DRUG REGULATORY AGENCIES’ ROLE IN THE INTERACTION BETWEEN CLOPIDOGREL AND
PROTON PUMP INHIBITORS
Over the last three years, scientific community has followed with great interest the discussion
about the potential interaction and its clinical impact between clopidogrel and proton pump
inhibitors (PPI). Moreover, and in parallel with the publication of clinical studies, drug
regulatory agencies issued successive official statements that deserve, in our opinion, a
specific analysis and assessment.
The Food and Drug Administration (FDA) has been leading this issue since its first statement in
January 2009. In this document(1) the FDA warned about the potential interaction and advised
to reassess the appropriate use of each PPIs. Ten months later, they issued a second report(2)
based primarily on the findings of two unpublished pharmacodynamic studies requested to the
clopidogrel manufacturers(3). This new recommendation, which is currently in force, puts the
emphasis on discouraging the concomitant use of clopidogrel with omeprazole or
esomeprazole, claiming insufficient information for the rest of PPIs.
On the other hand, each FDA statement was followed shortly after by a report published by
the European Medicines Agency (EMA)(4,5). National drug regulatory agencies such as the
British MHRA(6) or the Spanish Medicines Agency (AEMPS)(7,8) transferred the European
recommendations to the healthcare professionals, providing the scientific references that
could justify them.
What considerations can be made after a detailed reading of these documents? Initially we
find it reasonable and positive that drug regulatory agencies publish their findings even in the
absence of conclusive data. However, there are important questions that must be analyzed
carefully. For example, have been properly selected and weighted key trials that support the
new recommendation? Is it possible to improve the transparency and quality of the scientific
references provided? In short, are the new recommendations appropriate in the light of up-todate scientific evidence?
In our view, the current approach discouraging exclusively the concomitant use of either
omeprazole or esomeprazole with clopidogrel is biased for several reasons:
 The main argument supporting the recommendation, first advocated by the FDA and then
assumed by the rest of agencies, seems to come from the small pharmacodynamic trials
previously mentioned(Error! Bookmark not defined.). In these studies unusually high doses of
omeprazole (80 mg daily) were used, the clinical relevance of the interaction was not
considered and no comparative information with respect to other PPIs, except for
pantoprazole 80 mg, has been provided(3). A question raise immediately: if omeprazole 20 mg
or pantoprazole 40 mg is commonly recommended for the protection of gastrointestinal
injury, why were selected so unusual doses of PPI in these trials? Secondly, omeprazole 80 mg
and pantoprazole 80 mg are not equipotent doses, so this suggests that the outcomes of the
studies could be biased twice: a very high and also no comparable dose selected, promoting a
more favourable outcome for pantoprazole. And last but not least, surprisingly pantoprazole
is directly claimed as a safe PPI, even though the degree of platelet inhibition observed
with high doses of pantoprazole was less than observed with clopidogrel alone, as the FDA
report says literally(3). We think it's necessary to clarify without delay all these questions,
in order to maintain or not a different recommendation about particular PPIs.
 At the same time, it is quite surprising the low significance given to the information
provided by experimental studies focused on clinical outcomes. Furthermore, although the
latter also have some limitations, they are better designed to minimize the selection bias
than observational trials, and have shown that adding a PPI to clopidogrel provides
gastrointestinal protection(9) without increasing cardiovascular risk(9,10).
 Moreover, scientific references cited by national drug health authorities to support their
conclusions are not really convincing. While the EMA published its two documents without
attaching any related reference(4,5), the AEMPS based its new recommendation on incomplete
sources such as the following(8): pharmacodynamic studies previously considered in its first
report(7), two trials whose findings do not match the recommendations of the report(9,10) and
two observational studies with limited novelty in one case(11) and no assessment of the
interaction in the other one(12). The MHRA was more accurate in selecting the references
provided(6), but their findings clearly disagree (9,10,13) with the final recommendations of the
document.
 Considering the lower gastroprotective efficacy of the H2 antihistaminic drugs, the absence
of interaction between clopidogrel and H2 antihistaminics (and even antiacids) mentioned by
the FDA(2) calls for a critical appraisal of their place in therapy, which is crucial to be
addressed especially in haemorrhagic high-risk patients.
 Finally, from a practical point of view, both clopidogrel and omeprazole are very useful
drugs when used appropriately, being a first-line treatment in well defined conditions. Thus,
a warning published on the grounds of a poor clinical outcome can promote a quick shift to
drugs with similar uncertainties and a less favorable efficiency profile.
In summary, we could say that the new recommendations made by the drug agencies are
primarily based on a few pharmacodynamic data, not available for all PPIs, and of uncertain
clinical relevance. Thinking about future statements, it would be needed to optimize the
scientific references support. In relation to clopidogrel and PPIs interaction, drug authorities
should call for caution on all PPIs to the same extent, outweigh properly their
gastroprotective benefit, clarify the role of H2 antihistaminics and promote studies with all
PPIs at standard and equipotent doses. In this regard, recent articles such as full publication
of COGENT study(14) or AHA/ACC/AGA 2010 consensus(15) emphasize the central role of PPIs in
reducing serious gastrointestinal complications related with antiplatelet therapy.
In brief, we demand comprehensive recommendations based on the best available clinical
evidence. Otherwise, we will extend the confusion and distrust among healthcare
professionals.
1
Food and Drug Administration. Early Communication about an Ongoing Safety Review of clopidogrel bisulfate (marketed as
Plavix). [26 january 2009]. Free access on: http://www.fda.gov/cder/drug/early_comm/clopidogrel_bisulfate.htm
2
Food and Drug Administration. Information for Healthcare Professionals: Update to he labeling of clopidogrel bisulfato
(marketed as Plavix) to alert healthcare professionals about a drug interaction with omeprazole (marketed as Prilosec and
Prilosec OTC). [17 november 2009]. Free access on:
http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm190848.htm
3
Plavix (clopidogrel bisulfate) US label [august 2010]. Free access on:
http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020839s048lbl.pdf
4
European Medicines Agency. Public statement on possible interaction between clopidogrel and proton pump inhibitors. [29 may
2009]. Free access on: http://www.ms.public.lu/fr/activites/pharmacie-medicament/clopidogrel-emea-statement.pdf
5
European Medicines Agency. Interaction between clopidogrel and proton-pump inhibitors. [17 march 2010]. Free access on:
http://www.ema.europa.eu/docs/en_GB/document_library/Public_statement/2010/03/WC500076346.pdf
6
Clopidogrel and proton pump inhibitors: interaction-updated advice. Drug Safety Update. April 2010;3(9):4-5. Free access on:
http://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON087711
7
Spanish Medicines Agency. Informative note 2009/07 [3 juin 2009] “Clopidogrel and proton pump inhibitors possible interaction”
[Posible interacción de clopidogrel con los inhibidores de la bomba de protones]. Free access (in Spanish) on:
http://www.aemps.es/actividad/alertas/usoHumano/seguridad/NI_2009-07_clopidogrel.htm
8
Spanish Medicines Agency. Informative note 2010/04 [26 april 2010] “Clopidogrel and proton pump inhibitors interaction:
information updated and use recommendations” [Interacción de clopidogrel con los inhibidores de la bomba de protones:
actualización de la información y recomendaciones de uso]. Free access (in Spanish) on:
http://www.aemps.es/actividad/alertas/usoHumano/seguridad/2010/NI_2010-04_clopidogrel.htm
9
Bhatt DL, Cryer B, Contant CF, et al. The COGENT Trial: A prospective, randomized, placebo-controlled trial of omeprazole in
patients receiving aspirin and clopidogrel. Presented at: Annual Meeting of Transcatheter Cardiovascular Therapeutics;
September 24, 2009; San Francisco, CA, USA.
10
O’Donoghue ML, Braunwald E, Antman EM, et al. Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel
with or without a proton-pump inhibitor: an analysis of two randomised trials. Lancet. 2009;374:989-97.
11
Stanek EJ, Aubert R, Flockhart D, et al. A national study of the effect of individual proton pump inhibitors on cardiovascular
outcomes in patients treated with clopidogrel following coronary stenting: the clopidogrel Medco Outcomes Study. Presented at
SCAI, Las Vegas 2009:Abstract O-11.
12
Wallentin L, Becker RC, Budaj AB, et al. for the PLATO investigators. Ticagrelor versus clopidogrel in patients with acute
coronary syndromes. NEJM. 2009;361:1045-57.
13
Yasuda H, Yamada M, Sawada S, et al. Upper gastrointestinal bleeding in patients receiving dual antiplatelet therapy after
coronary stenting. Intern Med. 2009;48(19):1725-30.
14
Bhatt DL, Cryer BL, Contant CF, et al. for the COGENT Investigators. Clopidogrel with or without omeprazole in coronary artery
disease. N Engl J Med. 2010;363:1909-17.
15
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;56:2051-66.