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Ticlopidine could be an alternative therapy in the case of pharmacological resistance to clopidogrel: a report of three cases

2007; Elsevier BV; Volume: 5; Issue: 4 Linguagem: Inglês

10.1111/j.1538-7836.2007.02338.x

1538-7933

Boris Aleil, G Rochoux, Jean‐Pierre Monassier, Jean‐Pierre Cazenave, Christian Gachet,

Venous Thromboembolism Diagnosis and Management

Ticlopidine and clopidogrel are antiplatelet agents that have proven their efficacy in the prevention of vascular ischemic events following percutaneous coronary intervention (PCI) [1Leon M.B. Baim D.S. Popma J.J. Gordon P.C. Cutlip D.E. Ho K.K. Giambartolomei A. Diver D.J. Lasorda D.M. Williams D.O. Pocock S.J. Kuntz RE. A clinical trial comparing three antithrombotic‐drug regimens after coronary‐artery stenting. Stent Anticoagulation Restenosis Study Investigators.N Engl J Med. 1998; 339: 1665-71Crossref PubMed Scopus (1691) Google Scholar, 2Steinhubl S.R. Berger P.B. Mann III, J.T. Fry E.T. DeLago A. Wilmer C. Topol E.J. CREDO InvestigatorsClopidogrel for the reduction of events during observation. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial.JAMA. 2002; 288: 2411-20Crossref PubMed Scopus (3043) Google Scholar]. After hepatic metabolization, these thienopyridines inhibit adenosine diphosphate (ADP)‐induced platelet aggregation by specific blockade of the platelet P2Y12 receptor [3Savi P. Herbert JM. Clopidogrel and ticlopidine: P2Y12 adenosine diphosphate‐receptor antagonists for the prevention of atherothrombosis.Semin Thromb Hemost. 2005; 31: 174-83Crossref PubMed Scopus (300) Google Scholar, 4Gachet C. Regulation of platelet functions by P2 receptors.Annu Rev Pharmacol Toxicol. 2006; 46: 277-300Crossref PubMed Scopus (239) Google Scholar]. Clopidogrel is preferred to ticlopidine on account of its safety and tolerability [5Bertrand M.E. Rupprecht H.J. Urban P. Gershlick A.H. CLASSICS InvestigatorsDouble‐blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting: the clopidogrel aspirin stent international cooperative study (CLASSICS).Circulation. 2000; 102: 624-29Crossref PubMed Scopus (1038) Google Scholar]. However, a wide interindividual variability of platelet responsiveness is observed in patients receiving a standard regimen of clopidogrel [6Gurbel P.A. Bliden K.P. Hiatt B.L. O'Connor CM. Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity.Circulation. 2003; 107: 2908-13Crossref PubMed Scopus (1459) Google Scholar], and the concept of 'clopidogrel resistance' has been proposed [7Barragan P. Bouvier J.L. Roquebert P.O. Macaluso G. Commeau P. Comet B. Lafont A. Camoin L. Walter U. Eigenthaler M. Resistance to thienopyridines: clinical detection of coronary stent thrombosis by monitoring of vasodilator‐stimulated phosphoprotein phosphorylation.Catheter Cardiovasc Interv. 2003; 59: 295-302Crossref PubMed Scopus (449) Google Scholar]. An association between weak reduction of ADP‐induced platelet aggregation under clopidogrel treatment and recurrence of cardiovascular events after PCI has been suggested [8Matetzky S. Shenkman B. Guetta V. Shechter M. Bienart R. Goldenberg I. Novikov I. Pres H. Savion N. Varon D. Hod H. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction.Circulation. 2004; 109: 3171-75Crossref PubMed Scopus (1302) Google Scholar]. In the case of acute stent thrombosis associated with a poor biological response to clopidogrel, alternative therapy is as yet limited. We report here three patients in whom clopidogrel therapy was ineffective despite double dosing whereas a pharmacological response to a standard regimen of ticlopidine was obtained. Flow cytometric analysis of vasodilator‐stimulated phosphoprotein (VASP) phosphorylation (VASP‐FCM; Stago, Asnières, France) was used to measure the platelet response to thienopyridines [9Schwarz U.R. Geiger J. Walter U. Eigenthaler M. Flow cytometry analysis of intracellular VASP phosphorylation for the assessment of activating and inhibitory signal transduction pathways in human platelets – definition and detection of ticlopidine/clopidogrel effects.Thromb Haemost. 1999; 82: 1145-52Crossref PubMed Scopus (287) Google Scholar, 10Aleil B. Ravanat C. Cazenave J.P. Rochoux G. Heitz A. Gachet C. Flow cytometric analysis of intraplatelet VASP phosphorylation for the detection of clopidogrel resistance in patients with ischemic cardiovascular diseases.J Thromb Haemost. 2005; 3: 85-92Abstract Full Text Full Text PDF PubMed Scopus (380) Google Scholar]. A 62‐year‐old type 2 diabetic woman was admitted for acute myocardial infarction caused by left anterior descending (LAD) coronary artery occlusion. The obstruction was removed after 2 h by PCI with stent implantation (DRIVER®, Medtronic, Minneapolis, MN, USA). The patient received a 300 mg loading dose of clopidogrel followed by a 75 mg day−1 maintenance dose. Other drugs administered were aspirin (75 mg day−1), bisoprolol, perindopril, pravastatin and metformin. Three days later, the patient presented with acute stent thrombosis, which was treated by urgent revascularization using PCI. VASP phosphorylation analysis showed no platelet response to clopidogrel with a high platelet reactivity index (PRI) to ADP (89%). Clopidogrel was increased to 150 mg once daily. After 9 days the VASP result remained high and the PRI was 77%, although without recurrence of stent thrombosis. Clopidogrel was replaced by ticlopidine at 250 mg twice daily and 15 days later the VASP assay showed a platelet response with a PRI of 46%. A 68‐year‐old woman was admitted for unstable angina related to LAD and right coronary artery (RCA) stenosis (> 90%). Clopidogrel was administered (300 mg followed by 75 mg once daily) in association with aspirin (325 mg day−1), atorvastatin and atenolol. The coronary stenosis was dilated 4 days later and drug‐eluting stents (CYPHER®, Cordis Corporation, Miami Lakes, FL, USA) were implanted in the LAD and RCA. Two days after PCI, the patient experienced acute stent thrombosis in the RCA, which was treated by revascularization. VASP analysis showed a high PRI (78%) and clopidogrel was increased to 150 mg day−1. After 3 days, the patient again required revascularization due to acute stent thrombosis, this time in the LAD coronary artery, while the PRI was 86%. Clopidogrel was replaced by ticlopidine (250 mg twice daily). After 3 and 11 days the PRI decreased to 62% and 37%, respectively, without recurrence of ischemic events. A 47‐year‐old man presenting with acute myocardial infarction was treated with urgent PCI and stent implantation (DRIVER) in the LAD coronary artery. He subsequently received clopidogrel (75 mg day−1), aspirin (160 mg day−1), atenolol, furosemide and fluvastatin. Eight days later, the patient developed acute stent thrombosis, which was resolved by thromboaspiration. Clopidogrel was increased to 150 mg once daily but after 3 and 10 days of this therapy, VASP analysis showed a persistently high PRI (83% and 82% respectively). Although there was no recurrence of an ischemic event, clopidogrel was replaced by ticlopidine (250 mg twice daily) and 4 weeks later the PRI had decreased to 60%. These three patients presented acute stent thrombosis and showed biological non‐responsiveness to clopidogrel, despite overdosing to 150 mg day−1 and a sufficient duration of the treatment. Platelet P2Y12 inhibition was finally obtained with a standard regimen of ticlopidine (Table 1). The effects of possible poor compliance would appear limited because each patient was his/her own control and was under surveillance in hospital. Although one case of ticlopidine unresponsiveness has been reported [11Obergfell A. Strotmann J. Bonz A. Bauersachs J. Ertl G. Walter U. Grossmann R. Impaired platelet responses to clopidogrel and ticlopidine in a patient with recurrent coronary stent stenosis.Thromb Haemost. 2004; 92: 1446-47Crossref Scopus (5) Google Scholar], it appears that the variability of the individual's response to the treatment is not similar between clopidogrel and ticlopidine. Because the common mechanism of action of antiplatelet thienopyridines is direct and irreversible blockade of the P2Y12 ADP receptor by their reactive thiol [3Savi P. Herbert JM. Clopidogrel and ticlopidine: P2Y12 adenosine diphosphate‐receptor antagonists for the prevention of atherothrombosis.Semin Thromb Hemost. 2005; 31: 174-83Crossref PubMed Scopus (300) Google Scholar, 12Savi P. Zachayus J.L. Delesque‐Touchard N. Labouret C. Herve C. Uzabiaga M.F. Pereillo J.M. Culouscou J.M. Bono F. Ferrara P. Herbert JM. The active metabolite of Clopidogrel disrupts P2Y12 receptor oligomers and partitions them out of lipid rafts.Proc Natl Acad Sci U S A. 2006; 103: 11069-74Crossref PubMed Scopus (279) Google Scholar, 13Niitsu Y. Jakubowski J.A. Sugidachi A. Asai F. Pharmacology of CS‐747 (prasugrel, LY640315), a novel, potent antiplatelet agent with in vivo P2Y12 receptor antagonist activity.Semin Thromb Hemost. 2005; 31: 184-94Crossref PubMed Scopus (253) Google Scholar], the different effects of the two molecules could be due to differences in pharmacokinetics and/or pharmacodynamics. In fact, the pharmacokinetics and pharmacodynamics of clopidogrel and ticlopidine have never been compared in a PCI study. Differences in intestinal absorption are unlikely as both drugs display rapid and complete absorption [14Caplain H. Donat F. Gaud C. Necciari J. Pharmacokinetics of clopidogrel.Semin Thromb Hemost. 1999; 25: 25-8PubMed Google Scholar, 15Desager JP. Clinical pharmacokinetics of ticlopidine.Clin Pharmacokinet. 1994; 26: 347-55Crossref PubMed Scopus (81) Google Scholar]. The different administration of clopidogrel (once daily) and ticlopidine (twice daily) also appears unlikely to have an effect because these compounds irreversibly block the P2Y12 receptors for the remainder of the life span of the platelet (8–10 days) [3Savi P. Herbert JM. Clopidogrel and ticlopidine: P2Y12 adenosine diphosphate‐receptor antagonists for the prevention of atherothrombosis.Semin Thromb Hemost. 2005; 31: 174-83Crossref PubMed Scopus (300) Google Scholar]. Clopidogrel is more potent than ticlopidine and at 75 mg day−1 achieves a similar inhibition of platelet aggregation and prolongation of the bleeding time as ticlopidine at 500 mg day−1 [16Boneu B. Destelle G. Platelet anti‐aggregating activity and tolerance of clopidogrel in atherosclerotic patients.Thromb Haemost. 1996; 76: 939-43Crossref PubMed Scopus (130) Google Scholar]. A difference in liver metabolization could provide an explanation: (i) clopidogrel and ticlopidine metabolization do not produce exactly the same metabolites [17Gordon JL. Ticlopidine: Quo Vadis? Birkhäuser Verlag Basel, 1984Google Scholar, 18Savi P. Pereillo J.M. Uzabiaga M.F. Combalbert J. Picard C. Maffrand J.P. Pascal M. Herbert JM. Identification and biological activity of the active metabolite of clopidogrel.Thromb Haemost. 2000; 84: 891-6Crossref PubMed Scopus (709) Google Scholar]; and (ii) several isoforms of CYP450 including 1A2, 2B6, 2D6, 2C9, 2C19 and 3A4 are involved in the metabolism of ticlopidine and clopidogrel [19Savi P. Combalbert J. Gaich C. Rouchon M.C. Maffrand J.P. Berger Y. Herbert JM. The antiaggregating activity of clopidogrel is due to a metabolic activation by the hepatic cytochrome P450‐1A.Thromb Haemost. 1994; 72: 313-17Crossref PubMed Scopus (295) Google Scholar, 20Ko J.W. Desta Z. Soukhova N.V. Tracy T. 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Bates ER. Contribution of hepatic cytochrome P450 3A4 metabolic activity to the phenomenon of clopidogrel resistance.Circulation. 2004; 109: 166-71Crossref PubMed Scopus (482) Google Scholar, 24Angiolillo D.J. Fernandez‐Ortiz A. Bernardo E. Ramirez C. Cavallari U. Trabetti E. Sabate M. Hernandez R. Moreno R. Escaned J. Alfonso F. Banuelos C. Costa M.A. Bass T.A. Pignatti P.F. Macaya C. Contribution of gene sequence variations of the hepatic cytochrome P450 3A4 enzyme to variability in individual responsiveness to clopidogrel.Arterioscler Thromb Vasc Biol. 2006; 26: 1895-900Crossref PubMed Scopus (224) Google Scholar, 25Hulot J.S. Bura A. Villard E. Azizi M. Remones V. Goyenvalle C. Aiach M. Lechat P. Gaussem P. Cytochrome P450 2C19 loss‐of‐function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects.Blood. 2006; 108: 2244-7Crossref PubMed Scopus (825) Google Scholar]. Conversely, the active metabolite and metabolic pathway of ticlopidine are not yet known and not necessarily dependent on these isoforms. One limitation of these observations is that the greater antiplatelet effect of ticlopidine as compared with clopidogrel measured in this work could have been enhanced by modification of the platelet reactivity to ADP, which decreases with time following PCI [6Gurbel P.A. Bliden K.P. Hiatt B.L. O'Connor CM. Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity.Circulation. 2003; 107: 2908-13Crossref PubMed Scopus (1459) Google Scholar, 26Gurbel P.A. Bliden KP. Durability of platelet inhibition by clopidogrel.Am J Cardiol. 2003; 91: 1123-25Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar].Table 1Vasodilator‐stimulated phosphoprotein (VASP) analysis of the platelet reactivity index (PRI) after treatment with clopidogrel or ticlopidineClopidogrel 75 mg day−1Clopidogrel 150 mg day−1Ticlopidine 2 × 250 mg day−1ASTTreatment durationVASP (PRI)ASTTreatment durationVASP (PRI)ASTTreatment durationVASP (PRI)Case 1Yes3 days89%No9 days77%No15 days46%Case 2Yes2 days78%Yes3 days86%No3 days 11 days62% 37%Case 3Yes8 days–No3 days 10 days83% 82%No28 days60%AST, acute stent thrombosis. Open table in a new tab AST, acute stent thrombosis. Our observations nevertheless suggest that the 'old' thienopyridine ticlopidine could represent an alternative for patients presenting clinical and biological non‐responsiveness to clopidogrel. This replacement should of course be subject to hematological monitoring in order to avoid any serious neutropenia. Other platelet P2Y12 inhibitors such as prasugrel, a new thienopyridine with high potency, fast onset and a long duration of action, or AZD6140, a direct competitive antagonist theoretically offering fast blockade of the P2Y12 receptor and less interindividual variability of the response, are under clinical evaluation and may overcome clopidogrel 'resistance' [13Niitsu Y. Jakubowski J.A. Sugidachi A. Asai F. Pharmacology of CS‐747 (prasugrel, LY640315), a novel, potent antiplatelet agent with in vivo P2Y12 receptor antagonist activity.Semin Thromb Hemost. 2005; 31: 184-94Crossref PubMed Scopus (253) Google Scholar, 27Jernberg T. Payne C.D. Winters K.J. Darstein C. Brandt J.T. Jakubowski J.A. Naganuma H. Siegbahn A. Wallentin L. Prasugrel achieves greater inhibition of platelet aggregation and a lower rate of non‐responders compared with clopidogrel in aspirin‐treated patients with stable coronary artery disease.Eur Heart J. 2006; 27: 1166-73Crossref PubMed Scopus (527) Google Scholar, 28Husted S. Emanuelsson H. Heptinstall S. Sandset P.M. Wickens M. Peters G. Pharmacodynamics, pharmacokinetics, and safety of the oral reversible P2Y12 antagonist AZD6140 with aspirin in patients with atherosclerosis: a double‐blind comparison to clopidogrel with aspirin.Eur Heart J. 2006; 27: 1038-47Crossref PubMed Scopus (695) Google Scholar]. However, unlike ticlopidine, these new molecules are not yet available in clinical practice. The authors state that they have no conflict of interest. This work was supported by EFS – Alsace and ARMESA. The authors would like to thank A. Egri and A. Wuillermin for their collaboration, P. Laeuffer for her technical assistance and J. Mulvihill for reviewing the English.