Journal of the American College of Cardiology Vol. 51, No.

3, 2008
© 2008 by the American College of Cardiology Foundation ISSN 0735-1097/08/$34.00
Published by Elsevier Inc. doi:10.1016/j.jacc.2007.06.064

CLINICAL RESEARCH Clinical Trials

Influence of Omeprazole on the Antiplatelet

Action of Clopidogrel Associated With Aspirin
The Randomized, Double-Blind OCLA
(Omeprazole CLopidogrel Aspirin) Study

Martine Gilard, MD,* Bertrand Arnaud, PHARMD,† Jean-Christophe Cornily, MD,* Grégoire Le Gal, MD,§
Karine Lacut, MD,‡ Geneviève Le Calvez, PHARMD,† Jacques Mansourati, MD,* Dominique Mottier, MD,§
Jean-François Abgrall, MD,† Jacques Boschat, MD*
Brest, France

Objectives This trial sought to assess the influence of omeprazole on clopidogrel efficacy.

Background Clopidogrel has proved its benefit in the treatment of atherothrombotic diseases. In a previous observational
study, we found clopidogrel activity on platelets, tested by vasodilator-stimulated phosphoprotein (VASP) phos-
phorylation, to be diminished in patients receiving proton pump inhibitor (PPI) treatment.

Methods In this double-blind placebo-controlled trial, all consecutive patients undergoing coronary artery stent implanta-
tion received aspirin (75 mg/day) and clopidogrel (loading dose, followed by 75 mg/day) and were randomized
to receive either associated omeprazole (20 mg/day) or placebo for 7 days. Clopidogrel effect was tested on
days 1 and 7 in both groups by measuring platelet phosphorylated-VASP expressed as a platelet reactivity index
(PRI). Our main end point compared PRI value at the 7-day treatment period in the 2 groups.

Results Data for 124 patients were analyzed. On day 1, mean PRI was 83.2% (standard deviation [SD] 5.6) and 83.9%
(SD 4.6), respectively, in the placebo and omeprazole groups (p ⫽ NS), and on day 7, 39.8% (SD 15.4) and
51.4% (SD 16.4), respectively (p ⬍ 0.0001).

Results Omeprazole significantly decreased clopidogrel inhibitory effect on platelet P2Y12 as assessed by VASP phos-
phorylation test. Aspirin-clopidogrel antiplatelet dual therapy is widely prescribed worldwide, with PPIs frequently
associated to prevent gastrointestinal bleeding. The clinical impact of these results remains uncertain but merits
further investigation. (OCLA: Influence of Omeprazole on the Antiplatelet Action of Clopidogrel Associated to As-
pirin; http://www.clinicaltrials.gov/ct2/show/NCT00349661; NCT00349661) (J Am Coll Cardiol 2008;51:
256–60) © 2008 by the American College of Cardiology Foundation

Platelet activation and aggregation play an important role in dogrel requires several biotransformation steps, mediated
the pathogenesis of arterial thrombosis and lead to acute mainly by cytochrome P-450 isoenzymes, to generate
coronary syndrome and complications during and after an active metabolite. It exerts its antiplatelet effect by
percutaneous coronary intervention. Clopidogrel, a thieno- forming an inactivating disulfide bond with the platelet
pyridine, inhibits platelet activation induced by adenosine P2Y12 ADP receptor. Clopidogrel inhibits the effect of
diphosphate (ADP). Alone or in association with aspirin,
clopidogrel has successfully proved its benefit in the treat- See page 261
ment of atherothrombotic disease (1,2). It also decreases the
incidence of coronary artery stent thrombosis (2). ADP on the P2Y12 receptor. This is associated with
Clopidogrel is a prodrug, and must be metabolized in dephosphorylation of intraplatelet vasodilator-stimulated
the liver to acquire its antiaggregation properties. Clopi- phosphoprotein (VASP). Vasodilator-stimulated phos-
phoprotein phosphorylation provides an index of platelet
From the *Department of Cardiology, †Department of Hematology, INSERM 0502,
reactivity to clopidogrel: the higher the platelet reactivity
‡Center for Clinical Investigation, EA3878, and §Department of Internal Medicine index (PRI), the more frequently thrombosis occurs
and Chest Diseases, Brest University Hospital, Brest, France. Drs. Abgrall and under clopidogrel (3).
Boschat contributed equally to this study.
Manuscript received March 19, 2007; revised manuscript received June 7, 2007, Several functional polymorphisms have been found in
accepted June 12, 2007. genes encoding cytochrome P-450 isoforms involved in the
JACC Vol. 51, No. 3, 2008 Gilard et al. 257
January 22, 2008:256–60 Omeprazole and Clopidogrel Efficacy

metabolic activation of clopidogrel upstream of P2Y12 This ratio is expressed as mean Abbreviations
(4,5). The isoenzyme CYP2C19 seems to be one of the percentage platelet reactivity, in- and Acronyms
determinants of the pharmacodynamic response to clopi- versely correlated with clopidogrel
ADP ⴝ adenosine
dogrel (6), and is also involved in the metabolism of proton treatment efficiency. According to diphosphate
pump inhibitors (PPIs), such as omeprazole (7). Patients the criteria of Barragan et al. (3), MFI ⴝ mean fluorescence
receiving clopidogrel and aspirin dual therapy after coronary patients are good responders to intensity
stenting are commonly treated with PPIs. clopidogrel if PRI is ⬍50% and PPI ⴝ proton pump
We previously showed in an observational study of 105 poor responders if PRI is ⬎50%. inhibitor
consecutive patients that PPI users had significantly higher Statistics. The number to treat PRI ⴝ platelet reactivity
PRI values (8). Our hypothesis is that PPIs reduce the was estimated on the basis of our index
biological action of clopidogrel, probably by competitive previous observational study (8). SD ⴝ standard deviation
metabolic effects on CYP2C19. The aim of the present We estimated that a study sam- VASP ⴝ vasodilator-
prospective, randomized, double-blind study was to assess ple size of 120 would enable a stimulated phosphoprotein
whether the action of clopidogrel would be reduced in one-half standard deviation (SD)
patients receiving associated omeprazole treatment. difference (i.e., a 10% difference
in PRI between groups) to be detected, with an 80%
Methods statistical power and a 5% alpha risk. To ensure that this
sample size would be available for analysis, 20 extra patients
Patients and study protocol. We conducted a prospective, were randomized and included.
double-blind, placebo-controlled, randomized trial. All The characteristics of the 2 groups were compared using
consecutive patients undergoing elective coronary stent chi-square tests for qualitative and t tests for continuous
implantation were considered for inclusion. They received variables. The main end point compared the PRI value at
aspirin (75 mg/day) and clopidogrel (loading dose 300 mg, the 7-day treatment period in the 2 groups by a Student t
followed by 75 mg/day). After written informed consent test. The secondary end points were the PRI variation
was obtained, patients were randomized to 2 treatment during the 7-day treatment period in the 2 groups and a
groups: associated 20 mg/day omeprazole or placebo, for 7 chi-square comparison of the proportion of patients with
days.
Exclusion criteria were previous treatment with clopi-
dogrel or PPI, history of thrombocytopenia (⬍150,000 Assessed for eligibility (n=354)

platelets/ml) or bleeding disorder, liver disease, gastrointes-

tinal ulcer, or pregnancy. -Excluded (n= 214)

-Not meeting inclusion criteria: (n=197)

Patients were documented for atherosclerosis risk factors. Enrollment
• Previous treatment with
clopidogrel (n=158)
Concomitant cardiovascular medication—statins, beta- Randomization (n=140) • Previous treatment with
PPI(n=39)
blockers, or angiotensin-converting enzyme inhibitors—at
-Refused to participate: (n=17)
inclusion was also recorded. The institutional review board
approved the study protocol. -Allocated to omeprazole group -Allocated to placebo group
Platelet reactivity. Blood samples were collected on so- (n= 70)
-Received omeprazole 20mg Allocation
(n= 70)
-Received placebo
dium citrate on Day 1 before the loading dose of clopi- (n= 70) (n= 70)

dogrel, and 7 days afterward. Laboratory physicians per-

formed VASP phosphorylation analysis blinded to
treatment group and to whether the sample was from Day 1
or Day 7. Platelet reactivity was assessed by measuring -Lost to follow-up -Lost to follow-up
• No Day 7 blood sample (n= 1) • No Day 7 blood sample (n= 4)
platelet-phosphorylated VASP in whole blood using a new Follow-Up
-Discontinued intervention -Discontinued intervention
commercially available Platelet VASP kit (Biodis-Stago, • Consent withdrawal (n= 4) • Consent withdrawal (n= 4)

Asnières, France) adapted from the method of Schwartz -Serious adverse event
• In stent thrombosis (n= 1)
-Serious adverse event
• In stent thrombosis (n= 1)
et al (9). Briefly, after initial incubation with prostaglandin
E1 (PGE1) with or without 10 ␮mol/l ADP, platelets were
fixed. The second stage consists of coupling phosphorylated -Analyzed (n=64) -Analyzed (n=60)

VASP with a monoclonal fluorescein isothiocyanate–labeled Analysis

-Excluded from analysis (n= 1)
• Previous missed PPI
antibody specific to the phosphorylated form of VASP. treatment

Platelet mean fluorescence intensity (MFI) was then deter-

mined using a flow cytometer counting 10,000 platelets. Figure 1 Consort Statement and Flow Diagram
Platelet reactivity was expressed as a PRI calculated as:
From 354 eligible patients, 140 were included. Finally, 64 patients were ana-
lyzed in the omeprazole group and 60 in the placebo group. PPI ⫽ proton
PRI% ⫽ (MFI [PGE1] ⫺ pump inhibitor.
MFI 关PGE1 ⫹ ADP兴)/MFI 共PGE1兲 ⫻ 100
258 Gilard et al. JACC Vol. 51, No. 3, 2008
Omeprazole and Clopidogrel Efficacy January 22, 2008:256–60

Patient Baseline Characteristics and Treatments

Results
Table 1 Patient Baseline Characteristics and Treatments
Between July 2006 and November 2006, 354 patients were
Placebo Group Omeprazole Group
(n ⴝ 60) (n ⴝ 64) p assessed for eligibility. Following predetermined exclusion
Characteristics criteria, 140 patients were included and randomized, 70 in
Age (yrs) 63.67 ⫾ 12.22 62.28 ⫾ 15.04 NS the omeprazole group and 70 in the placebo group. The
Male gender 45 (75%) 52 (81.3%) NS patient flowchart is shown in Figure 1. No patient was lost
Smoker 43 (71.7%) 41 (64.1%) NS to follow-up. Data for 16 of the 140 patients were not
Hypertension 32 (47.1%) 36 (52.9%) NS
analyzed: 1 was receiving PPIs at inclusion, 5 failed to
Family history of CAD 26 (43.3%) 22 (34.4%) NS
return on Day 7 for blood sampling (they had no adverse
Diabetes mellitus 11 (18.3%) 6 (9.4%) NS
events); 8 excluded themselves from the study, using their
Body mass index (kg/m2) 27.51 ⫾ 4.3 26.66 ⫾ 4.7 NS
Dyslipidemia 43 (71.6%) 42 (65.6%) NS
right to withdraw consent; and 2 experienced a serious
Previous MI 5 (8.3%) 7 (10.9%) NS
adverse event (2 in-stent thromboses, both on Day 4, 1 in
Treatment each group). No other serious adverse event was noted.
Beta-blocker 58 (90.6%) 50 (83.3%) NS Finally, 64 patients were analyzed in the omeprazole group
ACE inhibitor 32 (50%) 29 (48.3%) NS and 60 in the placebo group.
Atorvastatin 41 (68.3%) 43 (67.2%) NS Baseline characteristics were similar in the 2 groups
Other statin 18 (28.1%) 14 (23.3%) NS (Table 1). On Day 1 the mean PRI was similar, 83.2% (SD
ACE ⫽ angiotensin-converting enzyme; CAD ⫽ coronary artery disease; MI ⫽ myocardial infarction;
5.6) and 83.9% (SD 4.6), and on Day 7 the mean PRI was
NS ⫽ not significant. 39.8% (SD 15.4) and 51.4% (SD 16.4), respectively, in the
placebo and omeprazole groups (p ⬍ 0.0001) (Fig. 2). The
PRI below 50% in the 2 groups (3). A value of p ⬍ 0.05 was mean PRI variation was ⫺43.3% (SD 15.9) and ⫺32.6%
considered statistically significant. Statistical analysis was (SD 16.4), respectively, in the placebo and omeprazole
performed blind to randomization group. groups (p ⬍ 0.0001) (Fig. 3).
On Day 7, 16 patients (26.7%) were poor responders in
the placebo group compared with 39 (60.9%) in the ome-
prazole group (p ⬍ 0.0001). The odds ratio of being a poor
responder to clopidogrel when concomitantly treated with
omeprazole was 4.31 (95% confidence interval 2.0 to 9.2).

Discussion
In this double-blind, placebo-controlled, randomized trial,
omeprazole significantly decreased the effect of clopidogrel
on platelet activation as tested by VASP phosphorylation.

Figure 2 Mean PRI on Days 1 and 7 in the Two Groups

On Day 1, mean platelet reactivity index (PRI) was 83.2% and 83.9%,
respectively, in the placebo and omeprazole groups (nonsignificant). On Figure 3 Variation of Platelet Reactivity Index
Day 7, mean PRI was 39.8% and 51.4%, respectively, in the placebo and
omeprazole groups (p ⬍ 0.0001). VASP ⫽ vasodilator-stimulated The platelet reactivity index (PRI) decrease was ⫺43.3% in the placebo group
phosphoprotein. and ⫺32.6% in the omeprazole group after 7 days of treatment (p ⬍ 0.0001).
JACC Vol. 51, No. 3, 2008 Gilard et al. 259
January 22, 2008:256–60 Omeprazole and Clopidogrel Efficacy

Platelet function test. After percutaneous coronary inter- lated with between-subject variability in clopidogrel
vention or acute coronary syndrome, clopidogrel–aspirin responsiveness.
dual therapy has become the standard antiplatelet manage- The PPIs are eliminated by the hepatic route, and the
ment approach (1,2). Previous studies indicated that clopi- polymorphically expressed CYP2C19 is involved in the
dogrel resistance might indicate increased risk of cardiovas- metabolism of omeprazole, lansoprazole, rabeprazole, es-
cular event recurrence (3,10). The mechanisms underlying omeprazole, and pantoprazole (7). As with clopidogrel,
clopidogrel resistance are still controversial. Possible expla- genotypic differences in CYP2C19 status affect the action of
nations include increased reactivity in remaining platelets, PPIs (20).
genetic polymorphisms of the ADP receptor, differences in
resorption, or a combination of these factors (4,5,11). Conclusions
Dysfunctional cytochrome P450 metabolism has also been
shown when clopidogrel was associated with various drugs In this randomized study, omeprazole significantly decreased
such as atorvastatin (4,12). However, no such significant the effect of clopidogrel on platelet as tested by VASP
effect emerged in further placebo-controlled studies (13,14). phosphorylation. Aspirin–clopidogrel antiplatelet dual ther-
Standard platelet aggregometry measures the inhibition apy is widely prescribed worldwide, with PPIs frequently
of ADP-induced aggregation (15). Other methods include associated to prevent gastrointestinal bleeding. The clin-
measuring fibrinogen binding or platelet adhesion, moni- ical impact of these results must be assessed by further
toring platelet activation. These general platelet function investigations, but we recommend not adding systemat-
indices are relatively unspecific and are of limited clinical use ically a PPI treatment to the antiplatelet dual therapy
because patients typically receive several drugs affecting without formal indication.
platelet function (e.g., aspirin) concomitantly. Analysis of
Acknowledgments
VASP phosphorylation is more reliable than previous assays
The authors thank Anne-Sophie Nedelec, Françoise Martin,
for quantifying clopidogrel effects, with a high measurement
and Christelle Lann for their technical assistance, the
precision and reproducibility (16,17). Because the VASP
cardiology and clinical investigation center staff who were
assay directly measures the function of the clopidogrel target
involved in the protocol, and the Direction de la Recherche
(the P2Y12 receptor), it is selective for thienopyridine
Clinique (DRC) of Brest University Hospital.
effects and is not affected by other commonly used platelet
inhibitors such as aspirin (16). Potential benefits of VASP
measurements would be helpful for multicenter trials and Reprint requests and correspondence: Dr. Martine Gilard,
Département de Cardiologie, CHU de la Cavale Blanche, Boulevard
contrast with unspecific platelet function measurements that
Tanguy Prigent, 29609 Brest Cédex, France. E-mail: martine.
are usually performed. [email protected].
Potential clinical impact. The clinical implications of our
results remain uncertain but merit further investigation. The
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