Proton Pump Inhibitors (PPIs) May Reduce the haldol im Efficacy of Clopidogrel

The following discussion relates to drug interactions that may reduce haldol im the efficacy of clopidogrel (plavix®). A related issue is the resistance to clopidogrel in individual haldol im patients which has been reviewed elsewhere on clotcare at clotcare.Org/clotcare/geneticclopidogrelresistance.Aspx.

Clopidogrel (plavix®) is a widely used anti-platelet agent that is commonly combined with aspirin to reduce haldol im the risk of various cardiovascular events. Because of the associated increased risk of gastrointestinal bleeding with haldol im this combination, a proton pump inhibitor (PPI) is often prescribed during such therapy. Because clopidogrel is an inactive product that has to be haldol im converted to its active metabolite in order to be effective, there is considerable concern that some ppis may reduce or haldol im block this conversion and, thereby, reduce the effect of clopidogrel. As discussed below, such inhibition of the effect of clopidogrel may be associated haldol im with a 25% or greater increase in recurrent events. The available data (as summarized in the table below) suggest that omeprazole (and perhaps 1 or 2 other ppis) may reduce or block the effect of clopidogrel, while esomeprazole (nexium®) and pantoprazole (protonix®) probably do not.

Clopidogrel must be converted enzymatically in the liver to its haldol im active form (the metabolite responsible for inhibition of platelet function) by the cytochrome P450 (CYP450) system, mainly CYP2C19. Certain ppis may inhibit the enzymatic conversion of clopidogrel to haldol im its active metabolite, thus reducing the anti-platelet effect of the drug.

Omeprazole appears to have the most detrimental effect on clopidogrel haldol im efficacy, likely due to relatively strong inhibition of CYP2C19. Among the ppis, omeprazole is the oldest PPI, the most widely prescribed, and is available as an over-the-counter product. Gilard and colleagues reported in a 2008 study that patients haldol im treated concomitantly with aspirin (75mg/d) and clopidogrel (300mg loading dose and 75mg/d) and then randomized to receive either omeprazole (20mg/d) or placebo for 7 days showed differences in platelet activity haldol im (represented by a poor response in platelet reactivity index) 1. The platelet reactivity index (PRI) is calculated from measuring platelet-phosphorylated VASP (vasodilator stimulated phophoprotein) assay and a poor response was defined if the PRI haldol im remained >50%. Of patients in the omeprazole group, 60.9% had a poor response versus 26.7% in the placebo group, indicating an interaction between omeprazole and the activity of clopidogrel. 1

Two large studies addressed the interaction between clopidogrel and a haldol im variety of proton pump inhibitors 2, 3. These studies demonstrated an interaction between clopidogrel and omeprazole and haldol im suggested an interaction between clopidogrel and rabeprazole or lansoprazole. Additionally, the study by juurlink and colleagues failed to demonstrate a haldol im reduction in clopidogrel efficacy with pantoprazole. 2

Ho and colleagues published a study earlier in 2009 in haldol im the journal of the american medical association which evaluated adverse haldol im outcomes in VA patients discharged on clopidogrel following an acute haldol im coronary syndrome (ACS) hospitalization. 3 this retrospective cohort study included 8,205 patients, 5,244 (63.9%) of whom were prescribed a PPI either at discharge or haldol im at some point during follow-up. The primary outcome, death or rehospitalization for ACS, occurred in 20.8% of patients not taking a PPI and 29.8% of patients on concomitant PPI and clopidogrel therapy. The adjusted odds ratio for this composite endpoint was 1.25 (95% CI 1.11-1.41), indicating an increased risk of death or rehospitalization with use haldol im of the combination of drugs. The combination of the two drugs also showed statistically significant haldol im increases in rehospitalization (14.6% vs. 6.9%) and revascularization procedures (15.5% vs. 11.9%), but the increase in all-cause mortality (19.9% vs. 16.6%) was not statistically significant. Almost 60% of patients on PPI treatment in this study were taking haldol im omeprazole, compared to 3% on rabeprazole, 0.4% on lansoprazole, 0.2% on pantoprazole, and 36.7% who took more than one PPI during follow-up. 3

The findings of this study were confirmed in a canadian haldol im population-based study by juurlink and colleagues. 2 this group assessed patients readmitted for a recurrent acute haldol im myocardial infarction (AMI) within 90 days of discharge for an AMI. Out of a total of 13,636 patients who were discharged on clopidogrel after hospitalization for haldol im AMI, 734 patients were readmitted for recurrence. These recurrent cases were each matched to 3 control patients haldol im with similar baseline characteristics who did not experience recurrent AMI. The results of this study demonstrated a significant association between haldol im recurrence of AMI and current PPI use (adjusted odds ratio 1.27, 95% CI 1.03-1.57). In subgroup analysis, pantoprazole was not associated with increased risk of rehospitalization (OR = 1.02, 95% CI 0.70-1.47), however the group comprised of omeprazole, rabeprazole, and lansoprazole demonstrated an increased recurrence of AMI (OR = 1.40, 95% CI 1.10-1.77). 2

Siller-matula and colleagues evaluated the effect of pantoprazole or esomeprazole haldol im and clopidogrel on platelet activity by calculating PRI (derived from VASP assay) and measuring aggregation and concluded neither PPI was associated with haldol im decreased clopidogrel response. 4 the investigators conducted a non-randomized observational study of 300 patients with ACS undergoing percutaneous haldol im coronary intervention (PCI). Patients received anti-platelet therapy with clopidogrel (600mg loading dose followed by 75mg/d) and aspirin (100mg/d) for at least 5 days at the time of inclusion. Comparisons were made between three groups of patients — those on anti-platelet therapy and pantoprazole, anti-platelet therapy and esomeprazole, and anti-platelet therapy and no PPI. In the group treated with pantoprazole and clopidogrel (n = 152), the PRI mean was 50% and the platelet aggregation was 47 U. In the esomeprazole plus clopidogrel group (n = 74), the PRI mean was 54% with an aggregation of 42 U. The patients in the group treated only with anti-platelet therapy and no PPI (n = 74), the PRI mean was 49% with an aggregation of 41 U. The p-value for the comparison was 0.3824. Thus, the results of this trial demonstrate the lack of interaction haldol im between either pantoprazole or esomeprazole and clopidogrel, and, therefore, there does not appear to be a reduction in clopidogrel haldol im efficacy with the concomitant utilization of these two specific ppis.

The data to support an interaction between clopidogrel and lansoprazole haldol im are conflicting. In addition to the small percentage of patients taking lansoprazole haldol im in the previously mentioned studies, li and colleagues investigated the in vitro inhibitory effects of haldol im omeprazole, lansoprazole, esomeprazole, pantoprazole, and rabeprazole on four CYP450 enzyme isotypes (CYP2C9, 2C19, 2D6, and 3A4). Of note, lansoprazole appeared to inhibit CYP2C19 to the highest degree, followed by a rabeprazole metabolite, omeprazole, esomeprazole, and, to the least degree, pantoprazole. 5 however, a study by small and colleagues published in 2008 concluded haldol im lansoprazole had little or no effect on clopidogrel metabolism in haldol im vivo. 6

In conclusion, the drug-drug interaction between clopidogrel and proton pump inhibitors is likely haldol im mediated by inhibition of CYP2C19, especially in light of studies which showed decreased clopidogrel efficacy haldol im in patients with a CYP2C19 reduced-function allele. 7, 8 the current literature supports an interaction between clopidogrel and haldol im certain ppis, principally omeprazole, rabeprazole, and lansoprazole . While only a small percentage of patients in the above haldol im mentioned trials received rabeprazole, those who did appeared to exhibit a similar response to haldol im those who received omeprazole. Additionally, the study by li and colleagues show in vitro inhibition haldol im of CYP2C19 via a rabeprazole metabolite. Similarly, the data behind the lansoprazole interaction do not provide a haldol im clear answer. Given the availability of alternatives that do not interact, it may be prudent to er on the side of haldol im caution in the case of both rabeprazole and lansoprazole. If acid-suppression is required, one may choose to utilize an H2-receptor antagonist (with the exception of cimetidine), which have not been shown to interact. 9 however, if a PPI is selected, one should exercise caution when using omeprazole, rabeprazole, or lansoprazole and clopidogrel concomitantly. Instead, one may choose to use either esomeprazole or pantoprazole, which appear to have little, if any, effect on clopidogrel’s inhibition of platelet function.

• gilard M, arnaud B, cornily JC, et al. Influence of omeprazole on the antiplatelet action of clopidogrel associate haldol im with aspirin: the randomized, double-blind OCLA (omeprazole clopidogrel aspirin) study. J am coll cardiol. 2008; 51(3): 256-260.

• li XQ, andersson TB ahlstrom M, et al. Comparison of inhibitory effect of the proton pump-inhibiting drugs omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole on human cytochrome P450 activities. Drug metab dispos. 2004; 32(8): 821-827.