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Platelet aggregation and thrombus production is the primary mechanism of acute coronary syndrome (ACS).1 The efficacy of clopidogrel in combination with ASA therapy has been clearly demonstrated to reduce recurrent coronary events following acute myocardial infarction and the adverse cardiovascular outcomes associated with percutaneous cardiovascular interventions (PCI).2,3 The use of platelet inhibitor drugs in combination or as mono-therapy is now common place and has changed the management of ACS and the “standard of care” after PCI.4,5 Unfortunately, the improved cardiovascular survival provided by antiplatelet therapy has been confounded by a parallel increase in the occurrence of upper gastrointestinal events (UGIE). In 2008, leaders of the ACCF/ACG/AHA convened and published, “Expert Consensus Document on Reducing the Gastrointestinal Risks of Antiplatelet Therapy and NSAID Use.”6 These societies have carefully reviewed the risks and benefits of instituting prophylactic PPI therapy to minimizing UGIE and have recommended PPI prophylaxis, Figure 1.
Paralleling the observed increase in UGIE associated with antiplatelet therapy, has been an unexpected observation of a decrease in the effectiveness of clopidogrel to prevent adverse cardiovascular events after acute myocardial infarction and PCI.7,8,9 Pharmacokinetic studies of clopidogrel have shown that this “prodrug” requires bioactivation through the hepatic cytochrome P450 isoenzyme pathway, with CYP2C19 isoenzyme being most important, Figure 2.13 Genetic polymorphisms of the CYP2C19 isoenzyme have been identified. These polymorphisms are associated with decreased metabolic activity and direct decrease in clopidogrel activation in select patient groups (30% whites, 40% blacks, and 55% east Asian).14,15,16
Increased awareness and understanding of the need for CYP2C19 activation of clopidogrel to effectively prevent ACS, has prompted reconsideration of the ACCF/ACG/AHA recommendations for the reduction of UGIE using PPIs, which are also metabolized through the CYP450 pathway, see Figures 3 and 4. The study by Gilard M, et al,16 reviewed in this issue of VHJOE, highlights the inhibitory pharmacokinetic effect of omperazole to decrease clopidogrel CYP2C19 activation and thereby a pharmacodynamic effect to increase platelet adhesiveness as measured by the Platelet Reactivity Index (PRI). Clopidogrel “poor” responders (defined as PRI >50%) were more common in the Omperazole group 60.9% vs. 26.7% in the placebo group (p < 0.0001).16
New research data from two independent and large health care systems have identified adverse outcomes with the use of clopidogrel together with a PPI among patients discharged after hospitalization with a diagnosis of ACS.17,18 Juurlink, et al,17 conducted a large (n=13,636) population-based, nested case control study among Canadian patients aged > 66 yrs following discharge after acute myocardial infarction and observed that patients that experienced reinfarction within 90 days of discharge were more likely than event-free patients in the control group to have received concomitant therapy with clopidogrel and PPI. They further estimated that compared to no treatment, CYP2C19-inhibiting PPIs were collectively associated with a 40% relative increase in risk for recurrent myocardial infarction. Ho, et al,18 conducted a similar large (n=8,250) retrospective multicenter cohort study from 127 Veterans Affairs hospitals to assess the outcomes of patients taking clopidogrel with or without a PPI after hospitalization for acute coronary syndrome. Death or rehospitalization for ACS occurred in 20.8% (n=615) of patients taking clopidogrel without PPI and 29.8% (n=1,561) of patients taking clopidogrel with PPI, adjusted odds ration (AOR), 1.25, 95% (confidence interval, 1.11-1.41).
Results of these and other studies, have prompted the Food and Drug Administration to launch an FDA: Early Communication about an Ongoing Safety Review of clopidogrel bisulfate (Plavix*) http://www.fda.gov/Cder/drug/early_comm/clopidogrel_bisulfate.htm19
This FDA communication warns of the potential serious drug interaction between clopidogrel and the entire class of proton pump inhibitors (PPIs) including PrilosecOTC, Figure 5. Confounding this class recommendation, is the knowledge that there is significant variance in the CYP450 metabolism of each of the PPIs, some being preferentially metabolized by non-CYP2C19 pathways, i.e., pantoprazole (CYP2C9). It will require both pharmacokinetic and pharmacodynamic data, as well as other clinical outcome studies that can further address possible harm from this interaction, to show which, if any PPIs are safe to use in conjunction with clopidogrel.
Fortunately, the makers of clopidogrel (Plavix*), Sanofi-Aventis and Bristol-Meyers Squibb are working with the FDA to sponsor research to evaluate this issue. Until such time that safety studies are complete, all physicians will need to carefully evaluate the risk benefit ratio of coadministration of clopidogrel and PPIs. When both medications are required, selection of a PPI not metabolized through the CYP2C19 pathway, such as pantoprazole may be beneficial. Other alternatives include use of a H2-blocker not metabolized through the CYP2C19 pathway, such as, ranitidine, famotidine or nizatidine or spacing the administration of clopidogrel and a PPI by several hours since the serum half-life is short (1-2 hours) for most PPIs and competitive CYP450 interactions may be lessened.20,21
References:
1. Yusuf S, Zhao F, Mehta SR, et al. Clopidogrel in unstable angina to prevent recurrent events trial investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345:494-502.
2. Gurbel PA, Bliden KP, Samara W, et al. Clopidogrel effect on platelet reactivity in patients with stent thrombosis: results of the CREST study. J Am Coll Cardiol. 2005;46:1827-32.
3. Bliden KP, DiChiara J, Tantry US, et al. Increased risk in patients with high platelet aggregation receiving chronic clopidogrel therapy undergoing percutaneous coronary intervention: Is current antiplatelet therapy adequate? J Am Coll Cardiol. 2007;49:657-66.
4. Antman EM, Hand M, Armstrong PW, et al. 2007 focused update of the ACC/AHA 2004 guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J AM Coll Cardiol. 2008;51:210-47.
5. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J AM Coll Cardiol. 2007;50:e1-157.
6. Bhatt DL, Scheiman J, Abraham NS, et al. ACCF/ACG/AHA 2008 Expert Consensus Document on Reducing the Gastrointestinal Risks of Antiplatelet Therapy and NSAID Use. A Report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. Circulation 2008;118:1894-1909.
7. Kim KA, Park PW, Hong SJ, et al. The effect of CYP2C19 polymorphism on the pharmacokinetics and pharmacodynamics of clopidogrel: a possible mechanism for clopidogrel resistance. Clin Pharm Ther. 2008;84:735-41.
8. Desta Z, Zhao X, Shin JG, Flockhart DA. Clinical significance of the cytochrome P450 2C19 genetic polymorphism. Clin Pharmacokinetic 2002;41:913-58.
9. Mega JC, Close SC, Wivott SD, Shen L, et al. Cytochrome P-450 Polymorphisms and Response to Clopidogrel. Engl J Med 2009;360:354-62.
10. Pezalla E, Day D, Pulliadath I. Initial assessment of clinical impact of drug interaction between clopidogrel and proton pump inhibitors. J Am Coll Cardiol. 2008;52:1038-9.
11. Aubert RE, Epstein RS, Teagarden JR, et al. Abstract 3998: Proton pump inhibitors effect on clopidogrel effectiveness: the Clopidogrel Medco Outcomes Study. Circulation. 2008;118:S_815.
12. Mega JL. Close SL, Wivott SD, et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med. 2009;360:354-62.
13. Frere C et al, Effect of cytochrome P450 polymorphisms on platelet reactivity after treatment with clopidogrel in acute coronary syndrome. Am J Cardiol 2008; 101:1088-93.
14. Trenk et al. Cytochrome P450 2C19 681G polymorphism and high on-clopidogrel platelet reactivity associated with adverse 1-year clinical outcome of elective percutaneous coronary intervention with drug eluting or bare-metal stents. J Am Coll Cardiol 2008; 51: 1925-34.
15. Gilard M et al. Influence of omeprazole on the antiplatelet action of clopidogrel associated to aspirin. J Thromb Haemost 2006; 4:2508-9.
16. Gilard M et al. Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin: the randomized, double-blind OCLA (Omeprazole Clopidogrel Aspirin) Study. J Am Coll Cardiol 2008: 51:256-60.
17. Juurlink DN, Gomes T, Ko DT, Szmitko PE, et al. A population-based study of the drug interaction between proton pump inhibitors and clopidogrel. CMJA. 2009;180:713-8.
18. Ho PM, Maddox TM, Wang L, Fihn SD, et al. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA. 2009;301:937-944.
19. FDA: Early Communication about an Ongoing Safety Review of clopidogrel bisulfate (marketed as Plavix) http://www.fda.gov/Cder/drug/early_comm/clopidogrel_bisulfate.htm
20. Li XQ, Andersson TB, Ahlstrom M, Weidolf L. Comparison of inhibitory effects of the proton pump inhibiting drugs omperazole, esomprazole, lansoprazole, pantoprazole, and rabeprazole on human cytochrome P450 activities. Drug Metabolism and Disposition. 2004;32:821-827.
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