Antiplatelet therapy in myocardial infarction and coronary stent thrombosis Heestermans, Antonius Adrianus Cornelius Maria

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1 University of Groningen Antiplatelet therapy in myocardial infarction and coronary stent thrombosis Heestermans, Antonius Adrianus Cornelius Maria IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2010 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Heestermans, A. A. C. M. (2010). Antiplatelet therapy in myocardial infarction and coronary stent thrombosis Groningen: s.n. Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date:

2 7 Clopidogrel resistance caused by a failure to metabolize clopidogrel into its metabolites A.A.C.M. Heestermans, J.W. van Werkum, E. Schömig, J.M. ten Berg, D. Taubert J Thromb Haemost. 2006;4:1143-5

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4 Coronary stent thrombosis Introduction The combination of clopidogrel and aspirin has become standard therapy in patients undergoing percutaneous coronary intervention (PCI) to prevent stent thrombosis. Clopidogrel is a prodrug that is absorbed in the intestine. About 85% of the drug is hydrolyzed by esterases to an inactive carboxylic acid derivative. However, a small fraction is converted into the intermediate metabolite 2-oxo-clopidogrel by hepatic cytochrome P450 (CYP3A4) monooxygenase [1]. The instable 2-oxo-clopidogrel is non-enzymatically hydrolyzed to the active thiol metabolite that irreversibly binds to the adenosine diphosphate (ADP) P2Y12 receptor resulting in a partial inhibition of platelet aggregation [1,2]. However, several studies have demonstrated a considerable interindividual variability in the response to clopidogrel and Matetzky et al. have recently demonstrated the clinical relevance of an inadequate platelet response to clopidogrel [5]. Case A thirty-eight-year-old woman with no medical history presented at our catheterisation laboratory with an acute myocardial infarction. The patient gave informed consent to obtain additional blood samples to investigate platelet response to a 600 mg loading dose of clopidogrel. Before catheterisation clopidogrel 600 mg and aspirin 300 mg were administered orally and heparin 70 IU/kg was given intravenously. Coronary angiography of the right coronary artery showed a thrombotic occlusion with TIMI I flow. The left coronary artery appeared to be normal. The thrombus was aspirated and two TAXUS Express stents (3.5x32 mm and 3.5x24 mm) were placed resulting in TIMI III flow. A post procedural ECG showed resolution of ST segment elevation and the complaints of chest pain diminished. During the procedure an acetone odour was distinctly present. Laboratory testing revealed severe hyperglycaemic metabolic acidosis and increased inflammatory markers. Two hours after the PCI procedure, the patient developed severe progressive cardiogenic shock, and the patient died five hours after PCI. Histological examination of the aspirated material showed that it consisted of fresh thrombus. Macroscopic examination of the heart revealed a myocardial infarction of the inferior wall and of the right ventricle. Examination of the right coronary artery showed two fully expanded stents with a fresh in-stent thrombus. Clopidogrel action was monitored with the commercially available Plateletworks (Helena Laboratories, Beaumont, Texas) platelet aggregation test that is previously described [7,10]. The patient demonstrated no significant inhibition of ADP (20µM)-induced platelet aggregation at 2 and 4 hours as compared to baseline (before clopidogrel administration). In addition, we measured the plasma concentrations of clopidogrel, the inactive carboxyl metabolite and the active thiol metabolite with a recently developed liquid chromatography tandem mass 109

5 Chapter 7 spectrometric (LC-MS/MS) method [6]. The pharmacokinetics of a 600 mg loading dose of clopidogrel in this patient and in four consecutive control ST-Elevation Myocardial Infarction (STEMI) patients undergoing primary PCI are depicted in fig 1. As compared to the control group, which showed a significant platelet response (mean inhibition of ADP induced platelet aggregation was 27% ± 7 at 4 hours), high levels of clopidogrel and extreme low levels of the carboxyl metabolite and the active thiol metabolite were measured. Concentrations of the active metabolite were approximated from the linear calibration of the clopidogrel standard as previously described [6]. 䌀氀漀瀀椀搀漀最爀攀氀 㠀 䌀愀猀攀 䌀漀渀琀爀漀氀 䌀氀漀瀀椀搀漀最爀攀氀 渀最 洀氀 㘀 㐀 アハ ート 㐀 㔀 㘀 吀椀洀攀 栀爀猀 䌀愀爀戀漀砀礀氀䴀攀琀愀戀漀氀椀琀攀 䌀愀猀攀 䌀漀渀琀爀漀氀 䌀愀爀戀漀砀礀氀洀攀琀愀戀漀氀椀琀攀 渀最 洀氀 アハ ート アハ ート 㐀 㔀 㘀 吀椀洀攀 栀爀猀 110

6 Coronary stent thrombosis 䄀挀琀椀瘀攀䴀攀琀愀戀漀氀椀琀攀 䌀愀猀攀 䌀漀渀琀爀漀氀 䄀挀琀椀瘀攀䴀攀琀愀戀漀氀椀琀攀 渀最 洀氀 㐀アハ ート アハ ート 㐀 㔀 㘀 吀椀洀攀 栀爀猀 Figure 1: Pharmacokinetics of a 600 mg dose of clopidogrel in our patient with clopidogrel resistance as compared to four STEMI control patients. The plasma concentrations of clopidogrel (A), its inactive carboxyl metabolite (B) and its active metabolite (C) were determined before and serially after administration of a 600 mg loading dose of clopidogrel in patients undergoing primary PCI. Blue squares denote measurements in the patient with clopidogrel resistance whereas red dots denote measurements (mean concentrations) in the control patients. Measurements were performed with LC-MS/MS 6. Discussion Several factors have been associated with clopidogrel resistance: impaired intestinal absorption, the availability and activity of cytochrome P450 isoenzymes [7, 8], baseline platelet reactivity [3], and polymorphisms in the gene coding for the P2Y12 receptor [9]. In the present case, we have demonstrated that the peak plasma concentration of clopidogrel in this patient is much higher as compared to the four consecutive control patients suggesting that intestinal absorption of clopidogrel in this patient was not impaired. Furthermore, our data suggest that this patient was not able to metabolize clopidogrel into its inactive carboxyl acid derivative, and in its intermediate and subsequent active metabolite. Failure to metabolize clopidogrel to its intermediate metabolite is a new finding in clopidogrel resistance. In the present case, this may have been due to a malfunction of the CYP3A4 monooxygenase-dependent metabolism. This important isoenzyme is involved in the biotransformation of clopidogrel. Lau and colleagues has shown that the 111

7 Chapter 7 activity of CYP3A4 is related to the extent of platelet inhibition achieved with clopidogrel [8]. Furthermore, expression and function of CYP3A4 is influenced by many factors including administration of commonly prescribed drugs. However, in the present case no medication with a major influence on CYP3A4 activity was administrated. Interestingly, our patient presented with a severe hyperglycaemic ketoacidosis. Therefore, the decreased clopidogrel metabolism may also have been due to the metabolic acidosis with an ph of 7.0 at presentation. However, the activity of CYP3A4 is usually not reduced at this level of ph [11]. Moreover, simultaneous impairment of CYP3A4 independent formation of the carboxyl metabolite points towards overall reduction of hepatic enzyme activity. In addition, clinical situations with elevated pro-inflammatory cytokines (like diabetic ketoacidosis) have been shown to play an important role in the down-regulation of cytochrome P 450 dependent drug metabolism [12,13]. We hypothesize that this is a possible explanation for the decreased clopidogrel metabolism in this patient. The increased CRP (309 mg/l) and leucocytes (18.0 G/L) at presentation are supportive for this hypothesis. Given the fact that diabetic patients have an increased platelet reactivity, it is likely that the severe hyperglycaemic metabolic acidosis and elevated inflammatory parameters have contributed to the fatal thrombotic complication in this patient. The currently used techniques for monitoring the response to clopidogrel are time consuming and labour intensive. Subsequently, it is impossible to implement the results into immediate change of treatment strategies which could improve clinical outcome. Conclusion We report about a patient with acute stent thrombosis, unimpaired clopidogrel absorption but failure to metabolize clopidogrel into its metabolites. Although the mechanism of this failure remains speculative, this is the first documented case that links an inadequate clopidogrel response to clinical outcome. 112

8 Coronary stent thrombosis References 1. Savi P, Pereillo JM, Uzabiaga MF, Combalbert J, Picard C, Maffrand JP, Pascal M, Herbert JM. Identification and biological activity of the active metabolite of clopidogrel. Thromb Haemost. 2000;84(5): Hollopeter G, Jantzen HM, Vincent D, Li G, England L, Ramakrishnan V, Yang RB, Nurden P, Nurden A, Julius D, Conley PB. Identification of the platelet ADP receptor targeted by antithrombotic drugs. Nature. 2001;409(6817): Gurbel PA, Bliden KP, Hiatt BL, O Connor CM. Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation. 2003;107(23): Muller I, Besta F, Schulz C, Massberg S, Schonig A, Gawaz M. Prevalence of clopidogrel nonresponders among patients with stable angina pectoris scheduled for elective coronary stent placement. Thromb Haemost. 2003;89(5): Matetzky 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(25): Taubert D, Kastrati A, Harlfinger S, Gorchakova O, Lazar A, von Beckerath N, Schomig A, Schomig E. Pharmacokinetics of clopidogrel after administration of a high loading dose. Thromb Haemost. 2004;92(2): Lau WC, Waskell LA, Watkins PB, Neer CJ, Horowitz K, Hopp AS, Tait AR, Carville DG, Guyer KE, Bates ER. Atorvastatin reduces the ability of clopidogrel to inhibit platelet aggregation: a new drug-drug interaction. Circulation. 2003;107(1): Lau WC, Gurbel PA, Watkins PB, Neer CJ, Hopp AS, Carville DG, Guyer KE, Tait AR, Bates ER. Contribution of hepatic cytochrome P450 3A4 metabolic activity to the phenomenon of clopidogrel resistance. Circulation. 2004;109(2): Fontana P, Dupont A, Gandrille S, Bachelot-Loza C, Reny JL, Aiach M, Gaussem P. Adenosine diphosphate-induced platelet aggregation is associated with P2Y12 gene sequence variations in healthy subjects. Circulation. 2003;108(8): Lakkis NM, George S, Thomas E, Ali M, Guyer K, Carville D. Use of ICHOR-platelet works to assess platelet function in patients treated with GPIIb/IIIa inhibitors. Catheter Cardiovasc Interv. 2001;53(3): Lee AJ, Kosh JW, Conney AH, Zhu BT. Characterization of the NADPH-dependent metabolism of 17beta-estradiol to multiple metabolites by human liver microsomes and selectively expressed human cytochrome P450 3A4 and 3A5. J Pharmacol Exp Ther. 2001;298(2): Stentz FB, Umpierrez GE, Cuervo R, Kitabchi AE. Proinflammatory cytokines, markers of cardiovascular risks, oxidative stress, and lipid peroxidation in patients with hyperglycemic crises. Diabetes. 2004;53(8): Jover R, Bort R, Gomez-Lechon MJ, Castell JV. Down-regulation of human CYP3A4 by the inflammatory signal interleukin-6: molecular mechanism and transcription factors involved. FASEB J. 2002;16(13):

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