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Selected Proton Pump Inhibitors May Reduce the Efficacy of Clopidogrel

Andrew C. Faust, Pharm.D Candidate, The University of Texas at Austin
ClotCare Editorial Review by Henry I. Bussey, Pharm.D., FCCP, FAHA
May, 2009

The following discussion relates to drug interactions that may reduce the efficacy of clopidogrel (Plavix®). A related issue is the resistance to clopidogrel in individual 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 the risk of various cardiovascular events. Because of the associated increased risk of gastrointestinal bleeding with this combination, a proton pump inhibitor (PPI) is often prescribed during such therapy. Because clopidogrel is an inactive product that has to be converted to its active metabolite in order to be effective, there is considerable concern that some PPIs may reduce or block this conversion and, thereby, reduce the effect of clopidogrel. As discussed below, such inhibition of the effect of clopidogrel may be associated 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.

Proton Pump Inhibitor Effect to Reduce Clopidogrel Conversion to Its Active Metabolite

Clopidogrel must be converted enzymatically in the liver to its 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 its active metabolite, thus reducing the anti-platelet effect of the drug.

Omeprazole appears to have the most detrimental effect on clopidogrel 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 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 (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 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 variety of proton pump inhibitors^2,3. These studies demonstrated an interaction between clopidogrel and omeprazole and suggested an interaction between clopidogrel and rabeprazole or lansoprazole. Additionally, the study by Juurlink and colleagues failed to demonstrate a reduction in clopidogrel efficacy with pantoprazole.²

Ho and colleagues published a study earlier in 2009 in the Journal of the American Medical Association which evaluated adverse outcomes in VA patients discharged on clopidogrel following an acute 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 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 of the combination of drugs. The combination of the two drugs also showed statistically significant 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 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 population-based study by Juurlink and colleagues.² This group assessed patients readmitted for a recurrent acute 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 AMI, 734 patients were readmitted for recurrence. These recurrent cases were each matched to 3 control patients with similar baseline characteristics who did not experience recurrent AMI. The results of this study demonstrated a significant association between 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 and clopidogrel on platelet activity by calculating PRI (derived from VASP assay) and measuring aggregation and concluded neither PPI was associated with decreased clopidogrel response.⁴ The investigators conducted a non-randomized observational study of 300 patients with ACS undergoing percutaneous 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 between either pantoprazole or esomeprazole and clopidogrel, and, therefore, there does not appear to be a reduction in clopidogrel efficacy with the concomitant utilization of these two specific PPIs.

The data to support an interaction between clopidogrel and lansoprazole are conflicting. In addition to the small percentage of patients taking lansoprazole in the previously mentioned studies, Li and colleagues investigated the in vitro inhibitory effects of 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 lansoprazole had little or no effect on clopidogrel metabolism in vivo.⁶

In conclusion, the drug-drug interaction between clopidogrel and proton pump inhibitors is likely mediated by inhibition of CYP2C19, especially in light of studies which showed decreased clopidogrel efficacy in patients with a CYP2C19 reduced-function allele.^{7, 8} The current literature supports an interaction between clopidogrel and certain PPIs, principally omeprazole, rabeprazole, and lansoprazole . While only a small percentage of patients in the above mentioned trials received rabeprazole, those who did appeared to exhibit a similar response to those who received omeprazole. Additionally, the study by Li and colleagues show in vitro inhibition of CYP2C19 via a rabeprazole metabolite. Similarly, the data behind the lansoprazole interaction do not provide a clear answer. Given the availability of alternatives that do not interact, it may be prudent to er on the side of 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.

References

1. Gilard M, Arnaud B, Cornily JC, et al. Influence of omeprazole on the antiplatelet action of clopidogrel associate with aspirin: the randomized, double-blind OCLA (Omeprazole CLopidogrel Aspirin) study. J Am Coll Cardiol. 2008; 51(3): 256-260.
   
   
2. Juurlink DN, Gomes T, Ko DT, et al. A population-based study of the drug interaction between proton pump inhibitors and clopidogrel. CMAJ. 2009 March 31; 180(7): 713-718.
   
   
3. Ho PM, Maddox TM, Wang L, et al. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA. 2009; 301(9): 937-943.
   
   
4. Siller-Matula JM, Spiel AO, Lang IM, et al. Effects of pantoprazole and esomeprazole on platelet inhibition by clopidogrel. Am Hear J. 2009; 157(1): 148.e1-148.e5.
   
   
5. 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.
   
   
6. Small DS, Farid NA, Payne CD, et al. Effects of the proton pump inhibitor lansoprazole on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel. J Clin Pharmacol. 2008; 48(4): 475-484.
   
   
7. Mega JL, Close SL, Wiviott SD, et al. Cytochrome P-450 polymorphisms and response to clopidogrel. N Engl J Med. 2009; 360(4): 354-362.
   
   
8. Simon T, Verstuyft C, Mary-Krause M, et al. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med. 2009; 360(4): 363-375.
   
   
9. Small DS, Farid NA, Li YG, et al. Effect of ranitidine on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel. Curr Med Res Opin. 2008; 24(8): 2251-2257.

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