Journal of the American College of Cardiology Vol. 57, No.

11, 2011
© 2011 by the American College of Cardiology Foundation ISSN 0735-1097/$36.00
Published by Elsevier Inc. doi:10.1016/j.jacc.2010.11.024

STATE-OF-THE-ART PAPER

Clopidogrel–Drug Interactions
Eric R. Bates, MD,* Wei C. Lau, MD,† Dominick J. Angiolillo, MD, PHD‡
Ann Arbor, Michigan; and Jacksonville, Florida

Multidrug therapy increases the risk for drug–drug interactions. Clopidogrel, a prodrug, requires hepatic cytochrome
P450 (CYP) metabolic activation to produce the active metabolite that inhibits the platelet P2Y12 adenosine diphos-
phate (ADP) receptor, decreasing platelet activation and aggregation processes. Atorvastatin, omeprazole, and sev-
eral other drugs have been shown in pharmacodynamic studies to competitively inhibit CYP activation of clopidogrel,
reducing clopidogrel responsiveness. Conversely, other agents increase clopidogrel responsiveness by inducing CYP
activity. The clinical implications of these pharmacodynamic interactions have raised concern because many of these
drugs are coadministered to patients with coronary artery disease. There are multiple challenges in proving that a
pharmacodynamic drug–drug interaction is clinically significant. To date, there is no consistent evidence that clopi-
dogrel–drug interactions impact adverse cardiovascular events. Statins and proton pump inhibitors have been shown
to decrease adverse clinical event rates and should not be withheld from patients with appropriate indications for
therapy because of concern about potential clopidogrel–drug interactions. Clinicians concerned about clopidogrel–
drug interactions have the option of prescribing either an alternative platelet P2Y12 receptor inhibitor without
known drug interactions, or statin and gastro-protective agents that do not interfere with clopidogrel metabolism.
(J Am Coll Cardiol 2011;57:1251–63) © 2011 by the American College of Cardiology Foundation

Dual antiplatelet therapy with aspirin and clopidogrel is
recommended treatment for percutaneous coronary inter-
vention (PCI) (1) and acute coronary syndromes (ACS)
(2,3). Whereas multidrug therapy with antiplatelet drugs,
lipid-lowering and glucose-lowering agents, antihyperten-
sive drugs, and even antidepressants has been suggested as a
therapeutic strategy to reduce cardiovascular risk, multiple
drug prescriptions increase the risk for drug– drug inter-
actions. This is particularly true if more than 1 agent
requires significant hepatic metabolism (4). Clopidogrel,
atorvastatin, omeprazole, and many other drugs require
hepatic cytochrome P450 (CYP) metabolism. Importantly,
clopidogrel–atorvastatin (5) and clopidogrel– omeprazole (6)
drug interactions have been described that limit the ability of
clopidogrel to inhibit platelet activation and aggregation pro-
cesses. The clinical implications of these pharmacodynamic
From the *Division of Cardiovascular Diseases, Department of Internal Medicine,
University of Michigan, Ann Arbor, Michigan; †Division of Cardiovascular Thoracic
Anesthesiology, Department of Anesthesiology, University of Michigan, Ann Arbor,
Michigan; and the ‡Division of Cardiology, University of Florida College of
Medicine–Jacksonville, Jacksonville, Florida. Dr. Bates has relationships with Daiichi
Sankyo, Eli Lilly, Bristol-Myers Squibb, Sanofi-Aventis, Merck, GlaxoSmithKline,
Takeda, and Dat. Dr. Lau was a consultant to and has received an educational grant
for an investigator-initiated study from Eli Lilly. Dr. Angiolillo reports receiving
honoraria for lectures from Bristol-Myers Squibb, Sanofi-Aventis, Eli Lilly Co.,
Daiichi Sankyo, Inc.; consulting fees from Bristol-Myers Squibb, Sanofi-Aventis, Eli
Lilly Co., Daiichi Sankyo, Inc., The Medicines Company, Portola, Novartis,
Medicure, Accumetrics, Arena Pharmaceuticals, AstraZeneca, Merck; and research
grants from Bristol-Myers Squibb, Sanofi-Aventis, GlaxoSmithKline, Otsuka, Eli
Lilly Co., Daiichi Sankyo, Inc., The Medicines Company, Portola, Accumetrics,
Schering-Plough, AstraZeneca, and Eisai.
Manuscript received October 7, 2010; revised manuscript received November 8,
2010; accepted November 19, 2010.
interactions have raised concern because many of these drugs
are concomitantly administered to patients with coronary
artery disease (7,8). The purpose of this review is to summarize
the pharmacodynamic and clinical evidence regarding these
drug interactions and other clopidogrel– drug interactions.
Drug Metabolism
The most important metabolic pathway for most medications
involves oxidation by 1 or more CYP isoenzymes. These
isoenzymes are generally most highly expressed in hepatocytes,
but are also present in other tissues including the intestines and
skin. As oxidative metabolism is the first step in the clearance
of many drugs, CYP isoenzymes are central to many clinically
relevant drug– drug interactions. The activity of CYP isoen-
zymes may also be a necessary step for conversion of a prodrug
to a clinically beneficial active metabolite.
Clopidogrel bisulfate, an inactive thienopyridine prodrug,
is 85% hydrolyzed in vivo by esterases to an inactive
carboxylic acid derivative (Fig. 1). The remaining drug
undergoes oxidative biotransformation to its active thiol
metabolite by a 2-step, CYP-dependent process in which
CYP3A4/5 and CYP2C19 have the greatest roles, with
lesser involvement from CYP2B6, CYP1A2, and CYP2C9
(9). The active metabolite then irreversibly inhibits the
platelet P2Y12 adenosine diphosphate (ADP) receptor by
forming an inactivating disulfide bond with cysteine on the
P2Y12 receptor (10). This blocks ADP from binding to the
receptor and stimulating platelet activation and aggregation.
Physical and genetic factors that induce, inhibit, or compete
for CYP activity can modulate biotransformation of clopi-
1252 Bates et al. JACC Vol. 57, No. 11, 2011
Clopidogrel–Drug Interactions March 15, 2011:1251–63

Abbreviations dogrel to its active metabolite metabolized by this isoenzyme. Atorvastatin is the most
and Acronyms and result in interindividual vari- commonly prescribed statin, and its extensive hepatic metab-
ability of clopidogrel responsive- olism has the potential to result in significant interactions with
ACS ⴝ acute coronary
syndrome ness. For instance, the degree of other drugs (13). Atorvastatin calcium is initially converted to
cAMP ⴝ cyclic adenosine
CYP3A4 metabolic activity is in- the acid and lactone metabolites of the parent drug. Whereas
monophosphate versely related to the antiplatelet the acid form inhibits HMG-CoA reductase, the dominant
CYP ⴝ cytochrome P450
effects of clopidogrel (11). pathway of elimination is through the lactone form that binds
H2RA ⴝ histamine2
CYP2C19 polymorphisms asso- more tightly to CYP3A4 than many other substrates and
receptor antagonist ciated with enzymatic activity competes with a large number of medications, including
HMG-CoA ⴝ 3-hydroxy-3-
also impact clopidogrel metabo- itraconazole, nelfinavir, ritonavir, cyclosporine, fibrates, eryth-
methylglutaryl coenzyme A lism and responsiveness (12). romycin, amiodarone, verapamil, fluoxetine, and nefazadone,
MI ⴝ myocardial infarction Statins act by inhibiting 3- as well as grapefruit juice.
PCI ⴝ percutaneous
hydroxy-3-methylglutaryl coen- Proton pump inhibitors (PPIs) are prodrugs that are
coronary intervention zyme A (HMG-CoA) reductase, activated in gastric parietal cells. PPIs irreversibly inhibit the
PPI ⴝ proton pump
the rate-limiting enzyme of cho- gastric H⫹/K⫹ ATPase (the proton pump) that accom-
inhibitor lesterol synthesis in the liver. plishes the final step in acid secretion. Omeprazole, the
VASP ⴝ vasodilator- CYP3A4 is important for the most widely used PPI, is metabolized to hydroxyomeprazole
stimulated phosphoprotein elimination of lipophilic statins and omeprazole sulphate primarily by CYP2C19 and
(lovastatin, simvastatin, and ator- CYP3A4 (14). Omeprazole has a greater affinity for
vastatin), but hydrophilic statins CYP2C19 than CYP3A4, compared with the other PPIs
(fluvastatin, pravastatin, and rosuvastatin) are not significantly that are also metabolized by these isoenzymes, and therefore

Figure 1 Clopidogrel–Drug Interactions

After ingestion and absorption, 85% of clopidogrel bisulfate is hydrolyzed by esterases to an inactive carboxylic acid metabolite and the remaining drug is oxidized in a
2-step process by hepatic P450 cytochromes. Multiple pharmacodynamic drug interactions can influence active thiol metabolite levels. cAMP ⫽ cyclic adenosine mono-
phosphate; PPI ⫽ proton pump inhibitor.
JACC Vol. 57, No. 11, 2011
March 15, 2011:1251–63
has a greater potential for drug– drug interactions mediated
by CYP2C19. Omeprazole has been shown to reduce the
clearance of diazepam, phenytoin, and warfarin. Conversely,
ketaconazole and clarithromycin have a high affinity for
CYP3A4 and increase omeprazole concentrations. Another
mechanism by which omeprazole may induce drug interac-
tions is by elevating gastric pH and altering drug absorption
rates.
Due to their common requirement for CYP3A4 metab-
olism, a clopidogrel–atorvastatin interaction may exist. Sim-
ilarly, due to their common requirement for CYP2C19
metabolism, a clopidogrel– omeprazole interaction may ex-
ist. These interactions could result in competitive inhibition
decreasing the conversion of the clopidogrel prodrug to the
active metabolite and could potentially translate into an
increased risk for cardiovascular events because of inade-
quate platelet P2Y12 receptor inhibition. This is a particu-
larly important issue since many patients receiving treat-
ment to prevent recurrent cardiovascular events are suitable
candidates for all 3 drugs.
Pharmacodynamic Studies
The clopidogrel–atorvastatin interaction. We initially
surmised that clopidogrel was metabolized in humans by
CYP3A4, not CYP1A2 as described in the rat (15), when
we serendipitously noted that patients on atorvastatin were
not achieving the expected platelet inhibition with a clopi-
dogrel 300-mg loading dose (5), an observation confirmed
by Neubauer et al. (16). Responding to criticism that our
initial study was observational and used a point-of-care
platelet aggregometer, we subsequently performed a pro-
spective randomized trial with standard light transmission
aggregometry and demonstrated an interaction with a 300-
mg, but not a 600-mg, clopidogrel loading dose (17).
Consistent with these findings, results from an in vitro study
using human microsomes containing single CYP isozymes
indicated that both CYP3A4 and CYP3A5 were primarily
responsible for oxidation of clopidogrel to its active metab-
olite. Exposure of human microsomes to clopidogrel and
atorvastatin lactone at equimolar concentrations resulted in
a ⬎90% inhibition of clopidogrel metabolism (18).
However, other studies (Table 1) have shown no impact
with clopidogrel and atorvastatin coadministration (19 –22),
especially when a higher clopidogrel loading dose (600 mg)
was tested (23–26), when measurements were made several
weeks later (21,27-29), or when atorvastatin was added to
clopidogrel (31–32). Limitations of the ex vivo platelet
aggregation studies include small sample sizes, different
drug doses, heterogeneous patient populations on multiple
medications, and differences in measurement techniques
and protocols. Moreover, it is unknown how the variability
in clopidogrel metabolism due to CYP2C19 polymor-
phisms and CYP3A4 expression might have impacted the
results. Expression of CYP3A4 varies 40-fold in humans,
Bates et al. 1253
Clopidogrel–Drug Interactions
and metabolism of CYP3A4 substrates varies 10-fold in
vivo (33).
In summary, no one disputes our initial finding that
clopidogrel is metabolized by CYP3A4, recognized by
platelet aggregometry because of a presumed clopidogrel–
atorvastatin interaction, but many other reports have not
been able to confirm this interaction for various reasons.
The clopidogrel– omeprazole interaction. Gilard et al. (6)
initially observed an association between PPI use and poor
clopidogrel response (Table 2). They subsequently demon-
strated that more patients on omeprazole than placebo were
nonresponders after clopidogrel administration (34). Cuis-
set et al. (35) found more nonresponders on omeprazole
compared with pantoprazole despite a high clopidogrel
maintenance dose of 150 mg/day. Sibbing et al. (36)
demonstrated less platelet inhibition and more nonre-
sponders in patients taking omeprazole compared with
non-PPI users or those given esomeprazole or pantoprazole.
Neubauer et al. (37) also found more clopidogrel nonre-
sponders with omeprazole, but no interaction with panto-
prazole. Staggering the administration times of clopidogrel
and omeprazole does not decrease the interaction (38).
O’Donoghue et al. (39) measured decreased platelet
inhibition after a clopidogrel loading dose in patients taking
PPIs. Likewise, Zuern et al. (40) noted less platelet inhibi-
tion in patients on PPIs, but no difference between agents,
although only 36 of 1,425 patients were given omeprazole.
Sibbing et al. (36) and Siller-Matula et al. (41) found no
impairment of clopidogrel responsiveness with pantoprazole
or esomeprazole. Similarly, Small et al. (42) described no
overall impact of coadministration with lansoprazole in 24
healthy volunteers, although there was decreased clopi-
dogrel responsiveness in 8 high clopidogrel responders.
Recently, Angiolillo et al. (43) confirmed a pharmacoki-
netic/pharmacodynamic interaction between clopidogrel
(administered at both standard and double loading/
maintenance dose regimens) and omeprazole (administered
concomitantly or staggered), but found no interaction be-
tween clopidogrel and pantoprazole.
In summary, omeprazole has consistently been shown to
attenuate clopidogrel responsiveness (34-38,43), whereas no
or limited interaction has been shown with pantoprazole
(35–37,41,43) and other PPIs.
The SPICE (Evaluation of the Influence of Statins and
Proton Pump Inhibitors on Clopidogrel Antiplatelet
Effects) trial. The SPICE trial (44) is enrolling 320 pa-
tients treated with dual antiplatelet therapy for at least 60
days after bare-metal stent implantation. Patients will re-
ceive either atorvastatin 80 mg or the comparator rosuvas-
tatin 20 mg daily for 12 months. After 1 month, they will
also receive either omeprazole 20 mg, pantoprazole 40 mg,
esomeprazole 40 mg, or the histamine2-receptor antagonist
(H2RA) comparator ranitidine 300 mg daily for 11 months.
Percentage change in residual platelet aggregation by light
transmittance aggregometry and percentage change in
platelet reactivity index by flow cytometry will be measured
 1254
Clopidogrel–Drug Interactions
Bates et al.
Pharmacodynamic Studies ThatStudies
Table 1 Pharmacodynamic Evaluated the
That Administration
Evaluated of Clopidogrel
the Administration of to Subjects Receiving
Clopidogrel Atorvastatin
to Subjects Receiving Atorvastatin

First Author (Ref. #)

(Year) Population Clopidogrel Dose Atorvastatin Dose Main Outcome Comment
Lau et al. (5) 19 pts, 16 controls 300 mg 10–40 mg/day Atorvastatin dose-related decrease First demonstration that clopidogrel
(2003) undergoing PCI of platelet aggregation is activated by CYP3A4
inhibition by clopidogrel at 24 h
Neubauer et al. (16) 17 pts, 22 controls 300 mg then 20–40 mg/day Dose-related decrease of platelet Diminished interaction at 48 h
(2003) undergoing PCI 75 mg/day aggregation inhibition by compared with 5 h
atorvastatin at 5 and 48 h
Muller et al. (23) 7 pts, 12 controls undergoing 600 mg 20 mg/day No inhibition of platelet No inhibition with high clopidogrel
(2003) angiography aggregation at 2–4 h loading dose
Mitsios et al. (27) 13 pts, 8 controls with ACS 375 mg then 10 mg/day No inhibition of platelet No inhibition with sustained
(2004) 75 mg/day aggregation at 5 weeks coadministration
Piorkowski et al. (19) 17 volunteers, 15 pts with 300 mg then 20 mg/day No inhibition of platelet No inhibition with standard
(2004) CAD, 17 controls 75 mg/day aggregation at 4, 24, and 96 h clopidogrel loading dose
Serebruany et al. (20) 25 pts, 25 controls 300 mg 10–40 mg/day No inhibition of platelet No inhibition with standard
(2004) undergoing PCI aggregation at 24 h clopidogrel loading dose
Gorchakova et al. (24) 58 pts, 90 controls 600 mg 10–40 mg/day No inhibition of platelet No inhibition with high clopidogrel
(2004) undergoing PCI aggregation at 2 h loading dose
Smith et al. (21) 20 pts, 5 controls 300 mg then Not stated No inhibition of platelet No inhibition with standard
(2004) undergoing PCI 75 mg/day aggregation at 4 h, 10 days, clopidogrel loading dose and
and 28 days sustained coadministration
Mitsios et al. (28) 26 pts, 25 controls 375 mg then 20 mg/day No inhibition of platelet No inhibition with sustained
(2005) undergoing PCI for ACS 75 mg/day aggregation at 5 weeks coadministration
Lau et al. (17) 36 volunteers, 24 controls 300, 450, 600 mg 40 mg/day Dose related decrease of platelet Inhibition with 300 mg, less
(2005) inhibition by atorvastatin at inhibition with 450 mg,
2, 4, 6, and 8 h no inhibition with 600 mg
Trenk et al. (25) 255 pts, 682 controls 600 mg Not stated No inhibition of platelet No inhibition with high clopidogrel
(2008) undergoing angiography aggregation at 2 h loading dose
Geisler et al. (26) 262 pts, 142 controls 600 mg Not stated No inhibition of platelet No inhibition with high clopidogrel
(2008) undergoing PCI aggregation at 6 h loading dose
Farid et al. (22) 31 volunteers 300 mg 80 mg/day No inhibition of platelet No inhibition with standard
(2008) aggregation at 2–24 h clopidogrel loading dose
Malmstrom et al. (29) 22 pts with CAD 75 mg/day 20–80 mg/day No inhibition of platelet No inhibition with sustained
(2009) aggregation at 2 weeks coadministration

JACC Vol. 57, No. 11, 2011

March 15, 2011:1251–63
ACS ⫽ acute coronary syndrome; CAD ⫽ coronary artery disease; PCI ⫽ percutaneous coronary intervention; pts ⫽ patients.
 March 15, 2011:1251–63
JACC Vol. 57, No. 11, 2011
Pharmacodynamic Studies ThatStudies
Table 2 Pharmacodynamic Evaluated the
That Administration
Evaluated of Clopidogrel
the Administration of to Subjects Receiving
Clopidogrel Proton
to Subjects PumpProton
Receiving Inhibitors
Pump Inhibitors

First Author (Ref. #) Clopidogrel

(Year) Design Population End Point Dose n Main Outcome Comments
Gilard et al. (6) Cohort High-risk PCI VASP (PRI) 300 mg then No PPI: 81 No PPI: 49.5% PPI decreased platelet inhibition
(2006) 75 mg/day PPI: 24 PPI: 61.4%
p ⫽ 0.007
Gilard et al. (34) Prospective, Double-blind Elective coronary stent VASP (PRI) at 7 day 300 mg then Placebo: 60 Placebo: 39.8% Omeprazole decreased platelet
(2008) RCT implantation 75 mg/day Omeprazole: 64 Omeprazole: 51.4% inhibition
p ⬍ 0.0001
Cuisett et al. (35) Prospective RCT PCI for ACS VASP (PRI) at 1 month 600 mg then Pantoprazole: 52 Pantoprazole: 36% Omeprazole decreased platelet
(2009) 150 mg/day Omeprazole: 52 Omeprazole: 48% inhibition vs. pantoprazole
p ⫽ 0.007
Sibbing et al. (36) Cohort Prior coronary stent Platelet aggregation 75 mg/day No PPI: 732 No PPI: 220 AU⫻min Omeprazole decreased platelet
(2009) implantation Esomeprazole: 42 Esomeprazole: 209 AU⫻min inhibition; esomeprazole and
Pantoprazole: 162 Pantoprazole: 226 AU⫻min pantoprazole did not
Omeprazole: 64 Omeprazole: 296 AU⫻min decrease platelet inhibition
p ⫽ 0.001 vs. omeprazole
Siller-Matula et al. (41) Cohort Undergoing PCI VASP (PRI) after PCI 600 mg then No PPI: 74 No PPI: 49% Esomeprazole and pantoprazole
(2009) 75 mg/day Esomeprazole: 74 Esomeprazole: 54% did not decrease platelet
Pantoprazole: 152 Pantoprazole: 50% inhibition
O’Donoghue et al. (39) Retrospective RCT cohort ACS with planned PCI Inhibition of platelet 600 mg then No PPI: 71 No PPI: 35.2% PPI decreased platelet inhibition
(2009) aggregation at 6 h 150 mg/day PPI: 28 PPI: 23.2%
p ⫽ 0.02
Zuern et al. (40) Cohort Undergoing PCI Platelet aggregation 600 mg then No PPI: 1,001 No PPI: 29.8% PPI decreased platelet inhibition
(2009) at 20 h 75 mg/day Esomeprazole: 108 PPI: 34%
Pantoprazole: 280 p ⫽ 0.001
Omeprazole: 36
Neubauer et al. (37) Cohort Undergoing PCI Platelet aggregation 600 mg then No PPI: 188 No PPI: 2.75 ⍀ Nonresponders: no PPI, 21.9%,

Clopidogrel–Drug Interactions
(2010) at 48 h 75 mg/day Esomeprazole or Esomeprazole or esomeprazole or omeprazole,
omeprazole: 26 omeprazole: 3.00 ⍀ 30.8%, pantoprazole, 16.4%.
Pantoprazole: 122 Pantoprazole: 2.33 ⍀

AU ⫽ aggregation unit; PPI ⫽ proton pump inhibitor; PRI ⫽ platelet reactivity index; RCT ⫽ randomized clinical trial; VASP ⫽ vasodilator-stimulated phosphoprotein; other abbreviations as in Table 1.

Bates et al.
1255
1256 Bates et al. JACC Vol. 57, No. 11, 2011
Clopidogrel–Drug Interactions March 15, 2011:1251–63

at 30 and 60 days. Death, myocardial infarction (MI),

Increased risk
ischemia-driven repeat revascularization, stroke, gastroin-

Comment
testinal bleeding, and peptic ulcer disease will be docu-

No risk

No risk

No risk

No risk
mented at 30 days, 60 days, and 1 year. Unfortunately, this
protocol will not evaluate the interaction we described when
a loading dose of clopidogrel is given to a patient on chronic
atorvastatin therapy, nor will it measure the early potential

OR: 1.26 (95% CI: 0.67–1.70)

OR: 1.65 (95% CI: 1.07–2.54)

interaction between omeprazole and clopidogrel.

No atorvastatin: 3.09%
Atorvastatin: 4.54%
Results
Atorvastatin: 3.2%

Atorvastatin: 6.5%

Atorvastatin: 4.6%

Atorvastatin: 5.7%
Other statin: 2.7%

Pravastatin: 4.6%

Pravastatin: 3.5%

Pravastatin: 5.1%
No statin: 10.1%
Clinical Studies

No statin: 3.7%

No statin: 8.7%
The clopidogrel–atorvastatin interaction. REGISTRY REPORTS.
The MITRA-Plus (Maximal Individual Therapy of Acute
Myocardial Infarction PLUS) registry (45) reported no
significant difference in mortality in 2,086 patients who
received clopidogrel for ACS with atorvastatin versus other

No atorvastatin: 2,200
statins (3.2% atorvastatin, 2.7% other statins) (Table 3). A

Atorvastatin: 4,127
Other statin: 1,203

CI ⫽ confidence interval; CV ⫽ cardiovascular; MI ⫽ myocardial infarction; OR ⫽ odds ratio; TIA ⫽ transient ischemic attack; UA ⫽ unstable angina; other abbreviations as in Tables 1 and 2.
Pravastatin: 1,440
Atorvastatin: 883

Atorvastatin: 727
Atorvastatin: 564

Atorvastatin:388
Pravastatin: 142

Pravastatin: 319
registry report (46) from Nova Scotia including 1,537

No statin: 5,496
No statin: 944

No statin: 512
patients with PCI found no significant difference in death,

n
MI, or unstable angina rates (4.6% atorvastatin, 3.5%
pravastatin). A single-center study (47) with 211 patients
undergoing coronary stenting receiving pretreatment with
clopidogrel described a lower rate of periprocedural MI for
patients on pravastatin and fluvastatin compared with ator-

Death/MI or repeat hospitalization

CV death/MI/stroke at 28 months
vastatin and simvastatin. A single-center registry (48) found

revascularization at 30 days
benefit with the combination of statin therapy and clopi-

Death/MI/UA at 30 days
Death/MI/stroke at 1 yr
End Point

dogrel in patients with ACS that was not influenced by

for UA, stroke, TIA,

Death at 14 months
and Atorvastatin

statin choice. Two German single-center registries (25,26)

of patients undergoing coronary artery stenting found no
significant difference in clinical outcomes when clopidogrel
600 mg was initiated in patients on statin therapy. A report
Atorvastatin

from the GRACE (Global Registry of Acute Coronary

Clopidogrel

Events) (49) did not analyze differences between statins, so

did not address the possibility of an atorvastatin– clopidogrel
15,603 pts with high
2,086 pts with ACS

interaction.
1,159 pts with PCI

1,537 pts with PCI

2,927 pts with PCI

of and

Population

Brophy et al. (50)

of Clopidogrel

ADMINISTRATIVE DATABASE REPORTS.

the Coadministration

CV risk

reported on 2,927 consecutive patients discharged after PCI

on clopidogrel and found a significantly increased risk for
the 30-day composite outcome of death, MI, unstable
angina, cerebrovascular events, and repeat revascularization
Coadministration

for those treated with atorvastatin (4.54% vs. 3.0%). Risk

Retrospective registry cohort

Retrospective registry cohort

Retrospective administrative

was also increased with other prescriptions for drugs inhib-

Retrospective RCT cohort

Retrospective RCT cohort

iting CYP3A4 enzyme activity (odds ratio [OR]: 1.56, 95%

theReported

database cohort
Design

confidence interval [CI]: 1.02 to 2.37) and for those who

delayed filling the clopidogrel prescription. A subsequent
report (51) on 10,491 patients, with a different reference
That
Reported

group (nonstatin users) and 62-day follow-up, found no

ThatStudies

significant risk for adverse outcomes with CYP-metabolized

statins compared with non–CYP-metabolized statins, but
could not exclude a small risk (hazard ratio [HR]: 1.16; 95%
Clinical

Wienbergen et al. (45)

First Author (Ref. #)

CI: 0.91 to 1.47).

Table 3Studies

Wahab et al. (46)

Brophy et al. (50)

Saw et al. (52)

Saw et al. (53)

(Year)

POST HOC RANDOMIZED CLINICAL TRIAL REPORTS. A re-

(2003)

(2003)

(2003)

(2006)

(2007)

port from the CREDO (Clopidogrel for the Reduction of

Clinical

Events During Observation) trial (52) concluded that there

was no statistically significant interaction on the 1-year
JACC Vol. 57, No. 11, 2011
March 15, 2011:1251–63
composite end point of death, MI, and stroke with clopi-
dogrel and statin coadministration (7.6% CYP3A4 statins,
5.4% non-CYP3A4 statins) or atorvastatin (6.5% atorvasta-
tin, 4.6% pravastatin). Similar findings were found in a post
hoc analysis of the CHARISMA (Clopidogrel for High
Atherothrombotic Risk and Ischemic Stabilization, Man-
agement, and Avoidance) trial (5.9% CYP3A4 statins, 5.7%
non-CYP3A4 statins; 5.7% atorvastatin, 5.1% pravastatin)
(53). A post hoc analysis from the PROVE IT–TIMI 22
(Pravastatin or Atorvastatin Evaluation and Infection Ther-
apy–Thrombolysis In Myocardial Infarction 22) trial (54)
addressed a different question and found no impact of
adding atorvastatin to patients already on clopidogrel.
In summary, increased risk was seen in 2 studies (47,50),
but not in 3 studies (25,26,48), 2 of which used a high
clopidogrel loading dose (25,26). In other studies, there was
an insignificant trend for worse outcomes with atorvastatin
compared with pravastatin or no statin (45,46,52,53) and
with CYP-metabolized statins compared with non–CYP-
metabolized statins (51–53), but no consistent signal for
increased cardiovascular risk with drug coadministration.
The clopidogrel–omeprazole interaction. REGISTRY REPORTS.
A letter to the editor first suggested that PPI exposure
increased the rate of MI in patients on clopidogrel (55).
Two small (56,57) and 1 large (58) single-center reports
supported increased adverse cardiac events in patients dis-
charged on a PPI after PCI. Conversely, omeprazole and
other PPIs had no effect on the clinical response to
clopidogrel in the FAST-MI (French Registry of Acute
ST-Elevation and Non–ST-Elevation Myocardial Infarc-
tion) registry that enrolled 2,208 patients with MI and
assessed 1-year risk for death, MI, and stroke (59).
ADMINISTRATIVE DATABASE REPORTS. Ho et al. (60) stud-
ied 8,205 veterans discharged after hospitalization for ACS
and found an increased risk for mortality or rehospitaliza-
tion for ACS for patients treated with clopidogrel plus PPI
compared with clopidogrel without PPI (OR: 1.25, 95% CI:
1.11 to 1.41). The increased risk was present in patients
taking omeprazole (Table 4). Similarly, Juurlink et al. (61)
conducted a nested case-control study including 782 elderly
Canadian patients readmitted to the hospital for recurrent
MI within 90 days following hospital discharge for MI, of
whom 46 were taking pantoprazole and 148 were taking
omeprazole, lansoprazole, or rabeprazole. Risk was in-
creased with PPI use (OR: 1.27, 95% CI: 1.03 to 1.57), but
not with pantoprazole or H2RAs. Kreutz et al. (62) studied
16,690 patients with commercial insurance in the Medco
Health Solutions, Inc. (Franklin Lakes, New Jersey) data-
base after coronary stent implantation and described an
increased 1-year risk for the composite outcome of hospi-
talization for cardiovascular death, ACS, cerebrovascular
event, or revascularization in patients prescribed a PPI (HR:
1.51, 95% CI: 1.39 to 1.64). Risk was increased for all PPIs,
but not with H2RAs. Huang et al. (63) also noted an
increased risk of rehospitalization and death in East Asian
Bates et al. 1257
Clopidogrel–Drug Interactions
patients prescribed PPIs after PCI. Stockl et al. (64)
attempted to address some of the limitations of performing
an administrative claims– based analysis by using propensity
scoring, but the results illustrate the analytical challenges.
The negative impact of PPIs on risk (HR: 1.93, 95% CI:
1.05 to 3.54) was greater than the incremental benefit of
adding clopidogrel to aspirin in any randomized clinical
trial, and risk was demonstrated with pantoprazole (HR:
1.91, 95% CI: 1.19 to 3.06), despite no prior pharmacody-
namic evidence of a clopidogrel–pantoprazole interaction.
Rassen et al. (65) noted low event rates in 18,565 elderly
patients with ACS or PCI followed for MI hospitalization
or death. The excess risk with PPI therapy (risk ratio [RR]:
1.22, 95% CI: 0.99 to 1.51) was progressively reduced with
additional statistical analyses that controlled for confound-
ing variables and was considered inconclusive. Ray et al. (66)
studied 20,596 Medicaid patients hospitalized for ACS or
revascularization. There was no cardiovascular risk during
follow-up with PPI use (HR: 0.99; 95% CI: 0.82 to 1.19),
but hospitalizations for gastroduodenal bleeding were 50%
lower than in nonusers. Charlot et al. (67) described
increased risk for PPI use regardless of clopidogrel use in
56,406 Danish patients, but no risk with individual PPIs. A
recent meta-analysis (68) of 23 studies on clopidogrel–PPI
interactions, many unpublished, further describes the limi-
tations of observational study design on accurately deter-
mining risk. Another meta-analysis concluded that patient
risk for cardiovascular events impacted PPI risk (69).
POST-HOC RANDOMIZED CLINICAL TRIAL REPORTS. Dunn
et al. (70) reported preliminary results in 366 patients from
the CREDO trial and found no difference in the 1-year risk
of death, stroke, or MI when PPI was added to clopidogrel.
O’Donoghue et al. (39) studied 13,608 patients in the
TRITON–TIMI 38 (Trial to Assess Improvement in Ther-
apeutic Outcomes by Optimizing Platelet Inhibition with
Prasugrel–Thrombolysis In Myocardial Infarction 38),
4,529 of whom were taking a PPI. No risk was found for the
composite end point of cardiovascular death, MI, or stroke
compared with the no PPI group (HR: 0.94, 95% CI: 0.80
to 1.11). Both studies showed higher risk for patients on
PPIs, suggesting that comorbidities, rather than a clopi-
dogrel–PPI interaction, may make patients higher risk for
adverse cardiac events.
RANDOMIZED CLINICAL TRIAL. The COGENT (Clopi-
dogrel and the Optimization of Gastrointestinal Events
Trial) randomized 3,627 patients with ACS or PCI to a
fixed-dose combination of controlled-release omeprazole 20
mg– clopidogrel 75 mg/day or clopidogrel alone, but was
terminated early because of sponsor bankruptcy (71). Al-
though underpowered, the secondary combined cardiovas-
cular end point of cardiovascular death, ischemic stroke,
nonfatal MI, or revascularization was not different (HR:
1.02, 95% CI: 0.70 to 1.51), but the composite primary
gastrointestinal event rate was reduced with PPI use (HR:
0.55, 95% CI: 0.36 to 0.85).
 1258
Clopidogrel–Drug Interactions
Bates et al.
Clinical
Table 4Studies ThatStudies
Clinical Evaluated the
That Coadministration
Evaluated of Clopidogrel
the Coadministration of and Omeprazole
Clopidogrel and Omeprazole

First Author (Ref. #) Results, RR/OR/HR

(Year) Design Population End Point n (95% CI) Comments
Simon et al. (49) Retrospective registry cohort Acute MI Death, MI, stroke at 1 yr Omeprazole: 1,147 RR: 0.85 (0.69–1.05) No risk
(2009) No PPI: 602
Ho et al. (60) Retrospective administrative Hospital discharge Death or rehospitalization for Omeprazole: 3,132 OR: 1.24 (1.08–1.41) Increased risk in male veterans
(2009) database cohort for ACS UA/MI at 17 months No PPI: 2,961
O’Donoghue et al. (39) Retrospective RCT cohort ACS undergoing CV death, MI, stroke at Esomeprazole: 613 HR: 1.07 (0.75–1.52) Risk associated with PPI use,
(2009) PCI 15 months Lansoprazole: 441 HR: 1.00 (0.63–1.59) not coadministration
Omeprazole: 1,675 HR: 0.91 (0.72–1.15)
Pantoprazole: 1,844 HR: 0.94 (0.74–1.18)
No PPI: 4,538
Rassen et al. (65) Retrospective administrative ACS or PCI Death, MI hospitalization at Omeprazole; NA RR: 1.17 (0.68–2.01) No risk
(2009) database cohort 30 days Pantoprazole: NA RR: 1.26 (0.93–1.71) Low event rates
No PPI: NA
Ray et al. (66) Retrospective administrative UA, MI, PCI, CABG CV death, MI, stroke Esomeprazole: 690 HR: 0.71 (0.48–1.06) No risk in Medicaid pts
(2010) database cohort Lansoprazole: 1,042 HR: 1.06 (0.77–1.45)
Omeprazole: 660 HR: 0.79 (0.54–1.15)
Pantoprazole: 4,349 HR: 1.08 (0.88–1.32)
No PPI: 13,003
Kreutz et al. (62) Retrospective administrative Stent implantation Hospitalization for CV death, ACS, Esomeprazole: 3,257 HR: 1.57 (1.40–1.76) Increased risk for each PPI
(2010) database cohort cerebrovascular event, Lansoprazole: 785 HR: 1.39 (1.16–1.67)
revascularization at 1 yr Omeprazole: 2,307 HR: 1.39 (1.22–1.57)
Pantoprazole: 1,653 HR: 1.61 (1.41–1.88)
No PPI: 9,390
Charlot et al. (67) Retrospective administrative 30 days after MI CV death or rehospitalization for Esomeprazole: 5,316 Not quantitated Risk associated with PPI use,
(2010) database cohort MI or stroke Lansoprazole: 2,798 not coadministration
Omeprazole: 2,717
Pantoprazole: 4,698
No PPI: 40,764

CABG ⫽ coronary artery bypass graft; HR ⫽ hazard ratio; RR ⫽ risk ratio; other abbreviations as in Tables 1, 2, and 3.

JACC Vol. 57, No. 11, 2011

March 15, 2011:1251–63
JACC Vol. 57, No. 11, 2011
March 15, 2011:1251–63
In summary, patients who receive PPIs are older and have
more comorbidity, making confounding and selection bias a
likely explanation for increased clinical risk in some obser-
vational studies. Whereas observational studies have pro-
duced discordant results for a clopidogrel– omeprazole in-
teraction, post hoc randomized clinical trial reports (39,70)
and 1 randomized clinical trial (71) have shown no signal for
increased cardiovascular risk with drug coadministration.
Other Clopidogrel–Drug Interactions
We initially demonstrated that CYP3A4 inhibitors (eryth-
romycin, troleandomycin, ketoconazole) decreased and
CYP3A4 inducers (rifampin) increased the antiplatelet
activity of clopidogrel (5,11). Several other clopidogrel–
drug interactions have subsequently been described (Fig. 1).
CYP inhibitors. Ketoconazole is a potent inhibitor of both
CYP3A4 and CYP3A5. Healthy subjects given loading and
maintenance doses of clopidogrel had decreased production
of active metabolite and significantly reduced platelet inhi-
bition on ketoconazole compared with control (72). Simi-
larly, the CYP3A inhibitor itraconazole significantly de-
creased the ability of clopidogrel to inhibit platelet
aggregation (73).
Dihydropyridine calcium channel blockers (nifedipine,
amlodipine) also inhibit CYP3A4. In observational studies,
they have been shown to decrease clopidogrel responsive-
ness as measured by the vasodilator-stimulated phosphopro-
tein (VASP) assay and electrical impedance aggregometry
(74) and by light transmission aggregometry and the
VerifyNow P2Y12 assay (Accumetrics, San Diego, Cali-
fornia) (75).
Phenprocoumon, an oral anticoagulant used in Europe, is
a coumarin derivative metabolized by CYP3A4 and
CYP2C9. Concomitant treatment with clopidogrel attenu-
ated the antiplatelet effect of clopidogrel and increased the
number of nonresponders (76).
Cangrelor, an ATP analogue, is a parenteral reversible
P2Y12 receptor inhibitor with a short half-life that results in
normalization of platelet aggregation approximately 30 min
after discontinuation of the infusion. When clopidogrel was
given simultaneously with cangrelor and cangrelor was
continued for 2 h, there was no inhibition of the P2Y12
receptor by clopidogrel after the infusion was stopped
because the clopidogrel active metabolite was unavailable for
binding due to its short half-life (77). When clopidogrel was
started at the time the cangrelor infusion was discontinued,
there was inhibition of the P2Y12 receptor. Importantly, it
takes 2 to 4 h for clopidogrel to reach maximal effect.
Therefore, there could be an important gap in platelet
inhibition while the patient transitions from cangrelor to
clopidogrel.
CYP inducers. We initially demonstrated that clopidogrel
responsiveness could be increased by coadministration with
rifampin, a CYP3A4 and CYP2C19 inducer, and that
nonresponders could become responsive (5,11). Judge et al.
Bates et al. 1259
Clopidogrel–Drug Interactions
(78) have recently proven that this response is due to
increased production of the clopidogrel active metabolite
and increased P2Y12 receptor blockade.
By inhibiting the platelet P2Y12 receptor, clopidogrel
increases intracellular cyclic adenosine monophosphate
(cAMP), a key signaling molecule in inhibiting platelet
aggregation. Caffeine also increases cAMP levels and has
been shown to enhance platelet inhibition by clopidogrel
(79). Other methylxanthines (theophylline) and phospho-
diesterase inhibitors (cilostazol) also increase platelet cAMP
levels (80).
Smoking is a known CYP1A2 inducer, and several
studies have demonstrated increased platelet inhibition (81),
fewer ischemic events (82,83), and increased bleeding risk
(83) in smokers following clopidogrel administration.
Omega-3 polyunsaturated fatty acids (PUFA) were shown
in 1 small prospective randomized trial to increase clopidogrel
responsiveness, but the mechanism is unclear (84).
St. John’s wort (Hypericum perforatum) is an herbal
product used to treat depression. It also induces CYP3A4
activity. In healthy volunteers who were nonresponders to
clopidogrel, St. John’s wort 300 mg thrice daily for 14 days
improved the platelet inhibitory activity of clopidogrel by
increasing CYP3A4 metabolic activity (85).
Confounding Variables in
the Drug Interaction Debate
There are many confounding variables that have contributed
to the discordant results regarding potential clopidogrel–
drug interactions:
1. Dose effect. Inhibition of clopidogrel activation by ator-
vastatin appears to be dose-dependent (5), consistent
with the hypothesis that atorvastatin is a competitive
inhibitor of CYP3A4. Studies with high loading doses of
clopidogrel (600 mg) and lower doses of atorvastatin (10
to 20 mg) could miss the inhibitory effect of high-dose
atorvastatin on a lower clopidogrel loading dose (17).
2. Time effect. Suboptimal production of active metabolite
following clopidogrel loading dose administration could
eventually be overcome as active metabolite production
eventually accumulates from maintenance dosing and
binds to initially unblocked platelet receptors. Moreover,
only 10% to 15% of the platelet pool is regenerated daily
and platelet reactivity decreases with time after the
initiating event, making it unlikely that a sustained
inhibition of platelet aggregation could be maintained by
a drug interaction. Additionally, 3 recent reports suggest
that the interaction between CYP2C19 polymorphisms
and the effect of clopidogrel on clinical events is limited
to a few weeks (86 – 88).
3. Class effect. Only clopidogrel interactions with a single
statin (atorvastatin) and a single PPI (omeprazole) ap-
pear to be important. Studies that evaluate clopidogrel–
statin and clopidogrel–PPI interactions miss the point
that these drug– drug interactions do not appear to be a
1260 Bates et al.
Clopidogrel–Drug Interactions
class effect because of pharmacokinetic and pharmaco-
dynamic differences between agents within a drug class.
4. Clopidogrel response variability. Genetic, cellular, and
metabolic factors influence clopidogrel responsiveness
(89). Drug interactions may only be important in pa-
tients with borderline platelet inhibition, where small
reductions in platelet inhibition might result in post-
treatment platelet reactivity above therapeutic thresh-
olds. Additionally, alternative CYP isoenzyme pathways
may become more active in patients with concomitant
treatment of competing agents.
5. Ex vivo platelet function testing. The role of platelets in
thrombosis is complex; platelet function tests on isolated
platelets measure only part of this process. Test hetero-
geneity, lack of standardization, operator dependency,
and lack of an accepted gold standard challenge the
accurate measurement of variable platelet reactivity.
6. Offsetting clinical effects. Atorvastatin has a number of
beneficial pleiotropic effects (LDL reduction, decreased
inflammation, plaque stabilization, fibrinolysis stimula-
tion, improved endothelial function), including platelet
inhibition, associated with decreased MI and death rates
that could offset the negative clinical effect of any
potential reduction in platelet inhibition with clopi-
dogrel. Likewise, omeprazole reduces bleeding events,
linked to risk for acute and future ischemic events,
potentially neutralizing an adverse clinical effect on
platelet inhibition.
Research Challenges in
the Drug Interaction Debate
There are many research challenges in scientifically measur-
ing the clinical importance of drug– drug interactions.
1. Study design. Treatment in observational studies is based
on clinical need or physician preference, creating selec-
tion bias, so these studies can only suggest association,
not conclude causality. Claims-based studies are partic-
ularly limited by missing or misclassified data. Outcome
events in randomized trials are often adjudicated, but
multivariable or propensity score analyses in post hoc
studies cannot completely adjust for differences in un-
known or unmeasured confounders. Only a randomized
clinical trial could confirm the importance of a drug–
drug interaction at the population level, although the
generalizability of the results would be modified by
inclusion and exclusion criteria and the potential cost of
such a trial would probably be prohibitive.
2. Sample size. The published studies have not been appro-
priately powered to address clopidogrel– drug interac-
tions. The absolute reduction in major adverse cardiac
events at 30 days when clopidogrel is added to aspirin
compared with aspirin monotherapy is only 1% (90),
making it possible that studies demonstrating no clopi-
dogrel– drug interactions were insufficiently powered to
detect a small, but clinically meaningful, difference in
JACC Vol. 57, No. 11, 2011
March 15, 2011:1251–63
event rates when millions of patients are prescribed these
drugs.
3. Composite primary end point. Increased individual events
related to attenuation of platelet inhibition by a drug–
drug interaction (MI, transient ischemic attack) might be
neutralized by other events not mediated by platelet
aggregation (noncardiac death, target vessel revascular-
ization), producing a net effect that obscures a potential
drug interaction.
4. Clinical risk. Only specific patient subgroups may have
clinical risk. Low CYP 3A4 metabolic activity,
CYP2C19 polymorphisms, age, sex, diabetes mellitus,
increased body mass index, and renal insufficiency also
decrease clopidogrel responsiveness. Drug– drug interac-
tions in subgroups of patients may not be recognized in
population analyses. Moreover, the small reduction in
platelet aggregation (10% to 15%) with clopidogrel– drug
interactions may not be clinically significant in many
subgroups.
5. Patient compliance. A major obstacle to finding a clinical
clopidogrel– drug interaction is assuring patient compli-
ance with coadministration of both medications during
the study period. Measuring medication use at 1 point in
time does not assure continued use of both medications.
Conclusions
There are many pharmacodynamic clopidogrel– drug inter-
actions, but there is no consistent evidence that these
interactions have clinical significance. Because the benefit of
dual antiplatelet therapy is well established and the existing
clinical data on clopidogrel– drug interactions are inconclu-
sive, clinicians should concentrate on initiating proper statin
therapy in patients with coronary artery disease and pre-
scribing PPIs for patients at increased risk for gastroduode-
nal bleeding. The therapeutic benefit of coadministering
these medications to appropriate patients should greatly
exceed any theoretical harm from clopidogrel– drug inter-
actions that appear to be dose-dependent, time-dependent,
and mild compared with the larger challenges of patient
compliance and interindividual variability in clopidogrel
responsiveness. Clinicians concerned about these interac-
tions have the option of prescribing a different platelet
P2Y12 receptor inhibitor without known drug interactions
(39,72,91). Another option is to prescribe a hydrophilic
statin in place of atorvastatin; or pantoprazole or ranitidine,
an H2RA not metabolized by CYP isoenzymes, in place of
omeprazole (92).
Reprint requests and correspondence: Dr. Eric R. Bates, CVC Car-
diovascular Medicine, 1500 East Medical Center Drive, SPC 5869, Ann
Arbor, Michigan 48109-5869. E-mail: ebates@umich.edu.
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Key Words: atorvastatin y clopidogrel y drug interactions y
omeprazole y proton pump inhibitors y statins.