Clopidogrel and Omeprazole: Interaction Details

a) In a crossover clinical study, 72 healthy subjects were administered clopidogrel (300 mg loading dose followed by 75 mg per day) alone and with omeprazole (80 mg at the same time as clopidogrel) for 5 days. The exposure to the active metabolite of clopidogrel was decreased by 46% (Day 1) and 42% (Day 5) when clopidogrel and omeprazole were administered together. Results from another crossover study in healthy subjects showed a similar pharmacokinetic interaction between clopidogrel (300 mg loading dose/75 mg daily maintenance dose) and omeprazole 80 mg daily when coadministered for 30 days. Exposure to the active metabolite of clopidogrel was reduced by 41% to 46% over this time period. In another study, 72 healthy subjects were given the same doses of clopidogrel and 80 mg omeprazole, but the drugs were administered 12 hours apart; the results were similar, indicating that administering clopidogrel and omeprazole at different times does not prevent their interaction ¹³.

b) 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 ⁴.

c) In dedicated drug-drug interaction studies, proton pump inhibitor (dexlansoprazole 60 mg, lansoprazole 30 mg, pantoprazole 80 mg, and omeprazole 80 mg) use significantly reduced the AUC of the clopidogrel active metabolite versus clopidogrel alone following multiple doses of clopidogrel 75 mg. Omeprazole use resulted in the greatest reduction in clopidogrel metabolite AUC, dexlansoprazole was associated with the least reduction ¹⁰.

d) Concomitant use of clopidogrel 75 mg and omeprazole 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 (47.2% 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 esomeprazole, 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) ¹.

e) 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 ².

f) Coadministration of clopidogrel and omeprazole led to a significant decrease in Cmax and AUC of clopidogrel active metabolite (H4), and consequently, a decrease in platelet aggregation inhibition in 3, randomized, placebo-controlled, crossover studies in healthy subjects. Compared with levels when clopidogrel was administered alone, coadministration of clopidogrel (300-mg loading dose; 75 mg/day maintenance dose) and omeprazole (80 mg/day; study 1; n=64) led to a 46% and 45% decrease in H4 Cmax and AUC, respectively on day 1, and a 42% and 40% decrease, respectively on day 5. The decrease in H4 Cmax and AUC corresponded to a decrease in mean inhibition of platelet aggregation (IPA) of 39% on day 1. and 21% on day 5. Results were similar when clopidogrel and omeprazole were administered 12 hours apart at the same doses (study 2; n=66), and when clopidogrel loading- and maintenance doses were doubled (study 3; n=62). In a fourth study (n=56), substitution of omeprazole with pantoprazole 80 mg/day coadministered with clopidogrel (300-mg loading dose; 75 mg/day maintenance dose), led to a smaller but still significant decrease in H4 Cmax and AUC of 24% and 20%, respectively on day 1, and 28% and 14%, respectively on day 5 compared with levels when clopidogrel was administered alone ³.

g) In a prospective study, significantly better platelet response was observed with clopidogrel 150 mg concomitantly used 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. There were significantly fewer nonresponders with pantoprazole compared with omeprazole concomitant therapy (23% vs 44%; odds ratio, 2.6; 95% CI, 1.2 to 6.2) emphasizing preferential choice of pantoprazole over omeprazole for clopidogrel-treated patients ⁵.

h) Concomitant use 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% confidence interval (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. Further study is needed to determine if RABEprazole or dexlansoprazole reduces clopidogrel efficacy with concomitant administration ⁶.

i) The concomitant use of clopidogrel and proton pump inhibitors (PPI) including omeprazole 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. The odds ratio (OR) of adverse outcomes associated with concomitant clopidogrel and omeprazole (n=3132) was 1.24 (95% confidence interval (CI), 1.08 to 1.41). 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) vs 20.8% of patients taking clopidogrel without PPI (n=2961) (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, 1.3 to 1.71), and death of all causes occurred in 19.9% vs 16.6% (OR, 0.91; 95% CI, 0.8 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) ⁷.

j) 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 discharge 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 with 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 was 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, 1.1 to 1.77) ⁸.

k) 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. 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 ⁹.