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Impaired bioavailability and antiplatelet effect of high-dose clopidogrel in patients after cardiopulmonary resuscitation (CPR)

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Abstract

Purpose

Bioavailability of clopidogrel in the form of crushed tablets administered via nasogastric tube (NGT) has not been established in patients after cardiopulmonary resuscitation. Therefore, we performed a study comparing pharmacokinetic and pharmacodynamic response to high loading dose of clopidogrel in critically ill patients after cardiopulmonary resuscitation (CPR) with patients scheduled for elective coronary angiography with stent implantation.

Methods

In the NGT group (nine patients, after cardiopulmonary resuscitation, mechanically ventilated, therapeutic hypothermia), clopidogrel was administered in the form of crushed tablets via NGT. Ten patients undergoing elective coronary artery stenting took clopidogrel per os (po) in the form of intact tablets. Pharmacokinetics of clopidogrel was measured with high-performance liquid chromatography (HPLC) before and at 0.5, 1, 6, 12, 24 h after administration of a loading dose of 600 mg. In five patients in each group, antiplatelet effect was measured with thrombelastography (TEG; Platelet Mapping) before and 24 h after administration.

Results

The carboxylic acid metabolite of clopidogrel was detected in all patients in the po group. In eight patients, the maximum concentration was measured in the range of 0.5–1 h after the initial dose. In four patients in the of NGT group, the carboxylic acid metabolite of clopidogrel was undetectable and in the remaining patients was significantly delayed (peak values at 12 h). All patients in the po group reached clinically relevant (>50 %) inhibition of thrombocyte adenosine diphosphate (ADP) receptor after 24 h compared with only two in the NGT group (p = 0.012). There was a close correlation between peak of inactive clopidogrel metabolite plasmatic concentration and inhibition of the ADP receptor (r = 0.79; p < 0.001).

Conclusion

The bioavailability of clopidogrel in critically ill patients after cardiopulmonary resuscitation is significantly impaired compared with stable patients. Therefore, other drugs, preferentially administered intravenously, should be considered.

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References

  1. Mills DC, Puri R, Hu CJ, Minniti C, Grana GF, Colman RF, Colman RW (1992) Clopidogrel inhibits the binding of ADP analogues to the receptor mediating inhibition of platelet adenylate cyclase. Arteriosc Thromb 12(4):430–436

    Article  CAS  Google Scholar 

  2. Alstrom U, Tyden H, Oldgren J, Siegbahn A, Stahle E (2007) The platelet inhibiting effect of a clopidogrel bolus dose in patients on long-term acetylsalicylic acid treatment. Thromb Res 120(3):353–359

    Article  PubMed  Google Scholar 

  3. CAPRIE Steering Committee (1996) A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 348(9038):1329–1339

    Article  Google Scholar 

  4. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK (2001) Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 345(7):494–502

    Article  PubMed  CAS  Google Scholar 

  5. Antman EM, Hand M, Amstrong PW, Bate ER, Green LA, Halasyamani LK, Hochman JS, Krumholz HM, Lamas GA, Mullany CJ, Pearle DL, Sloan MA, Smith SC (2008) 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 practise guidelines. Circulation 117(2):296–329

    Article  PubMed  Google Scholar 

  6. Mehta SR, Bassand JP, Chrolavicius S, Diaz R, Fox KA, Granger CB, Jolly S, Rupprecht HJ, Widimsky P, Yusuf S (2008) Design and rationale of CURRENT-OASIS: a randomized, 2 × 2 factorial trial evaluating optimal dosing strategies for clopidogrel and aspirin in patients with ST and non-ST-elevation acute coronary syndromes managed with an early invasive strategy. Am Heart J 156(6):1080–1088

    Article  PubMed  CAS  Google Scholar 

  7. Silber S, Albertsson P, Aviles FF, Camici PG, Colombo A, Hamm C, Jorgensen E, Marco J, Nordrehaug JE, Ruzyllo W, Urban P, Stone GW, Wijns W (2005) Guidelines for percutaneous coronary interventions. The Task Force for Percutaneous Coronary Interventions of the European Society of Cardiology. Eur Heart J 26(8):804–847

    Article  PubMed  Google Scholar 

  8. Sabatine MS, Cannon CP, Gibson CM, López-Sendón JL, Montalescot G, Theroux P, Lewis BS, Murphy SA, McCabe CH, Braunwald E (2005) Effect of clopidogrel pretreatment before percutaneous coronary intervention in patients with ST-elevation myocardial infarction treated with fibrinolytics: the PCI-CLARITY Study. JAMA 294(10):1224–1232

    Article  PubMed  CAS  Google Scholar 

  9. Berger PP, Steinhubl S (2002) Clinical implications of Percutaneous Coronary Intervention-Clopidogrel in Unstable angina to prevent Recurrent Events (PCI-CURE) Study: a US perspective. Circulation 106(17):2284–2287

    Article  PubMed  Google Scholar 

  10. PLAVIXTM, RxMed: Pharmaceutical Information, Sanofi/Bristol- Mayers Squibb www.RXlist.com

  11. Pereillo JM, Maftouh M, Andrieu A, Uzabiaga MF, Fedeli O, Savi P, Pascal M, Herbert JM, Maffrand JP, Picard C (2001) Structure and stereochemistry of the active metabolite of clopidogrel. Drug Metab Dispos 30(11):1288–1295

    Article  Google Scholar 

  12. Chapman MJ, Nguyen NQ, Fraser RJ (2007) Gastrointestinal motility nad prokinetics in the critically ill. Curr Opin Crit Care 13(2):187–194

    Article  PubMed  Google Scholar 

  13. Beckwith MC, Feddema SS, Barton RG, Graves C (2004) A guide to drug therapy in patients with enteral feeding tubes: dosage form selection and administration methods. Hosp Pharm 39(3):225–237

    Google Scholar 

  14. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, Alfonso F, Macaya C, Bass TA (2007) Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives. J Am Coll Cardiol 49(14):1505–1516

    Article  PubMed  CAS  Google Scholar 

  15. Gurbel PA, Bliden KP, Hiatt BL, O’Connor CM (2003) Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation 107(23):2908–2929

    Article  PubMed  Google Scholar 

  16. O’Donoghue M, Wiviott SD (2006) Clopidogrel response variability and future therapies: clopidogrel: does one size fit all? Circulation 114(22):600–606

    Article  Google Scholar 

  17. Taubert D, Kastrati A, Harlfinger S, Gorchakova O, Lazar A, von Beckerath N, Schömig A, Schömig E (2004) Pharmacokinetics of clopidogrel after administration of a high loading dose. Thromb Haemost 92(2):311–316

    PubMed  CAS  Google Scholar 

  18. Gurbel PA, Bliden KP, Hayes KM, Yoho JA, Herzog WR, Tantry US (2005) The relation of dosing to clopidogrel responsiveness and the incidence of high posttreatment platelet aggregation in patients undergoing coronary stenting. J Am Coll Cardiol 45(9):1392–1396

    Article  PubMed  CAS  Google Scholar 

  19. Ernesto O, Martin H, Ronald D (2007) Clopidogrel resistance. Heart Lung Circ 16(3):17–28

    Google Scholar 

  20. Michelson AD (2009) Methods for the measurement of platelet function. Am J Cardiol 103(3):20–26

    Article  Google Scholar 

  21. Coulter SA, Cannon CP, Ault KA, Antman EM, Van de Werf F, Adgey AA, Gibson CM, Giugliano RP, Mascelli MA, Scherer J, Barnathan ES, Braunwald E, Kleiman NS (2000) High levels of platelet inhibition with abciximab despite heightened platelet activation and aggregation during thrombolysis for acute myocardial infarction: results from TIMI (thrombolysis in myocardial infarction). Circulation 101(23):2690–2695

    Article  PubMed  CAS  Google Scholar 

  22. Vocilkova L, Opatrilova R, Sramek V (2009) Determination of clopidogrel by chromatography. Curr Pharm Anal 5(4):424–431

    Article  CAS  Google Scholar 

  23. Caplain H (1999) Pharmacokinetics od clopidogrel. Semin Thromb Hemost 25(2):25–28

    PubMed  CAS  Google Scholar 

  24. Nirogi RVS (2006) Quantification of clopidogrel in human plasma by sensitive liquid chromatography/tandem mass spectrometry. Mass Spectrom 20(11):1695–1700

    CAS  Google Scholar 

  25. Harlfinger S (2004) Pharmacokinetics of clopidogrel and its active matabolite in human plasma. Annual Scientific Session of the American College of Cardiology. New Orleans, LA. March 7–10

  26. Kastrati A (2004) Are we making efficient use of clopidogrel? Eur Hear J 25(6):454–456

    Article  CAS  Google Scholar 

  27. Collyer TC, Gray DJ, Sandhu R, Berridge J, Lyons G (2009) Assesment of platelet inhibition secondary to clopidogrel and aspirin therapy in preoperative acute surgical patients measured by Thrombelastography Platelet Mapping. Br J Anaesth 102(4):492–498

    Article  PubMed  CAS  Google Scholar 

  28. Craft RM, Chavez JJ, Bresee SJ, Wortham DC, Cohen E, Carroll RC (2004) A novel modification of the Thrombelastograph assay, isolating platelet function, correlates with optical platelet aggregation. J Lab Clin Med 143(5):301–309

    Article  PubMed  Google Scholar 

  29. Bochsen L, Wiinberg B, Kjelgaard-Hansen M, Steinbruchel DA, Johanson PI (2007) Evaluation of TEG platelet mapping assay in blood donors. Thromb J 5(3):509–518

    Google Scholar 

  30. Hobson AR, Agarwala RA, Swallow RA, Dawkins KD, Curzen NP (2006) Thrombelastography: current clinical applications and its potential role in interventional cardiology. Platelets 17(8):509–518

    Article  PubMed  CAS  Google Scholar 

  31. Gurbel PA, Tantry US (2007) Clopidogrel resistance? Thromb Res 120(3):311–321

    Article  PubMed  CAS  Google Scholar 

  32. Uchiyama S (2011) Clopidogrel resistance: identifying and overcoming a barrier to effective antiplatelet treatment. Cardiovasc Ther 29(6):100–111

    Article  Google Scholar 

  33. Michelson AD (2004) Platelet function testing in cardiovascular diseases. Circulation 110(19):489–493

    Article  Google Scholar 

  34. Nguyen TA, Diodati JG, Pharand CH (2005) Resistance to clopidogrel: a review of the evidence. J Am Coll Cardiol 45(8):1157–1164

    Article  PubMed  CAS  Google Scholar 

  35. Heestermans CM, van Werkum JW, Seesing TH, von Beckerath CM, Hackeng CM, Schömig E, Verheugt FW, ten Berg JM (2008) Impaired bioavalability of clopidogrel in patients with ST-segment elevation myocardial infarction. Thromb Response 122(6):776–777

    Article  CAS  Google Scholar 

  36. Preisman S, Kogan A, Itzkovsky K, Leikin G, Raanani E (2010) Modified Thromboelastography evaluation of platelet dysfunction in patients undergoing coronary artery surgery. Eur J Cardiothorac Surg 37(6):1367–1374

    Article  PubMed  Google Scholar 

  37. Blinden KP, DiCiara J, Tantry US, Bassi AK, Chaganti SK, Gurbel PA (2007) Increased risk in patients with high platelet aggregation receiving chronic clopidogrel therapy undergoing percutaneous coronary intervention. J Am Coll Cardiol 49(6):657–666

    Article  Google Scholar 

  38. von Beckerath N, Taubert D, Pogatsa-Murray G, Schömig E, Kastrati A, Schömig A (2005) Absorption, metabolization, and antiplatelet effects of 300-, 600-, and 900-mg loading doses of clopidogrel: results of the ISAR-CHOICE (Intracoronary Stenting and Antithrombotic Regimen: Choose Between 3 High Oral Doses for Immediate Clopidogrel Effect) Trial. Circulation 112(19):2946–2950

    Google Scholar 

  39. Zafar MU, Farkouh ME, Fuster V, Chesebro JH (2009) Crushed clopidogrel administred via nasogasrtic tube has faster and greater absorption than oral whole tablets. J Interv Cardiol 22(4):385–389

    Article  PubMed  Google Scholar 

  40. Rafferty G, Tham TCK (2010) Endoscopically placed enteral feeding tubes. World J Gastrointest Endosc 2(5):155–164

    PubMed  Google Scholar 

  41. Müller I, Seyfarth M, Rüdiger S, Wolf B, Pogatsa-Murray G, Schömig A (2001) Effect of a high loading dose of clopidogrel on platelet function in patients undergoing coronary stent placement. Heart 85(1):92–93

    Article  PubMed  Google Scholar 

  42. Deniz T, Agalar C, Agalar F, Comu FM, Caglayan O, Alpay Y, Saygun O (2010) The effect of hypothermia on splanchnic flows and lung in a two-hit hemorrhagic shock model. J Surg Res 158(1):121–126

    Article  PubMed  Google Scholar 

  43. Croughwell ND, Newman MF, Lowry E et al (1997) Effect of temperature during cardiopulmonary bypass on gastric mucosal perfusion. Br J Anaesth 78:34–38

    Article  PubMed  CAS  Google Scholar 

  44. Thoren A, Elam M, Ricksten SE (2001) Jejunal mucosal perfusion is well maintained during mild hypothermic cardiopulmonary bypass in humans. Anesth Analg 92:5–11

    Article  PubMed  CAS  Google Scholar 

  45. Rokyta R Jr, Matejovic M, Krouzecky A, Opatrny K Jr, Ruzicka J, Novak I (2004) Effects of continuous venovenous haemofiltration-induced cooling on global haemodynamics, splanchnic oxygen and energy balance in critically ill patients. Nephrol Dial Transplant 19(3):623–630

    Article  PubMed  Google Scholar 

  46. Tortorici MA, Kochanek PM, Poloyac SM (2007) Effects of hypothermia on drug disposition, metabolism, and response: a focus of hypothermia-mediated alterations on the cytochrome P450 enzyme system. Crit Care Med 35(9):2196–2204

    Article  PubMed  CAS  Google Scholar 

  47. Polderman KH (2009) Mechanisms of action, physiological effects, and complications of hypothermia. Crit Care Med 37(7):S186–S202

    Article  PubMed  Google Scholar 

  48. Cundrle I Jr, Sramek V, Zvonicek V (2010) Influence of temperature adjustment on thrombelasthography results. Intensive Care Med 36(2):152

    Google Scholar 

  49. Ruzicka J, Stengl M, Bolek L, Benes J, Matejovic M, Krouzecky A (2012) Hypothermic anticoagulation: testing individual responses to graded severe hypothermia with thromboelastography. Blood Coagul Fibrinolysis. Mar 3. [Epub ahead of print]

  50. Kafian S, Mobarrez F, Kalani M, Wallén H, Samad BA (2011) Comparison of venous and arterial blood sampling for the assessment of platelet aggregation with whole blood impedance aggregometry. Scand J Clin Lab Invest 71(8):637–640

    Article  PubMed  Google Scholar 

  51. Durila M, Kalinčík T, Jurčenko S, Pelichovská M, Hadačová I, Cvachovec K (2010) Arteriovenous differences of hematological and coagulation parameters in patients with sepsis. Blood Coagul Fibrinolysis 21(8):770–774

    PubMed  CAS  Google Scholar 

  52. Price MJ, Coleman JL, Steinhubl SR, Wong GB, Cannon CP, Teirstein PS (2006) Onset and offset of platelet inhibition after high-dose clopidogrel loading and standard daily therapy measured by a point-of-care assay in healthy volunteers. Am J Cardiol 98(5):681–684

    Article  PubMed  CAS  Google Scholar 

  53. Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT, Walker JR, Antman EM, Macias W, Braunwald E, Sabatine MS (2009) Cytochrome P-450 polymorphisms and response to clopidogrel. N Engl J Med 360(4):354–362

    Article  PubMed  CAS  Google Scholar 

  54. Simon T, Verstuyft C, Mary-Krause M, Quteineh L, Drouet E, Méneveau N, Steg PG, Ferrières J, Danchin N, Becquemont L, French Registry of Acute ST-Elevation and Non-ST-Elevation Myocardial Infarction (FAST-MI) Investigators (2009) Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 360(4):363–375

    Article  PubMed  CAS  Google Scholar 

  55. Brand JT, Close SL, Iturria SJ, Payne CD, Farid NA, Ernest CS 2nd, Lachno DR, Salazar D, Winters KJ (2007) Common polymorhism of CYP2C19 and CYP2C9 affect the pharmacokinetc and pharmacodynamic response to clopidogrel but not prasugrel. J Thromb Haemost 5(12):2429–2436

    Article  Google Scholar 

  56. Steinhubl SR, Talley JD, Braden GA (2001) Point of care measured platelet inhibition correlates with a reduced risk of an adverse cardiac event after percutaneous coronary intervention: results of the GOLD(AU-Assessing Ultegra) multicenter study. Circulation 103(21):2528–2530

    Article  Google Scholar 

  57. Rao SV, Melloni C, Myles-Dimauro S, Broderick S, Kosinski AS, Kleiman NS, Dzavík V, Tanguay JF, Chandna H, Gammon R, Rivera E, Alexander JH, Fier I, Roach J, Becker RC, EMINENCE Investigators (2010) Evaluation of a new heparin agent in percutaneous coronary intervention: results of the phase 2 evaluation of M118 IN pErcutaNeous Coronary intErvention (EMINENCE) Trial. Circulation 121(15):1713–1721

    Article  PubMed  CAS  Google Scholar 

  58. Mahan CE, Fanikos J (2011) New antithrombotics: the impact on global health care. Thromb Res 127:518–524

    Article  PubMed  CAS  Google Scholar 

  59. Christian W, Hamm CW, Bassand JP, Agewall S, Bax J, Boersma E, Bueno H, Caso P, Dudek D, Gielen S, Huber K, Ohman M, Petrie MC, Sonntag F, Uva MS, Storey RF, Wijns W, Zahger D (2011) ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J 1–56

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Authors and Affiliations

  1. Department of Anaesthesiology and Intensive Care, University Hospital St. Anne’s Brno, Brno, Czech Republic

    L. Součková, P. Suk, I. Čundrle Jr., M. Pavlík, V. Zvoníček, O. Hlinomaz & V. Šrámek

  2. Faculty of Medicine, Masaryk University, Brno, Czech Republic

    P. Suk, I. Čundrle Jr., M. Pavlík, V. Zvoníček, O. Hlinomaz & V. Šrámek

  3. Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences Brno, Brno, Czech Republic

    R. Opatřilová

  4. International Clinical Research Center, University Hospital St. Anne’s Brno, Brno, Czech Republic

    L. Součková & O. Hlinomaz

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  1. L. Součková
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Correspondence to V. Šrámek.

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Součková, L., Opatřilová, R., Suk, P. et al. Impaired bioavailability and antiplatelet effect of high-dose clopidogrel in patients after cardiopulmonary resuscitation (CPR). Eur J Clin Pharmacol 69, 309–317 (2013). https://doi.org/10.1007/s00228-012-1360-0

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