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The Clinical Relevance of the Clopidogrel–Proton Pump Inhibitor Interaction

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J. of Cardiovasc. Trans. Res. (2012) 5:547–552
DOI 10.1007/s12265-011-9334-7
The Clinical Relevance of the Clopidogrel–Proton Pump
Inhibitor Interaction
Atif Mohammad & Emmanouil S. Brilakis &
Rick A. Weideman & Bertis B. Little & Subhash Banerjee
Received: 30 September 2011 / Accepted: 9 November 2011 / Published online: 14 February 2012
# Springer Science+Business Media, LLC (outside the USA) 2012
Abstract Proton pump inhibitors are often prescribed
concomitantly with clopidogrel and aspirin to patients
post-percutaneous coronary interventions and/or an acute
coronary syndrome to mitigate the risk of potential
gastrointestinal bleeding, associated primarily with clopi-
dogrel use. Over the last several years, there have been data
both supporting and refuting a clopidogrel–proton pump
inhibitor interaction. This review critically considers the
current evidence and provides practical recommendations
to healthcare providers.
Keywords Clopidogrel . Proton pump inhibitor .
Percutaneous coronary intervention . Drug interaction
Clopidogrel and aspirin have been the cornerstone of
antiplatelet therapy (APT) for patients with acute coronary
syndromes (ACS) and in patients undergoing percutaneous
coronary interventions (PCI) [1]. This medical regimen has
been associated with an increased risk of gastrointestinal (GI)
bleeding [2]. Concomitant use of APT and proton pump
inhibitors (PPIs) or other gastroprotective drugs has been
A. Mohammad : E. S. Brilakis : R. A. Weideman : B. B. Little :
S. Banerjee (*)
VA North Texas Health Care System,
4500 S Lancaster Road (111a),
Dallas, TX 75216, USA
e-mail: Subhash.banerjee@va.gov
A. Mohammad : E. S. Brilakis : S. Banerjee
University of Texas Southwestern, Medical Center,
Dallas, TX, USA
B. B. Little
Tarleton State University,
Stephenville, TX, USA
used frequently to mitigate GI bleeding risk [2]. However,
concerns have been raised regarding the concomitant use of
clopidogrel and PPIs. This concern stems from the need for
clopidogrel, a prodrug, to be activated through metabolism
by cytochrome P (CYP) 450 isoenzymes, primarily
CYP2C19 to its active thiol derivative [3, 4]. Clopidogrel
and PPIs compete for the CYP2C19 enzyme metabolic
pathway. Competition by clopidogrel and PPIs for metabolism
by CYP2C19 may result in incomplete activation of clopi-
dogrel (Fig. 1) [5]. Evidence from ex vivo studies and
numerous observational reports [5–8] support the possibility
that clopidogrel–PPI drug interactions could result in less
clopidogrel being converted to its active thiol metabolite in
the presence of PPIs. In contrast, two randomized clinical
trials indicate no clinically significant effect of concomitant
clopidogrel APT and PPI interaction [6]. Clinical signifi-
cance of these apparently conflicting data on the interaction
of clopidogrel and PPIs needs to be further evaluated for
implications for clinical practice.
Ex Vivo Studies
Approximately 15% of clopidogrel is converted to its active
thiol derivative by a two-step oxidative process primarily
by CYP2C19. Eighty-five percent of ingested clopidogrel is
hydrolyzed by plasma esterases to an inactive carboxylic
acid derivative. Other isoenzymes (CYP2C9, CYP3A4,
CYP1A2, and CYP2B6) may also convert clopidogrel to its
active thiol metabolite, although they are minor pathways.
The active thiol metabolite irreversibly binds to platelet
receptor P2Y12, preventing adenosine diphosphate-induced
platelet aggregation [7]. In the GI tract, PPIs (e.g.,
omeprazole) irreversibly bind to and inhibit H+/K+ ATPase,
inhibiting gastric acid production. Omeprazole is metabo-
548
15%
85%
Fig. 1 Clopidogrel–proton pump inhibitor drug interaction. Clopidogrel
is converted by CYP450 isoenzymes, in particular CYP2C19 to its active
thiol form. Omeprazole metabolized by CYP450 has greater affinity for
CYP2C19 compared to other PPI which could potentially lead to
lized by CYP2C19 and CYP3A4, but has demonstrated a
higher affinity for CYP2C19 than for CYP3A4. Competi-
tion for the CYP2C19 pathway may lead to decreased
levels of active clopidogrel thiol metabolite, possibly
resulting in lowered platelet inhibition. Clopidogrel–PPI
interaction was documented by ex vivo studies and showed
attenuation of platelet response compared to patients
receiving clopidogrel alone [6, 7].
Pharmacogenetic Effects on Clopidogrel and PPI
Metabolism
Genetic polymorphisms of CYP2C19 also contribute to
poor metabolism of clopidogrel in some patients post-
PCI. Genetic polymorphisms associated with reduced
function in clopidogrel metabolism are CYP2C19*2,*3,
and *4. Increased prevalence of reduced function
CYP2C19*2 allelic variants in post-PCI patients treated
with clopidogrel and PPIs was associated with in-
creased CV risk in several studies [8–10] (Table 1).
Interethnic differences in the prevalence reduced function
alleles exist. CYP2C19*2 is the most common reduced
function allele and occurs among 50% of Asians, 35%
African-Americans, 25% Caucasians, and 18% of
Mexican-Americans.
Decreased platelet inhibition, determined by higher
levels of vasodilator-stimulated phosphoroprotein, was
observed in patients given clopidogrel and omeprazole.
J. of Cardiovasc. Trans. Res. (2012) 5:547–552
competitive inhibition of clopidogrel activation. Potential for competitive
inhibition for CYP450 enzyme-mediated metabolism between PPI and
clopidogrel activation pathway
Mean platelet reactivity index (PRI) was significantly
higher (51.4%) after 7 days of APT and PPI combina-
tion compared to a mean PRI on clopidogrel alone
(39.8%, p < 0.0001). Two other research groups [11, 12]
also found increased PRI among clopidogrel and ome-
prazole nonresponders compared to patients on clopidog-
rel with pantoprazole therapy. Reduced clopidogrel
antiplatelet effect in patients on clopidogrel in patients
taking PPIs (omeprazole in particular) was reported in
several observational studies [13, 14, 20, 21]. Thus, loss
of function CYP2C19 alleles may be associated with
even poorer outcomes with use of PPI because they may
further enhance the pharmacokinetic consequences of this
interaction [15].
Observational Studies
The Factores de Reisgo y ENfermedad Arterial [16] and
Danish registries [17] reported increased cardiovascular
(CV) event rates associated with concomitant use of
clopidogrel and omeprazole [hazard rates (HR) = 1.8;
95% confidence intervals (95% CI) 1.1–2.7 and HR=
1.61; 95% CI 1.45–1.79, respectively]. In contrast, a
propensity-adjusted analysis from the French Registry of
Acute ST-Elevation and Non-ST-Elevation Myocardial
Infarction registry reported no increased risk of death,
myocardial infarction (MI), or stroke associated with
combined use of clopidogrel and omeprazole [18, 19]. A
J. of Cardiovasc. Trans. Res. (2012) 5:547–552
Table 1 Proton pump inhibitor,
corresponding CYP 450 Drug
enzyme pathway, and half-life
in hours Clopidogrel
Esomeprazole
Dexlansoprazole
Lansoprazole
Omeprazole
Pantoprazole
Rabeprazole
Canadian population-based study of 786 patients between
2002 and 2007 readmitted to the hospital for recurrent MI
within 90 days of discharge showed a 40% increase in
recurrent MI [odds ratio (OR)=1.4; 95% CI 1.10–1.77]
associated with combined use of clopidogrel and omepra-
zole but not with clopidogrel plus pantoprazole or H2-
blocking agents. Aspirin use and length of combined
exposure of drug regimens were not reported [20]. A
Veterans Administration (VA) retrospective cohort of
8,205 patients found an increased risk of rehospitalization
and mortality associated with clopidogrel and PPI use (OR
1.27, 95% CI 1.10–1.46) [21]. Risk for CV events was
particularly elevated for patients using clopidogrel with
omeprazole. The investigators also found that clopidog-
rel use with rabeprazole, a PPI with potent CYPC19
inhibition [22], was associated with an elevated risk of
CV events (OR 2.83, 95% CI 1.96–4.09) [21]. Raber-
azole’s thioether analog is a potent inhibitor of P450
enzymes [22]. Stockl et al. [23] performed a study on
insured patients in five states. They used propensity
analysis to reduce the effects of confounding variables
and reported an increased risk of CV events with PPI use
in clopidogrel-treated patients, including pantoprazole
(HR=1.91; 95% CI 1.19–3.06) [23]. It should be noted
that patients taking clopidogrel and PPI had significantly
higher comorbidity indices compared to clopidogrel alone.
The MEDCO study used logistic regression techniques
and found a 50% increase in risk of adverse CV events in
patients on clopidogrel and a PPI. The effect was
significant for omeprazole (p<0.0001), esomeprazole (p<
0.0001), and lansoprazole (p<0.0004) [24]. In a retrospec-
tive, propensity-adjusted cohort analysis, risk of cardiovas-
cular events with pantoprazole and clopidogrel were not
significantly different from clopidogrel alone [25]. In
analysis of a national VA database (n=23,200), our research
group found significant HR for death, MI, and major adverse
cardiac events (MACE) for clopidogrel and PPIs compared
to clopidogrel only, but on matched propensity score
analysis, the associations were not statistically significant
[30]. Notably, patient dosing patterns had a significant effect
on frequency of outcomes.
549
CYP 450 enzyme affected Half-life
2C19, 3A4, 2B6, 1A2 6 h parent, 0.5 h active metabolite
2C19, 3A 1.05–1.4 h
2C19, 3A 1–2 h
2C19, 3A 1.9–2.9 h
2C19, 1A2 0.5–1.0 h
2C19, 2C9, 3A4, 2D6 1h
2C19, 3A4 1–2 h
Randomized Trials
The data from observational studies that do not use
propensity score matching are, however, not supported by
findings from randomized clinical trials. The TRITON–
TIMI 38 (Trial to Assess Improvement in Therapeutic
Outcomes by Optimizing Platelet Inhibition With Prasu-
grel–Thrombolysis In Myocardial Infarction 38) reported
no increased risk (HR=0.94, 95% CI=0.80 to 1.11) for CV
death, MI, and stroke (n=13,608) at 15 months follow-up
among clopidogrel and PPI users compared to clopidogrel
only [26]. The most recent data on CV events in patients on
PPIs and clopidogrel are the COGENT trial (Clopidogrel
and the Optimization of Gastrointestinal Events Trial) [27–
29]. Among 3,267 patients with ACS or post-PCI, the risk
of CV events was not increased (HR=1.02, 95% CI=0.70–
1.51) among patients randomized to omeprazole (20 mg/day)
and clopidogrel (75 mg/day) compared to clopidogrel
with placebo. The primary endpoint was MACE (a composite
of CV death, nonfatal MI, repeat revascularization or
ischemic stroke). .
Dosing Patterns and Misindication Bias
Lack of agreement between findings from observational
studies and randomized clinical trials is important to
recognize. The causes are likely multifactorial and not
attributable to a single confounder. One of the fundamental
limitations of most observational studies is reliance on
discharge prescriptions as a single data point when a point
of fact is that patients have varying degrees of compliance
and physicians may vary prescriptions according to patient
symptomatology during the follow-up period.
Large pharmacy database analyses by our group classi-
fied dosing patterns as [1]: continuous—uninterrupted use
of the same medication regimen throughout the follow-up
period [2], switching—drug regimen varied across time in
the follow-up period [3], and discontinued—drug regimen
were ceased during the follow-up period [30]. Multivariable
Cox regression and propensity score analyses were done
550 J. of Cardiovasc. Trans. Res. (2012) 5:547–552

Table 2 Unadjusted and adjusted hazard rates (HR) for concomitant PPI use post-PCI at 1 and over 6 years for all exposure groups

Even rates First year post-PCI Up to 6 years post-PCI

Unadjusted Multivariable Adjusted Unadjusted Multivariable Adjusted

No PPI (%) PPI (%) HR 95% CI HRa 95% CI HR 95% CI HRa 95% CI

Continuous
Death 21.4 26.8 1.37 (1.03–1.82) 1.16 (0.87–1.55) 1.48 (1.13–1.19) 1.32 (1.00–1.73)
Death or MI 44.4 48.3 1.26 (1.07–1.48) 1.20 (1.02–1.41) 1.31 (1.12–1.53) 1.26 (1.08–1.48)
RR 44.1 49.5 1.11 (0.95–1.29) 1.18 (1.01–1.30) 1.16 (1.00–1.35) 1.22 (1.05–1.42)
MACE 68.9 73.9 1.18 (1.05–1.31) 1.19 (1.06–1.33) 1.23 (1.10–1.37) 1.24 (1.11–1.38)
Switchers
Death 17.5 17.2 1.33 (1.03–1.71) 1.25 (0.97–1.61) 1.29 (1.09–1.53) 1.26 (1.06–1.49)
Death or MI 28.2 32.4 1.25 (1.05–1.50) 1.19 (0.99–1.42) 1.19 (1.05–1.34) 1.14 (1.01–1.29)
RR 25.4 27.5 0.99 (0.83–1.18) 1.01 (0.84–1.21) 1.01 (0.97–1.25) 1.09 (0.96–1.24)
MACE 46.4 51.0 1.11 (0.98–1.26) 1.10 (0.97–1.25) 1.14 (1.05–1.25) 1.12 (1.03–1.22)
Quitters
Death 47.9 23.7 1.09 (0.83–1.44) 1.00 (0.76–1.33) 1.19 (1.03–1.38) 1.11 (0.96–1.29)
Death or MI 56.4 35.4 0.93 (0.75–1.15) 0.88 (0.71–1.09) 1.07 (0.95–1.20) 1.00 (0.89–1.13)
RR 19.6 26.3 0.93 (0.72–1.18) 0.96 (0.75–1.23) 1.08 (0.92–1.27) 1.06 (0.92–1.27)
MACE 65.0 52.4 0.93 (0.79–1.09) 0.91 (0.77–1.07) 1.14 (1.05–1.25) 1.03 (0.94–1.13)
a
Cox regression analysis with HR adjusted for covariates

within these homogeneous groups to control for differing
dosing patterns. The adjusted HR for MACE in patients
taking clopidogrel with and without PPIs exposure patterns
6 years post-PCI was 1.24 (95% CI 1.11 to 1.38) and 1.12
(95% CI 1.03 to 1.22) for “continuous” exposure (consis-
tent clopidogrel with or without PPI) and “switched” or
varying exposure (clopidogrel with or without various PPI),
respectively. However, after propensity score adjustment
OR for MACE and PPI use was 0.97 (95% CI 0.65 to 1.44)
for “continuous” and 1.0 (95% CI 0.87 to 1.25) for
“switched.” Of clinical importance, in the first year after
PCI, the use of “rescue” nitroglycerin (<30 days before
MACE) was greater among patients taking clopidogrel and
PPIs compared to those taking clopidogrel alone (p<0.001).

Table 3 Propensity score anal-

ysis for PPI use over 1 and First year post-PCI Up to 6 years post-PCI
6 years post-PCI for all expo-
sure groups n OR n OR

Continuous
Death 225 1.34 (0.68–2.66) 278 1.18 (0.64–2.16)
Death or MI 390 1.49 (0.92–2.42) 493 1.46 (0.94–2.66)
RR 281 0.86 (0.47–1.60) 363 0.93 (0.55–1.59)
MACE 498 0.92 (0.58–1.45) 680 0.97 (0.65–1.44)
Switchers
Death 189 0.80 (0.44––1.45) 607 1.02 (0.73–1.43)
Death or MI 341 0.95 (0.61–1.49) 1,173 0.89 (0.71–1.13)
RR 255 0.71 (0.41–1.23) 930 0.90 (0.69–1.18)
MACE 514 0.98 (0.69–1.39) 2,105 1.04 (0.89–1.25)
Quitters
Death 84 1.27 (0.50–3.26) 809 1.29 (0.93–1.75)
Death or MI 160 1.24 (0.61–2.51) 1,634 1.07 (0.84–1.37)
RR 133 1.59 (0.72–3.47) 1,423 1.00 (0.76–1.30)
n number of matched cases and MACE 213 0.87 (0.46–1.67) 3,218 1.21 (1.01–1.44)
controls
J. of Cardiovasc. Trans. Res. (2012) 5:547–552
It was concluded that PPI use in clopidogrel-treated post-PCI
patients was not associated with an increased risk of MACE
with matched propensity score analysis (Tables 2 and 3). Of
particular concern, the potential for a “misindication bias,”
i.e., a misdiagnosis of angina symptoms as GI symptomatol-
ogy may be a factor that confounded previous observational
analyses, falsely indicating a clopidogrel–PPI interaction
effect. The data strongly suggest that chest pain may be
diagnosed as upper GI discomfort, when in fact the upper
abdominal pain was an impending MI or other CV event.
The clinical perspective from this review is that the risk
of adverse CV events associated with concomitant use of
clopidogrel and PPI is minimal to small and is probably
limited to select patient subgroups such as those with
CYP2C19 loss of function genetic polymorphisms (*2, *3,
*4), and possibly the elderly, diabetics, or those with
chronic renal disease. Our group is currently analyzing
possible risk to these select patient subgroups of clopidog-
rel and PPIs because these patients may have compromised
CYP activity.
The fact that PPIs are available over the counter, are
often indiscriminately prescribed, and likely given to
patients with atypical anginal symptoms perhaps warrants
greater attention. Thus, published evidence may not
strongly support the “Black Box Warning” that the US
Food and Drug Administration issued for the concomitant
use of clopidogrel and PPIs. It could be challenged.
However, it is understandable from a public health policy
perspective given the potential for risk, a pharmacodynamic/
pharmacokinetic basis, and near absence of “gold standard”
data, double-blind, prospective randomized, placebo-
controlled clinical trial data.
Common sense clinical recommendations include the
following:
& Avoid empiric use of PPI with clopidogrel.
& Preferentially prescribe pantoprazole over other PPIs [1]
because pantoprazole has been demonstrated to not
inhibit CYP2C19 [2] and can be used as an efficacious
alternative to omeprazole for GI protection [5, 31].
& Although it has not been shown to avoid the interaction
[5], separate the dosing of clopidogrel and omeprazole
by at least 6 h. This recommendation is based on the
mechanism of interaction (competitive inhibition of
clopidogrel metabolism) and the pharmacokinetics of
both drugs as most PPIs have a short half-life (30 min
to 2 h). PPIs will largely have been eliminated in 6 h as
will clopidogrel.
& Prasugrel may be used as an alternative APT because its
metabolism has not been affected when given concom-
itantly with PPI.
& When patient’s genotype data are available and low-
functioning alleles 2C19 alleles (*2, *3, *4) are present,
551
it is advisable to prescribe prasugrel with PPI because
prasugrel is metabolized mainly by CYP3A4, eliminat-
ing a possible drug interaction with PPIs [13].
& However, prasugrel must be administered with caution
because of increased bleeding risk in select patient
subgroups.
These common sense recommendations may minimize
potential risks associated with concomitant use of clopi-
dogrel and PPI.
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