Clopidogrel and Rabeprazole: Interaction Details

a) In a study of healthy subjects who were CYP2C19 extensive and intermediate metabolizers (n=36), the mean AUC of the active metabolite of clopidogrel (CYP2C19 substrate) was reduced by approximately 12% (mean AUC ratio, 88%; 90% CI, 81.7% to 95.5%) with coadministration of rabeprazole compared with administration of clopidogrel alone. Patients received clopidogrel 75 mg once daily, alone or concomitantly with rabeprazole 20 mg for 7 days ¹¹.

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) Concomitant use of clopidogrel 75 mg and rabeprazole 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 (47.3% vs 56%) in a study of healthy Japanese subjects with different CYP2C19 genotypes (N=41). In an additional evaluation, when rabeprazole was given after lunch (4 hours after or 20 hours prior to clopidogrel), inhibition of platelet aggregation was decreased only 1.9%, which was significantly less of a decrease when compared with the decrease observed with concomitant administration in the morning (decreased 10.6%) or when given 12 hours apart (decreased 7.8%) ².

d) 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 ⁵.

e) The concomitant administration of clopidogrel and proton pump inhibitors (PPI) including rabeprazole 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 of adverse outcomes associated with concomitant clopidogrel and rabeprazole (n=151) was 2.83 (95% CI, 1.96 to 4.09). 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) ⁶.

f) 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 to 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) ⁷.

g) 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 to 220 AU*min for without-PPI group. Compared to no concomitant PPI treatment, platelet aggregation was not significantly different with esomeprazole (209 AU*min; p=0.88) or with pantoprazole (226 AU*min) ⁸.

h) 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 to 49% in those not receiving a PPI (n=74). There was no significant difference in platelet aggregation in the PPI group compared to 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) ⁹.

i) 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 to 83.9% for the omeprazole group. On day 7, mean PRI was 39.8% (SD 15.4) and 51.4% (SD 16.4), 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) ³.

j) 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 to 11.38% (95% CI, 8.69 to 14.07) in the high PPI exposure group ¹⁰.