Effects of Omeprazole on the Antiplatelet Activity of Clopidogrel

Kyeong Ho Yun,1,2 MD, Sang Jae Rhee,1 MD, Hyun-Young Park,2 MD, Nam Jin Yoo,1 MD,
Nam-Ho Kim,1,2 MD, Seok Kyu Oh,1,2 MD, and Jin-Won Jeong,1,2 MD
Summary
Clopidogrel is used with aspirin as a standard combined treatment in patients with acute coronary syndrome.
A proton pump inhibitor (PPI) is often administered to patients receiving antiplatelet therapy. However, PPI use
with clopidogrel was recently shown to result in increased risk of major cardiovascular events when compared to
clopidogrel use alone. Therefore, the aim of the present study was to evaluate the effects of omeprazole, a PPI, on
the antiplatelet effect of clopidogrel.
We divided 20 healthy volunteers into 2 groups (n = 10 each). Twenty-four hours after a 300 mg loading dose
of clopidogrel, one group received a dosage of 75 mg/day of clopidogrel and a placebo for 14 days, followed 3
weeks later by the same protocol but with coadministration of 75 mg/day clopidogrel and 20 mg/day omeprazole
instead. The other group received the same treatment but in reverse order. Antiplatelet activity was assessed in
terms of the P2Y12 reaction unit (PRU) and percentage inhibition using a VerifyNow P2Y12 assay system.
The PRU of the omeprazole-treated subjects was significantly higher than that of the omeprazole-untreated
subjects on day 14 (281.3 54.0 versus 240.0 72.2, P = 0.048). The percentage inhibition showed a decrease
after the 14-day omeprazole treatment (22.7 29.9% versus 35.1 18.7%, P = 0.014).
Consequently, omeprazole reduces the antiplatelet effect of clopidogrel, suggesting that careful treatment
planning is required when administering omeprazole to patients on clopidogrel therapy. (Int Heart J 2010; 51: 1316)
Key words: Platelet, Clopidogrel, Omeprazole, Drug resistance

he use of powerful antiplatelet agents is increasing as

drug-eluting stents (DES) become more widely
used. Clopidogrel is used with aspirin as a standard
combined treatment for secondary prevention of acute coronary syndrome and prevention of stent thrombosis in patients with coronary stents.1-3) Despite its proven benefit, the
individual patient responses to clopidogrel show considerable heterogeneity. Recent data show that an adequate antiplatelet effect is not achieved in 4 - 30% of the patients on
clopidogrel, suggesting that many patients are resistant or
only partially responsive to the antiplatelet effect of the
drug.4-7)
A number of different factors may influence the antiplatelet effect of clopidogrel. Drug interaction could be
one important factor. Clopidogrel is an inactive prodrug that
requires in vivo conversion to an active metabolite by the
cytochrome P450 3A4 enzyme system in the liver.8,9) Therefore, the drug component that involves the cytochrome
P450 enzyme system may be the cause of clopidogrel
resistance. A proton pump inhibitor (PPI) is often administered to patients receiving antiplatelet therapy for treating
gastrointestinal symptoms or bleeding. However, results
from a recent large population-based study have suggested
that PPI use with clopidogrel results in increased risk of
major cardiovascular events as compared to clopidogrel use

alone.10)
In this study, to evaluate the interaction between clopidogrel and omeprazole, we compared the antiplatelet effect
of clopidogrel when administered alone with that when
clopidogrel was coadministered with the PPI omeprazole.

Methods
Subjects and study protocol: We recruited 20 healthy vol-

unteers with no history of drug treatment in the previous

3 months. Exclusion criteria were previous treatment with
clopidogrel or a PPI, history of thrombocytopenia or bleeding disorder, liver disease or increase of liver enzymes over
2 times higher the normal upper limit, gastrointestinal ulcer,
or pregnancy. All subjects gave informed consent according
to a protocol approved by the institutional review board.
The subjects were divided into two groups of 10 subjects each. One group received an initial loading dose of
clopidogrel 300 mg and, after 24 hours, these subjects were
administered a dosage of 75 mg/day of clopidogrel and a
placebo for the next 14 days. After a 3 week interval, they
were administered a clopidogrel loading dose of 300 mg
again, followed 24 hours later with a dosage of 75 mg/day
of clopidogrel and 20 mg/day of omeprazole for 14 days.

From the 1 Department of Cardiovascular Medicine, Wonkwang University Hospital, and 2 Institute of Wonkwang Medical Science, Iksan, Korea.
This study was supported by grants from Wonkwang University in 2009.
Address for correspondence: Kyeong Ho Yun, MD, Department of Cardiovascular Medicine, The Heart Center of Wonkwang University Hospital, 344-2
Shinyong-dong, Iksan, Jeonbuk 570-711, Korea.
Received for publication August 6, 2009.
Revised and accepted September 18, 2009.
13

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Int Heart J
January 2010

YUN, ET AL

The other group was treated in reverse order; the subjects

received the combination of omeprazole and clopidogrel
first followed by administration of clopidogrel with the placebo after 3 weeks. Blood samples were taken at baseline,
after 24 hours, and on day 7 and day 14, and platelet activity was measured (Figure 1).
Data collection: Complete blood count and blood chemistry
analyses, including liver and renal function tests, were performed before and two weeks after the therapy. The samples
were obtained by antecubital venipuncture, and the initial 3
- 4 mL of blood was discarded to avoid spontaneous platelet activation. The second samples were collected in tubes
containing 3.2% citrate for the rapid platelet-function assay.
Platelet reactivity was assessed using a VerifyNowP2Y12 assay (Accumetrics, San Diego, CA). The VerifyNow-P2Y12 system is a rapid platelet-function, cartridgebased assay designed to directly measure the effects of
clopidogrel on the P2Y12 receptor. 11) The results are
expressed as the P2Y12 reaction unit (PRU) and percentage inhibition. The PRU indicates the amount of P2Y12

receptor mediated aggregation specific to platelets and is

calculated as a function of the rate and extent of platelet aggregation in the ADP-channel. Percentage inhibition is the
percent change from baseline aggregation and is calculated
from the PRU result and estimated baseline result, which
is an independent measure based on the rate and extent of
platelet aggregation in the thrombin receptor activating peptide (TRAP) channel. Therefore, percentage inhibition = (1PRU/estimated baseline) 100.
Both placebo and omeprazole were administered during clopidogrel treatment and PRU and percentage inhibition were compared before and 24 hours after the treatment,
on day 7 and on day14.
Statistical analysis: Continuous variables are reported as
the mean standard deviation and categorical variables are
presented as frequencies and percentage. Intergroup analysis was performed with the independent t-test, chi-square
test, and Fishers exact test using SPSS 11.0 for Windows
(SPSS Inc., Chicago, IL). To compare the PRU and percentage inhibition before and after the omeprazole treatment,
we used a paired t test. Statistical significance was set at
P < 0.05.

Results

Figure 1. Study protocol. Blood samples were collected from both

treatment groups on days 0 and 14 for blood count and chemistry analyses, and on days 0, 1, 7, and 14 for VerifyNow-P2Y12 assay.

The average age of the subjects was 33 7 years.

There were 12 males (60%) and 5 subjects were current
smokers. No patient had diabetes or hypertension or was
on any medication. Platelet level, liver function, and kidney
function showed no differences between the measurements
before and 14 days after the treatment (Table I).

Table I. Changes in Laboratory Parameters After 14-day Omeprazole Treatment

Platelet count
At baseline (/103 L)
After 14 days (/103 L)
P by paired t test
Aspartate aminotransferase
At baseline (IU/L)
After 14 days (IU/L)
P by paired t test
Alanine aminotransferase
At baseline (IU/L)
After 14 days (IU/L)
P by paired t test
Serum creatinine
At baseline (mg/dL)
After 14 days (mg/dL)
P by paired t test
P2Y12 reaction unit
At baseline
After 14 days
P by paired t test
Percentage inhibition
At baseline (%)
After 14 days (%)
P by paired t test

Clopidogrel + Placebo
(n = 20)

Clopidogrel +
Omeprazole
(n = 20)

254.9 36.5
252.4 35.4
0.622

247.8 32.2
250.8 27.9
0.559

0.364
0.820

21.9 5.5
22.4 6.4
0.713

21.3 5.5
22.9 6.7
0.115

0.692
0.793

25.7 15.0
26.7 15.1
0.644

25.2 15.0
27.8 14.2
0.319

0.922
0.810

0.8 0.2
0.9 0.1
0.171

0.8 0.2
0.9 0.2
0.230

0.984
0.838

362.2 51.2
240.0 72.2
< 0.001

355.2 65.5
281.3 54.0
< 0.001

0.709
0.048

6.7 6.5
35.1 18.7
< 0.001

5.5 5.5
22.7 10.0
< 0.001

0.489
0.014

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15

OMEPRAZOLE AND CLOPIDOGREL EFFICACY

Table II. Time Course of P2Y12 Reaction Unit in Each Group
Group

Figure 2. Changes in P2Y12 reaction unit and percentage inhibition

in clopidogrel-placebo group (n = 20) and clopidogrel-omeprazole
group (n = 20). Treatment with omeprazole significantly increased the
P2Y12 reaction unit (P = 0.048) and significantly reduced the percentage inhibition (P = 0.014) measured on day 14.

Table II presents the entire time course of PRU in each

group. The PRU in the omeprazole treated group was 355.2
65.5 before treatment, 294.5 59.4 after 24 hours, 264.8
61.1 on day 7, and 281.3 54.0 on day 14, while that in
the omeprazole untreated group was 362.2 51.2 before
treatment, 288.8 94.7 after 24 hours, 257.2 76.1 on day
7, and 240.0 72.2 on day 14 (P = 0.048, day 14). The
percentage inhibition was 5.5 5.5% before treatment, 21.7
10.7% after 24 hours, 28.5 11.1% on day 7, and 22.7
9.9% on day 14 following omeprazole treatment, and 6.7
6.2% before treatment, 26.4 20.2% after 24 hours, 31.5
20.7% on day 7, and 35.1 18.7% on day 14 without omeprazole treatment (P = 0.014, day 14) (Figure 2).
Seven patients showed an increase in percentage inhibition after 2 weeks of treatment that was less than 20%
higher than the baseline level, however, this result was
unrelated to the omeprazole treatment. During the study period, 2 cases of slight bruising and 2 cases of nausea were
observed, but no serious adverse effect occurred in any patient.

Discussion
Treatment with omeprazole significantly increased
the PRU and significantly reduced the percentage inhibition measured on day 14, suggesting that omeprazole significantly decreased the inhibitory effect of clopidogrel on
platelet activation.
Dual antiplatelet therapy for 12 months is currently
believed to be mandatory after DES insertion for the prevention of stent thrombosis. 12) However, recent data indicate that an adequate antiplatelet effect is not achieved
in 4 - 30% of patients taking clopidogrel.4-7) Small-scale
investigations have suggested that clopidogrel resistance
may be associated with a heightened risk of adverse clinical
events.13-16)
The mechanisms underlying clopidogrel resistance
are still controversial. Possible mechanisms include drug
interaction involving the cytochrome P450 enzyme, insulin
resistance, poor bioavailability, and polymorphisms of the
cytochrome P450 3A and P2Y12 receptor genes.17-19) Clopidogrel metabolism is associated with the cytochrome P450

Clopidogrel + Placebo

Clopidogrel + Omeprazole

Day

14

14

1
2
3
4
5
6
7
8
9
10

283
372
297
386
306
365
343
439
355
430

148
372
220
236
265
416
279
412
299
105

172
350
194
125
330
330
235
360
282
250

152
315
220
139
290
325
167
325
257
214

220
387
284
401
292
369
316
448
340
417

170
319
274
351
272
335
319
268
289
250

88
279
259
340
257
272
273
301
255
275

140
297
263
334
289
290
282
267
248
302

Group

Clopidogrel + Omeprazole

Clopidogrel + Placebo

Day

14

14

1
2
3
4
5
6
7
8
9
10

260
417
289
424
310
454
331
386
369
390

185
343
296
348
233
425
299
347
303
264

149
322
227
292
222
359
278
312
275
261

186
362
282
303
251
383
267
328
292
260

292
388
303
435
331
455
355
369
357
383

253
382
137
435
256
324
374
336
226
304

195
320
90
350
249
246
310
280
209
266

186
240
100
325
250
316
325
286
168
200

3A4 enzyme system. In fact, human cytochrome P450 3A4

is the most abundant hepatic and intestinal phase I enzyme
and metabolizes approximately 50% of the drugs on the
market. Clinically important CYP3A4 inhibitors identified thus far mainly include macrolide antibiotics (e.g.,
clarithromycin, and erythromycin), anti-HIV agents (e.g.,
ritonavir and delavirdine), antidepressants (e.g., fluoxetine
and fluvoxamine), calcium channel blockers (e.g., verapamil and diltiazem), steroids and their modulators (e.g.,
gestodene and mifepristone), and several herbal and dietary
components.17)
Omeprazole is eliminated by the hepatic route, and
cytochrome 2C19 is involved in the metabolism of omeprazole and other PPIs. Cytochrome 2C19 does not appear
to be a major hepatic pathway for clopidogrel metabolism,
and its influence on clopidogrel-induced platelet inhibition
may be limited.20) However, the results of our study have
demonstrated that omeprazole significantly inhibits the
antiplatelet effect of clopidogrel. This finding was also observed in a recent prospective, randomized study. Gilard, et
al have reported that omeprazole significantly decreases the
inhibitory effect of clopidogrel on the platelet P2Y12 receptor, assessed by the vasodilator-stimulated phosphoprotein
phosphorylation test.21) The difference in the incidences of
genetic polymorphism may be related to the fact that their
observation was based on results from different groups of
patients. However, such a hypothesis was not justifiable in
our study because we conducted the tests on the same subjects. A large population-based study showed an odds ratio
of 1.79 for major cardiovascular events within 1 year among
patients receiving both PPIs and clopidogrel compared with
those on clopidogrel treatment alone.10) This study sug-

16

YUN, ET AL

gested that omeprazole and rabeprazole are more associated

with adverse outcomes than the other PPIs. Siller-Matula,
et al reported that pantoprazole and esomeprazole are not
associated with an impaired response to clopidogrel, in contrast to the negative omeprazole-clopidogrel interaction.22)
Therefore, the decreased antiplatelet effect of clopidogrel
may be influenced by only omeprazole and not all PPIs. Although the underlying mechanism is unknown, it is obvious
that omeprazole has an inhibitory effect on clopidogrel.
The limitations of our study include the small number
of subjects and the single blind protocol. Moreover, we did
not conduct any mechanistic investigations. In a real clinical setting, patients are prescribed clopidogrel with aspirin,
cilostazole, or another antiplatelet agent, but we did not test
such a situation. Accordingly, further clinical and experimental studies are required.
In conclusion, omeprazole reduces the antiplatelet effect of clopidogrel. Therefore, omeprazole administration
to patients on clopidogrel medication must be planned more
carefully.

7.

8.

9.

10.

11.

12.

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