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C L I N I C A L F E AT U R E S

Proton-Pump Inhibitors in Patients Requiring

Antiplatelet Therapy: New FDA Labeling

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DOI: 10.3810/pgm.2014.05.2772

David A. Johnson, MD,

MACG, FASGE, FACP 1
Robert Chilton, DO, FACC 2
Harley R. Liker, MD 3
1
Chief of Gastroenterology,
Professor of Medicine, Division of
Gastroenterology, Eastern Virginia
Medical School, Norfolk, VA;
2
Associate Professor, Department
of Medicine, Division of Cardiology,
University of Texas Health Science
Center, San Antonio, TX; 3Assistant
Clinical Professor, David Geffen
School of Medicine, University of
California, Los Angeles, CA

Abstract: Proton-pump inhibitors (PPIs) are recommended for patients who require antiplatelet
therapy and have a history of upper gastrointestinal bleeding. Proton-pump inhibitors should
also be considered for patients receiving antiplatelet therapy who have other risk factors for
gastrointestinal bleeding, including use of aspirin. Thus, evidence of pharmacokinetic and pharmacodynamic interactions between PPIs and consequent impaired effectiveness of the antiplatelet
agent clopidogrel has caused concern. Here, we discuss comparative studies suggesting that the
extent to which a PPI reduces exposure to the active metabolite of clopidogrel and attenuates
its antithrombotic effect differs among PPIs. Although a clinically meaningful effect of the
interaction between PPIs and clopidogrel on cardiovascular outcomes has not been established,
these studies provided the basis for recent changes in US Food and Drug Administration (FDA)
labeling for several PPIs and clopidogrel. New labeling suggests that PPI use among patients
taking clopidogrel be limited to pantoprazole, rabeprazole, lansoprazole, or dexlansoprazole.
Because comparative studies indicate that omeprazole and esomeprazole have a greater effect
on the CYP2C19-mediated conversion of clopidogrel to its active metabolite and, consequently,
clopidogrels effect on platelet reactivity, FDA labeling recommends avoiding omeprazole and
esomeprazole in patients taking clopidogrel. Even a 12-hour separation of dosing does not appear
to prevent drug interactions between omeprazole and clopidogrel.
Keywords: proton-pump inhibitors; platelet aggregation inhibitors; antiplatelet therapy; aspirin

Introduction

Correspondence: David A. Johnson,

MD, MACG, FASGE, FACP,
Eastern Virginia Medical School,
Norfolk, VA 23529.
Tel: 757-466-0165
Fax: 757-466-9082
E-mail: Dajevms@aol.com

Guidelines published by the American College of Cardiology Foundation (ACCF)

and American Heart Association (AHA) have established dual antiplatelet therapy as
the cornerstone in the management of thrombotic risk in patients undergoing coronary stenting and those with acute coronary syndrome (ACS) with or without stent
implantation.1,2 The addition of clopidogrel to aspirin reduced the risk of cardiovascular
events by approximately 20% versus aspirin alone when administered to patients for 3
to 12months following nonST-elevation ACS.3 Unfortunately, the benefits of a dual
antiplatelet regimen are accompanied by an increased risk for bleeding events, including
gastrointestinal (GI) bleeding.35 The risk of major GI bleeding events was doubled in
randomized controlled trials comparing the dual regimen (1.1% to 1.3%) with aspirin
alone (0.5% to 0.7%).3,5 Although not recommended for routine prophylaxis in ACCF/
AHA guidelines,1 concomitant use of proton-pump inhibitors (PPIs) attenuates the risk
for GI bleeding associate with clopidogrel use68 and may prevent premature discontinuation of antiplatelet therapy.9 However, in November 2009, the US Food and Drug
Administration (FDA) warned that the PPI omeprazole may reduce the anticlotting
effect of the antiplatelet agent clopidogrel by approximately half and s uggested that
neither omeprazole nor esomeprazole should be used with clopidogrel.10 Since then,

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Johnson etal

many published reports have evaluated the pharmacokinetic,

pharmacodynamic, and clinical effects of coadministration of
PPIs with clopidogrel. This article reviews evidence for risks
and benefits of PPI use in patients who take clopidogrel and
provides practical guidance for the primary care physician
in the management of patients who require gastroprotection
in the setting of antiplatelet therapy.

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The Evidence
Dual Antiplatelet Therapy Is Widely
Prescribed for Secondary Prevention

In the ACCF/AHA guidelines, the use of aspirin is recommended indefinitely in patients with unstable angina (UA),
nonST-elevation myocardial infarction (NSTEMI),1 or
ST-elevation myocardial infarction (STEMI).2 The guidelines
further state that patients with UA/NSTEMI treated medically
or undergoing percutaneous coronary intervention (PCI) with
a bare metal stent should receive an additional antiplatelet
agent (eg, clopidogrel) for #12months, and those receiving a
drug-eluting stent should take an additional antiplatelet agent
for $12months1; STEMI patients undergoing primary PCI
with placement of any stent should be prescribed an antiplatelet agent in addition to aspirin for $12months.2
Clopidogrel inhibits platelet activation via binding of its
active metabolite to the P2Y12 class of adenosine diphosphate
(ADP) receptors.11 It is the most commonly prescribed antiplatelet companion to aspirin and is indicated for reduction
in risk of cardiovascular events and death in patients with
nonST-segment elevation ACS (ie, UA or NSTEMI) or
STEMI.11 Clopidogrel has recently become available in
lower-cost generic forms and may be used alone in patients
with hypersensitivity or intolerance to aspirin.4

Many Patients Taking Aspirin or

Clopidogrel Require Gastroprotection

Although most physicians are aware of the tendency of

aspirin to increase the risk of gastric injury, they may not
realize that clopidogrel has a similar effect, even when
used alone. A prospective, randomized, double-blind trial
comparing aspirin plus esomeprazole (20mg twice daily)
against clopidogrel alone in patients who were Helicobacter
pylorinegative demonstrated a significantly higher proportion of recurrent ulcer bleeding in the clopidogrel arm (8.6%)
versus the aspirin-plus-esomeprazole arm (0.7%) during the
12-month study.12 A subsequent randomized trial with very
similar design returned comparable results. Rates of recurrent
ulcer complications were 13.6% in the clopidogrel group
versus 0% in the aspirin-plus-esomeprazole (20mg daily)
240

group.13 These data suggest that use of clopidogrel alone as

an alternative to aspirin in patients with major GI intolerance
to aspirin is not a safe strategy and support cotherapy with
once-daily PPI in patients who experience aspirin intolerance.
Observational studies have also suggested that PPI cotherapy
is beneficial in reducing the risk of upper GI bleeding with
clopidogrel monotherapy.7
It remains unclear whether clopidogrel exerts an independent injurious effect on the GI mucosa or whether it
merely induces bleeding in already damaged mucosa via its
antiplatelet effects. Platelet aggregation, critical for promoting initial stages of wound healing in cases of erosion or
mucosal disruption, is accompanied by local induction of
both epidermal growth factor and angiogenesis factor release,
both of which are integral for wound healing. In the presence
of gastric acid and the antiplatelet effects of clopidogrel,
mucosal disruptions can progress to more formidable injury,
including ulcers and related bleeding (Figure1).1416 Thus,
gastroprotection needs to be considered in patients receiving
aspirin, clopidogrel, or both. An ACCF/American College of
Gastroenterology (ACG)/AHA consensus4 recommended the
use of PPIs in patients who require antiplatelet therapy and
have either a history of upper GI bleeding or multiple other
risk factors for GI bleeding. This recommendation has been
widely implemented. Recent data from a large representative
retail pharmacy network in the United States suggested that
nearly 25% of patients taking clopidogrel were also taking
a prescription PPI.17

PPIs Compete With Clopidogrel for

CYP2C19

Proton-pump inhibitors are converted to their active

metabolites in the gastric parietal cell and undergo hepatic
metabolism via cytochrome P450 (CYP) enzymes, including
CYP2C19.1823 Clopidogrel is a prodrug that also relies on
the CYP system, particularly CYP2C19, to be converted
to its active metabolite.11 Patients who are heterozygous or
Figure 1. Mechanism of clopidogrel-induced ulceration.1416

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Proton-Pump Inhibitor and Antiplatelet Therapy

homozygous for CYP2C19 loss-of-function alleles form less

of the active metabolite of clopidogrel, demonstrate reduced
antiplatelet effects, and exhibit higher cardiovascular event
rates at recommended doses than do patients with normal
CYP2C19 function.2426 Because PPIs are believed to reduce
the antiplatelet effects of clopidogrel via competition for
CYP2C19,4 the risk for a clinically significant interaction
may be increased in patients with reduced CYP2C19 function. Although the pharmacodynamic impact of PPIs on the
antiplatelet effects of clopidogrel have not been compared
in CYP2C19 extensive, intermediate, and poor metabolizer
phenotypes, an analysis of patients with a single reducedfunction CYP2C19 allele who were assigned to clopidogrel in
the TRial to assess Improvement in Therapeutic Outcomes by
optimizing platelet inhibitioN with prasugrel-Thrombolysis
in Myocardial Infarction 38 (TRITON-TIMI 38) study
showed no significant differences in cardiovascular event
rates among patients taking a PPI versus patients not taking
a PPI.27

PPIs Interact With Clopidogrel to

Different Degrees

Comparative studies suggest that the degree of interaction

between a PPI and clopidogrel depends on the PPI. A 2-period
crossover study compared the effects of coadministration of
dexlansoprazole 60mg, lansoprazole 30mg, esomeprazole
40mg, or omeprazole 80mg (positive control to maximize
potential interaction and demonstrate assay sensitivity) on
the pharmacokinetics and pharmacodynamics of clopidogrel
in 160 healthy CYP2C19 extensive metabolizers.28 Exposure
to the active metabolite of clopidogrel was reduced by 8%,
13%, 16%, and 30%, respectively. Increases in the platelet
reactivity index (PRI) were greater than the prespecified
no-effect limit when clopidogrel was administered with
omeprazole (positive control) or esomeprazole, but not with
lansoprazole or dexlansoprazole. Dexlansoprazole was the
only PPI that did not significantly increase ADP-induced
maximal platelet aggregation (MPA) measured by light
transmission aggregometry.
The Evaluation of the Influence of Statins and Proton
Pump Inhibitors on Clopidogrel Antiplatelet Effects (SPICE)
study29 carried out a similar comparison in 302 patients with
post-PCI who were discharged while continuing to receive
clopidogrel and also received statin therapy for 30days.
Patients were randomized to 1 of 4gastroprotective agents:
esomeprazole, pantoprazole, omeprazole, or the H2-blocker
ranitidine for 60days. Esomeprazole had the largest effect
on platelet reactivity, with .35% and .50% of patients

demonstrating a.10% change in MPA and PRI from baseline, respectively. Omeprazole showed significant increases
in PRI and non-significant increases in MPA. Neither panto
prazole nor ranitidine significantly affected either measure
of platelet reactivity.
The results of these and other studies led to recent changes
in FDA labeling for esomeprazole,19 dexlansoprazole,18
rabeprazole,23 and clopidogrel.11 The new labeling cautions
against the use of omeprazole or esomeprazole with clopidogrel and suggests that dexlansoprazole, lansoprazole, and
pantoprazole have less effect on the antiplatelet a ctivity
of clopidogrel (Table1).11 Still, data collected between
January1 and March 31, 2012, from .18 000 retail pharmacies (representing 40% of US retail prescriptions) showed
that, among patients taking clopidogrel and a prescription
PPI, 40% were taking omeprazole and 17% were taking
esomeprazole (Figure2).17

Whether the PPIClopidogrel Interaction

Increases Thrombotic Risk Is Unknown

The existence of a pharmacokinetic and pharmacodynamic

interaction between clopidogrel and PPIs, particularly
omeprazole and esomeprazole, is indisputable. However, the
clinical significance of this interaction has been a topic of
great debate. Retrospective and secondary analyses evaluating clinical outcomes associated with the interaction between
clopidogrel and PPIs have yielded inconsistent results and
have been summarized previously.4,30,31 Meta-analyses are
limited by significant heterogeneity and have done little to
clarify the issue.32,33 The only prospective, randomized study
to evaluate the clinical implication of coadministration of
PPIs and clopidogrel, Clopidogrel and the Optimization
of Gastrointestinal Events (COGENT), was discontinued
Table 1. FDA Labeling Pertinent to Coadministration of
Proton-Pump Inhibitors and Antiplatelet Agents
Yes
PPIs: safe to use with clopidogrel?
Dexlansoprazole (Dexilant)18
Esomeprazole (Nexium)19
Lansoprazole (Prevacid)20
Omeprazole (Prilosec)21
Pantoprazole (Protonix)22
Rabeprazole (AcipHex)23
Antiplatelet agents: safe to use
with PPI?
Clopidogrel (Plavix)11
Prasugrel (Effient)37
Ticagrelor (Brilinta)38

No

Other

X
X
X
X
X
X

Avoid omeprazole
or esomeprazole
X
X

Abbreviations: FDA, US Food and Drug Administration; PPI, proton-pump inhibitor.

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Figure 2. Distribution of PPI type among patients co-prescribed clopidogrel and a prescription PPI.17

prematurely owing to lack of funding. The COGENT

study randomized patients taking dual antiplatelet therapy
(clopidogrel and aspirin) to omeprazole or placebo.8 The
primary cardiovascular endpoint was a composite of death
from cardiovascular causes, nonfatal myocardial infarction,
revascularization, or stroke. Of 3761 patients included in
the final analysis, 109 had a cardiovascular event. Event
rates were comparable between the omeprazole (4.9%) and
placebo (5.7%) groups. No prospective study has compared
PPIs with respect to cardiovascular event rates in patients
receiving clopidogrel.

Strategies to Reduce the Risk for

a Clinically Significant DrugDrug
Interaction Between PPI and
Clopidogrel

Several clinical scenarios may confront the primary care

provider with a decision related to PPI and clopidogrel
coadministration: 1) A patient taking clopidogrel is also
taking a prescription or over-the-counter PPI that is not consistent with FDA labeling; 2) a patient taking a PPI develops
acardiovascular condition requiring long-term clopidogrel

242

therapy; and 3) a patient taking clopidogrel develops characteristics that increase the risk of GI bleeding.
The ACCF/ACG/AHA 2010 Expert Consensus on the
Concomitant Use of Proton-Pump Inhibitors and Thienopyridines defines risk characteristics for GI bleeding as a history
of GI bleeding; advanced age; concurrent use of anticoagulants, steroids, or non-steroidal anti-inflammatory drugs;
and H. pylori infection.4 A suggested algorithm for GI risk
stratification and PPI selection in patients taking clopidogrel
based on the ACCF/ACG/AHA consensus and current FDA
labeling is provided in Figure3. Several strategies to reduce
the potential for a clinically significant drugdrug interaction
are discussed in the following section.

Use FDA Labeling to Guide PPI Choice

Based on comparative pharmacokinetic and pharmacodynamics studies,28,29,34 FDA labeling now recommends
against co-administration of omeprazole or esomeprazole
with clopidogrel.11,19,21 Table1summarizes current FDA
labeling regarding co-administration of individual PPIs with
clopidogrel or other antiplatelet agents. It is unclear whether
the results of a recent randomized, placebo-controlled
study showing that pantoprazole significantly reduces the

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Figure 3. Suggested algorithm for use of PPI in patients taking clopidogrel.

Abbreviations: GI, gastrointestinal; NSAID, nonsteroidal anti-inflammatory drug;

PPI, proton-pump inhibitor.

antiplatelet effect of clopidogrel will cause a change in

pantoprazole labeling.
From a practical standpoint, it should be noted that step
edits may not have been updated to reflect the new labeling, and generic omeprazole remains the preferred PPI in
most step-therapy programs. A physician-initiated appeal
may be required for insurance coverage of an alternate PPI.
This may be particularly relevant if the formulary does not
offer FDA-approved PPI alternatives for patients receiving
concomitant clopidogrel.
35

H2-Receptor Antagonists May Be a

Suitable Alternative to PPIs

The H2-receptor antagonists (H2RAs) suppress gastric acid

production, and there are no prohibitions on their use with
clopidogrel. However, clinical data suggest that H2RAs
reduce the risk for upper GI bleeding to a lesser extent
than do PPIs in patients requiring antiplatelet therapy.7,36
The ACCF/ACG/AHA Consensus states that H2RAs may
be a reasonable alternative in patients at lower risk for GI
bleeding, and in those who do not require PPI for refractory
gastroesophageal reflux disease.4

Next-Generation Antiplatelet Agents May

Be Substituted for Clopidogrel

Prasugrel is a new thienopyridine prodrug that is hydrolyzed in the intestine to a thiolactone and then converted
to the active metabolite via a one-step process catalyzed

predominantly by CYP3A4 and CYP2B6. Prasugrel is indicated for the reduction of thrombotic cardiovascular events
(including stent thrombosis) in patients with ACS who are to
be managed with PCI.37 Ticagrelor is a non-thienopyridine
adenosine triphosphate analogue indicated to reduce the rate
of thrombotic cardiovascular events in patients with ACS
treated invasively or medically. Ticagrelor is metabolized
by CYP3A4 and CYP3A5.38 Because of their lack of dependence on the CYP2C19 enzyme, prasugrel and ticagrelor can
be used with any PPI. Although these agents gained FDA
approval by demonstrating superiority over clopidogrel for
prevention of some cardiovascular outcomes,39,40 they are
more costly than generic clopidogrel, which is a substantial
barrier to long-term use. Furthermore, prasugrel is contraindicated in patients with a history of transient ischemic attack
or stroke.37

Temporal Separation of Dosing Is Not a

Solution

If one considers the half-lives of PPIs and clopidogrel

(all ,2hours), it would appear that temporal separation
of their administration would obviate any drug interaction.
However, a study in healthy volunteers found that administration of clopidogrel and omeprazole 12hours apart
significantly decreased exposure to the active metabolite
of clopidogrel (47%), and significantly increased ADPinduced MPA (+5.6%) and PRI (+27%) versus administration
of clopidogrel alone.41 These findings may be explained by
the time-dependent, irreversible nature of CYP2C19inhibition by omeprazole established in vitro.42 The FDA labeling
for clopidogrel and omeprazole specifies that the interaction
between these 2 agents is not mitigated by administration
12hours apart.11,21

Conclusion

Many patients taking clopidogrel, with or without aspirin,

require gastroprotective therapy to protect against GI bleeding.
The PPIs are the most effective anti-secretory agents in these
patients. However, a significant pharmacokinetic and pharmacodynamic interaction, believed to involve competition for
the CYP2C19 enzyme, has been demonstrated between some
PPIs and clopidogrel. Although studies evaluating the potential effects of this interaction on thrombotic risk have yielded
conflicting results, the FDA has taken steps to ensure that PPIs
co-prescribed with clopidogrel are limited to pantoprazole,
rabeprazole, lansoprazole, and d exlansoprazole. Compared
with omeprazole or esomeprazole, these PPIs are less likely
to reduce exposure to the active metabolite of clopidogrel

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Johnson etal

and attenuate antiplatelet activity of clopidogrel. Beyond

the choice of PPI, strategies to avoid the PPI-clopidogrel
interaction include use of an H2RA instead of PPI or the use
of ticagrelor or prasugrel instead of clopidogrel. A 12-hour
separation between omeprazole and clopidogrel dosing
does not prevent the interaction between these agents. In the
future, platelet function testing or pharmacogenomic testing
to identify patients with CYP2C19 variants may allow more
individualized management of patients requiring gastroprotection in the setting of antiplatelet therapy.

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Acknowledgments

Medical writing support was provided by Melinda Ramsey,

PhD, from Complete Healthcare Communications, Inc.,
with funding from Takeda Pharmaceuticals. All authors
participated in each draft. No original data are included in
this review article. Takeda Pharmaceutical Company provided funding.

Conflict of Interest Statement

David A. Johnson, MD, MACG, FASGE, FACP, is a consultant for Takeda Pharmaceuticals, Pfizer Inc, Janssen/Centacor,
Abbvie, Medigus, AstraZeneca, MedScape/WebMD, CRH
Medical, and Epigenomics; he is also a member of the
speakers bureau for Takeda Pharmaceuticals and AstraZeneca.
RobertChilton, DO, FACC, is a consultant, member of the
speakers bureau, and a member of the advisory board for
Takeda Pharmaceuticals; he is a member of the research advisory board for MSD, Boston Scientific, and Eli-Lilly. Harley
R. Liker, MD, is a consultant for Roll Global.

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Postgraduate Medicine, Volume 126, Issue 3, May 2014, ISSN 0032-5481, e-ISSN 1941-9260 245
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