Response variability to clopidogrel: is tailored treatment, based on laboratory testing, the right solution?
2012; Elsevier BV; Volume: 10; Issue: 3 Linguagem: Inglês
10.1111/j.1538-7836.2011.04602.x
ISSN1538-7933
Autores Tópico(s)Venous Thromboembolism Diagnosis and Management
ResumoSummaryClopidogrel is an antithrombotic prodrug, whose active metabolite inhibits platelet function by irreversibly binding to the platelet receptor for adenosine diphosphate, P2Y12. Wide inter‐individual variability of response to clopidogrel has been reported in several studies: a significant proportion of treated patients (about one‐third) exhibit a suboptimal inhibition of platelet function. Genetic and environmental factors that influence the absorption and/or the extent of metabolism of clopidogrel to its active metabolite account for the observed variability of response. Tailored treatment based on the results of laboratory tests of platelet function has been proposed as a solution to this problem, which has important clinical implications. Although it is often considered a desirable evolution of modern medicine, tailored treatment based on laboratory tests is actually an old remedy (of yet unproven efficacy, in the case of antiplatelet therapy) for the problem of response variability to antithrombotic drugs with unpredictable bioavailability. When possible, the use of alternative drugs with more uniform and predictable bioavailability, and with favourable profiles in terms of risk/benefit and cost‐benefit ratios should be preferred. Moreover, tailored treatment with laboratory tests must be validated in randomized clinical trials before its implementation can be recommended. We still need to identify and standardize the laboratory test for this purpose, as well as answer basic questions on its clinical utility and cost‐effectiveness, before tailoring clopidogrel therapy based on laboratory tests can be recommended in clinical practise. Clopidogrel is an antithrombotic prodrug, whose active metabolite inhibits platelet function by irreversibly binding to the platelet receptor for adenosine diphosphate, P2Y12. Wide inter‐individual variability of response to clopidogrel has been reported in several studies: a significant proportion of treated patients (about one‐third) exhibit a suboptimal inhibition of platelet function. Genetic and environmental factors that influence the absorption and/or the extent of metabolism of clopidogrel to its active metabolite account for the observed variability of response. Tailored treatment based on the results of laboratory tests of platelet function has been proposed as a solution to this problem, which has important clinical implications. Although it is often considered a desirable evolution of modern medicine, tailored treatment based on laboratory tests is actually an old remedy (of yet unproven efficacy, in the case of antiplatelet therapy) for the problem of response variability to antithrombotic drugs with unpredictable bioavailability. When possible, the use of alternative drugs with more uniform and predictable bioavailability, and with favourable profiles in terms of risk/benefit and cost‐benefit ratios should be preferred. Moreover, tailored treatment with laboratory tests must be validated in randomized clinical trials before its implementation can be recommended. We still need to identify and standardize the laboratory test for this purpose, as well as answer basic questions on its clinical utility and cost‐effectiveness, before tailoring clopidogrel therapy based on laboratory tests can be recommended in clinical practise. P2Y12 is one of the two platelet receptors for adenosine diphosphate (ADP), which plays a key role in the pathogenesis of arterial thrombi: it mediates ADP‐induced platelet aggregation, the potentiation of platelet secretion induced by strong agonists, the stabilization of thrombin‐induced platelet aggregates, shear‐induced platelet aggregation and the inhibition of the antiplatelet effects of the natural regulator of platelet function prostacyclin [1Cattaneo M. The platelet P2Y12 receptor for adenosine diphosphate: congenital and drug‐induced defects.Blood. 2011; 117: 2102-12Crossref PubMed Scopus (150) Google Scholar]. These characteristics and its selective tissue distribution make it an attractive molecular target for therapeutic intervention. Indeed, P2Y12 is the target of efficacious antithrombotic agents, including the thienopyridines (ticlopidine, clopidogrel and prasugrel) and ticagrelor, which belongs to the new chemical class of cyclopentyl‐triazolo‐pyrimidines [2Cattaneo M. New P2Y(12) inhibitors.Circulation. 2010; 121: 171-9Crossref PubMed Scopus (190) Google Scholar]. Clopidogrel is effective in secondary prevention of coronary artery and cerebrovascular events, and, in combination with aspirin, is the mainstay in the prevention of major adverse cardiovascular events (MACE) in patients with acute coronary syndromes [2Cattaneo M. New P2Y(12) inhibitors.Circulation. 2010; 121: 171-9Crossref PubMed Scopus (190) Google Scholar]. However, its clinical utility is hampered by the high inter‐individual variability of inhibition of P2Y12‐dependent platelet function, which is mostly caused by the variable bioavailability of its active metabolite [3Bonello L. Tantry U.S. Marcucci R. Blindt R. Angiolillo D.J. Becker R. Bhatt D.L. Cattaneo M. Collet J.P. Cuisset T. Gachet C. Montalescot G. Jennings L.K. Kereiakes D. Sibbing D. Trenk D. van Werkum J.W. Paganelli F. Price M.J. Waksman R. et al.Consensus and future directions on the definition of high on‐treatment platelet reactivity to adenosine diphosphate.J Am Coll Cardiol. 2010; 56: 919-33Crossref PubMed Scopus (1013) Google Scholar, 4Cattaneo M. Resistance to antiplatelet drugs: molecular mechanisms and laboratory detection.J Thromb Haemost. 2007; 1: 230-7Crossref Scopus (175) Google Scholar]: about 25% of treated patients display suboptimal response to the drug [3Bonello L. Tantry U.S. Marcucci R. Blindt R. Angiolillo D.J. Becker R. Bhatt D.L. Cattaneo M. Collet J.P. Cuisset T. Gachet C. Montalescot G. Jennings L.K. Kereiakes D. Sibbing D. Trenk D. van Werkum J.W. Paganelli F. Price M.J. Waksman R. et al.Consensus and future directions on the definition of high on‐treatment platelet reactivity to adenosine diphosphate.J Am Coll Cardiol. 2010; 56: 919-33Crossref PubMed Scopus (1013) Google Scholar, 4Cattaneo M. Resistance to antiplatelet drugs: molecular mechanisms and laboratory detection.J Thromb Haemost. 2007; 1: 230-7Crossref Scopus (175) Google Scholar]. Like the other thienopyridines, clopidogrel is a prodrug that needs to be metabolized to an active metabolite to exert its pharmacological effect. The formation of the active metabolite of clopidogrel involves a two‐step process, which is regulated by isoforms of the hepatic cytochrome P450 (CYP). CYP2C19, CYP1A2 and CYP2B6 are responsible for the first metabolic step, whereas CYP2C19, CYP2C9, CYP2B6 and CYP3A are responsible for the second step [2Cattaneo M. New P2Y(12) inhibitors.Circulation. 2010; 121: 171-9Crossref PubMed Scopus (190) Google Scholar, 3Bonello L. Tantry U.S. Marcucci R. Blindt R. Angiolillo D.J. Becker R. Bhatt D.L. Cattaneo M. Collet J.P. Cuisset T. Gachet C. Montalescot G. Jennings L.K. Kereiakes D. Sibbing D. Trenk D. van Werkum J.W. Paganelli F. Price M.J. Waksman R. et al.Consensus and future directions on the definition of high on‐treatment platelet reactivity to adenosine diphosphate.J Am Coll Cardiol. 2010; 56: 919-33Crossref PubMed Scopus (1013) Google Scholar] (Fig. 1). Loss‐of‐function (e.g. CYP2C19*2 and CYP2C19*3) and gain‐of‐function (e.g. CYP2C19*17) genotypes are associated with variable degrees of production of the active metabolite and, hence, of the pharmacodynamic response to the drug [2Cattaneo M. New P2Y(12) inhibitors.Circulation. 2010; 121: 171-9Crossref PubMed Scopus (190) Google Scholar, 3Bonello L. Tantry U.S. Marcucci R. Blindt R. Angiolillo D.J. Becker R. Bhatt D.L. Cattaneo M. Collet J.P. Cuisset T. Gachet C. Montalescot G. Jennings L.K. Kereiakes D. Sibbing D. Trenk D. van Werkum J.W. Paganelli F. Price M.J. Waksman R. et al.Consensus and future directions on the definition of high on‐treatment platelet reactivity to adenosine diphosphate.J Am Coll Cardiol. 2010; 56: 919-33Crossref PubMed Scopus (1013) Google Scholar]. However, it has been hypothesized that the impaired pharmacodynamic response to clopidogrel in association with CYP2C19*2 may be due to an imbalance in the formation of pro‐inflammatory and anti‐inflammatory cytokines, which could contribute to altered platelet aggregability, rather than to impairment of the formation of the active metabolite of clopidogrel [5Bouman H.J. Schömig E. van Werkum J.W. Velder J. Hackeng C.M. Hirschhäuser C. Waldmann C. Schmalz H.G. ten Berg J.M. Taubert D. Paraoxonase‐1 and clopidogrel efficacy – reply.Nat Med. 2011; 17: 1042-4Crossref Scopus (6) Google Scholar]. The same authors identified paraoxonase‐1 (PON‐1) as the crucial enzyme for clopidogrel bioactivation [6Bouman H.J. Schömig E. van Werkum J.W. Velder J. Hackeng C.M. Hirschhäuser C. Waldmann C. Schmalz H.G. ten Berg J.M. Taubert D. Paraoxonase‐1 is a major determinant of clopidogrel efficacy.Nat Med. 2011; 17: 110-6Crossref PubMed Scopus (430) Google Scholar], but this finding was not confirmed by several subsequent studies [7Hulot J.S. Collet J.P. Cayla G. Silvain J. Allanic F. Bellemain‐Appaix A. Scott S.A. Montalescot G. CYP2C19 but not PON1 genetic variants influence clopidogrel pharmacokinetics, pharmacodynamics, and clinical efficacy in post‐myocardial infarction patients.Circ Cardiovasc Interv. 2011; 4: 422-8Crossref PubMed Scopus (101) Google Scholar, 8Camps J. Joven J. Mackness B. Mackness M. Tawfik D. Draganov D. Costa L.G. Paragh G. Seres I. Horke S. James R. Hernández A. Reddy S. Shih D. Navab M. Rochu D. Aviram M. Paraoxonase‐1 and clopidogrel efficacy.Nat Med. 2011; 17: 1041-2Crossref PubMed Scopus (2) Google Scholar, 9Dansette P.M. Rosi J. Bertho G. Mansuy D. Paraoxonase‐1 and clopidogrel efficacy.Nat Med. 2011; 17: 1040-1Crossref PubMed Scopus (30) Google Scholar, 10Cuisset T. Morange P.E. Quilici J. Bonnet J.L. Gachet C. Alessi M.C. Paraoxonase‐1 and clopidogrel efficacy.Nat Med. 2011; 17: 1039Crossref PubMed Scopus (25) Google Scholar, 11Fontana P. James R. Barazer I. Berdagué P. Schved J.F. Rebsamen M. Vuilleumier N. Reny J.L. Relationship between paraoxonase‐1 activity, its Q192R genetic variant and clopidogrel responsiveness in the ADRIE study.J Thromb Haemost. 2011; 9: 1664-6Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, 12Trenk D. Hochholzer W. Fromm M.F. Zolk O. Valina C.M. Stratz C. Neumann F.J. Paraoxonase‐1 Q192R polymorphism and antiplatelet effects of clopidogrel in patients undergoing elective coronary stent placement.Circ Cardiovasc Genet. 2011; 4: 429-36Crossref PubMed Scopus (97) Google Scholar, 13Sibbing D. Koch W. Massberg S. Byrne R.A. Mehilli J. Schulz S. Mayer K. Bernlochner I. Schömig A. Kastrati A. No association of paraoxonase‐1 Q192R genotypes with platelet response to clopidogrel and risk of stent thrombosis after coronary stenting.Eur Heart J. 2011; 32: 1605-13Crossref PubMed Scopus (172) Google Scholar]. Variable levels of active metabolite generation and/or of pharmacodynamic response to clopidogrel are also associated with: (i) limited intestinal absorption, which is associated with the homozygous 3435C→T mutation of ATP‐binding cassette subfamily B member 1 (ABCB1), a gene encoding for the efflux pump P‐glycoprotein, a key protein involved in thienopyridine absorption; (ii) interaction with other drugs, including some proton pump inhibitors (PPIs), calcium channel blockers and lipophilic statins, which are metabolized by CYP2C19 and CYP3A isoenzymes; (iii) stimulation of CYP1A2 activity by tobacco smoking; and (iv) pre‐existent variability in platelet response to ADP [2Cattaneo M. New P2Y(12) inhibitors.Circulation. 2010; 121: 171-9Crossref PubMed Scopus (190) Google Scholar, 3Bonello L. Tantry U.S. Marcucci R. Blindt R. Angiolillo D.J. Becker R. Bhatt D.L. Cattaneo M. Collet J.P. Cuisset T. Gachet C. Montalescot G. Jennings L.K. Kereiakes D. Sibbing D. Trenk D. van Werkum J.W. Paganelli F. Price M.J. Waksman R. et al.Consensus and future directions on the definition of high on‐treatment platelet reactivity to adenosine diphosphate.J Am Coll Cardiol. 2010; 56: 919-33Crossref PubMed Scopus (1013) Google Scholar]. Other variables that influence the response to clopidogrel include advanced age, high body mass index, diabetes mellitus and renal insufficiency in diabetes mellitus, which are associated with decreased response to the drug (Table 1) [2Cattaneo M. New P2Y(12) inhibitors.Circulation. 2010; 121: 171-9Crossref PubMed Scopus (190) Google Scholar, 3Bonello L. Tantry U.S. Marcucci R. Blindt R. Angiolillo D.J. Becker R. Bhatt D.L. Cattaneo M. Collet J.P. Cuisset T. Gachet C. Montalescot G. Jennings L.K. Kereiakes D. Sibbing D. Trenk D. van Werkum J.W. Paganelli F. Price M.J. Waksman R. et al.Consensus and future directions on the definition of high on‐treatment platelet reactivity to adenosine diphosphate.J Am Coll Cardiol. 2010; 56: 919-33Crossref PubMed Scopus (1013) Google Scholar]. Needless to say, non‐compliance is to be considered an obvious and frequent cause of poor response to clopidogrel [14Cattaneo M. Aspirin and clopidogrel. Efficacy, safety and the issue of drug resistance.Arterioscler Thromb Vasc Biol. 2004; 24: 1980-7Crossref PubMed Scopus (403) Google Scholar].Table 1Main variables affecting the pharmacodynamic response to clopidogrelLack of complianceReduced absorption (e.g. in carriers of the TT3435 mutation of ABCB1, encoding for P‐glycoprotein)Loss‐of‐function or gain‐of‐function mutations of CYP2C19 (and other CYP isoforms)Interaction of other drugs (proton pump inhibitors, lipophilic statins, calcium channel blockers)AgeHigh body mass indexDiabetes mellitusRenal insufficiency in diabetes mellitusPre‐existent variability in platelet response to ADPIncreased platelet turnover (theoretical)Tobacco smoking (heightened response)ABCB1, ATP‐binding cassette subfamily B member 1; CYP, cytochrome P450; ADP, adenosine diphosphate. Open table in a new tab ABCB1, ATP‐binding cassette subfamily B member 1; CYP, cytochrome P450; ADP, adenosine diphosphate. Several independent studies demonstrated an association between suboptimal generation of the active metabolite of clopidogrel, decreased inhibition of platelet function, presence of enzyme polymorphisms and clinical outcomes [2Cattaneo M. New P2Y(12) inhibitors.Circulation. 2010; 121: 171-9Crossref PubMed Scopus (190) Google Scholar, 3Bonello L. Tantry U.S. Marcucci R. Blindt R. Angiolillo D.J. Becker R. Bhatt D.L. Cattaneo M. Collet J.P. Cuisset T. Gachet C. Montalescot G. Jennings L.K. Kereiakes D. Sibbing D. Trenk D. van Werkum J.W. Paganelli F. Price M.J. Waksman R. et al.Consensus and future directions on the definition of high on‐treatment platelet reactivity to adenosine diphosphate.J Am Coll Cardiol. 2010; 56: 919-33Crossref PubMed Scopus (1013) Google Scholar, 15Campo G. Parrinello G. Ferraresi P. Lunghi B. Tebaldi M. Miccoli M. Marchesini J. Bernardi F. Ferrari R. Valgimigli M. Prospective evaluation of on‐clopidogrel platelet reactivity over time in patients treated with percutaneous coronary intervention relationship with gene polymorphisms and clinical outcome.J Am Coll Cardiol. 2011; 57: 2474-83Crossref PubMed Scopus (303) Google Scholar, 16Brar S.S. Ten Berg J. Marcucci R. Price M.J. Valgimigli M. Kim H.S. Patti G. Breet N.J. Disciascio G. Cuisset T. Dangas G. Impact of platelet reactivity on clinical outcomes after percutaneous coronary intervention a collaborative meta‐analysis of individual participant data.J Am Coll Cardiol. 2011; 58: 1945-54Crossref PubMed Scopus (359) Google Scholar]. However, no study has yet associated all of these parameters in the same patient population, and some uncertainties still persist. For instance, no clear negative association with clinical outcomes of the co‐administration of clopidogrel with drugs that potentially interfere with its metabolism has been documented so far, despite their negative interaction with the pharmacodynamic response to the drug [17Bates E.R. Lau W.C. Angiolillo D.J. Clopidogrel‐drug interactions.J Am Coll Cardiol. 2011; 57: 1251-63Crossref PubMed Scopus (174) Google Scholar, 18Chen M. Wei J.F. Xu Y.N. Liu X.J. Huang D.J. A Meta‐Analysis of Impact of Proton Pump Inhibitors on Antiplatelet Effect of Clopidogrel.Cardiovasc Ther. 2011; 10.1111/j.1755‐5922.2011.00289.xGoogle Scholar]. This is true not only for lipophilic statins and calcium channel blockers [3Bonello L. Tantry U.S. Marcucci R. Blindt R. Angiolillo D.J. Becker R. Bhatt D.L. Cattaneo M. Collet J.P. Cuisset T. Gachet C. Montalescot G. Jennings L.K. Kereiakes D. Sibbing D. Trenk D. van Werkum J.W. Paganelli F. Price M.J. Waksman R. et al.Consensus and future directions on the definition of high on‐treatment platelet reactivity to adenosine diphosphate.J Am Coll Cardiol. 2010; 56: 919-33Crossref PubMed Scopus (1013) Google Scholar, 17Bates E.R. Lau W.C. Angiolillo D.J. Clopidogrel‐drug interactions.J Am Coll Cardiol. 2011; 57: 1251-63Crossref PubMed Scopus (174) Google Scholar], but also for omeprazole and other PPIs interfering with CYP2C19. The evidence of the negative interaction of some PPIs with the pharmacodynamic response to clopidogrel activity [19Gilard M. Arnaud B. Le Gal G. Abgrall J.F. Boschat J. Influence of omeprazol on the antiplatelet action of clopidogrel associated to aspirin.J Thromb Haemost. 2006; 4: 2508-9Crossref PubMed Scopus (251) Google Scholar, 20Gilard M. Arnaud B. Cornily J.C. Le Gal G. Lacut K. Le Calvez G. Mansourati J. Mottier D. Abgrall J.F. Boschat J. 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: 256-60Crossref PubMed Scopus (0) Google Scholar, 21Angiolillo D.J. Gibson C.M. Cheng S. Ollier C. Nicolas O. Bergougnan L. Perrin L. LaCreta F.P. Hurbin F. Dubar M. 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: 65-74Crossref PubMed Scopus (250) Google Scholar, 22Sibbing D. Morath T. Stegherr J. Braun S. Vogt W. Hadamitzky M. Schömig A. Kastrati A. von Beckerath N. Impact of proton pump inhibitors on the antiplatelet effects of clopidogrel.Thromb Haemost. 2009; 101: 714-9Crossref PubMed Scopus (393) Google Scholar], albeit controversial [23Gremmel T. Steiner S. Seidinger D. Koppensteiner R. Panzer S. Kopp C.W. The influence of proton pump inhibitors on the antiplatelet potency of clopidogrel evaluated by 5 different platelet function tests.J Cardiovasc Pharmacol. 2010; 56: 532-9Crossref PubMed Scopus (31) Google Scholar], and the demonstration in observational studies, case‐control studies and post‐hoc analyses of some randomized clinical trials that the risk of MACE was higher in patients on combined treatment with clopidogrel and a PPI, compared with patients on clopidogrel not in combined treatment with a PPI [24Hulot J.S. Collet J.P. Silvain J. Pena A. Bellemain‐Appaix A. Barthélémy O. Cayla G. Beygui F. Montalescot G. Cardiovascular risk in clopidogrel‐treated patients according to cytochrome P450 2C19*2 loss‐of‐function allele or proton pump inhibitor coadministration: a systematic meta‐analysis.J Am Coll Cardiol. 2010; 56: 134-43Crossref PubMed Scopus (351) Google Scholar, 25Siller‐Matula J.M. Jilma B. Schrör 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: 2624-41Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar, 26Ho P.M. Maddox T.M. Wang L. Fihn S.D. Jesse R.L. Peterson E.D. Rumsfeld J.S. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome.JAMA. 2009; 301: 937-44Crossref PubMed Scopus (944) Google Scholar], prompted drug regulating authorities to issue a warning for the use of these drugs in combination with clopidogrel [27Abraham N.S. Hlatky M.A. Antman E.M. Bhatt D.L. Bjorkman D.J. Clark C.B. Furberg C.D. Johnson D.A. Kahi C.J. Laine L. Mahaffey K.W. Quigley E.M. Scheiman J. Sperling L.S. Tomaselli G.F. ACCF/ACG/AHAACCF/ACG/AHA 2010 Expert Consensus Document o the concomitant use of proton pump inhibitors and thienopyridines: a focused update of the 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 Expert Consensus Documents.Circulation. 2010; 122: 2619-33Crossref PubMed Scopus (209) Google Scholar]. However, the existence of this negative interaction stemming from randomized clinical trials was less evident [24Hulot J.S. Collet J.P. Silvain J. Pena A. Bellemain‐Appaix A. Barthélémy O. Cayla G. Beygui F. Montalescot G. Cardiovascular risk in clopidogrel‐treated patients according to cytochrome P450 2C19*2 loss‐of‐function allele or proton pump inhibitor coadministration: a systematic meta‐analysis.J Am Coll Cardiol. 2010; 56: 134-43Crossref PubMed Scopus (351) Google Scholar, 28O’Donoghue M.L. Braunwald E. Antman E.M. Murphy S.A. Bates E.R. Rozenman Y. Michelson A.D. Hautvast R.W. Ver Lee P.N. Close S.L. Shen L. Mega J.L. Sabatine M.S. Wiviott S.D. 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: 989-97Abstract Full Text Full Text PDF PubMed Scopus (705) Google Scholar, 29Ray W.A. Murray K.T. Griffin M.R. Chung C.P. Smalley W.E. Hall K. Daugherty J.R. Kaltenbach L.A. Stein C.M. Outcomes with concurrent use of clopidogrel and proton‐pump inhibitors: a cohort study.Ann Intern Med. 2010; 152: 337-45Crossref PubMed Scopus (212) Google Scholar, 30Rassen J.A. Choudhry N.K. Avorn J. Schneeweiss S. Cardiovascular outcomes and mortality in patients using clopidogrel with proton pump inhibitors after percutaneous coronary intervention or acute coronary syndrome.Circulation. 2009; 120: 2322-9Crossref PubMed Scopus (199) Google Scholar, 31Simon T. Steg P.G. Gilard M. Blanchard D. Bonello L. Hanssen M. Lardoux H. Coste P. Lefèvre T. Drouet E. Mulak G. Bataille V. Ferrières J. Verstuyft C. Danchin N. Clinical events as a function of proton pump inhibitor use, clopidogrel use, and cytochrome P450 2C19 genotype in a large nationwide cohort of acute myocardial infarction: results from the French Registry of Acute ST‐Elevation and Non‐ST‐Elevation Myocardial Infarction (FAST‐MI) registry.Circulation. 2011; 123: 474-82Crossref PubMed Scopus (133) Google Scholar, 32Hsiao F.Y. Mullins C.D. Wen Y.W. Huang W.F. Chen P.F. Tsai Y.W. Relationship between cardiovascular outcomes and proton pump inhibitor use in patients receiving dual antiplatelet therapy after acute coronary syndrome.Pharmacoepidemiol Drug Saf. 2011; 20: 1043-9Crossref PubMed Scopus (28) Google Scholar]. Moreover, the only randomized controlled trial that prospectively tested the interaction between omeprazole and clopidogrel, which was terminated prematurely due to bankruptcy of the sponsor, failed to show that the co‐administration of the two drugs increases the incidence of MACE [33Bhatt D.L. Cryer B.L. Contant C.F. Cohen M. Lanas A. Schnitzer T.J. Shook T.L. Lapuerta P. Goldsmith M.A. Laine L. Scirica B.M. Murphy S.A. Cannon C.P. COGENT InvestigatorsClopidogrel with or without omeprazole in coronary artery disease.N Engl J Med. 2010; 363: 1909-17Crossref PubMed Scopus (992) Google Scholar]. A third, more recent meta‐analysis indicated an obvious discrepancy between the negative results of randomized clinical trials and the positive results of observational studies, concerning the clinical consequences of the negative pharmacological interaction of PPIs with clopidogrel [18Chen M. Wei J.F. Xu Y.N. Liu X.J. Huang D.J. A Meta‐Analysis of Impact of Proton Pump Inhibitors on Antiplatelet Effect of Clopidogrel.Cardiovasc Ther. 2011; 10.1111/j.1755‐5922.2011.00289.xGoogle Scholar]. The association between poor clinical outcomes of patients on treatment with clopidogrel and the presence of loss of function mutations of CYP has been demonstrated in observational and intervention studies. However, it must be emphasized that the testing and validation of statistical hypotheses in genetic epidemiology is a task of unprecedented scale [34Ioannidis J.P. Ntzani E.E. Trikalinos T.A. Contopoulos‐Ioannidis D.G. Replication validity of genetic association studies.Nat Genet. 2001; 29: 306-9Crossref PubMed Scopus (1624) Google Scholar]. Ioannidis et al. [34Ioannidis J.P. Ntzani E.E. Trikalinos T.A. Contopoulos‐Ioannidis D.G. Replication validity of genetic association studies.Nat Genet. 2001; 29: 306-9Crossref PubMed Scopus (1624) Google Scholar] showed that significant between‐study heterogeneity is frequent, and that the results of the first studies (usually suggesting a strong genetic defect) correlate only modestly with subsequent research on the same association. Both bias and genuine population diversity might explain why early association studies tend to overestimate the disease protection or predisposition conferred by a genetic polymorphism [34Ioannidis J.P. Ntzani E.E. Trikalinos T.A. Contopoulos‐Ioannidis D.G. Replication validity of genetic association studies.Nat Genet. 2001; 29: 306-9Crossref PubMed Scopus (1624) Google Scholar]. As a matter of fact, three meta‐analyses, which included the early published studies, demonstrated an increased risk of MACE and, particularly, of stent thrombosis in carriers of either one or two mutated CYP2C19*2 alleles [24Hulot J.S. Collet J.P. Silvain J. Pena A. Bellemain‐Appaix A. Barthélémy O. Cayla G. Beygui F. Montalescot G. Cardiovascular risk in clopidogrel‐treated patients according to cytochrome P450 2C19*2 loss‐of‐function allele or proton pump inhibitor coadministration: a systematic meta‐analysis.J Am Coll Cardiol. 2010; 56: 134-43Crossref PubMed Scopus (351) Google Scholar, 35Mega J.L. Simon T. Collet J.P. Anderson J.L. Antman E.M. Bliden K. Cannon C.P. Danchin N. Giusti B. Gurbel P. Horne B.D. Hulot J.S. Kastrati A. Montalescot G. Neumann F.J. Shen L. Sibbing D. Steg P.G. Trenk D. Wiviott S.D. et al.Reduced‐function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta‐analysis.JAMA. 2010; 304: 1821-30Crossref PubMed Scopus (912) Google Scholar, 36Sofi F. Giusti B. Marcucci R. Gori A.M. Abbate R. Gensini G.F. Cytochrome P450 2C19*2 polymorphism and cardiovascular recurrences in patients taking clopidogrel: a meta‐analysis.Pharmacogenomics J. 2011; 11: 199-206Crossref PubMed Scopus (138) Google Scholar], while two more recent meta‐analyses did not indicate a substantial or consistent influence of loss‐of‐function CYP2C19 gene polymorphisms on the clinical efficacy of clopidogrel [37Bauer T. Bouman H.J. van Werkum J.W. Ford N.F. ten Berg J.M. Taubert D. Impact of CYP2C19 variant genotypes on clinical efficacy of antiplatelet treatment with clopidogrel: systematic review and meta‐analysis.BMJ. 2011; 343: d4588Crossref PubMed Scopus (221) Google Scholar, 38Zabalza M. Subirana I. Sala J. Lluis‐Ganella C. Lucas G. Tomás M. Masiá R. Marrugat J. Brugada R. Elosua R. Meta‐analyses of the association between cytochrome CYP2C19 loss‐ and gain‐of‐function polymorphisms and cardiovascular outcomes in patients with coronary artery disease treated with clopidogrel.Heart. 2012; 98: 100-8Crossref PubMed Scopus (129) Google Scholar]. In line with these results, a very recent meta‐analysis showed that, although there was an association between the CYP2C19 genotype and clopidogrel responsiveness, overall there was no significant association of genotype with MACE [39Holmes M.V. Perel P. Shah T. Hingorani A.D. Casas J.P. CYP2C19 genotype, clopidogrel metabolism, platelet function, and cardiovascular events: a systematic review and meta‐analysis.JAMA. 2011; 306: 2704-14Crossref PubMed Scopus (420) Google Scholar]. The different results of these latter meta‐analyses are likely to be due to the fact that they included studies published after the year 2010 (which showed weaker effects compared with the previous ones) [37Bauer T. Bouman H.J. van Werkum J.W. Ford N.F. ten Berg J.M. Taubert D. Impact of CYP2C19 variant genotypes on clinical efficacy of antiplatelet treatment with clopidogrel: systematic review and meta‐analysis.BMJ. 2011; 343: d4588Crossref PubMed Scopus (221) Google Scholar, 38Zabalza M. Subirana I. Sala J. Lluis‐Ganella C. Lucas G. Tomás M. Masiá R. Marrugat J. Brugada R. Elosua R. Meta‐analyses of the association between cytochrome CYP2C19 loss‐ and gain‐of‐function polymorphisms and cardiovascular outcomes in patients with coronary artery disease treated with clopidogrel.Heart. 2012; 98: 100-8Crossref PubMed Scopus (129) Google Scholar] and extracted only data of prespecified clinical events that conformed to unbiased and standardized definitions [37Bauer T. Bouman H.J. van Werkum J.W. Ford N.F. ten Berg J.M. Taubert D. Impact of CYP2C19 variant genotypes on clinical efficacy of antiplatelet treatment with clopidogrel: systematic review and meta‐analysis.BMJ. 2011; 343: d4588Crossref PubMed Scopus (221) Google Scholar]. Moreover, the meta‐analysis by Zabalza et al. [38Zabalza M. Subirana I. Sala J. Lluis‐Ganella C. Lucas G. Tomás M. Masiá R. Marrugat J. Brugada R. Elosua R. Meta‐analyses of the association between cytochrome CYP2C19 loss‐ and gain‐of‐function polymorphisms and cardiovascular outcomes in patients with coronary artery disease treated with clopidogrel.Heart. 2012; 98: 100-8Crossref PubMed Scopus (129) Google Scholar] showed that a significant association between the loss‐of‐fun
Referência(s)