Clopidogrel and Dexlansoprazole: Interaction Details

a) In a study of healthy subjects who were CYP2C19 extensive metabolizers (n=40), the mean AUC of the active metabolite of clopidogrel (CYP2C19 substrate) was reduced by approximately 9% (mean AUC ratio, 91%; 90% CI, 86% to 97%) with coadministration of dexlansoprazole compared with administration of clopidogrel alone. Patients received clopidogrel 75 mg once daily, alone or concomitantly with dexlansoprazole 60 mg for 9 days. Pharmacodynamic parameters demonstrated that the change in inhibition of platelet aggregation (induced by 5 mcM ADP) was related to the change in the exposure to clopidogrel active metabolite ¹.

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 ³.

c) Concomitant use of clopidogrel 75 mg and lansoprazole 15 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 (46.4% 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, esomeprazole, 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) ⁴.

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) 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 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 ⁸.