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C L I N I C A L F E AT U R E S
Proton-Pump Inhibitors in Patients Requiring Antiplatelet Therapy: New FDA Labeling
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DOI: 10.3810/pgm.2014.05.2772
David A. Johnson, MD, MACG, FASGE, FACP 1 Robert Chilton, DO, FACC 2 Harley R. Liker, MD 3 1 Chief of Gastroenterology, Professor of Medicine, Division of Gastroenterology, Eastern Virginia Medical School, Norfolk, VA; 2 Associate Professor, Department of Medicine, Division of Cardiology, University of Texas Health Science Center, San Antonio, TX; 3Assistant Clinical Professor, David Geffen School of Medicine, University of California, Los Angeles, CA
Abstract: Proton-pump inhibitors (PPIs) are recommended for patients who require antiplatelet therapy and have a history of upper gastrointestinal bleeding. Proton-pump inhibitors should also be considered for patients receiving antiplatelet therapy who have other risk factors for gastrointestinal bleeding, including use of aspirin. Thus, evidence of pharmacokinetic and pharmacodynamic interactions between PPIs and consequent impaired effectiveness of the antiplatelet agent clopidogrel has caused concern. Here, we discuss comparative studies suggesting that the extent to which a PPI reduces exposure to the active metabolite of clopidogrel and attenuates its antithrombotic effect differs among PPIs. Although a clinically meaningful effect of the interaction between PPIs and clopidogrel on cardiovascular outcomes has not been established, these studies provided the basis for recent changes in US Food and Drug Administration (FDA) labeling for several PPIs and clopidogrel. New labeling suggests that PPI use among patients taking clopidogrel be limited to pantoprazole, rabeprazole, lansoprazole, or dexlansoprazole. Because comparative studies indicate that omeprazole and esomeprazole have a greater effect on the CYP2C19-mediated conversion of clopidogrel to its active metabolite and, consequently, clopidogrel’s effect on platelet reactivity, FDA labeling recommends avoiding omeprazole and esomeprazole in patients taking clopidogrel. Even a 12-hour separation of dosing does not appear to prevent drug interactions between omeprazole and clopidogrel. Keywords: proton-pump inhibitors; platelet aggregation inhibitors; antiplatelet therapy; aspirin
Introduction
Correspondence: David A. Johnson, MD, MACG, FASGE, FACP, Eastern Virginia Medical School, Norfolk, VA 23529. Tel: 757-466-0165 Fax: 757-466-9082 E-mail: [email protected]
Guidelines published by the American College of Cardiology Foundation (ACCF) and American Heart Association (AHA) have established dual antiplatelet therapy as the cornerstone in the management of thrombotic risk in patients undergoing coronary stenting and those with acute coronary syndrome (ACS) with or without stent implantation.1,2 The addition of clopidogrel to aspirin reduced the risk of cardiovascular events by approximately 20% versus aspirin alone when administered to patients for 3 to 12 months following non–ST-elevation ACS.3 Unfortunately, the benefits of a dual antiplatelet regimen are accompanied by an increased risk for bleeding events, including gastrointestinal (GI) bleeding.3–5 The risk of major GI bleeding events was doubled in randomized controlled trials comparing the dual regimen (1.1% to 1.3%) with aspirin alone (0.5% to 0.7%).3,5 Although not recommended for routine prophylaxis in ACCF/ AHA guidelines,1 concomitant use of proton-pump inhibitors (PPIs) attenuates the risk for GI bleeding associate with clopidogrel use6–8 and may prevent premature discontinuation of antiplatelet therapy.9 However, in November 2009, the US Food and Drug Administration (FDA) warned that the PPI omeprazole may reduce the anticlotting effect of the antiplatelet agent clopidogrel by approximately half and s uggested that neither omeprazole nor esomeprazole should be used with clopidogrel.10 Since then,
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many published reports have evaluated the pharmacokinetic, pharmacodynamic, and clinical effects of coadministration of PPIs with clopidogrel. This article reviews evidence for risks and benefits of PPI use in patients who take clopidogrel and provides practical guidance for the primary care physician in the management of patients who require gastroprotection in the setting of antiplatelet therapy.
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The Evidence Dual Antiplatelet Therapy Is Widely Prescribed for Secondary Prevention
In the ACCF/AHA guidelines, the use of aspirin is recommended indefinitely in patients with unstable angina (UA), non–ST-elevation myocardial infarction (NSTEMI),1 or ST-elevation myocardial infarction (STEMI).2 The guidelines further state that patients with UA/NSTEMI treated medically or undergoing percutaneous coronary intervention (PCI) with a bare metal stent should receive an additional antiplatelet agent (eg, clopidogrel) for # 12 months, and those receiving a drug-eluting stent should take an additional antiplatelet agent for $ 12 months1; STEMI patients undergoing primary PCI with placement of any stent should be prescribed an antiplatelet agent in addition to aspirin for $ 12 months.2 Clopidogrel inhibits platelet activation via binding of its active metabolite to the P2Y12 class of adenosine diphosphate (ADP) receptors.11 It is the most commonly prescribed antiplatelet companion to aspirin and is indicated for reduction in risk of cardiovascular events and death in patients with non–ST-segment elevation ACS (ie, UA or NSTEMI) or STEMI.11 Clopidogrel has recently become available in lower-cost generic forms and may be used alone in patients with hypersensitivity or intolerance to aspirin.4
Many Patients Taking Aspirin or Clopidogrel Require Gastroprotection
Although most physicians are aware of the tendency of aspirin to increase the risk of gastric injury, they may not realize that clopidogrel has a similar effect, even when used alone. A prospective, randomized, double-blind trial comparing aspirin plus esomeprazole (20 mg twice daily) against clopidogrel alone in patients who were Helicobacter pylori–negative demonstrated a significantly higher proportion of recurrent ulcer bleeding in the clopidogrel arm (8.6%) versus the aspirin-plus-esomeprazole arm (0.7%) during the 12-month study.12 A subsequent randomized trial with very similar design returned comparable results. Rates of recurrent ulcer complications were 13.6% in the clopidogrel group versus 0% in the aspirin-plus-esomeprazole (20 mg daily) 240
group.13 These data suggest that use of clopidogrel alone as an alternative to aspirin in patients with major GI intolerance to aspirin is not a safe strategy and support cotherapy with once-daily PPI in patients who experience aspirin intolerance. Observational studies have also suggested that PPI cotherapy is beneficial in reducing the risk of upper GI bleeding with clopidogrel monotherapy.7 It remains unclear whether clopidogrel exerts an independent injurious effect on the GI mucosa or whether it merely induces bleeding in already damaged mucosa via its antiplatelet effects. Platelet aggregation, critical for promoting initial stages of wound healing in cases of erosion or mucosal disruption, is accompanied by local induction of both epidermal growth factor and angiogenesis factor release, both of which are integral for wound healing. In the presence of gastric acid and the antiplatelet effects of clopidogrel, mucosal disruptions can progress to more formidable injury, including ulcers and related bleeding (Figure 1).14–16 Thus, gastroprotection needs to be considered in patients receiving aspirin, clopidogrel, or both. An ACCF/American College of Gastroenterology (ACG)/AHA consensus4 recommended the use of PPIs in patients who require antiplatelet therapy and have either a history of upper GI bleeding or multiple other risk factors for GI bleeding. This recommendation has been widely implemented. Recent data from a large representative retail pharmacy network in the United States suggested that nearly 25% of patients taking clopidogrel were also taking a prescription PPI.17
PPIs Compete With Clopidogrel for CYP2C19
Proton-pump inhibitors are converted to their active metabolites in the gastric parietal cell and undergo hepatic metabolism via cytochrome P450 (CYP) enzymes, including CYP2C19.18–23 Clopidogrel is a prodrug that also relies on the CYP system, particularly CYP2C19, to be converted to its active metabolite.11 Patients who are heterozygous or Figure 1. Mechanism of clopidogrel-induced ulceration.14–16
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Proton-Pump Inhibitor and Antiplatelet Therapy
homozygous for CYP2C19 loss-of-function alleles form less of the active metabolite of clopidogrel, demonstrate reduced antiplatelet effects, and exhibit higher cardiovascular event rates at recommended doses than do patients with normal CYP2C19 function.24–26 Because PPIs are believed to reduce the antiplatelet effects of clopidogrel via competition for CYP2C19,4 the risk for a clinically significant interaction may be increased in patients with reduced CYP2C19 function. Although the pharmacodynamic impact of PPIs on the antiplatelet effects of clopidogrel have not been compared in CYP2C19 extensive, intermediate, and poor metabolizer phenotypes, an analysis of patients with a single reducedfunction CYP2C19 allele who were assigned to clopidogrel in the TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet inhibitioN with prasugrel-Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38) study showed no significant differences in cardiovascular event rates among patients taking a PPI versus patients not taking a PPI.27
PPIs Interact With Clopidogrel to Different Degrees
Comparative studies suggest that the degree of interaction between a PPI and clopidogrel depends on the PPI. A 2-period crossover study compared the effects of coadministration of dexlansoprazole 60 mg, lansoprazole 30 mg, esomeprazole 40 mg, or omeprazole 80 mg (positive control to maximize potential interaction and demonstrate assay sensitivity) on the pharmacokinetics and pharmacodynamics of clopidogrel in 160 healthy CYP2C19 extensive metabolizers.28 Exposure to the active metabolite of clopidogrel was reduced by 8%, 13%, 16%, and 30%, respectively. Increases in the platelet reactivity index (PRI) were greater than the prespecified no-effect limit when clopidogrel was administered with omeprazole (positive control) or esomeprazole, but not with lansoprazole or dexlansoprazole. Dexlansoprazole was the only PPI that did not significantly increase ADP-induced maximal platelet aggregation (MPA) measured by light transmission aggregometry. The Evaluation of the Influence of Statins and Proton Pump Inhibitors on Clopidogrel Antiplatelet Effects (SPICE) study29 carried out a similar comparison in 302 patients with post-PCI who were discharged while continuing to receive clopidogrel and also received statin therapy for 30 days. Patients were randomized to 1 of 4 gastroprotective agents: esomeprazole, pantoprazole, omeprazole, or the H2-blocker ranitidine for 60 days. Esomeprazole had the largest effect on platelet reactivity, with . 35% and . 50% of patients
demonstrating a . 10% change in MPA and PRI from baseline, respectively. Omeprazole showed significant increases in PRI and non-significant increases in MPA. Neither panto prazole nor ranitidine significantly affected either measure of platelet reactivity. The results of these and other studies led to recent changes in FDA labeling for esomeprazole,19 dexlansoprazole,18 rabeprazole,23 and clopidogrel.11 The new labeling cautions against the use of omeprazole or esomeprazole with clopidogrel and suggests that dexlansoprazole, lansoprazole, and pantoprazole have less effect on the antiplatelet a ctivity of clopidogrel (Table 1).11 Still, data collected between January 1 and March 31, 2012, from . 18 000 retail pharmacies (representing ∼40% of US retail prescriptions) showed that, among patients taking clopidogrel and a prescription PPI, 40% were taking omeprazole and 17% were taking esomeprazole (Figure 2).17
Whether the PPI–Clopidogrel Interaction Increases Thrombotic Risk Is Unknown
The existence of a pharmacokinetic and pharmacodynamic interaction between clopidogrel and PPIs, particularly omeprazole and esomeprazole, is indisputable. However, the clinical significance of this interaction has been a topic of great debate. Retrospective and secondary analyses evaluating clinical outcomes associated with the interaction between clopidogrel and PPIs have yielded inconsistent results and have been summarized previously.4,30,31 Meta-analyses are limited by significant heterogeneity and have done little to clarify the issue.32,33 The only prospective, randomized study to evaluate the clinical implication of coadministration of PPIs and clopidogrel, Clopidogrel and the Optimization of Gastrointestinal Events (COGENT), was discontinued Table 1. FDA Labeling Pertinent to Coadministration of Proton-Pump Inhibitors and Antiplatelet Agents Yes PPIs: safe to use with clopidogrel? Dexlansoprazole (Dexilant)18 Esomeprazole (Nexium)19 Lansoprazole (Prevacid)20 Omeprazole (Prilosec)21 Pantoprazole (Protonix)22 Rabeprazole (AcipHex)23 Antiplatelet agents: safe to use with PPI? Clopidogrel (Plavix)11 Prasugrel (Effient)37 Ticagrelor (Brilinta)38
No
Other
X X X X X X
Avoid omeprazole or esomeprazole X X
Abbreviations: FDA, US Food and Drug Administration; PPI, proton-pump inhibitor.
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Figure 2. Distribution of PPI type among patients co-prescribed clopidogrel and a prescription PPI.17
prematurely owing to lack of funding. The COGENT study randomized patients taking dual antiplatelet therapy (clopidogrel and aspirin) to omeprazole or placebo.8 The primary cardiovascular endpoint was a composite of death from cardiovascular causes, nonfatal myocardial infarction, revascularization, or stroke. Of 3761 patients included in the final analysis, 109 had a cardiovascular event. Event rates were comparable between the omeprazole (4.9%) and placebo (5.7%) groups. No prospective study has compared PPIs with respect to cardiovascular event rates in patients receiving clopidogrel.
Strategies to Reduce the Risk for a Clinically Significant Drug–Drug Interaction Between PPI and Clopidogrel
Several clinical scenarios may confront the primary care provider with a decision related to PPI and clopidogrel coadministration: 1) A patient taking clopidogrel is also taking a prescription or over-the-counter PPI that is not consistent with FDA labeling; 2) a patient taking a PPI develops a cardiovascular condition requiring long-term clopidogrel
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therapy; and 3) a patient taking clopidogrel develops characteristics that increase the risk of GI bleeding. The ACCF/ACG/AHA 2010 Expert Consensus on the Concomitant Use of Proton-Pump Inhibitors and Thienopyridines defines risk characteristics for GI bleeding as a history of GI bleeding; advanced age; concurrent use of anticoagulants, steroids, or non-steroidal anti-inflammatory drugs; and H. pylori infection.4 A suggested algorithm for GI risk stratification and PPI selection in patients taking clopidogrel based on the ACCF/ACG/AHA consensus and current FDA labeling is provided in Figure 3. Several strategies to reduce the potential for a clinically significant drug–drug interaction are discussed in the following section.
Use FDA Labeling to Guide PPI Choice
Based on comparative pharmacokinetic and pharmacodynamics studies,28,29,34 FDA labeling now recommends against co-administration of omeprazole or esomeprazole with clopidogrel.11,19,21 Table 1 summarizes current FDA labeling regarding co-administration of individual PPIs with clopidogrel or other antiplatelet agents. It is unclear whether the results of a recent randomized, placebo-controlled study showing that pantoprazole significantly reduces the
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Proton-Pump Inhibitor and Antiplatelet Therapy
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Figure 3. Suggested algorithm for use of PPI in patients taking clopidogrel.
Abbreviations: GI, gastrointestinal; NSAID, nonsteroidal anti-inflammatory drug; PPI, proton-pump inhibitor.
antiplatelet effect of clopidogrel will cause a change in pantoprazole labeling. From a practical standpoint, it should be noted that step edits may not have been updated to reflect the new labeling, and generic omeprazole remains the preferred PPI in most step-therapy programs. A physician-initiated appeal may be required for insurance coverage of an alternate PPI. This may be particularly relevant if the formulary does not offer FDA-approved PPI alternatives for patients receiving concomitant clopidogrel. 35
H2-Receptor Antagonists May Be a Suitable Alternative to PPIs
The H2-receptor antagonists (H2RAs) suppress gastric acid production, and there are no prohibitions on their use with clopidogrel. However, clinical data suggest that H2RAs reduce the risk for upper GI bleeding to a lesser extent than do PPIs in patients requiring antiplatelet therapy.7,36 The ACCF/ACG/AHA Consensus states that “H2RAs may be a reasonable alternative in patients at lower risk for GI bleeding, and in those who do not require PPI for refractory gastroesophageal reflux disease.”4
Next-Generation Antiplatelet Agents May Be Substituted for Clopidogrel
Prasugrel is a new thienopyridine prodrug that is hydrolyzed in the intestine to a thiolactone and then converted to the active metabolite via a one-step process catalyzed
predominantly by CYP3A4 and CYP2B6. Prasugrel is indicated for the reduction of thrombotic cardiovascular events (including stent thrombosis) in patients with ACS who are to be managed with PCI.37 Ticagrelor is a non-thienopyridine adenosine triphosphate analogue indicated to reduce the rate of thrombotic cardiovascular events in patients with ACS treated invasively or medically. Ticagrelor is metabolized by CYP3A4 and CYP3A5.38 Because of their lack of dependence on the CYP2C19 enzyme, prasugrel and ticagrelor can be used with any PPI. Although these agents gained FDA approval by demonstrating superiority over clopidogrel for prevention of some cardiovascular outcomes,39,40 they are more costly than generic clopidogrel, which is a substantial barrier to long-term use. Furthermore, prasugrel is contraindicated in patients with a history of transient ischemic attack or stroke.37
Temporal Separation of Dosing Is Not a Solution
If one considers the half-lives of PPIs and clopidogrel (all , 2 hours), it would appear that temporal separation of their administration would obviate any drug interaction. However, a study in healthy volunteers found that administration of clopidogrel and omeprazole 12 hours apart significantly decreased exposure to the active metabolite of clopidogrel (−47%), and significantly increased ADPinduced MPA (+5.6%) and PRI (+27%) versus administration of clopidogrel alone.41 These findings may be explained by the time-dependent, irreversible nature of CYP2C19 inhibition by omeprazole established in vitro.42 The FDA labeling for clopidogrel and omeprazole specifies that the interaction between these 2 agents is not mitigated by administration 12 hours apart.11,21
Conclusion
Many patients taking clopidogrel, with or without aspirin, require gastroprotective therapy to protect against GI bleeding. The PPIs are the most effective anti-secretory agents in these patients. However, a significant pharmacokinetic and pharmacodynamic interaction, believed to involve competition for the CYP2C19 enzyme, has been demonstrated between some PPIs and clopidogrel. Although studies evaluating the potential effects of this interaction on thrombotic risk have yielded conflicting results, the FDA has taken steps to ensure that PPIs co-prescribed with clopidogrel are limited to pantoprazole, rabeprazole, lansoprazole, and d exlansoprazole. Compared with omeprazole or esomeprazole, these PPIs are less likely to reduce exposure to the active metabolite of clopidogrel
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and attenuate antiplatelet activity of clopidogrel. Beyond the choice of PPI, strategies to avoid the PPI-clopidogrel interaction include use of an H2RA instead of PPI or the use of ticagrelor or prasugrel instead of clopidogrel. A 12-hour separation between omeprazole and clopidogrel dosing does not prevent the interaction between these agents. In the future, platelet function testing or pharmacogenomic testing to identify patients with CYP2C19 variants may allow more individualized management of patients requiring gastroprotection in the setting of antiplatelet therapy.
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Acknowledgments
Medical writing support was provided by Melinda Ramsey, PhD, from Complete Healthcare Communications, Inc., with funding from Takeda Pharmaceuticals. All authors participated in each draft. No original data are included in this review article. Takeda Pharmaceutical Company provided funding.
Conflict of Interest Statement
David A. Johnson, MD, MACG, FASGE, FACP, is a consultant for Takeda Pharmaceuticals, Pfizer Inc, Janssen/Centacor, Abbvie, Medigus, AstraZeneca, MedScape/WebMD, CRH Medical, and Epigenomics; he is also a member of the speakers bureau for Takeda Pharmaceuticals and AstraZeneca. Robert Chilton, DO, FACC, is a consultant, member of the speakers bureau, and a member of the advisory board for Takeda Pharmaceuticals; he is a member of the research advisory board for MSD, Boston Scientific, and Eli-Lilly. Harley R. Liker, MD, is a consultant for Roll Global.
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Proton-Pump Inhibitor and Antiplatelet Therapy 27. O’Donoghue ML, Braunwald E, Antman EM, et al. Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: an analysis of two randomised trials. Lancet. 2009;374(9694):989–997. 28. Frelinger AL 3rd, Lee RD, Mulford DJ, et al. A randomized, 2-period, crossover design study to assess the effects of dexlansoprazole, lansoprazole, esomeprazole, and omeprazole on the steady-state pharmacokinetics and pharmacodynamics of clopidogrel in healthy volunteers. J Am Coll Cardiol. 2012;59(14):1304–1311. 29. Déry JP. SPICE: a prospective, randomized trial of four antacid strategies in patients receiving clopidogrel. Presented at the Transcatheter Cardiovascular Therapeutics conference; November 9, 2011; San Francisco, CA. 30. Moukarbel GV, Bhatt DL. Antiplatelet therapy and proton pump inhibition: Clinician update. Circulation. 2012;125(2):375–380. 31. Depta JP, Bhatt DL. Antiplatelet therapy and proton pump inhibition: Cause for concern? Curr Opin Cardiol. 2012;27(6):642–650. 32. Kwok CS, Loke YK. Meta-analysis: The effects of proton pump inhibitors on cardiovascular events and mortality in patients receiving clopidogrel. Aliment Pharmacol Ther. 2010;31(8):810–823. 33. Siller-Matula JM, Jilma B, Schror K, Christ G, Huber K. Effect of proton pump inhibitors on clinical outcome in patients treated with clopidogrel: A systematic review and meta-analysis. J Thromb Haemost. 2010;8(12):2624–2641. 34. Andersson T, Nagy P, Niazi M, Nylander S, Wallentin L. Impact of omeprazole (OME), esomeprazole (ESO) +/− acetylsalicylic acid (ASA) and lansoprazole (LAN) on the pharmacodynamics (PD) and pharma cokinetics (PK) of clopidogrel in healthy volunteers. Eur Heart J. 2012;33(abstr suppl):343.
35. Parri MS, Gianetti J, Dushpanova A, et al. Pantoprazole significantly interferes with antiplatelet effect of clopidogrel: Results of a pilot randomized trial. Int J Cardiol. 2013;167(5):2177–2181. 36. Ng FH, Wong SY, Lam KF, et al. Famotidine is inferior to pantoprazole in preventing recurrence of aspirin-related peptic ulcers or erosions. Gastroenterology. 2010;138(1):82–88. 37. Effient (prasugrel). Full prescribing information. Indianapolis, IN: Eli Lilly and Company; 2012. 38. Brilinta (ticagrelor). Full prescribing information. Wilmington, DE: AstraZeneca LP; 2011. 39. Antman EM, Wiviott SD, Murphy SA, et al. Early and late benefits of prasugrel in patients with acute coronary syndromes undergoing percutaneous coronary intervention: A TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis in Myocardial Infarction) analysis. J Am Coll Cardiol. 2008;51(21):2028–2033. 40. Cannon CP, Harrington RA, James S, et al. Comparison of ticagrelor with clopidogrel in patients with a planned invasive strategy for acute coronary syndromes (PLATO): A randomised double-blind study. Lancet. 2010;375(9711):283–293. 41. Angiolillo DJ, Gibson CM, Cheng S, et al. Differential effects of omeprazole and pantoprazole on the pharmacodynamics and pharmacokinetics of clopidogrel in healthy subjects: Randomized, placebo-controlled, crossover comparison studies. Clin Pharmacol Ther. 2011;89(1):65–74. 42. Paris B, Yerino P, Ogilvie B, Parkinson A. The proton pump inhibitors (PPIs) omeprazole and rabeprazole but not lansoprazole and pantoprazole are in vitro time-dependent inhibitors of CYP2C19. Drug Metab Rev. 2008;40:89–90.
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C L I N I C A L F E AT U R E S
Proton-Pump Inhibitors in Patients Requiring Antiplatelet Therapy: New FDA Labeling
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DOI: 10.3810/pgm.2014.05.2772
David A. Johnson, MD, MACG, FASGE, FACP 1 Robert Chilton, DO, FACC 2 Harley R. Liker, MD 3 1 Chief of Gastroenterology, Professor of Medicine, Division of Gastroenterology, Eastern Virginia Medical School, Norfolk, VA; 2 Associate Professor, Department of Medicine, Division of Cardiology, University of Texas Health Science Center, San Antonio, TX; 3Assistant Clinical Professor, David Geffen School of Medicine, University of California, Los Angeles, CA
Abstract: Proton-pump inhibitors (PPIs) are recommended for patients who require antiplatelet therapy and have a history of upper gastrointestinal bleeding. Proton-pump inhibitors should also be considered for patients receiving antiplatelet therapy who have other risk factors for gastrointestinal bleeding, including use of aspirin. Thus, evidence of pharmacokinetic and pharmacodynamic interactions between PPIs and consequent impaired effectiveness of the antiplatelet agent clopidogrel has caused concern. Here, we discuss comparative studies suggesting that the extent to which a PPI reduces exposure to the active metabolite of clopidogrel and attenuates its antithrombotic effect differs among PPIs. Although a clinically meaningful effect of the interaction between PPIs and clopidogrel on cardiovascular outcomes has not been established, these studies provided the basis for recent changes in US Food and Drug Administration (FDA) labeling for several PPIs and clopidogrel. New labeling suggests that PPI use among patients taking clopidogrel be limited to pantoprazole, rabeprazole, lansoprazole, or dexlansoprazole. Because comparative studies indicate that omeprazole and esomeprazole have a greater effect on the CYP2C19-mediated conversion of clopidogrel to its active metabolite and, consequently, clopidogrel’s effect on platelet reactivity, FDA labeling recommends avoiding omeprazole and esomeprazole in patients taking clopidogrel. Even a 12-hour separation of dosing does not appear to prevent drug interactions between omeprazole and clopidogrel. Keywords: proton-pump inhibitors; platelet aggregation inhibitors; antiplatelet therapy; aspirin
Introduction
Correspondence: David A. Johnson, MD, MACG, FASGE, FACP, Eastern Virginia Medical School, Norfolk, VA 23529. Tel: 757-466-0165 Fax: 757-466-9082 E-mail: [email protected]
Guidelines published by the American College of Cardiology Foundation (ACCF) and American Heart Association (AHA) have established dual antiplatelet therapy as the cornerstone in the management of thrombotic risk in patients undergoing coronary stenting and those with acute coronary syndrome (ACS) with or without stent implantation.1,2 The addition of clopidogrel to aspirin reduced the risk of cardiovascular events by approximately 20% versus aspirin alone when administered to patients for 3 to 12 months following non–ST-elevation ACS.3 Unfortunately, the benefits of a dual antiplatelet regimen are accompanied by an increased risk for bleeding events, including gastrointestinal (GI) bleeding.3–5 The risk of major GI bleeding events was doubled in randomized controlled trials comparing the dual regimen (1.1% to 1.3%) with aspirin alone (0.5% to 0.7%).3,5 Although not recommended for routine prophylaxis in ACCF/ AHA guidelines,1 concomitant use of proton-pump inhibitors (PPIs) attenuates the risk for GI bleeding associate with clopidogrel use6–8 and may prevent premature discontinuation of antiplatelet therapy.9 However, in November 2009, the US Food and Drug Administration (FDA) warned that the PPI omeprazole may reduce the anticlotting effect of the antiplatelet agent clopidogrel by approximately half and s uggested that neither omeprazole nor esomeprazole should be used with clopidogrel.10 Since then,
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many published reports have evaluated the pharmacokinetic, pharmacodynamic, and clinical effects of coadministration of PPIs with clopidogrel. This article reviews evidence for risks and benefits of PPI use in patients who take clopidogrel and provides practical guidance for the primary care physician in the management of patients who require gastroprotection in the setting of antiplatelet therapy.
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The Evidence Dual Antiplatelet Therapy Is Widely Prescribed for Secondary Prevention
In the ACCF/AHA guidelines, the use of aspirin is recommended indefinitely in patients with unstable angina (UA), non–ST-elevation myocardial infarction (NSTEMI),1 or ST-elevation myocardial infarction (STEMI).2 The guidelines further state that patients with UA/NSTEMI treated medically or undergoing percutaneous coronary intervention (PCI) with a bare metal stent should receive an additional antiplatelet agent (eg, clopidogrel) for # 12 months, and those receiving a drug-eluting stent should take an additional antiplatelet agent for $ 12 months1; STEMI patients undergoing primary PCI with placement of any stent should be prescribed an antiplatelet agent in addition to aspirin for $ 12 months.2 Clopidogrel inhibits platelet activation via binding of its active metabolite to the P2Y12 class of adenosine diphosphate (ADP) receptors.11 It is the most commonly prescribed antiplatelet companion to aspirin and is indicated for reduction in risk of cardiovascular events and death in patients with non–ST-segment elevation ACS (ie, UA or NSTEMI) or STEMI.11 Clopidogrel has recently become available in lower-cost generic forms and may be used alone in patients with hypersensitivity or intolerance to aspirin.4
Many Patients Taking Aspirin or Clopidogrel Require Gastroprotection
Although most physicians are aware of the tendency of aspirin to increase the risk of gastric injury, they may not realize that clopidogrel has a similar effect, even when used alone. A prospective, randomized, double-blind trial comparing aspirin plus esomeprazole (20 mg twice daily) against clopidogrel alone in patients who were Helicobacter pylori–negative demonstrated a significantly higher proportion of recurrent ulcer bleeding in the clopidogrel arm (8.6%) versus the aspirin-plus-esomeprazole arm (0.7%) during the 12-month study.12 A subsequent randomized trial with very similar design returned comparable results. Rates of recurrent ulcer complications were 13.6% in the clopidogrel group versus 0% in the aspirin-plus-esomeprazole (20 mg daily) 240
group.13 These data suggest that use of clopidogrel alone as an alternative to aspirin in patients with major GI intolerance to aspirin is not a safe strategy and support cotherapy with once-daily PPI in patients who experience aspirin intolerance. Observational studies have also suggested that PPI cotherapy is beneficial in reducing the risk of upper GI bleeding with clopidogrel monotherapy.7 It remains unclear whether clopidogrel exerts an independent injurious effect on the GI mucosa or whether it merely induces bleeding in already damaged mucosa via its antiplatelet effects. Platelet aggregation, critical for promoting initial stages of wound healing in cases of erosion or mucosal disruption, is accompanied by local induction of both epidermal growth factor and angiogenesis factor release, both of which are integral for wound healing. In the presence of gastric acid and the antiplatelet effects of clopidogrel, mucosal disruptions can progress to more formidable injury, including ulcers and related bleeding (Figure 1).14–16 Thus, gastroprotection needs to be considered in patients receiving aspirin, clopidogrel, or both. An ACCF/American College of Gastroenterology (ACG)/AHA consensus4 recommended the use of PPIs in patients who require antiplatelet therapy and have either a history of upper GI bleeding or multiple other risk factors for GI bleeding. This recommendation has been widely implemented. Recent data from a large representative retail pharmacy network in the United States suggested that nearly 25% of patients taking clopidogrel were also taking a prescription PPI.17
PPIs Compete With Clopidogrel for CYP2C19
Proton-pump inhibitors are converted to their active metabolites in the gastric parietal cell and undergo hepatic metabolism via cytochrome P450 (CYP) enzymes, including CYP2C19.18–23 Clopidogrel is a prodrug that also relies on the CYP system, particularly CYP2C19, to be converted to its active metabolite.11 Patients who are heterozygous or Figure 1. Mechanism of clopidogrel-induced ulceration.14–16
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Proton-Pump Inhibitor and Antiplatelet Therapy
homozygous for CYP2C19 loss-of-function alleles form less of the active metabolite of clopidogrel, demonstrate reduced antiplatelet effects, and exhibit higher cardiovascular event rates at recommended doses than do patients with normal CYP2C19 function.24–26 Because PPIs are believed to reduce the antiplatelet effects of clopidogrel via competition for CYP2C19,4 the risk for a clinically significant interaction may be increased in patients with reduced CYP2C19 function. Although the pharmacodynamic impact of PPIs on the antiplatelet effects of clopidogrel have not been compared in CYP2C19 extensive, intermediate, and poor metabolizer phenotypes, an analysis of patients with a single reducedfunction CYP2C19 allele who were assigned to clopidogrel in the TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet inhibitioN with prasugrel-Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38) study showed no significant differences in cardiovascular event rates among patients taking a PPI versus patients not taking a PPI.27
PPIs Interact With Clopidogrel to Different Degrees
Comparative studies suggest that the degree of interaction between a PPI and clopidogrel depends on the PPI. A 2-period crossover study compared the effects of coadministration of dexlansoprazole 60 mg, lansoprazole 30 mg, esomeprazole 40 mg, or omeprazole 80 mg (positive control to maximize potential interaction and demonstrate assay sensitivity) on the pharmacokinetics and pharmacodynamics of clopidogrel in 160 healthy CYP2C19 extensive metabolizers.28 Exposure to the active metabolite of clopidogrel was reduced by 8%, 13%, 16%, and 30%, respectively. Increases in the platelet reactivity index (PRI) were greater than the prespecified no-effect limit when clopidogrel was administered with omeprazole (positive control) or esomeprazole, but not with lansoprazole or dexlansoprazole. Dexlansoprazole was the only PPI that did not significantly increase ADP-induced maximal platelet aggregation (MPA) measured by light transmission aggregometry. The Evaluation of the Influence of Statins and Proton Pump Inhibitors on Clopidogrel Antiplatelet Effects (SPICE) study29 carried out a similar comparison in 302 patients with post-PCI who were discharged while continuing to receive clopidogrel and also received statin therapy for 30 days. Patients were randomized to 1 of 4 gastroprotective agents: esomeprazole, pantoprazole, omeprazole, or the H2-blocker ranitidine for 60 days. Esomeprazole had the largest effect on platelet reactivity, with . 35% and . 50% of patients
demonstrating a . 10% change in MPA and PRI from baseline, respectively. Omeprazole showed significant increases in PRI and non-significant increases in MPA. Neither panto prazole nor ranitidine significantly affected either measure of platelet reactivity. The results of these and other studies led to recent changes in FDA labeling for esomeprazole,19 dexlansoprazole,18 rabeprazole,23 and clopidogrel.11 The new labeling cautions against the use of omeprazole or esomeprazole with clopidogrel and suggests that dexlansoprazole, lansoprazole, and pantoprazole have less effect on the antiplatelet a ctivity of clopidogrel (Table 1).11 Still, data collected between January 1 and March 31, 2012, from . 18 000 retail pharmacies (representing ∼40% of US retail prescriptions) showed that, among patients taking clopidogrel and a prescription PPI, 40% were taking omeprazole and 17% were taking esomeprazole (Figure 2).17
Whether the PPI–Clopidogrel Interaction Increases Thrombotic Risk Is Unknown
The existence of a pharmacokinetic and pharmacodynamic interaction between clopidogrel and PPIs, particularly omeprazole and esomeprazole, is indisputable. However, the clinical significance of this interaction has been a topic of great debate. Retrospective and secondary analyses evaluating clinical outcomes associated with the interaction between clopidogrel and PPIs have yielded inconsistent results and have been summarized previously.4,30,31 Meta-analyses are limited by significant heterogeneity and have done little to clarify the issue.32,33 The only prospective, randomized study to evaluate the clinical implication of coadministration of PPIs and clopidogrel, Clopidogrel and the Optimization of Gastrointestinal Events (COGENT), was discontinued Table 1. FDA Labeling Pertinent to Coadministration of Proton-Pump Inhibitors and Antiplatelet Agents Yes PPIs: safe to use with clopidogrel? Dexlansoprazole (Dexilant)18 Esomeprazole (Nexium)19 Lansoprazole (Prevacid)20 Omeprazole (Prilosec)21 Pantoprazole (Protonix)22 Rabeprazole (AcipHex)23 Antiplatelet agents: safe to use with PPI? Clopidogrel (Plavix)11 Prasugrel (Effient)37 Ticagrelor (Brilinta)38
No
Other
X X X X X X
Avoid omeprazole or esomeprazole X X
Abbreviations: FDA, US Food and Drug Administration; PPI, proton-pump inhibitor.
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Figure 2. Distribution of PPI type among patients co-prescribed clopidogrel and a prescription PPI.17
prematurely owing to lack of funding. The COGENT study randomized patients taking dual antiplatelet therapy (clopidogrel and aspirin) to omeprazole or placebo.8 The primary cardiovascular endpoint was a composite of death from cardiovascular causes, nonfatal myocardial infarction, revascularization, or stroke. Of 3761 patients included in the final analysis, 109 had a cardiovascular event. Event rates were comparable between the omeprazole (4.9%) and placebo (5.7%) groups. No prospective study has compared PPIs with respect to cardiovascular event rates in patients receiving clopidogrel.
Strategies to Reduce the Risk for a Clinically Significant Drug–Drug Interaction Between PPI and Clopidogrel
Several clinical scenarios may confront the primary care provider with a decision related to PPI and clopidogrel coadministration: 1) A patient taking clopidogrel is also taking a prescription or over-the-counter PPI that is not consistent with FDA labeling; 2) a patient taking a PPI develops a cardiovascular condition requiring long-term clopidogrel
242
therapy; and 3) a patient taking clopidogrel develops characteristics that increase the risk of GI bleeding. The ACCF/ACG/AHA 2010 Expert Consensus on the Concomitant Use of Proton-Pump Inhibitors and Thienopyridines defines risk characteristics for GI bleeding as a history of GI bleeding; advanced age; concurrent use of anticoagulants, steroids, or non-steroidal anti-inflammatory drugs; and H. pylori infection.4 A suggested algorithm for GI risk stratification and PPI selection in patients taking clopidogrel based on the ACCF/ACG/AHA consensus and current FDA labeling is provided in Figure 3. Several strategies to reduce the potential for a clinically significant drug–drug interaction are discussed in the following section.
Use FDA Labeling to Guide PPI Choice
Based on comparative pharmacokinetic and pharmacodynamics studies,28,29,34 FDA labeling now recommends against co-administration of omeprazole or esomeprazole with clopidogrel.11,19,21 Table 1 summarizes current FDA labeling regarding co-administration of individual PPIs with clopidogrel or other antiplatelet agents. It is unclear whether the results of a recent randomized, placebo-controlled study showing that pantoprazole significantly reduces the
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Proton-Pump Inhibitor and Antiplatelet Therapy
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Figure 3. Suggested algorithm for use of PPI in patients taking clopidogrel.
Abbreviations: GI, gastrointestinal; NSAID, nonsteroidal anti-inflammatory drug; PPI, proton-pump inhibitor.
antiplatelet effect of clopidogrel will cause a change in pantoprazole labeling. From a practical standpoint, it should be noted that step edits may not have been updated to reflect the new labeling, and generic omeprazole remains the preferred PPI in most step-therapy programs. A physician-initiated appeal may be required for insurance coverage of an alternate PPI. This may be particularly relevant if the formulary does not offer FDA-approved PPI alternatives for patients receiving concomitant clopidogrel. 35
H2-Receptor Antagonists May Be a Suitable Alternative to PPIs
The H2-receptor antagonists (H2RAs) suppress gastric acid production, and there are no prohibitions on their use with clopidogrel. However, clinical data suggest that H2RAs reduce the risk for upper GI bleeding to a lesser extent than do PPIs in patients requiring antiplatelet therapy.7,36 The ACCF/ACG/AHA Consensus states that “H2RAs may be a reasonable alternative in patients at lower risk for GI bleeding, and in those who do not require PPI for refractory gastroesophageal reflux disease.”4
Next-Generation Antiplatelet Agents May Be Substituted for Clopidogrel
Prasugrel is a new thienopyridine prodrug that is hydrolyzed in the intestine to a thiolactone and then converted to the active metabolite via a one-step process catalyzed
predominantly by CYP3A4 and CYP2B6. Prasugrel is indicated for the reduction of thrombotic cardiovascular events (including stent thrombosis) in patients with ACS who are to be managed with PCI.37 Ticagrelor is a non-thienopyridine adenosine triphosphate analogue indicated to reduce the rate of thrombotic cardiovascular events in patients with ACS treated invasively or medically. Ticagrelor is metabolized by CYP3A4 and CYP3A5.38 Because of their lack of dependence on the CYP2C19 enzyme, prasugrel and ticagrelor can be used with any PPI. Although these agents gained FDA approval by demonstrating superiority over clopidogrel for prevention of some cardiovascular outcomes,39,40 they are more costly than generic clopidogrel, which is a substantial barrier to long-term use. Furthermore, prasugrel is contraindicated in patients with a history of transient ischemic attack or stroke.37
Temporal Separation of Dosing Is Not a Solution
If one considers the half-lives of PPIs and clopidogrel (all , 2 hours), it would appear that temporal separation of their administration would obviate any drug interaction. However, a study in healthy volunteers found that administration of clopidogrel and omeprazole 12 hours apart significantly decreased exposure to the active metabolite of clopidogrel (−47%), and significantly increased ADPinduced MPA (+5.6%) and PRI (+27%) versus administration of clopidogrel alone.41 These findings may be explained by the time-dependent, irreversible nature of CYP2C19 inhibition by omeprazole established in vitro.42 The FDA labeling for clopidogrel and omeprazole specifies that the interaction between these 2 agents is not mitigated by administration 12 hours apart.11,21
Conclusion
Many patients taking clopidogrel, with or without aspirin, require gastroprotective therapy to protect against GI bleeding. The PPIs are the most effective anti-secretory agents in these patients. However, a significant pharmacokinetic and pharmacodynamic interaction, believed to involve competition for the CYP2C19 enzyme, has been demonstrated between some PPIs and clopidogrel. Although studies evaluating the potential effects of this interaction on thrombotic risk have yielded conflicting results, the FDA has taken steps to ensure that PPIs co-prescribed with clopidogrel are limited to pantoprazole, rabeprazole, lansoprazole, and d exlansoprazole. Compared with omeprazole or esomeprazole, these PPIs are less likely to reduce exposure to the active metabolite of clopidogrel
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and attenuate antiplatelet activity of clopidogrel. Beyond the choice of PPI, strategies to avoid the PPI-clopidogrel interaction include use of an H2RA instead of PPI or the use of ticagrelor or prasugrel instead of clopidogrel. A 12-hour separation between omeprazole and clopidogrel dosing does not prevent the interaction between these agents. In the future, platelet function testing or pharmacogenomic testing to identify patients with CYP2C19 variants may allow more individualized management of patients requiring gastroprotection in the setting of antiplatelet therapy.
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Acknowledgments
Medical writing support was provided by Melinda Ramsey, PhD, from Complete Healthcare Communications, Inc., with funding from Takeda Pharmaceuticals. All authors participated in each draft. No original data are included in this review article. Takeda Pharmaceutical Company provided funding.
Conflict of Interest Statement
David A. Johnson, MD, MACG, FASGE, FACP, is a consultant for Takeda Pharmaceuticals, Pfizer Inc, Janssen/Centacor, Abbvie, Medigus, AstraZeneca, MedScape/WebMD, CRH Medical, and Epigenomics; he is also a member of the speakers bureau for Takeda Pharmaceuticals and AstraZeneca. Robert Chilton, DO, FACC, is a consultant, member of the speakers bureau, and a member of the advisory board for Takeda Pharmaceuticals; he is a member of the research advisory board for MSD, Boston Scientific, and Eli-Lilly. Harley R. Liker, MD, is a consultant for Roll Global.
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