Indian Journal of Pharmacology Home 

RESEARCH ARTICLE
[Download PDF]
Year : 2011  |  Volume : 43  |  Issue : 2  |  Page : 183--186

Impact of proton pump inhibitors on efficacy of clopidogrel: Review of evidence

Suresh D Mistry, Hiren R Trivedi, Dinesh M Parmar, Prashant S Dalvi, Chacko Jiyo 
 Department of Pharmacology, M. P. Shah Medical College, Jamnagar, Gujarat, India

Correspondence Address:
Prashant S Dalvi
Department of Pharmacology, M. P. Shah Medical College, Jamnagar, Gujarat
India

Abstract

Clopidogrel is a prodrug which requires cytochrome P450 2C19 (CYP 2C19) enzyme for its conversion to an active thiol metabolite. Proton pump inhibitors (PPIs) inhibits enzyme CYP 2C19 interfering with the conversion of clopidogrel into its active metabolite. Studies document the possible interaction of clopidogrel and PPIs leading to a decrease in the antiplatelet efficacy of clopidogrel. A PubMed/MEDLINE database literature search was carried out and the bibliographies of found articles were checked for other relevant literature. Most retrospective cohort studies and studies using platelet markers found a significant association between PPI use especially omeprazole and decreased efficacy of clopidogrel while few comparative trials using clinical outcomes found no association between the same. Pantoprazole was not associated with the decrease in the antiplatelet efficacy of clopidogrel. Patients on dual antiplatelet therapy and/or with a history of gastrointestinal bleed will require gastroprotection in the form of PPIs. In such cases, pantoprazole should be the preferred PPI. Rabeprazole can be used as an alternative.



How to cite this article:
Mistry SD, Trivedi HR, Parmar DM, Dalvi PS, Jiyo C. Impact of proton pump inhibitors on efficacy of clopidogrel: Review of evidence.Indian J Pharmacol 2011;43:183-186


How to cite this URL:
Mistry SD, Trivedi HR, Parmar DM, Dalvi PS, Jiyo C. Impact of proton pump inhibitors on efficacy of clopidogrel: Review of evidence. Indian J Pharmacol [serial online] 2011 [cited 2022 Sep 25 ];43:183-186
Available from: https://www.ijp-online.com/text.asp?2011/43/2/183/77360


Full Text

 Introduction



The thienopyridine derivative clopidogrel is an antiplatelet drug approved in patients with acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI), stroke, and established peripheral artery disease. [1] In the long-term management of ACS and/or PCI, the combination of clopidogrel and aspirin is superior to monotherapy with aspirin. [2] The most serious adverse outcome of the dual antiplatelet therapy is gastrointestinal hemorrhage. The current consensus recommends gastroprotection in the form of proton pump inhibitors (PPIs) in patients on clopidogrel who are receiving aspirin and/or are with multiple risk factors like history of gastrointestinal bleeding, concomitant anticoagulant, age more than 60 years, on corticosteroids, and dyspepsia/gastroesophageal reflux disorder (GERD). [3] Recent evidences suggest a possible interaction between PPIs and clopidogrel, leading to a decreased efficacy of clopidogrel and thus increase in cardiovascular morbidity. [4]

Clopidogrel is a prodrug which requires the CYP 2C19 enzyme for its conversion to an active thiol metabolite which finally inhibits P2Y12 ADP receptors present on platelets. [5],[6] The enzyme cytochrome P450 3A4 may also be involved in the conversion. [7] Most of the PPIs inhibit enzyme CYP 2C19, which is required for their major metabolic pathway. The concomitant administration of PPIs reduces the conversion of clopidogrel into its active metabolite and reduces its antiplatelet action. Additional hypothesis suggested is that the absorption of clopidogrel is decreased in the presence of PPIs which reduces the gastric acidic environment. [8] Enzyme CYP 2C19 exhibits genetic polymorphism with 3-5% Caucasians and 12-25% Asians being poor metabolizers for the substrates. [9],[10] There were diminished levels of the active metabolite of clopidogrel in patients carrying CYP 2C19 loss-of-function alleles, exposing them to three times higher risk of cardiovascular events. [11]

 Methods of Review



A systematic literature search was conducted which consisted of a Pubmed/MEDLINE database search and a world wide web search using the keywords "Clopidogrel, Omeprazole, Proton pump inhibitors, Drug interactions and Platelet aggregation." Relevant original articles for clinical studies published in the English language were selected. The bibliographies of these articles were then reviewed for other literature and articles addressing the clopidogrel and PPI interaction. Studies selected for review included retrospective cohort studies, cross-sectional and randomized controlled trials using platelet markers, and comparative studies using clinical outcomes [Table 1].{Table 1}

 Results



Observational Studies

A nested population-based case control study in Canada included patients aged 66 years or older who received clopidogrel within 3 days following hospital discharge after acute myocardial infarction (MI). [4] Cases were defined as patients who died or were readmitted for MI within 90 days. Controls were matched and were defined as those who were not readmitted with MI. PPI use was categorized as either current within 30 days or previous within 31-90 days, or remote within 91-180 days with respect to readmission. After extensive multivariate adjustment, the current use of PPIs was associated with increased risk of recurrent MI. The study also showed no significant association of pantoprazole with recurrent MI. This study met with various drawbacks and imitations. There were major differences between control and case groups in terms of comorbidities like diabetes, renal failure, and heart failure. [12] Others included lack of data on cardiac risk factors, type of MI, use of over-the-counter aspirin, and no account of genetic polymorphism. Despite these limitations, this observational study was a landmark in proving the association between clopidogrel and PPIs and cardiovascular event. The Clopidogrel Medco Outcome Study was a retrospective cohort study which included patients with coronary stent on clopidogrel therapy. [13] There was an increased incidence of major cardiovascular events within 1 year in patients taking clopidogrel and PPIs.

In contrast to the above-mentioned studies, another observational study by Rassen et al. done in three large cohorts including 18,565 patients on clopidogrel found that the risk of subsequent MI associated with the PPI use was unlikely to exceed 20%. [14] In a recently published retrospective study, the primary composite endpoint was death due to cardiac cause and hospitalization due to myocardial infarction within 1 year in patients on clopidogrel after undergoing successful coronary stenting. This underpowered study found no association between the use of omeprazole and effectiveness of clopidogrel. [15]

Ex vivo platelet assays as surrogate markers

Most of the evidence of the interaction comes from studies using ex vivo platelet assays. These assays used vasodilator-stimulated phosphoprotein phosphorylation (VASP) expressed as a platelet reactivity index (PRI) and measurement of platelet aggregation induced by adenosine diphosphate (ADP) by light transmission aggregometry. In the double-blind placebo-controlled Omeprazole Clopidogrel Aspirin (OCLA) study, patients undergoing coronary stent implantation received aspirin and clopidogrel and were randomized to receive either omeprazole or placebo. [16] The mean PRI was significantly lower in omeprazole group compared to placebo. A cross-sectional study studied platelet aggregation with multiple electrode aggregometry (MEA) in patients under clopidogrel maintenance treatment. [17] Platelet aggregation was significantly higher in patients who were under omeprazole treatment at the time of the platelet function test. In another study, such attenuating effect on the platelet response to clopidogrel was not seen in patients on pantoprazole or esomeprazole. [18] In the double-blind PRINCIPLE-TIMI trial, the primary endpoint of the inhibition of platelet aggregation at 6 h was significantly lower for patients on clopidogrel and PPI. [8] Though this difference was modest on day 15, the proportion of patients with clopidogrel hyporesponsiveness (defined as the inhibition of ADP-induced platelet aggregation <20%) was more than sixfold higher in the PPI group than the non-PPI group.

TRITON -TIMI 38 trial

A comprehensive post hoc analysis of the TRITON -TIMI 38 trial was done by O'Donoghue et al. [8] In this study, patients with acute coronary syndrome (ACS) were randomly assigned to prasugrel or clopidogrel and were followed up for the composite of cardiovascular death, nonfatal MI, or nonfatal stroke. About 33% of patients were on PPIs at the time of randomization. The multivariable Cox proportional hazard model found no significant association between the use of PPIs and risk of primary endpoint for patients treated with clopidogrel or prasugrel. Notably, though this was a post hoc analysis and lacked randomization and blinding for the PPI use, it was adjusted for about 13 potential covariates and the propensity to treat with PPIs.

COGENT trial

The randomized double-blind, double dummy, placebo-controlled COGENT trial included 3761 patients for studying the safety and efficacy of the fixed dose combination (FDC) of clopidogrel and omeprazole compared with clopidogrel alone. [19] This study was a prematurely terminated study due to sponsor bankruptcy and had both cardiovascular and gastrointestinal endpoints. The authors found no clinically relevant adverse cardiovascular interaction between clopidogrel and omeprazole (HR 0.99, 95% CI 0.68-1.44).

 Discussion



In vitro studies using human liver microsomal preparations and recombinant CYP 2C19 found the inhibition of CYP 2C19 by PPIs in the following descending order: lansoprazole, omeprazole, esomeprazole, rabeprazole, and pantoprazole. [20] Omeprazole was found to be the most important PPI having an interaction with clopidogrel and is obvious from the fact that omeprazole is mostly metabolized by CYP 2C19. [4],[16],[17],[21],[22] Lansoprazole is the most potent inhibitor of CYP 2C19 but clear evidence from studies are lacking. [20] The case control study by Juurlink et al. [4] concluded that "other PPIs" (omeprazole, lansoprazole, rabeprazole) were associated with 40% increase in the risk of recurrent MI but the data regarding the contributions of individual PPIs to the odds ratio was lacking. This was important because rabeprazole is less likely to inhibit CYP 2C19 but its active thioether metabolite does inhibit CYP 2C19. [20] Siller-Matula et al. using their ex vivo study compared effects of pantoprazole and esomeprazole on the clopidogrel activity and found neither of them influencing the antiplatelet effect of clopidogrel. [18] Pantoprazole can be considered as a safe PPI as demonstrated in observational studies and ex vivo platelet studies. [4],[18],[23] The difference in the metabolism of individual PPIs may contribute to the lack of class effect of PPIs in interacting with clopidogrel.

An association could possibly exist between the use of PPIs especially omeprazole and the decrease in the antiplatelet efficacy of clopidogrel as evident by most of observational studies. [4] But the causal relationship and its clinical significance could not be ascertained due to conflicting results shown by prospective studies using clinical outcomes. [8],[19] In addition to limitations of observational studies, certain questions can be raised regarding ex vivo platelet assay studies. Atorvastatin was found to decrease the antiplatelet efficacy of clopidogrel in an ex vivo study which was proven clinically insignificant. [24],[25] In the PRINCIPLE-TIMI trial, the mean inhibition of platelet aggregation on day 15 was significantly lower in the prasugrel group using PPIs, though the antiplatelet effect of prasugrel is not dependent on CYP 2C19. [26]

The United States Food and Drug Administration (FDA) has issued information for healthcare professionals regarding the update on the labeling of clopidogrel about the drug interaction with omeprazole. [27] Following considerations are issued by FDA for healthcare professionals:



The concomitant use of omeprazole and clopidogrel should be avoided because of the effect on clopidogrel's active metabolite levels and anticlotting activity.Other drugs that should be avoided in combination with clopidogrel because they may have a similar interaction include esomeprazole and cimetidine.At this time, FDA does not have sufficient information about drug interactions between clopidogrel and PPIs other than omeprazole and esomeprazole to make specific recommendations.

Considering the extensive use of PPIs and clopidogrel, the interaction between them assumes immense importance. The beneficial effect of PPIs in preventing upper gastrointestinal bleeding in patients of antiplatelet therapy cannot be totally overweighed by observational studies and studies using platelet markers. Till further evidence becomes available, patients on clopidogrel maintenance therapy should be reevaluated for PPI use. Those having well-controlled symptoms may be candidates for H2 blockers, except cimetidine. Patients on dual antiplatelet therapy and/or with history of gastrointestinal bleed will require gastroprotection in the form of PPIs. In such cases, pantoprazole should be the preferred PPI. [28] Rabeprazole is less likely to inhibit CYP 2C19 and there is no direct evidence of the association of rabeprazole with the decreased efficacy of clopidogrel. Thus, rabeprazole can be considered for gastroprotection. Consequently, prospective, randomized clinical studies on patients on clopidogrel treatment taking PPIs for gastroprotection are highly warranted.[30]

References

1Majerus PW, Tollefsen DM. Drugs acting on blood and blood forming organs; blood coagulation and anti-coagulant, thrombolytic, and antiplatelet drugs: Introduction. In: Brunton LL, Lazo JS, Parker KL, editors. Goodman and Gilman′s The Pharmacological Basis of Therapeutics. 11 th ed. McGraw-Hill: New York; 2006. p. 1467-88.
2Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494-02.
3Bhatt DL, Scheiman J, Abraham NS, Antman EM, Chan FK, Furberg CD, et al. 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 Clinical Expert Consensus Documents. Circulation 2008;118:1894-09.
4Juurlink DN, Gomes T, Ko DT, Szmitko PE, Austin PC, Tu JV, et al. A population-based study of the drug interaction between proton pump inhibitors and clopidogrel. CMAJ 2009;180:713-8.
5Savi P, Pereillo JM, Uzabiaga MF, Combalbert J, Picard C, Maffrand JP, et al. Identification and biological activity of the active metabolite of clopidogrel. Thromb Haemost 2000;84:891-6.
6Savi P, Herbert JM, Pflieger AM, Dol F, Delebassee D, Combalbert J, et al. Importance of hepatic metabolism in the antiaggregating activity of the thienopyridine clopidogrel. Biochem Pharmacol 1992;44:527-32.
7Label of Plavix (Clopidogrel bisulphate). [Updated on 2010 mar 12] Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020839s042lbl.pdf . [accessed on 2010 mar 16].
8O′Donoghue ML, Braunwald E, Antman EM, Murphy SA, Bates ER, Rozenman Y, 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.
9Bertilsson L. Geographical/interracial differences in polymorphic drug oxidation. Current state of knowledge of cytochromes P450 (CYP) 2D6 and 2C19. Clin Pharmacokinet 1995;29:192-209.
10Desta Z, Zhao X, Shin JG, Flockhart DA. Clinical significance of the cytochrome P450 2C19 genetic polymorphism. Clin Pharmacokinet 2002;41:913-58.
11Simon T, Verstuyft C, Mary-Krause M, Quteineh L, Drouet E, Méneveau N, et al. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 2009;360:363-75.
12Juurlink DN, Gomes T, Ko DT, Szmitko PE, Austin PC, Tu JV, et al. A population-based study of the drug interaction between proton pump inhibitors and clopidogrel. CMAJ 2009;180:713-8.
13Aubert RE, Epstein RS, Teagarden JR. Abstract 3998: Proton pump inhibitors effect on clopidogrel effectiveness: The Clopidogrel Medco Outcomes Study. Circulation 2008;118:S815.
14Rassen JA, Choudhry NK, Avorn J, Schneeweiss S. Cardiovascular outcomes and mortality in patients using clopidogrel with proton pump inhibitors after percutaneous coronary intervention or acute coronary syndrome. Circulation 2009;120:2322-9.
15Zairis MN, Tsiaousis GZ, Patsourakos NG, Georgilas AT, Kontos CF, Adamopoulou EN, et al. The impact of treatment with omeprazole on the effectiveness of clopidogrel drug therapy during the first year after successful coronary stenting. Can J Cardiol 2010;26:e54-7
16Gilard M, Arnaud B, Cornily JC, Le Gal G, Lacut K, Le Calvez G, et al. Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin: The randomized, double-blind OCLA (Omeprazole CLopidogrel Aspirin) study. J Am Coll Cardiol 2008;5:256-60.
17Sibbing D, Morath T, Stegherr J, Braun S, Vogt W, Hadamitzky M, et al. Impact of proton pump inhibitors on the antiplatelet effects of clopidogrel. Thromb Haemost 2009;101:714-9.
18Siller-Matula JM, Spiel AO, Lang IM, Kreiner G, Christ G, Jilma B. Effects of pantoprazole and esomeprazole on platelet inhibition by clopidogrel. Am Heart J 2009;157:148.
19Bhatt DL, Cryer BL, Contant CF, Cohen M, Lanas A, Schnitzer TJ, et al. Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med 2010;363:1909-17.
20Li XQ, Andersson TB, Ahlström M, Weidolf L. Comparison of inhibitory effects of the proton pump-inhibiting drugs omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole on human cytochrome P450 activities. Drug Metab Dispos 2004;32:821-7.
21Ho PM, Maddox TM, Wang L, Fihn SD, Jesse RL, Peterson ED, et al. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA 2009;301:937-44.
22Gilard M, Arnaud B, Le Gal G, Abgrall JF, Boschat J. Infl uence of omeprazole on the antiplatelet action of clopidogrel associated to aspirin. J Thromb Haemost 2006;4:2508-09.
23Cuisset T, Frere C, Quilici J, Poyet R, Gaborit B, Bali L, et al. Comparison of omeprazole and pantoprazole influence on a high 150-mg clopidogrel maintenance dose the PACA (Proton Pump Inhibitors And Clopidogrel Association) prospective randomized study. J Am Coll Cardiol 2009;54:1149-53.
24Lau WC, Waskell LA, Watkins PB, Neer CJ, Horowitz K, Hopp AS, et al. Atorvastatin reduces the ability of clopidogrel to inhibit platelet aggregation: A new drug-drug interaction. Circulation 2003;107:32-7.
25Saw J, Steinhubl SR, Berger PB, Kereiakes DJ, Serebruany VL, Brennan D, et al. Lack of adverse clopidogrel-atorvastatin clinical interaction from secondary analysis of a randomized, placebo-controlled clopidogrel trial. Circulation 2003;108:921-4.
26Brandt JT, Close SL, Iturria SJ, Payne CD, Farid NA, Ernest CS 2 nd , Lachno DR, et al. Common polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel. J Thromb Haemost 2007;5:2429-31.
27Update to the labeling of Clopidogrel Bisulfate (marketed as Plavix) to alert healthcare professionals about a drug interaction with omeprazole (marketed as Prilosec and Prilosec OTC). Available from: http://www.fda.gov/Drugs/......./ucm190787.htm . [Updated on 2009 Nov 17] [cited 2010 Mar 24].
28Juhász M, Herszényi L, Tulassay Z. Current Standings of the Proton Pump Inhibitor and Clopidogrel Co-Therapy: Review on an Evolving Field with the Eyes of the Gastroenterologist. Digestion 2010;81:10-5.
29Dunn SP, Macaulay TE, Brennan DM. Baseline proton pump inhibitor use is associated with increased cardiovascular events with and without the use of clopidogrel in the CREDO trial. Circulation 2008;118:815A.
30Zuern CS, Geisler T, Lutilsky N, Winter S, Schwab M, Gawaz M. Effect of comedication with proton pump inhibitors (PPIs) on post-interventional residual platelet aggregation in patients undergoing coronary stenting treated by dual antiplatelet therapy. Thromb Res 2010;125:e51-4.