Reports
Investigating Interaction Between Thienopyridine Antiplatelet Activity and Proton Pump Inhibition
This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.
PHYSICIAN PERSPECTIVE Viewpoint based on presentations from the 58th Annual Scientific Session of the American College of Cardiology
Orlando, Florida / March 29-31, 2009
Reported by:
Robert C. Welsh, MD, FRCPC, FACC
Interventional Cardiologist, Director, Adult Cardiac Catheterization, Co-director, Chest Pain Program, University of Alberta Hospital
Associate Professor of Medicine, University of Alberta, Edmonton, Alberta
The thienopyridine clopidogrel is a potent antiplatelet agent used in combination with ASA to reduce the risk of cardiovascular (CV) events in a variety of populations, such as those with an acute coronary syndrome or those who have received a percutaneous intracoronary stent.1 A prodrug, clopidogrel is converted by the cytochrome P450 (CYP) system in the liver to its active metabolite, which blocks platelet activation by binding to the adenosine diphosphate (ADP) receptor.2 The conversion of the prodrug to the active metabolite is primarily mediated by CYP2C19. Due to the importance of CYP2C19, other drugs that employ this same isoenzyme pose a significant potential risk for drug-drug interactions.
Proton pump inhibitors (PPIs) are effective for the treatment of common acid-related disorders such as gastroesophageal reflux disease (GERD).3 They deserve particular attention for their potential to alter clopidogrel activity not only because they are among the most widely prescribed class of drugs in the world but also because they are often specifically prescribed in patients on dual antiplatelet therapy to reduce risk of gastric bleeding.4 Although most PPIs are largely metabolized in the liver, the dependence on specific CYP isoenzymes varies. Understanding the potential for an interaction is important because a reduction in the antiplatelet activity of clopidogrel may produce an increase in the risk of life-threatening thrombotic events.
The series of experimental and clinical studies evaluating the potential for a clinically significant interaction between PPIs and clopidogrel has generated inconsistent results. The reason for this inconsistency is likely to be attributable to differences between PPIs for their relative dependence on the CYP2C19 isoenzyme. The logical expectation is that PPIs, which compete with clopidogrel through mutual dependence on CYP2C19 for metabolism, diminish clopidogrel’s antiplatelet effect while PPIs that employ alternative CYP isoenzymes do not. Several recently published studies as well as data presented at the most recent scientific sessions of the American College of Cardiology (ACC) appear to confirm these expectations.
PATIENT EVALUATION
One of the most compelling demonstrations of the variable impact of specific PPIs on the antiplatelet effect of clopidogrel was generated by an evaluation of 1000 consecutive patients on clopidogrel treatment.5 All participants had undergone a percutaneous intervention (PCI) for coronary artery disease (CAD) and all were receiving an antithrombotic regimen of clopidogrel 75 mg and ASA. The objective of the study was to compare platelet function in those receiving a concomitant PPI and those not on a PPI. Patients on a PPI were further stratified by the specific agent. Platelet function testing was measured with multiple electrode platelet aggregometry (MEA) after aggregation was induced with ADP expressed as the area under the curve.
Of the 1000 patients evaluated, 268 patients were taking a PPI and 732 were not. Due to practice patterns at the study institution, omeprazole, esomeprazole, and pantoprazole were the only PPIs represented. As a whole, platelet aggregation was greater in those taking PPIs when compared to those not taking PPI, but when the PPIs were stratified, the difference was confined to omeprazole, which is known to be highly dependent on CYP2C19. In this group, the median platelet aggregation score was 295.5 arbitrary units (AU*min) vs. 220.0 AU*min for those not taking a PPI (P=0.001). In contrast, platelet aggregation was slightly but not statistically lower on esomeprazole (209.0 AU*min; P=0.69) and slightly but not statistically higher on pantoprazole (226.0 AU*min; P=0.88) when compared to those not taking a PPI.
METABOLIC PATHWAY KEY
These results are entirely consistent with the pharmacology of these three PPIs as well as much of the current data evaluating the relationship between PPIs and the clinical effects of clopidogrel. Compared to omeprazole, both esomeprazole and pantoprazole are far less dependent on CYP2C19, employing alternative isoenzymes, particularly CYP3A4, for hepatic metabolism. This would be expected to reduce the risk of significant interactions with CYP2C19-dependent agents such as clopidogrel.6
Other platelet function studies have previously associated omeprazole with an attenuation of the antiplatelet effect of clopidogrel. In a double-blind placebo-controlled trial, 124 consecutive patients undergoing coronary artery stent implantation who were receiving clopidogrel 75 mg/day and ASA 75 mg/day were randomized to omeprazole 20 mg or placebo.7 At the end of seven days, platelet function was evaluated with a platelet reactivity index (PRI) generated by a vasodilator-stimulated phosphoprotein phosphorylation assay (VASP). Although platelet function was similar at baseline, it remained almost 30% higher (P<0.0001) in those receiving seven days of omeprazole, therefore demonstrating less antiplatelet effect with dual antiplatelet therapy.
A subsequent study using the same methodology for measuring platelet function was unable to establish a similar effect with either esomeprazole or pantoprazole.8 In this study, PRI was assessed in 300 patients receiving clopidogrel and ASA after PCI. When the 226 patients taking either esomeprazole or pantoprazole were compared to the 74 not taking a PPI, there was no significant difference between either group for PRI or for platelet function assessed with ADP stimulation, which was also performed.
These findings may be important for understanding the inconsistency of evidence for a PPI-clopidogrel interaction when PPIs are examined as a class. In one of the largest of these studies, 8205 patients with an acute coronary syndrome (ACS) discharged on clopidogrel were evaluated retrospectively.9 The odds ratio (OR) of death or a rehospitalization in the PPI group was increased by 25% (OR 1.25; 95% CI, 1.11-1.41) when the 63.9% of patients who were taking both clopidogrel and a PPI at discharge were compared to the 36.1% who were not. Several secondary outcomes, such as risk of a revascularization procedure, also associated a concomitant PPI with increased risk.
Conversely, a study that evaluated prospectively collected data from 535 PCI patients enrolled in the National Heart, Lung, and Blood Institute Dynamic Registry at the University of Pittsburgh found no difference in adverse outcomes between the 138 patients (26%) on concomitant PPIs and the 397 (74%) who were not.10 For many outcomes, including myocardial infarction (MI) (3.7% vs. 4.2%; P=0.83), coronary artery bypass grafting (CABG) (3.1% vs. 4.1%; P=0.53), death (3.0% vs. 5.9%; P=0.18) and death plus MI (6.7% vs. 9.6%), the event rates were lower although not significantly different in those taking a PPI.
Based on the relative differences in the potential for drug interactions among specific PPIs, the representation of specific PPIs within these study populations may provide an explanation for the difference in results. Class effect cannot be assumed, making stratification according to specific PPIs essential for definitive risk assessment.
NOT A QUESTION OF CLASS
A nested case control study conducted in Canada illustrates the potential importance of PPI stratification.11 From a database of 13,636 patients over the age of 66 prescribed clopidogrel over a five-year study period, 734 cases of readmission for an acute MI within 90 days of discharge were identified. When those who were taking a PPI were compared to those who were not, the risk of readmission was 27% higher among PPI users (OR 1.27; 95% CI, 1.03-1.57). However, when patients taking pantoprazole, a PPI previously identified as posing a low risk of a clopidogrel interaction, were compared to non-PPI users, there was no significant difference (OR 1.02; 95% CI, 0.70-1.47). Conversely, if pantoprazole was excluded, the relative risk of a recurrent MI on a PPI was even higher than that produced by PPIs as a class (OR 1.40; 95% CI, 1.10-1.77).
Based on a more detailed analysis of these data, the authors estimated that if all clopidogrel patients were prescribed a PPI metabolized largely by CYP2C19, up to 14% of readmissions within the first 90 days would be caused by a PPI interaction with clopidogrel. The data suggest no increased risk for a PPI that is not metabolized on this pathway.
RISK-BENEFIT OF TWO CRITICAL, SEPARATE TREATMENT STRATEGIES
Avoiding PPI therapy altogether in patients who are candidates for antiplatelet agents may not be a viable option. In addition to the substantial number of patients with acid-related disease who require a PPI to maintain an adequate quality of life, PPIs provide important protection against life-threatening gastrointestinal (GI) hemorrhage. In doses as low as 75 mg/day, ASA can double the risk of GI bleeding, a complication that increases in prevalence with age.12 Clopidogrel can be offered without ASA in patients at very high risk of a GI bleed but at the cost of diminished protection for CV events. Nor is clopidogrel devoid of risk for GI bleeds. In a study that compared a strategy of ASA plus esomeprazole to clopidogrel alone in patients with a previous history of ulcer bleeding on ASA, the cumulative risk of recurrent bleeding over one year was 8.6% in the group receiving clopidogrel alone vs. 0.7% (P=0.001) in the group that received ASA with esomeprazole.13
Definitive, prospective randomized trials to compare PPIs for relative risk of drug interactions with clopidogrel are unlikely, but the preponderance of evidence from population-based studies as well as studies of platelet activity suggest that the clopidogrel interaction is not a class effect. In a relatively consistent series of studies those agents that are not dependent on the CYP2C19 pathway for metabolism do not appear to pose a risk of interaction. Both esomeprazole and pantoprazole appear to share this relative safety. Omeprazole has been most closely associated with increased relative risk. In individuals who may benefit from PPI therapy either for control of an upper GI disease or for gastroprotection against hemorrhage, PPI selection should be included in the context of individual risk management.
SUMMARY
Concern about the potential for PPI therapy to inhibit the antiplatelet effects of clopidogrel through a drug interaction has been based on an inconsistent body of largely retrospective data associating exposure to PPIs during clopidogrel therapy with an increased risk of a CV event. The inconsistency of this data is likely to be explained by an unequal risk for an interaction within the PPI class. Available data suggest that the risk of interaction may be entirely confined to those PPIs dependent on hepatic metabolism through the CYP2C19 pathway, which is important to activation of clopidogrel. PPIs that employ additional isoenzymes for metabolism, such as esomeprazole and pantoprazole, may not pose a significant risk of an interaction. The relative potential for any PPI to sufficiently inhibit the antiplatelet effects of clopidogrel to increase the risk of a CV event has not been definitively compared in a well-controlled prospective study, but the current data suggest that these agents are not interchangeable in individuals who require antithrombotic treatment that includes clopidogrel.
References
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2. Savi et al. Importance of hepatic metabolism in the anti-aggregating activity of the thienopyridine clopidogrel. Biochem Pharmacol 1992;44:527-32.
3. Richardson P, Hawkey C, Stack W. Proton pump inhibitors—pharmacology and rationale for use in gastrointestinal disorders. Drugs 1998;56:307-35.
4. Ng et al. Upper gastrointestinal bleeding in patients with aspirin and clopidogrel co-therapy. Digestion 2008;77:173-7.
5. Sibbing et al. Impact of proton pump inhibitors on platelet response to clopidogrel treatment. J Am Coll Cardiol 2009;53(suppl A):A67, Abstract 2515-736.
6. Li et al. Comparison of inhibitory effects of the proton pump-inhibiting drugs omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole on human cytochrome P450 activities. Drug Metabol Dispos 2004;32:821-7.
7. Gilard et al. Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin: the randomized, double-blind OCLA (Omeprazole Clopidogrel Aspiring) study. J Am Coll Cardiol 2008;51:256-60.
8. Siller-Matula et al. Effects of pantoprazole and esomeprazole on platelet inhibition by clopidogrel. Am Heart J 2009;157:148.e1-148.e5.
9. Ho et al. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pup inhibitors following acute coronary syndrome. JAMA 2009;301:937-44.
10. Ramirez et al. Proton pump inhibitor and clopidogrel combination is not associated with adverse clinical outcomes after PCI: the NHLBI Dynamic Registry. J Am Coll Cardiol 2009;53(suppl A):A27, Abstract 2903-7.
11. Juurlink et al. A population-based study of the drug interaction between proton pump inhibitors and clopidogrel. CMAJ 2009;180 [Epub January 28, 2009].
12. Weil et al. Prophylactic aspirin and risk of peptic ulcer bleeding. Br Med J 1995;310:827-30.
13. Chan et al. Clopidogrel versus aspirin and esomeprazole to prevent recurrent ulcer bleeding. N Engl J Med 2005;352(3):238-44.