1% in patients also taking PPIs (HR
1.51; 95% CI 1.39 to 1.64; p < 0.0001). The overall risk of
major cardiac events was 51% higher among patients tak-
ing any PPI. This included a 70% increase in the risk of
myocardial infarction or unstable angina, a 48% increase
in the risk of stroke or TIA, and a 35% increase in the need
for an urgent target vessel revascularization. The findings
were equally concerning when the effects of individual
PPIs were analyzed. Omeprazole correlated with a 39% in-
creased risk (p < 0.0001), esomeprazole with a 57% in-
creased risk (p < 0.0001), pantoprazole with a 61% in-
creased risk (p < 0.0001), and lansoprazole with a 39% in-
creased risk (p < 0.0004). Overall, the incidence of
hospitalization for upper gastrointestinal bleeding was only
1.1% among patients taking a PPI and 0.07% among those
not taking a PPI.
Also presented as an abstract at the AHA 2008 Scientif-
ic Sessions, the national Veterans Affairs (VA) registry was
used to evaluate 3311 patients with acute coronary syn-
drome (ACS) who were discharged from the hospital on
either clopidogrel alone or clopidogrel plus a PPI, based on
pharmacy dispensing data.35 In this case–control study,
about one third of patients were taking clopidogrel alone
and about two thirds were taking both clopidogrel and a
n The Annals of Pharmacotherapy n 2009 July/August, Volume 43
PPI. After a mean follow-up period of more than 1 year,
concomitant use of clopidogrel and a PPI after ACS was
associated with a higher risk of MI or death compared with
use of clopidogrel alone (HR 1.28; 95% CI 1.07 to 1.53).
The final abstract presented at the AHA 2008 Scientific
Sessions was an analysis of the CREDO trial, which inves-
tigated clopidogrel plus aspirin versus aspirin alone in pa-
tients undergoing PCI.36 In this retrospective analysis, sub-
jects were divided into those taking PPIs (374 pts.) and
those who were not taking PPIs (1742 pts.). The 28-day
rate of death/MI/urgent target vessel revascularization and
the 1-year rate of death/MI/stroke were analyzed based on
PPI use at study entry. The frequency of the primary out-
come was higher at both 28 days and 1 year in patients
who were on PPIs at baseline, regardless of antiplatelet
treatment assignment. However, clopidogrel reduced car-
diovascular events at 1 year to a similar degree, whether or
not patients were taking a PPI. A test for interaction be-
tween the randomized treatment and PPI use at entry
demonstrated nonsignificance (p = 0.69), suggesting that
PPI use does not inhibit clopidogrel’s protective effects.
The first large epidemiologic study published was a
case–control study investigating prescription records of the
Ontario Public Drug Program.37 The investigators isolated
13,636 patients with claims for clopidogrel within 3 days
of an acute MI. Prescription records were assessed to es-
tablish exposure to PPIs during clopidogrel therapy. Con-
current prescribing of PPIs was common, with 19.7% of
patients receiving PPIs within 30 days and 31.0% within
90 days. Subsequently, 734 patients with a recurrent acute
event within 90 days were identified and matched to at
least 1 control. A significant association was found be-
tween occurrence of MI and the concurrent use of a PPI
(adjusted OR 1.27; 95% CI 1.03 to 1.57). A stratified anal-
ysis based on the specific PPI used revealed that pantopra-
zole was not associated with an increased risk of MI in pa-
tients taking clopidogrel. In contrast, the other PPIs were
associated with a 40% increase in the risk of recurrent MI
(OR 1.40; 95% CI 1.10 to 1.77). In fact, the authors calcu-
lated that about 14% of all readmissions due to recurrent
MI could be attributed to the clopidogrel–PPI interaction.
Finally, in a retrospective cohort study, 8205 patients
with ACS, who were taking clopidogrel after discharge
from the hospital, were identified using national data from
the Veterans Health Administration.38 Using pharmacy re-
fill data, the investigators found that 64% (n = 5244) of the
patients were also prescribed a PPI at discharge or during
follow-up, while 36% (n = 2961) were not prescribed a
PPI. Patients prescribed a PPI tended to be older and have
higher rates of diabetes, prior MI, previous coronary artery
bypass graft surgery, peripheral vascular disease, and lung
and renal disease. Omeprazole was the most frequently
prescribed PPI (59.7%, n = 3132), while 2.9% (n = 151)
were prescribed rabeprazole, 0.4% (n = 22) were pre-
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 Drug–Drug Interaction Between Clopidogrel and the Proton Pump Inhibitors
scribed lansoprazole, 0.2% (n = 15) were prescribed panto-
prazole, and 36.7% (n = 1924) were prescribed more than
one type of PPI. There was a significantly higher rate of
death or rehospitalization for ACS in patients prescribed
clopidogrel plus a PPI (adjusted OR 1.25; 95% CI 1.11 to
1.41). However, PPIs were not associated with death or re-
hospitalization for ACS in patients not prescribed clopido-
grel, which supports the theory of an interaction between
PPI and clopidogrel. Evaluation of individual PPIs showed
that there was an association between omeprazole (OR
1.24; 95% CI 1.08 to 1.41) and rabeprazole (OR 2.83; 95%
CI 1.96 to 4.09) with adverse outcomes. A reliable evalua-
tion could not be performed on the other PPIs due to their
limited use.
The retrospective nature of these analyses is accompa-
nied by inherent limitations that hinder the strength of the
research. Notably, the availability of over-the-counter
omeprazole may lead to unaccounted PPI use. In addition,
clopidogrel response is dependent on several variables in-
cluding the underlying disease state, dose, genetic poly-
morphisms, and the administration of other medications. It
is difficult to control for the numerous confounders in ret-
rospective analyses and, in some cases, confounders can-
not be assessed (eg, over-the-counter aspirin use). Patients
receiving PPIs had more comorbid diseases in many of
these studies. It is also necessary to assess the role that
these confounders played in the aforementioned studies
and to evaluate whether the increased cardiovascular event
rates observed are a result of the drug interaction or be-
cause sicker patients tend to be prescribed PPIs.
Based on available research, the FDA has expressed
concern regarding the PPI/clopidogrel interaction. In an
early communication, the FDA recommended a thorough
investigation of the interaction and urged healthcare
providers to reevaluate the need for starting or continuing
treatment with a PPI in patients taking clopidogrel.39 In a
statement released at the time of the Clopidogrel Medco
Outcomes study, SCAI noted, “While more research is
needed on this topic, SCAI urges healthcare providers who
are treating poststenting patients on dual-antiplatelet thera-
py to consider prescribing a histaminergic (H2) blocker or
antacids instead of a PPI considering the high risk for ad-
verse events shown in this study.”40
Class Effect?
Another issue concerning the clinical evidence is that
analyses consider the effect of PPIs as a class. However,
should all PPIs be implicated in this interaction? Analyses
of individual PPIs have associated omeprazole and rabepra-
zole with adverse outcomes, while pantoprazole was shown
to be benign when analyzed separately.37,38 Conversely, the
Clopidogrel Medco Outcomes study noted a class effect but,
due to lack of use, did not analyze rabeprazole.34 Preliminary
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evidence suggests that CYP2C19 inhibition is the driving
factor of the interaction.31 Therefore, the magnitude of a
clopidogrel interaction could depend on the effect that each
PPI has on the CYP2C19 isoenzyme. The currently available
PPIs include omeprazole, its stereochemical S isomer es-
omeprazole, lansoprazole, pantoprazole, and rabeprazole.
All PPIs are hepatically metabolized to an extent via the
cytochrome P450 mixed oxidase system. The isoenzymes
CYP3A4 and, particularly, CYP2C19, are the major iso-
forms that cause PPI biotransformation. The relative con-
tribution of this latter pathway in general metabolism dif-
fers between drugs and has been reported to be omeprazole
= esomeprazole > pantoprazole > lansoprazole > rabepra-
zole.41 Although this scheme explains the importance of
the CYP2C19 pathway in the biotransformation of the
PPIs, some discrepancies exist when examining the en-
zyme inhibition potential of this class of drugs.
For example, in vitro experiments have suggested that
esomeprazole is metabolized to a greater extent by
CYP3A4 (and concurrently less by CYP2C19) than the
racemic form.42 Although this would suggest that signifi-
cant differences can occur in the interaction potential of the
PPIs, in vitro experiments may not translate into in vivo ef-
fects due to a host of confounding factors such as age,
ethanol consumption, nutritional status, other comorbidi-
ties that may affect hepatic function, and a subject current-
ly under intense study: genetic enzyme polymorphisms.
Drugs metabolized via cytochrome P450 pathways can in-
teract with other drugs metabolized through this system,
largely by competitive inhibition or by direct enzymatic in-
duction or inhibition of the system. Several investigators
have conducted in vitro experiments to determine any di-
rect induction or inhibition activity of the PPIs. Li et al.43
determined that lansoprazole was the most potent direct in-
hibitor of the CYP2C19 system by using recombinant en-
zyme and human microsomal preparations.
The individual PPIs do have differences in their metabo-
lism profiles. As mentioned above, omeprazole is metabo-
lized rapidly and extensively by CYP3A4 and CYP2C19.
Omeprazole has a 10-fold greater affinity with the latter
pathway and, considering the potential for competitive in-
hibition, clinically significant interactions with other
agents that are metabolized via CYP2C19 should be con-
sidered likely.44,45 Indeed, omeprazole has been shown to
decrease the metabolism of drugs such as diazepam,
phenytoin, and R-warfarin, all of which are biotransformed
through CYP2C19. Esomeprazole appears to follow a sim-
ilar metabolic pathway to the racemic mixture, but as men-
tioned above, slightly less of this enantiomer is metabo-
lized by CYP2C19: roughly 70% of esomeprazole com-
pared with 90% of omeprazole.42 However, esomeprazole
also has the potential to inhibit its own metabolism by
CYP2C19, which complicates interpretation of in vitro
drug– drug interaction studies.46 It would seem, based on
n 2009 July/August, Volume 43 n
NB Norgard et al.
the few studies conducted, that slight differences exist in
the metabolic pathways of omeprazole and esomeprazole;
these probably do not translate into clinically meaningful
variations in their drug– drug interaction profile. Pantopra-
zole has a lower affinity for CYP3A4 and CYP2C19 com-
pared with other PPIs.47 Additionally, the initial metabolite
of the drug undergoes phase II sulfate conjugation, unlike
the other currently available PPIs. These 2 attributes may
account for the limited number of interactions reported
with pantoprazole. Lansoprazole is also metabolized
through the CYP2C19 and CYP3A4 systems. As noted
above, in vitro data have suggested that this drug is the
most potent inhibitor of the CYP2C19 system. However,
several in vivo investigations have found only minor in-
creases of CYP2C19 substrate serum levels, which are un-
likely to cause clinically significant drug– drug interac-
tions.48 Patients who have poor CYP2C19 activity (see be-
low) may be at higher risk for interactions mediated by the
CYP3A4 system, as lansoprazole’s metabolism is shunted
to this pathway. Finally, rabeprazole is unique among cur-
rently available PPIs in that its major metabolic pathway is
nonenzymatic thioether reduction.49 As the cytochrome
P450 system is not responsible for the drug’s biotransfor-
mation, significant drug– drug interactions via these path-
ways would be expected to be limited. In summary,
omeprazole and esomeprazole would appear to have the
highest propensity for clinically relevant interactions,
while pantoprazole and rabeprazole have the lowest.
With regard to a clopidogrel interaction, omeprazole,
lansoprazole, esomeprazole, and pantoprazole have been
investigated. In a study of 300 patients taking clopidogrel,
esomeprazole and pantoprazole showed no evidence of an
interaction with clopidogrel.50 Patients on either of these
PPIs had a similar mean PRI as that of patients not on PPI
treatment (49% no PPI vs 50% pantoprazole vs 54% es-
omeprazole). ADP-induced platelet aggregation was also
similar between groups. As opposed to the previously
mentioned omeprazole study, this study used a one-time
measurement of platelet reactively in a nonrandomized
fashion, allowing for confounder influence. In addition,
poor response to clopidogrel appears to be more prevalent
during the beginning of treatment and becomes less com-
mon over time. In this study, PRI was measured during the
chronic phase of clopidogrel use, which could have made
any influence of either PPI less apparent.
Lansoprazole was shown to have a very minute nega-
tive impact on the response to a 300-mg clopidogrel load-
ing dose in healthy subjects.51 Lansoprazole did not affect
the exposure to the inactive carboxylic acid metabolite of
clopidogrel, suggesting that clopidogrel absorption was
uninhibited. However, the pharmacodynamic response
(platelet inhibition) was slightly reduced by lansoprazole,
presumably by cytochrome P450 – dependent metabolic
pathways. But this effect was significant only in patients
n The Annals of Pharmacotherapy n 2009 July/August, Volume 43
who responded best to clopidogrel. This suggests that a pa-
tient needs to be a clopidogrel responder before such a re-
sponse can be reduced.
Based on available data, the evidence for an interaction
with clopidogrel is most compelling for omeprazole. Un-
fortunately, the results from the studies using lansoprazole,
esomeprazole, and pantoprazole cannot be directly com-
pared with those shown with omeprazole. It is too soon to
say that an interaction between the other PPIs and clopido-
grel does not exist.
Although drug– drug interactions of omeprazole for
CYP2C19 are thought to be one of competitive inhibition,
the issue of its short plasma half-life (<1 h) has been
brought up as a refutation of this argument. However,
omeprazole has a high affinity for CYP2C19 and its bind-
ing is extensive and potent. It is unknown how long this in-
hibition persists. Although omeprazole has a very short
half-life, we cannot assume that simply separating the ad-
ministration time of the drugs will eliminate the interaction
because a significant amount of CYP2C19 activity may
yet be “bound” by omeprazole metabolism. In addition,
there has been no obvious dose–response relationship
found between PPI dose and adverse outcomes, which one
would expect from competitive inhibition.
A significant confounding factor is present when con-
sidering clopidogrel response, the metabolic pathways of
PPIs, and their potential for interactions: cytochrome P450
genetic polymorphisms. Pharmacogenetic studies have de-
termined that significant variance in cytochrome P450 ac-
tivity can occur within populations. With CYP2C19, 8
variant alleles have been described (in comparison with the
wild type CYP2C19*1 allele) that can significantly alter
this enzyme’s activity.52 The polymorphism of CYP2C19
has been grossly classified into 3 distinct groups: rapid me-
tabolizers, intermediate metabolizers, and poor metaboliz-
ers. Racial correlations exist with this classification
scheme, with 3–5% of white and African Americans and
up to 20% of Asians considered poor metabolizers of
CYP2C19.53 Conversely the genotype for rapid metaboliz-
ers is more common in white than in Asian populations.54
This genetically determined variability has been shown
to have clinical consequences for both clopidogrel and
PPIs. In regards to the latter, Furuta et al.55 found a direct
correlation between CYP2C19 genotype status and Heli-
cobacter pylori cure rates in patients treated with PPIs.
Poor metabolizers in this study had cures rates of 100%,
while rapid metabolizers’ cure rate was only 28.6%. Other
studies have validated this relationship.56 Genetic polymor-
phisms of CYP2C19 also modulate clopidogrel pharma-
cokinetics and pharmacodynamics.22 Carrying 1 or 2 loss-
of-function polymorphisms of CYP2C19 (*2 allele) is as-
sociated with decreased exposure to the active metabolite
of clopidogrel and a diminished antiplatelet effect of clopi-
dogrel.21 In addition, patients carrying 2 CYP2C19 loss-of-
www.theannals.com
 Drug–Drug Interaction Between Clopidogrel and the Proton Pump Inhibitors
function variant alleles had a higher event rate than did pa-
tients who did not have these alleles.57
From a drug– drug interaction perspective, differences
in genetic polymorphisms may be expected to result in dif-
ferent patient risk. Poor metabolizers of CYP2C19 may be
at risk for drug– drug interactions because the parent drug
may be shunted to other pathways such as CYP3A4.58 Of
course, a higher incidence of adverse effects of drugs bio-
transformed through this pathway would be expected in
poor metabolizers as well. Unfortunately, few clinical stud-
ies have examined the influence of genetic polymorphism
on interactions involving PPIs and the cytochrome P450
system. In fact, the influence of the CYP2C19 polymor-
phism was not accounted for in the studies investigating
the PPI–clopidogrel interaction. As rabeprazole clearance
is less dependent on CYP2C19 activity than is the clear-
ance of other PPIs, genetic polymorphic differences in me-
tabolism would be expected to have less effect.59
Summary
Preliminary pharmacodynamic evidence suggests that
omeprazole interacts with clopidogrel, reducing clopido-
grel’s antiplatelet effects, as measured by various laborato-
ry tests. Omeprazole is the only PPI to be tested for this in-
teraction in a randomized trial. The true mechanism of the
interaction is uncertain; however, most data indicate that it
involves the competitive inhibition of the CYP2C19 isoen-
zyme. Given the metabolism and results from nonrandom-
ized pharmacologic investigations using other PPIs, it ap-
pears that, based on currently available data, omeprazole is
the PPI most likely to have a significant interaction with
clopidogrel. Esomeprazole and lansoprazole are also
CYP2C19 inhibitors, but have not been shown to share
drug interactions with omeprazole; however, the potential
for an interaction with clopidogrel is there. Rabeprazole
and pantoprazole have little influence on CYP2C19, mak-
ing an interaction with clopidogrel unlikely, although at
times there is a lack of correlation between in vivo reports
and the predicted interaction potential from in vitro metab-
olism studies. This was shown in the Veterans Health Ad-
ministration study that showed a harmful effect with use of
rabeprazole. This was unexpected given the drug’s metab-
olism. A full understanding of the metabolism of rabepra-
zole or the mechanism of the drug interaction may remain
to be elucidated. Conversely, the results may have been in-
fluenced by patient comorbidities. It is too soon to say that
an interaction between the other PPIs and clopidogrel does
not exist. Further study is needed to assess the interaction
between PPIs and clopidogrel. Pharmacokinetic studies
should be performed to investigate the effect that each PPI
has on clopidogrel active metabolite production. In addi-
tion, using the OCLA study as a model, further studies that
compare the pharmacodynamic effects of the individual
www.theannals.com The Annals of Pharmacotherapy
PPIs on clopidogrel are needed. We know that CYP2C19
polymorphisms cannot only alter a person’s response to
clopidogrel, but may also influence the potential for an in-
teraction with a PPI. Therefore, CYP2C19 polymorphisms
must be taken into account in future studies.
Retrospective studies investigating the clinical signifi-
cance of general PPI use with clopidogrel have generated
data supporting the presence of an interaction and have
triggered the desire for prospective studies. In addition,
due to its over-the-counter availability, omeprazole use
may be unrecognized by healthcare providers. The poten-
tial clinical implications of the clopidogrel– omeprazole in-
teraction draw attention to the importance of patients’dis-
closing OTC omeprazole to their healthcare providers.
In the interim, we should not change our clopidogrel use
but rather rethink our PPI use. We anticipate an abundance
of research to elucidate the drug interaction. However, we
should err on the side of caution while information is lack-
ing. Therefore, if a patient has indications for both clopido-
grel and a PPI, the PPI least likely to interact with clopido-
grel should be used. Consequently, we recommend avoiding
omeprazole in combination with clopidogrel. It is also hard to
justify use of esomeprazole and lansoprazole, as they are also
CYP2C19 inhibitors. With the recent association between
rabeprazole and adverse outcomes shown in the Veterans
Health Administration study, pantoprazole becomes the PPI
of choice when a PPI is needed with clopidogrel. Pantopra-
zole has a small propensity for an interaction with clopido-
grel based on its metabolism and was identified as a PPI not
associated with an increased risk of MI in patients taking
clopidogrel in the Ontario Public Drug Program study.
Nicholas B Norgard PharmD BCPS, Clinical Assistant Professor,
School of Pharmacy and Pharmaceutical Sciences, University at
Buffalo, Buffalo, NY
Kathryn D Mathews PharmD BCPS, Cardiology Clinical Phar-
macist, Intermountain Medical Center; Adjunct Professor, College
of Pharmacy, University of Utah; Adjunct Professor, College of Phar-
macy, University of Southern Nevada
Geoffrey C Wall PharmD FCCP BCPS CGP, Internal Medicine
Clinical Pharmacist, Iowa Methodist Medical Center, Associate Pro-
fessor of Pharmacy Practice, College of Pharmacy and Health Sci-
ences, Drake University
Reprints: Dr. Norgard, School of Pharmacy and Pharmaceutical
Sciences, University at Buffalo, 313 Cooke Hall, Buffalo, NY, fax
716/645-3688, nnorgard@buffalo.edu
Financial disclosure: None reported.
References
1. Barragan P, Bouvier J, Roquebert P, et al. Resistance to thienopyridines:
clinical detection of coronary stent thrombosis by monitoring of va-
sodilator-stimulated phosphoprotein phosphorylation. Catheter Cardio-
vasc Interv 2003;59:295-302.
2. Matetzky S, Shenkman B, Guetta V, et al. Clopidogrel resistance is asso-
ciated with increased risk of recurrent atherothrombotic events in pa-
tients with acute myocardial infarction. Circulation 2004;109:3171-5.
3. Gurbel P, Bliden K, Guyer K, et al. Platelet reactivity in patients and re-
current events post-stenting: results of the PREPARE POST-STENTING
Study. J Am Coll Cardiol 2005;46:1820-6.
n 2009 July/August, Volume 43 n
NB Norgard et al.
4. Gurbel P, Bliden K, Samara W, et al. Clopidogrel effect on platelet reac-
tivity in patients with stent thrombosis: results of the CREST Study. J
Am Coll Cardiol 2005;46:1827-32.
5. Lev E, Alviar C, Arikan M, et al. Platelet reactivity in patients with suba-
cute stent thrombosis compared with non–stent-related acute myocardial
infarction. Am Heart J 2006;153:41.e1-6.
6. Hochholzer W, Trenk D, Bestehorn H, et al. Impact of the degree of peri-
interventional platelet inhibition after loading with clopidogrel on early
clinical outcome of elective coronary stent placement. J Am Coll Cardiol
2006;48:1742-50.
7. Bliden K, DiChiara J, Tantry U, Bassi A, Chaganti S, Gurbel P. Increased
risk in patients with high platelet aggregation receiving chronic clopido-
grel therapy undergoing percutaneous coronary intervention: is the cur-
rent antiplatelet therapy adequate? J Am Coll Cardiol 2007;49:657-66.
8. Cuisset T, Frere C, Quilici J, et al. High post-treatment platelet reactivity
is associated with a high incidence of myonecrosis after stenting for
non–ST elevation acute coronary syndromes. Thromb Haemost 2007;97:
282-7.
9. Bonello L, Paganelli F, Arpin-Bornet M, et al. Vasodilator-stimulated
phosphoprotein phosphorylation analysis prior to percutaneous coronary
intervention for exclusion of postprocedural major adverse cardiovascu-
lar events. J Thromb Haemost 2007;5:1630-6.
10. Erlinge D, Varenhorst C, Braun OO, et al. Patients with poor responsive-
ness to thienopyridine treatment or with diabetes have lower levels of
circulating active metabolite, but their platelets respond normally to ac-
tive metabolite added ex vivo. J Am Coll Cardiol 2008;52:1968-77.
11. Gurbel PA, Lau WC, Tantry US. Omeprazole: a possible new candidate
influencing the antiplatelet effect of clopidogrel. J Am Coll Cardiol
2008;51:261-3.
12. Bhatt DL, Scheiman J, Abraham NS, et al. F/ACG/AHA 2008 expert
consensus document on reducing the gastrointestinal risks of antiplatelet
therapy and NSAID use: a report of the American College of Cardiology
Foundation Task Force on Clinical Expert Consensus Documents. J Am
Coll Cardiol 2008;52:1502-17.
13. Anderson J, Adams C, Antman E, et al. American College of Cardiolo-
gy/American Heart Association 2007 Guidelines for the Management of
Patients with Unstable Angina/Non–ST-Elevation Myocardial Infarction.
J Am Coll Cardiol 2007;50:e1-e157.
14. Drug Topics. Top 200 generic and brand drugs by units in 2007.
http://drugtopics.modernmedicine.com/drugtopics/article/articleList.jsp?
categoryId=7604 (accessed 2009 Jan 10).
15. Savi P, Combalbert J, Gaich C, et al. The antiaggregating activity of
clopidogrel is due to a metabolic activation by the hepatic cytochrome
P450-1A. Thromb Haemost 1994;72:313-7.
16. Kurihara A, Hagihara K, Kazui M, Ozeki T, Farid NA, Ikeda T. In vitro
metabolism of antiplatelet agent clopidogrel: cytochrome P450 isoforms
responsible for two oxidation steps involved in the active metabolite for-
mation. Drug Metab Rev 2005;37(suppl 2):99.
17. Hagihara K, Nishiya Y, Kurihara A, Kazui M, Farid NA, Ikeda T. Com-
parison of human cytochrome p450 inhibition by the thienopyridines
prasugrel, clopidogrel, and ticlopidine. Drug Metab Pharmacokinet
2008;23:412-20.
18. Farid NA, Payne CD, Small DS, et al. Cytochrome P450 3A inhibition
by ketoconazole affects prasugrel and clopidogrel pharmacokinetics and
pharmacodynamics differently. Clin Pharmacol Ther 2007;81:735- 41.
19. Hulot JS, Bura A, Villard E, et al. Cytochrome P450 2C19 loss-of-func-
tion polymorphism is a major determinant of clopidogrel responsiveness
in healthy subjects. Blood 2006;108:2244-7.
20. Trenk D, Hochholzer W, Fromm MF, et al. Cytochrome P450 2C19
681G>A polymorphism and high on-clopidogrel platelet reactivity asso-
ciated with adverse 1-year clinical outcome of elective percutaneous
coronary intervention with drug-eluting or bare-metal stents. J Am Coll
Cardiol 2008;51:1925-34.
21. Umemura K, Furuta T, Kondo K. The common gene variants of
CYP2C19 affect pharmacokinetics and pharmacodynamics in an active
metabolite of clopidogrel in healthy subjects. J Thromb Haemost 2008;6:
1439-41.
n The Annals of Pharmacotherapy n 2009 July/August, Volume 43
22. Mega JL, Close SL, Wiviott SD, et al. Cytochrome p- 450 polymor-
phisms and response to clopidogrel. N Engl J Med 2009;360:354-62.
23. Pauli-Magnus C, Rekersbrink S, Klotz U, Fromm MF. Interaction of
omeprazole, lansoprazole and pantoprazole with P-glycoprotein. Naunyn
Schmiedebergs Arch Pharmacol 2001;364:551-7.
24. Taubert D, von Beckerath N, Grimberg G, et al. Impact of P-glycopro-
tein on clopidogrel absorption. Clin Pharmacol Ther 2006;80:486-501.
25. Mullangi R, Srinivas NR. Clopidogrel: review of bioanalytical methods,
pharmacokinetics/pharmacodynamics, and update on recent trends in
drug– drug interaction studies. Biomed Chromatogr 2009;23:26- 41.
26. Caplain H, Donat F, Gaud C, Necciari J. Pharmacokinetics of clopido-
grel. Semin Thromb Hemost 1999;25(suppl 2):25-8.
27. Mani H, Toennes SW, Linnemann B, et al. Determination of clopidogrel
main metabolite in plasma: a useful tool for monitoring therapy? Ther
Drug Monitor 2008;30:84-9.
28. Savi P, Pereillo JM, Uzabiaga MF, et al. Identification and biological ac-
tivity of the active metabolite of clopidogrel. Thromb Haemost 2000;84:
891-6.
29. Aleil B, Ravanat C, Cazenave JP, Rochoux G, Heitz A, Gachet C. Flow
cytometric analysis of intraplatelet VASP phosphorylation for the detec-
tion of clopidogrel resistance in patients with ischemic cardiovascular
diseases. J Thromb Haemost 2005;3:85-92.
30. Gilard M, Arnaud B, Le Gal G, Abgrall JF, Boschat J. Influence of
omeprazole on the antiplatelet action of clopidogrel associated to aspirin
(letter). J Thromb Haemost 2006;4:2508-9.
31. Gilard M, Arnaud B, Cornily JC, et al. Influence of omeprazole on the
antiplatelet action of clopidogrel associated with aspirin: the randomized,
double-blind OCLA (Omeprazole CLopidogrel Aspirin) study. J Am
Coll Cardiol 2008;51:256-60.
32. Pezalla E, Day D, Pulliadath I. Initial assessment of clinical impact of a
drug interaction between clopidogrel and proton pump inhibitors (letter).
J Am Coll Cardiol 2008;52:1038-9.
33. Aubert R, Epstein R, Teagarden J, et al. Proton pump inhibitors effect on
clopidogrel effectiveness: The Clopidogrel Medco Outcomes Study (ab-
stract 3998). Circulation 2008;118:S_815.
34. Medco MediaRoom. New study: a common class of GI medications re-
duce protection against heart attack in patients taking widely prescribed
cardiovascular drug. http://medco.mediaroom.com/index.php?s=43&
item=352 (accessed May 2009).
35. Ho P, Maddox T, Wang L, et al. Proton pump inhibitors may attenuate
the benefits of clopidogrel among ACS patients: empirical evidence
from 3,311 ACS patients (abstract 6241). Circulation 2008;118:S_1165.
36. Dunn S, Macaulay T, Brennan D, et al. Baseline proton pump inhibitor
use is associated with increased cardiovascular events with and without
use of clopidogrel in the CREDO trial (abstract 3999). Circulation 2008;
118:S_815.
37. Juurlink D, Gomes T, Ko D, et al. A population-based study of the drug
interaction between proton pump inhibitors and clopidogrel. CMAJ
2009;180:713-8. DOI 10.1503/cmaj.082001
38. Ho PM, Maddox TM, Wang L, et al. Risk of adverse outcomes associat-
ed with concomitant use of clopidogrel and proton pump inhibitors fol-
lowing acute coronary syndrome. JAMA 2009;301:937- 44.
39. Food and Drug Administration. Early communication about an ongoing
safety review of clopidogrel bisulfate (marketed as Plavix). www.fda.
gov/cder/drug/early_comm/clopidogrel_bisulfate.htm (accessed January
2009).
40. Society of Cardiovascular Angiography and Interventions. SCAI State-
ment on “A National Study of the Effect of Individual Proton Pump In-
hibitors on Cardiovascular Outcomes in Patients Treated with Clopidogrel
Following Coronary Stenting: The Clopidogrel Medco Outcomes Study.”
www.sci.org/drlt1.aspx?PAGE_ID = 5870 (accessed May 2009).
41. Fock KM, Ang TL, Bee LC, Lee EJ. Proton pump inhibitors: do differ-
ences in pharmacokinetics translate into differences in clinical out-
comes? Clin Pharmacokinet 2008;47:1-6.
42. Abelo A, Andersson TB, Antonsson M, Naudot AK, Skanberg I, Wei-
dolf L. Stereoselective metabolism of omeprazole by human cytochrome
P450 enzymes. Drug Metab Dispos 2000;28:966-72.
www.theannals.com
 Drug–Drug Interaction Between Clopidogrel and the Proton Pump Inhibitors
43. Li XQ, Andersson TB, Ahlstrom M, Weidolf L. Comparison of inhibito-
ry effects of the proton pump-inhibiting drugs omeprazole, esomepra-
zole, lansoprazole, pantoprazole, and rabeprazole on human cytochrome
P450 activities. Drug Metab Dispos 2004;32:821-7.
44. Howden CW. Clinical pharmacology of omeprazole. Clin Pharmaco-
kinet 1991;20:38-49.
45. Blume H, Donath F, Warnke A, Schug BS. Pharmacokinetic drug inter-
action profiles of proton pump inhibitors. Drug Saf 2006;29:769-84.
46. Hassan-Alin M, Andersson T, Niazi M, Rohss K. A pharmacokinetic
study comparing single and repeated oral doses of 20 mg and 40 mg
omeprazole and its two optical isomers, S-omeprazole (esomeprazole)
and R-omeprazole, in healthy subjects. Eur J Clin Pharmacol 2005;60:
779-84.
47. Jungnickel PW. Pantoprazole: a new proton pump inhibitor. Clin Ther
2000;22:1268-93.
48. Lefebvre RA, Flouvat B, Karolac-Tamisier S, Moerman E, Van Ganse E.
Influence of lansoprazole treatment on diazepam plasma concentrations.
Clin Pharmacol Ther 1992;52:458-63.
49. Horai Y, Kimura M, Furuie H, et al. Pharmacodynamic effects and kinet-
ic disposition of rabeprazole in relation to CYP2C19 genotypes. Aliment
Pharmacol Ther 2001;15:793-803.
50. Siller-Matula JM, Spiel AO, Lang IM, Kreiner G, Christ G, Jilma B. Ef-
fects of pantoprazole and esomeprazole on platelet inhibition by clopido-
grel. Am Heart J 2009;157:148:e1-5.
51. Small DS, Farid NA, Payne CD, et al. Effects of the proton pump in-
hibitor lansoprazole on the pharmacokinetics and pharmacodynamics of
prasugrel and clopidogrel. J Clin Pharmacol 2008;48:475-84.
52. Goldstein JA. Clinical relevance of genetic polymorphisms in the human
CYP2C subfamily. Br J Clin Pharmacol 2001;52:349-55.
53. Desta Z, Zhao X, Shin JG, Flockhart DA. Clinical significance of the cy-
tochrome P450 2C19 genetic polymorphism. Clin Pharmacokinet 2002;
41:913-58.
54. Sim SC, Risinger C, Dahl ML, et al. A common novel CYP2C19 gene
variant causes ultrarapid drug metabolism relevant for the drug response
to proton pump inhibitors and antidepressants. Clin Pharmacol Ther
2006;79:103-13.
55. Furuta T, Ohashi K, Kamata T, et al. Effect of genetic differences in
omeprazole metabolism on cure rates for Helicobacter pylori infection
and peptic ulcer. Ann Intern Med 1998;129:1027-30.
56. Padol S, Yuan Y, Thabane M, Padol IT, Hunt RH. The effect of
CYP2C19 polymorphisms on H. pylori eradication rate in dual and triple
first-line PPI therapies: a meta-analysis. Am J Gastroenterol 2006;101:
1467-75.
57. Simon T, Verstuyft C, Mary-Krause M, et al. Genetic determinants of re-
sponse to clopidogrel and cardiovascular events. N Engl J Med 2009;
360:363-75.
58. Gerson LB, Triadafilopoulos G. Proton pump inhibitors and their drug
interactions: an evidence-based approach. Eur J Gastroenterol Hepatol
2001;13:611-6.
59. Horn J. Review article: relationship between the metabolism and effica-
cy of proton pump inhibitors—focus on rabeprazole. Aliment Pharmacol
Ther 2004;20(suppl 6):11-9.
Interacción Entre el Clopidogrel y los Inhibidores de la Bomba de
Protón (IBP))
NB Norgard, KD Mathews, y GC Wall
Ann Pharmacother 2009;43:xxxx.
EXTRACTO
OBJETIVO: Evaluar la interacción entre el clopidogrel y los inhibidores de
la bomba de protón (IBP)
FUENTES DE INFORMACIÓN: PubMed (1980–enero 2009) y extractos
encontrados en las secciones científicas de la reunión de la American
www.theannals.com The Annals of Pharmacotherapy
Heart Association del 2008, usando los términos clopidogrel, inhibidores
de la bomba de protón, citocromo 2C19, polimorfismos del citocromo
P450 genético e interacciones de medicamentos. Además, referencias
citadas en las publicaciones identificadas.
SELECCIÓN Y MÉTODOS DE EXTRACCIÓN DE INFORMACIÓN: Se evaluaron
estudios originales de investigación publicados en inglés y enfocados en
las áreas anteriormente mencionadas.
SÍNTESIS: Recientemente se ha puesto atención a la posible interacción
entre el clopidogrel y los IBP. Existe evidencia preliminar que sugiere
que el omeprazol interactúa con el clopidogrel reduciendo sus efectos
antiplaquetarios medidos con distintas pruebas de laboratorio. La mayoría
de la información disponible indica que esta interacción involucra una
inhibición competitiva con la isoenzima CYP2C19. La interacción parece
ser clínicamente significativa ya que varios análisis retrospectivos han
mostrado un incremento en los resultados adversos cardiovasculares
cuando los IBP y el clopidogrel son usados conjuntamente. Sin embargo,
esta interacción puede que no ocurra con otro miembros de la clase de
IBP.
CONCLUSIONES: La información actualmente disponible sugiere que el
omeprazol es el IBP con más probabilidad de interactuar
significativamente con el clopidogrel. Es muy prematuro especular que
no existe una interacción entre otros IBP y el clopidogrel, y se
necesitarían estudios adicionales para llegar a esa conclusión. En
situaciones médicas donde se requiera el uso del clopidogrel con un IBP,
se recomienda el empleo del pantoprazol el cual es el IBP con menos
probabilidad de interactuar con el clopidogrel.
Traducido por Encarnación C Suárez
Interaction Médicamenteuse Entre le Clopidogrel et les Inhibiteurs
de la Pompe à Proton.
NB Norgard, KD Mathews, y GC Wall
Ann Pharmacother 2009;43:xxxx.
RÉSUMÉ
OBJECTIF: Évaluer l’interaction entre le clopidogrel et les inhibiteurs de
la pompe à proton (IPP).
REVUE DE LITTÉRATURE: Une recherche informatisée sur PubMed couvrant
la période de 1980 à janvier 2009 ainsi qu’une recherche parmi les abrégés
du congrès 2008 de l’American Heart Association utilisant les mots clés
suivants: clopidogrel, inhibiteurs de la pompe à proton, cytochrome 2C19,
polymorphisme génétique du cytochrome P450, et interaction médica-
menteuse furent effectuées. De plus, les bibliographies des articles
identifiés furent révisées.
SÉLECTION DES ÉTUDES ET DE L’INFORMATION: Les articles de recherche
originale et de revue furent évalués. Les articles furent choisis s’ils étaient
écrits en langue anglaise, s’ils utilisaient un des mots clés ou s’ils avaient
un contenu substantiel sur les interactions médicamenteuses.
RÉSUMÉ: Récemment, beaucoup d’attention a été portée sur l’interaction
potentielle observée entre le clopidogrel et les IPP. L’évidence préliminaire
suggère que l’oméprazole interagit avec le clopidogrel réduisant son effet
antiplaquettaire tel que mesuré par différents tests de laboratoire. La plupart
des données indiquent que l’interaction implique une inhibition compétitive
de l’isoenzyme CYP 2C19. L’interaction semble cliniquement significative
puisque de nombreuses études rétrospectives ont démontré une augmen-
tation de résultats cardiovasculaires négatifs lorsque les IPP et le clopido-
grel sont utilisés concomitamment. Cependant, l’effet résultant ne semble
pas lié à un effet de classe.
CONCLUSIONS: Les données actuelles suggèrent que l’oméprazole est l’IPP
le plus à risque de causer une interaction significative avec le clopidogrel. Il
semble prématuré de croire que l’interaction entre les autres IPP et le clo-
pidogrel n’existe pas. Des études additionnelles semblent nécessaires pour
évaluer cette interaction. Dans les situations où, à la fois, le clopidogrel et
les IPP sont indiqués, le pantoprazole devrait être préféré puisqu’il a le
moins de chance d’interagir avec le clopidogrel.
Traduit par Marc M Perreault
n 2009 July/August, Volume 43 n