Esomeprazole with Clopidogrel Interaction Details

Brand Names Associated with Esomeprazole

Brand Names Associated with Clopidogrel

Medical Content Editor Dr. Brian Staiger, PharmD
Last updated Nov 11, 2023

Interaction Effect

Reduced plasma concentrations of clopidogrel active metabolite and reduced antiplatelet activity

Interaction Summary

Coadministration of esomeprazole with clopidogrel resulted in a reduction in exposure to the active metabolite of clopidogrel and in inhibition of platelet aggregation was observed. Rabeprazole (given 4 hours after clopidogrel) , pantoprazole, lansoprazole, and dexlansoprazole have less effect on the antiplatelet activity of clopidogrel. Avoid concomitant use of clopidogrel with esomeprazole  or consider alternative antiplatelet therapy . Inhibition of platelet aggregation of clopidogrel was not significantly altered by coadministration of ranitidine, a histamine-2 receptor antagonist .

Severity

Major

Onset

Rapid

Evidence

Established

How To Manage Interaction

Administration of clopidogrel with esomeprazole reduces levels of the clopidogrel active metabolite and reduces antiplatelet activity when given either concomitantly or 12 hours apart. Avoid concomitant use of clopidogrel and esomeprazole. Rabeprazole (given 4 hours after clopidogrel) , pantoprazole, lansoprazole, and dexlansoprazole have less effect on the antiplatelet activity of clopidogrel . Consider using alternative antiplatelet therapy in patients requiring esomeprazole . The platelet aggregation of clopidogrel was not significantly altered by coadministration of ranitidine, a histamine-2 receptor antagonist .

Mechanism Of Interaction

Inhibition of CYP2C19-mediated clopidogrel metabolism to active metabolite by esomeprazole

Literature Reports

A) Treatment with a proton pump inhibitor and thienopyridine (clopidogrel or prasugrel) compared with a thienopyridine alone significantly increased risk of stroke (adjusted hazard ratio (HR), 1.3; 95% CI, 1.04 to 1.61; 4 studies) and composite stroke/MI/cardiovascular death (adjusted HR, 1.23; 95% CI, 1.03 to 1.47; 8 studies) in a systematic review and metaanalysis of 22 studies (N=131,714). There was no significant difference in myocardial infarction (7 studies), cardiovascular death (6 studies) or all-cause mortality (8 studies). Patient followup occurred for 6 to 30 months (median, 12 months) within the studies .

B) In dedicated drug-drug interaction studies, proton pump inhibitor (dexlansoprazole, lansoprazole, pantoprazole, and omeprazole) use significantly reduced the AUC of the clopidogrel active metabolite versus clopidogrel alone. Omeprazole use resulted in the greatest reduction in clopidogrel metabolite AUC, dexlansoprazole was associated with the least reduction .

C) Concomitant use of clopidogrel 75 mg and esomeprazole 10 mg (administered together in the morning or 12 hours apart in the evening) resulted in a significant reduction in mean inhibition of platelet aggregation compared with clopidogrel alone (43.2% vs 56%) measured 4 hours after the last clopidogrel dose on day 7, in a study of healthy Japanese subjects with different CYP2C19 genotypes (N=41). A similar significant reduction was seen with omeprazole, lansoprazole, and rabeprazole when given together in the morning or separately in the evening. However, the reduction in inhibition of platelet aggregation was not significant with clopidogrel given after breakfast and rabeprazole administered after lunch (4 hours after or 20 hours prior to clopidogrel) .

D) In a study of patients with coronary artery disease, the inhibition of platelet aggregation (IPA) of clopidogrel was significantly reduced with the addition of omeprazole (n=41; clopidogrel, 26.3%; combination therapy, 17.4%), but was not significantly changed with the addition of ranitidine therapy (n=44; 32.6%; combination therapy, 30.1%). All patients received aspirin 100 mg daily prior to and during the study and had a baseline IPA measurement (0% for each group). Patients then received clopidogrel 75 mg daily for one week prior to the second IPA measurement (time 1), then were randomized to receive combination therapy with clopidogrel and either omeprazole 20 mg twice daily or ranitidine 150 mg twice daily for one week before the next IPA measurement (time 2). There was not a significant difference between groups for either time 1 or time 2. After excluding patients who were homozygous for 2C19*2 (loss-of-function) genotype, there was a significant difference between groups at time 2 .

E) Coadministration of esomeprazole magnesium 44.6 mg orally once daily with clopidogrel 75 mg orally daily (following a clopidogrel 300 mg loading dose) for 30 days in healthy subjects resulted in a 35% to 40% reduction in exposure to the active metabolite of clopidogrel. A corresponding change in inhibition of platelet aggregation was observed .

F) In a prospective, randomized study (n=104), significantly better platelet response was observed with clopidogrel 150 mg concomitantly administered with pantoprazole compared with omeprazole when platelet reactivity was assessed by the platelet reactivity index-vasoactive stimulated phosphoprotein (PRI-VASP), but not when assessed by adenosine diphosphate-induced aggregation (ADP-Ag), suggesting that the omeprazole-clopidogrel interaction may not be due to a proton-pump inhibitor class effect. PRI-VASP precisely measures platelet activation/inactivation via phosphorylation of the P2Y12 receptor; whereas ADP-Ag is not specific solely to the P2Y12 receptor. In this study, patients with successful stenting for non-ST segment acute coronary syndrome were discharged on aspirin 75 mg and clopidogrel 150 mg daily, then randomized (1:1) to either pantoprazole or omeprazole 20 mg/day. After 1 month, the pantoprazole arm had significantly better platelet response (less aggregation) to clopidogrel compared with the omeprazole arm as measured by PRI-VASP (36% +/- 20% vs 48% +/- 17%). However, platelet response was not significantly different when measured by ADP-Ag (50 +/- 18% vs 52 +/- 15%) in the pantoprazole and omeprazole groups, respectively. Nonresponders to clopidogrel was significantly less with pantoprazole compared with omeprazole concomitant therapy (23% vs 44%; OR, 2.6; 95% CI, 1.2 to 6.2) emphasizing preferential choice of pantoprazole over omeprazole for clopidogrel-treated patients .

G) Concomitant administration of clopidogrel with a proton pump inhibitor (PPI) was associated with a significantly increased incidence and risk of major adverse cardiovascular events (MACE; a composite of myocardial infarction, unstable angina, transient ischemic attack/stroke, coronary revascularization, or cardiovascular death) compared with no concomitant PPI therapy, according to the Clopidogrel Medco Outcomes Study of 16,690 coronary-stent patients adherent to clopidogrel. Overall, patients on any PPI had a significantly higher risk of MACE (n=6828; 25.1%) compared with those receiving no PPI therapy (n=9862; 17.9%) with an adjusted hazard ratio (HR) of 1.51 (95% CI, 1.39 to 1.64). After a 1-year follow-up, all PPIs were associated with a significant increase in MACE compared with no PPI therapy: pantoprazole (n=1653; 29.2% vs 17.9%; HR, 1.61; 95% CI, 1.41 to 1.88); esomeprazole (n=3257; 24.9% vs 17.9%; HR 1.57; 95% CI, 1.4 to 1.76); omeprazole (n=2307; 25.1% vs 17.9%; HR, 1.39; 95% CI, 1.22 to 1.57); and lansoprazole (n=785; 24.3% vs 17.9%; HR, 1.39; 95% CI, 1.16 to 1.67). Data on rabeprazole (n=298) were inconclusive due to limited power and sample size .

H) The concomitant administration of clopidogrel and proton pump inhibitors (PPI) was associated with an increased risk of death or rehospitalization for acute coronary syndrome (ACS) in a retrospective cohort study of Veterans Health Administration patients with acute myocardial infarction or unstable angina (n=8205). Patients discharged between October 1, 2003 and January 31, 2006 with clopidogrel prescriptions, based on pharmacy refill data, were reviewed. Death and rehospitalization for ACS (primary endpoint) occurred in 29.8% of patients taking both clopidogrel and PPI at any point during the follow-up period (n=5244) versus 20.8% of patients taking clopidogrel without PPI (n=2961) (adjusted odds ratio (OR), 1.25; 95% confidence interval (CI), 1.11 to 1.41), rehospitalization for ACS occurred in 14.6% vs 6.9% (OR, 1.86; 95% CI, 1.57 to 2.20), revascularization procedures occurred in 15.5% vs 11.9% (OR, 1.49; 95% CI, 1.30 to 1.71), and death of all causes occurred in 19.9% vs 16.6% (OR, 0.91; 95% CI, 0.80 to 1.05) of patients, respectively. Of the PPI prescribed at discharge, 59.7% were for omeprazole, 2.9% for rabeprazole, 0.4% for lansoprazole, 0.2% for pantoprazole, and 36.7% for more than one type of PPI. Use of PPI without clopidogrel was not associated with death or rehospitalization for ACS (OR, 0.98; 95% CI, 0.85 to 1.13) .

I) In a population-based nested case-control study (n=2791) in Canada, concomitant treatment of clopidogrel and proton pump inhibitors (PPI), other than pantoprazole, was associated with an increased risk of recurrent myocardial infarction (MI) in elderly patients who were treated for acute MI. Over a 69-month study period, patients who died or had recurrent MI within 90 days after discharged from the hospital (n=734) were matched with controls (n=2057) within a cohort of elderly patients (median age 76 years) who were discharged with clopidogrel after being treated for acute MI. Compared with non-PPI users, the increased incidence of recurrent MI within 90 days was associated the concurrent therapy of clopidogrel with current use (within 30 days of the discharged date (index date)) of PPI (odds ratio (OR), 1.27; 95% confidence interval (CI) 1.03 to 1.57), but not with earlier use (31 to 90 days before the index date) or remote use (91 to 180 days before the index date) of PPI. There were no association between recurrent MI and use of histamine-2 receptor antagonists, use of pantoprazole, and patients not treated with clopidogrel. Whereas use of PPI (other than pantoprazole) was associated with significant increased risk of recurrent MI (OR, 1.4; 95% CI, 1.10 to 1.77) .

J) In a double-blind, placebo-controlled trial of 140 patients undergoing coronary artery stent implantation, omeprazole 20 mg/day significantly decreased clopidogrel inhibitory effect on platelet P2Y12 as assessed by vasodilator-stimulated phosphoprotein (VASP) phosphorylation assay. Clopidogrel exerts its antiplatelet effect by forming an inactivating disulfide bond with the platelet P2Y12 ADP receptor, which is then associated with dephosphorylation of VASP. This dephosphorylation provides an index of platelet reactivity to clopidogrel in which the higher the platelet reactivity index (PRI), the more frequently thrombosis occurs (clopidogrel resistance). Consecutive patients received aspirin 75 mg/day and a loading dose (300 mg) of clopidogrel (followed by 75 mg/day), followed by randomization to either omeprazole or placebo for 7 days. PRI was measured days 1 and 7, and data analyzed for 124 patients. The mean PRI was similar in both groups on day 1, 83.2%) for the placebo group compared with 83.9% for the omeprazole group. On day 7, mean PRI was 39.8%) and 51.4%, respectively. Mean PRI variation in the placebo group was -43.3% and -32.6% in the omeprazole group. Sixteen patients (26.7%) in the placebo group were determined to be poor responders to clopidogrel compared with 39 (60.9%) in the omeprazole group (odds ratio 4.31; 95% confidence interval 2 to 9.2) .

K) A cross-sectional, observational study of 1000 patients receiving clopidogrel plus aspirin with or without concomitant proton pump inhibitor (PPI) therapy (esomeprazole, omeprazole, or pantoprazole) revealed a significantly higher adenosine diphosphate (ADP)-induced platelet aggregation with omeprazole, but not with esomeprazole or pantoprazole. Patients with coronary artery disease who were already receiving clopidogrel 75 mg/day plus aspirin and had undergone percutaneous coronary intervention at a median of 7 months before study inclusion were analyzed. Among the 1000 patients, 268 were being treated with either esomeprazole (n=42), omeprazole (n=64), or pantoprazole (n=162) at the time of platelet function testing. Platelet aggregation was 295.5 AU*min for the omeprazole group compared with 220 AU*min for without-PPI group (p=0.001). Compared with no concomitant PPI treatment, platelet aggregation was not significantly different with esomeprazole (209 AU*min) or with pantoprazole (226 AU*min) .

L) An observational study of 300 patients receiving clopidogrel plus aspirin with or without concomitant proton pump inhibitor (PPI) therapy, including esomeprazole (n=74) or pantoprazole (n=152), showed similar results for mean platelet reactivity index (PRI) and adenosine diphosphate (ADP)-induced platelet aggregation. Patients with coronary artery disease who were already receiving clopidogrel 75 mg/day plus aspirin 100 mg/day and undergoing percutaneous coronary intervention were reviewed. The mean PRI was 51% in patients receiving a PPI (n=226) compared with 49% in those not receiving a PPI (n=74). There was no significant difference in platelet aggregation in the PPI group compared with the no PPI group (45 units vs 41 units). Mean PRI and platelet aggregation were also not significantly different between patients treated with esomeprazole (54% and 41 units, respectively), with pantoprazole (50% and 47 units), and without a PPI (49% and 41 units) .

M) In a study of healthy men, treatment with ranitidine did not significantly effect the AUC, Cmax, or Tmax of clopidogrel or prasugrel when used in combination. Patients were randomized to receive either prasugrel (n=23; 60 mg oral loading dose then 10 mg orally daily for 7 days) or clopidogrel (n=24; 600 mg oral loading dose then 75 mg orally daily for 7 days) for two 9-day treatment periods separated by a 14-day washout period. One period included treatment with only prasugrel or clopidogrel and the other treatment period included treatment with the same drug plus ranitidine 150 mg orally twice daily started one day before the loading dose. Inhibition of platelet aggregation (IPA) of clopidogrel was not significantly effected by coadministration of ranitidine. No clinically significant adverse effects occurred during the study .

N) A retrospective, claims-based analysis of medical and pharmacy databases for acute myocardial infarction (MI) rates in members receiving clopidogrel with or without concurrent proton pump inhibitor (PPI) therapy revealed a 1-year acute MI rate of 1.38% in the control group (no PPI exposure), 3.08% (low PPI exposure based on adherence rate), and 5.03% (high PPI exposure). When the control group MI incidence was used as the expected MI rate, the difference in MI rates between control and high exposure groups was significant (p less than 0.05). Analysis also indicated small but significant comorbidity differences between the groups, including more patients with preexisting hypertension, diabetes, and overall severity of illness at initiation of clopidogrel in the high exposure group. When comorbidity differences were adjusted out of analysis, the differences in acute MI rates remained significant; 2.6% (95% confidence interval (CI), 1.01 to 4.19) of those in the control group experienced MI events compared with 11.38% (95% CI, 8.69 to 14.07) in the high PPI exposure group .

Esomeprazole Overview

• Prescription esomeprazole is used to treat the symptoms of gastroesophageal reflux disease (GERD), a condition in which backward flow of acid from the stomach causes heartburn and possible injury of the esophagus (the tube between the throat and stomach) in adults and children 1 year of age and older. Prescription esomeprazole is used to treat damage from GERD in adults and children 1 month of age and older. Prescription esomeprazole is used to allow the esophagus to heal and prevent further damage to the esophagus in adults with GERD. Prescription esomeprazole is also used to decrease the chance that people who are taking nonsteroidal anti-inflammatory drugs (NSAIDs) will develop ulcers (sores in the lining of the stomach or intestine) in adults. It is also used with other medications to treat and prevent the return of stomach ulcers caused by a certain type of bacteria (H. pylori) in adults. Prescription esomeprazole is also used to treat conditions in which the stomach produces too much acid such as Zollinger-Ellison syndrome in adults. Nonprescription (over-the-counter) esomeprazole is used to treat frequent heartburn (heartburn that occurs at least 2 or more days a week) in adults. Esomeprazole is in a class of medications called proton pump inhibitors. It works by decreasing the amount of acid made in the stomach.

Clopidogrel Overview

• Clopidogrel is used alone or with aspirin to prevent serious or life-threatening problems with the heart and blood vessels in people who have had a stroke, heart attack, or severe chest pain. This includes people who have percutaneous coronary intervention (PCI; angioplasty; a type of heart surgery) that may involve inserting coronary stents (metal tubes surgically placed in clogged blood vessels to improve blood flow) or who have coronary artery bypass grafting (CABG; a type of heart surgery). Clopidogrel is also used to prevent serious or life-threatening problems with the heart and blood vessels in people who have peripheral arterial disease (poor circulation in the blood vessels that supply blood to the legs). Clopidogrel is in a class of medications called antiplatelet medications. It works by preventing platelets (a type of blood cell) from collecting and forming clots that may cause a heart attack or stroke.

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Definitions

Severity Categories

Contraindicated

These drugs, generally, should not be used together simultaneously due to the high risk of severe adverse effects. Combining these medications can lead to dangerous health outcomes and should be strictly avoided unless otherwise instructed by your provider.

Major

This interaction could result in very serious and potentially life-threatening consequences. If you are taking this drug combination, it is very important to be under close medical supervision to minimize severe side effects and ensure your safety. It may be necessary to change a medication or dosage to prevent harm.

Moderate

This interaction has the potential to worsen your medical condition or alter the effectiveness of your treatment. It's important that you are monitored closely and you potentially may need to make adjustments in your treatment plan or drug dosage to maintain optimal health.

Minor

While this interaction is unlikely to cause significant problems, it could intensify side effects or reduce the effectiveness of one or both medications. Monitoring for changes in symptoms and your condition is recommended, and adjustments may be made if needed to manage any increased or more pronounced side effects.

Onset

Rapid: Onset of drug interaction typically occurs within 24 hours of co-administration.

Delayed: Onset of drug interaction typically occurs more than 24 hours after co-administration.

Evidence

Level of documentation of the interaction.

Established: The interaction is documented and substantiated in peer-reviewed medical literature.

Theoretical: This interaction is not fully supported by current medical evidence or well-documented sources, but it is based on known drug mechanisms, drug effects, and other relevant information.

How To Manage The Interaction

Provides a detailed discussion on how patients and clinicians can approach the identified drug interaction as well as offers guidance on what to expect and strategies to potentially mitigate the effects of the interaction. This may include recommendations on adjusting medication dosages, altering the timing of drug administration, or closely monitoring for specific symptoms.

It's important to note that all medical situations are unique, and management approaches should be tailored to individual circumstances. Patients should always consult their healthcare provider for personalized advice and guidance on managing drug interactions effectively.

Mechanism Of Interaction

The theorized or clinically determined reason (i.e., mechanism) why the drug-drug interaction occurs.

Disclaimer: The information provided on this page is for informational purposes only and should not be considered medical advice. Always consult with a qualified healthcare professional regarding your specific circumstances and medical conditions.

Where Does Our Information Come From?

Information for our drug interactions is compiled from several drug compendia, including:

• Gold Standard Drug Database
• Micromedex
• Lexicomp
• DrugBank

The prescribing information for each drug, as published on DailyMED, is also used. 

Individual drug-drug interaction detail pages contain references specific to that interaction. You can click on the reference number within brackets '[]' to see what reference was utilized.

The information posted is fact-checked by HelloPharmacist clinicians and reviewed quarterly.