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Drug Interaction: Clopidogrel and PPIs........................................................................................p 39

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Drug Interaction: Clopidogrel and PPIs for its bioactivation.2 Concurrent use of clopidogrel and
drugs that inhibit CYP2C19 could inhibit conversion
The antiplatelet drug clopidogrel (Plavix, and others) of clopidogrel to its active form. Among the PPIs,
reduces major cardiovascular events, but can cause omeprazole and esomeprazole appear to be the
bleeding. Proton pump inhibitors (PPIs) are often strongest inhibitors of CYP2C19 and pantoprazole
used with clopidogrel to prevent gastrointestinal appears to be the weakest.3,4
bleeding, however, some evidence suggests that PPIs
may interfere with the activation of clopidogrel and CLINICAL STUDIES — Some pharmacodynamic and
diminish its antiplatelet effect.1 FDA-approved labeling pharmacokinetic studies have reported reductions
recommends avoiding concurrent use of the PPIs in platelet inhibition and the AUC of the clopidogrel
omeprazole and esomeprazole with clopidogrel. active metabolite in patients taking clopidogrel with
omeprazole or esomeprazole. Similar effects were
POSSIBLE MECHANISM — Clopidogrel is a prodrug; the not reported with pantoprazole, lansoprazole, or
CYP2C19 isozyme appears to be mainly responsible dexlansoprazole.5-8
Table 1. Oral Proton Pump Inhibitors Whether concurrent use of clopidogrel and PPIs
Usual results in clinically significant adverse cardiovascular
Drug Adult Dosage1,2 Cost3 outcomes is not clear. The results of several (mostly
Dexlansoprazole – Dexilant (Takeda) 30-60 mg once/d $244.10 observational) studies have been inconsistent.9,10
Esomeprazole magnesium – generic 20-40 mg once/d 140.40 In a case-control study in patients ≥66 years old
Nexium (AstraZeneca) 250.90 who were started on clopidogrel after an acute MI,
Nexium 24HR (OTC) (Pfizer) 17.904
concurrent use of a PPI (other than pantoprazole)
Lansoprazole – generic 15-30 mg once/d 29.10
Prevacid (Takeda) 415.10 was associated with an increased risk of recurrent
Prevacid Solutab (Takeda) 415.10 MI within 90 days.11 In a retrospective cohort study
Prevacid 24HR (OTC)5 (GSK) 18.504 in 8205 patients with acute coronary syndrome
Omeprazole – generic 20-40 mg once/d 11.80
(ACS), use of a PPI with clopidogrel after hospital
Prilosec OTC 5 (AstraZeneca/P&G) 16.804
Omeprazole/sodium bicarbonate6 – 20-40 mg once/d
discharge was associated with a higher risk of death
generic 2528.10 or rehospitalization due to ACS.12
Zegerid (Salix) 3033.80
Zegerid OTC5 (Bayer) 16.104 In a retrospective cohort study of patients who were
Pantoprazole – generic 40 mg once/d 6.00 prescribed clopidogrel after hospitalization for acute
Protonix (Pfizer) 359.40 MI, coronary artery revascularization, or unstable
Rabeprazole – generic 20 mg once/d 48.60 angina, concurrent use of a PPI was not associated
Aciphex (Eisai) 524.70
Aciphex Sprinkle (Eisai) 450.007 with a statistically significant increased risk of
OTC = over the counter serious cardiovascular disease.13
1. The lower end of the range is generally used for initial treatment of GERD.
Higher or more frequent doses may be needed for patients with erosive In a randomized, placebo-controlled trial (COGENT),
esophagitis, peptic ulcer disease, hypersecretory conditions such as
Zollinger-Ellison syndrome, or for treatment of Helicobacter pylori infection. use of omeprazole in patients taking clopidogrel
2. PPIs are generally taken 30-60 minutes before the first meal of the day. Taking
one before the evening meal or taking the drug twice daily may be more ef-
and aspirin decreased the incidence of GI bleeding
fective for nocturnal acid control. PPIs should generally be swallowed whole without increasing the risk of a cardiovascular event.14
and should not be crushed or chewed. Omeprazole/sodium bicarbonate
(Zegerid) should be taken on an empty stomach at least 1 hour before a meal. The FDA concluded, however, that because of study
Dexlansoprazole (Dexilant) can be taken with or without food. design limitations and a low number of reported
3. Approximate WAC for 30 days’ treatment with the lowest usual adult dosage.
WAC = wholesaler acquisition cost or manufacturer’s published price to cardiovascular events, the results do not prove that
wholesalers; WAC represents a published catalogue or list price and may concurrent use of clopidogrel and omeprazole is safe.15
not represent an actual transactional price. Source: AnalySource® Monthly.
February 5, 2017. Reprinted with permission by First Databank, Inc. All rights In addition, the fixed-dose combination of omeprazole
reserved. ©2017. www.fdbhealth.com/policies/drug-pricing-policy.
4. Approximate cost for 28 tablets or capsules.
and clopidogrel used in the trial was specifically
5. Also available generically. developed to delay absorption of omeprazole in order
6. Immediate-release formulation that contains sodium bicarbonate as a
buffer; it should be used with caution in patients on a low-sodium diet. to minimize an interaction.16
7. Approximate cost for 5-mg sprinkle capsules.

39
Published by The Medical Letter, Inc. • A Nonprofit Organization
 The Medical Letter ®
Vol. 59 (1515) February 27, 2017

Some studies have suggested that PPI use is a
confounder associated with, rather than the cause of,
adverse cardiovascular outcomes in patients taking
clopidogrel.17,18
CONCLUSION — Concurrent use of clopidogrel and a
proton pump inhibitor (PPI) may result in decreased
levels of the clopidogrel active metabolite, and possibly
its antiplatelet activity, but whether it results in
clinically significant adverse cardiovascular outcomes
is not clear. Since omeprazole and esomeprazole
appear to be most likely to affect the antiplatelet
activity of clopidogrel and the FDA specifically warns
against their concomitant use, it would be reasonable
to use another PPI such as pantoprazole in patients
taking clopidogrel. ■
1. NS Abraham et al. ACCF/ACG/AHA 2010 expert consensus
document on the concomitant use of proton pump inhibitors and
thienopyridines: a focused update of the ACCF/ACG/AHA 2008
expert consensus document on reducing the gastrointestinal
risks of antiplatelet therapy and NSAID use. A Report of the
American College of Cardiology Foundation Task Force on Expert
Consensus Documents. J Am Coll Cardiol 2010; 56:2051.
2. JL Mega et al. Cytochrome P-450 polymorphisms and response
to clopidogrel. N Engl J Med 2009; 360:354.
3. T Zvyaga et al. Evaluation of six proton pump inhibitors as inhibi-
tors of various human cytochromes P450: focus on cytochrome
P450 2C19. Drug Metab Dispos 2012; 40:1698.
4. RS Wedemeyer and H Blume. Pharmacokinetic drug interaction
profiles of proton pump inhibitors: an update. Drug Saf 2014;
37:201.
5. AL Frelinger 3rd et al. A randomized, 2-period, crossover
design study to assess the effects of dexlansoprazole,
lansoprazole, esomeprazole, and omeprazole on the steady-
state pharmacokinetics and pharmacodynamics of clopidogrel in
healthy volunteers. J Am Coll Cardiol 2012; 59:1304.
6. JM Siller-Matula et al. Effects of pantoprazole and esomeprazole
on platelet inhibition by clopidogrel. Am Heart J 2009;157:148.e1.
7. DJ Angiolillo et al. Differential effects of omeprazole and pan-
toprazole on the pharmacodynamics and pharmacokinetics of
clopidogrel in healthy subjects: randomized, placebo-controlled,
crossover comparison studies. Clin Pharmacol Ther 2011; 89:65.
8. N Simon et al. Omeprazole, pantoprazole, and CYP2C19 effects
on clopidogrel pharmacokinetic-pharmacodynamic relationships
in stable coronary artery disease patients. Eur J Clin Pharmacol
2015; 71:1059.
9. SA Scott et al. Antiplatelet drug interactions with proton pump
inhibitors. Expert Opin Drug Metab Toxicol 2014; 10:175.
10. SD Bouziana and K Tziomalos. Clinical relevance of clopidogrel-
proton pump inhibitors interaction. World J Gastrointest
Pharmacol Ther 2015; 6:17.
11. DN Juurlink et al. A population-based study of the drug inter-
action between proton pump inhibitors and clopidogrel. CMAJ
2009; 180:713.
12. PM Ho et al. Risk of adverse outcomes associated with con-
comitant use of clopidogrel and proton pump inhibitors following
acute coronary syndrome. JAMA 2009; 301:937.
13. WA Ray et al. Outcomes with concurrent use of clopidogrel and
proton pump inhibitors: a cohort study. Ann Intern Med 2010;
152:337.
14. DL Bhatt et al. Clopidogrel with or without omeprazole in coronary
artery disease. N Engl J Med 2010; 363:1909.
15. MR Southworth and R Temple. Interaction of clopidogrel and
omeprazole. N Engl J Med 2010; 363:1977.
16. DN Juurlink. Comment on: Clopidogrel with or without omepra-
zole in coronary artery disease. N Engl J Med 2011; 364:681.
17. SP Dunn et al. Impact of proton pump inhibitor therapy on the ef-
ficacy of clopidogrel in the CAPRIE and CREDO trials. J Am Heart
Assoc 2013; 2:e004564.
18. SG Goodman et al. Association of proton pump inhibitor use on
cardiovascular outcomes with clopidogrel and ticagrelor. Circula-
tion 2012; 125:978.
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