Clinical Research in Cardiology

, Volume 98, Issue 9, pp 533–540 | Cite as

Comparing the antiplatelet effect of clopidogrel hydrogensulfate and clopidogrel besylate: a crossover study

  • Horst Neubauer
  • Jan Christopher Krüger
  • Sebastian Lask
  • Heinz G. Endres
  • Fenena Pepinghege
  • Andreas Engelhardt
  • Daniel Bulut
  • Andreas Mügge
Original Paper



Clopidogrel hydrogensulfate is a thienopyridine acting as an important antiplatelet agent alone or in combination with acetyl salicylic acid to prevent cardiovascular complications. A different clopidogrel salt, clopidogrel besylate, was approved in Germany as a “new drug” in May 2008. Only one study with 46 healthy men compared the plasma concentrations of both clopidogrel formulas. In our crossover study we measured the antiplatelet effect of clopidogrel hydrogensulfate (CHS, clopidogrel bisulfate) and clopidogrel besylate (CB) using two techniques, whole blood impedance aggregometry and flow cytometry in healthy subjects.


Twenty-one healthy volunteers (14 male, 7 female, mean age 36.3 years) were treated either with CHS or CB (300 mg loading, followed by 75 mg/day) and after a wash-out period of at least 21 days, the participants were switched to the other clopidogrel salt in a crossover design. Blood samples were drawn before and 2, 4 and 48 h after the initial dose was taken. Flow cytometry measurements of CD62P (P-selectin) expression were done at baseline and 48 h thereafter with three different ADP concentrations (5, 15, 50 μmol/L ADP). Whole blood impedance aggregometry testing (Chrono-log Model 590) was performed at baseline and after 2, 4 and 48 h with two ADP concentrations (5 and 20 μmol/L ADP).


Using flow cytometry, the mean inhibitory effect of clopidogrel on the CD62P expression was similar and no significant differences were noted in subjects treated with either of the clopidogrel formulas for hydrogensulfate or besylate salt (5 μmol/L ADP: 8.12 ± 5.53 CHS vs. 6.48 ± 5.01 CB; 15 μmol/L ADP: 9.33 ± 6.44 CHS vs. 8.99 ± 8.27 CB; 50 μmol/L ADP: 11.17 ± 6.81 CHS vs. 9.52 ± 6.17 CB). It is important to note that clopidogrel CB shows similar and conspicuously high interindividual variability as was reported earlier on CHS. We observed both possibilities, subjects responding less to the hydrogensulfate salt, but better to the besylate salt, and vice versa. Using aggregometry, both salt formulas achieved similar inhibitory effects regarding initial platelet function (2 h/5 μmol/L ADP: CHS 4.5 ± 3.66 Ω; CB 3.89 ± 3.81 Ω and 4 h/5 μmol/L ADP: CHS 5.78 ± 3.51 Ω; CB 4.89 ± 4.03 Ω) as well as during the maintenance phase (48 h/5 μmol/L ADP: CHS 2.86 ± 2.92 Ω; CB 3.43 ± 3.06 Ω). Once again the aggregometry results for CB showed a similarly high interindividual variability as also holds true for CHS. Some subjects had a better antiplatelet effect with clopidogrel besylate and vice versa with clopidogrel hydrogensulfate.


The crossover study using whole blood aggregometry and flow cytometry shows no overall significant difference in the antiplatelet effect of clopidogrel hydrogensulfate as compared to clopidogrel besylate. However, it is important to note that besides high interindividual there is also high intraindividual variability between the two different clopidogrel formulas. We observed both: subjects responding less to besylate salt, but better to hydrogensulfate salt, and vice versa.


Clopidogrel hydrogensulfate Clopidogrel besylate Aggregometry Flow cytometry Platelet aggregation 


  1. 1.
    Savi P, Herbert JM (2005) Clopidogrel and ticlopidine: P2Y(12) adenosine diphosphate-receptor antagonists for the prevention of atherothrombosis. Semin Thromb Hemost 31:174–183PubMedCrossRefGoogle Scholar
  2. 2.
    Savi P, Pereillo JM, Uzabiaga MF, Combalbert J, Picard C, Maffrand JP, Pascal M, Herbert JM (2000) Identification and biological activity of the active metabolite of clopidogrel. Thromb Haemost 84:891–896PubMedGoogle Scholar
  3. 3.
    Müller I, Besta F, Schulz C, Massberg S, Schönig A, Gawaz M (2003) Prevalence of clopidogrel non-responders among patients with stable angina pectoris scheduled for elective coronary stent placement. Thromb Haemost 89:783–787PubMedGoogle Scholar
  4. 4.
    Serebruany VL, Steinhubl SR, Berger PB, Malinin AI, Bhatt DL, Topol EJ (2005) Variability in platelet responsiveness to clopidogrel among 544 individuals. J Am Coll Cardiol 45:246–251PubMedCrossRefGoogle Scholar
  5. 5.
    Siller-Matula J, Schrör K, Wojta J, Huber K (2007) Thienopyridines in cardiovascular disease: focus on clopidogrel resistance. Thromb Haemost 97:385–393PubMedGoogle Scholar
  6. 6.
    Maree AO, Fitzgerald DJ (2007) Variable platelet response to aspirin and clopidogrel in atherothrombotic disease. Circulation 115:2196–2207PubMedCrossRefGoogle Scholar
  7. 7.
    Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, Alfonso F, Macaya C, Bass TA, Costa MA (2007) Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives. J Am Coll Cardiol 49:1505–1516PubMedCrossRefGoogle Scholar
  8. 8.
    Ibrahim K, Hass N, Kolschmann S, Strasser RH, Braun-Dullaeus RC (2008) Reversible clopidogrel resistance due to right ventricular myocardial infarction: risk factor of recurrent stent thrombosis? Clin Res Cardiol 97:797–800PubMedCrossRefGoogle Scholar
  9. 9.
    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 107:2908–2913PubMedCrossRefGoogle Scholar
  10. 10.
    Möllmann H, Nef HM, Hamm CW, Elsässer A (2009) How to manage patients with need for antiplatelet therapy in the setting of (un-)planned surgery. Clin Res Cardiol 98:8–15PubMedCrossRefGoogle Scholar
  11. 11.
    Matetzky S, Shenkman B, Guetta V, Shechter M, Bienart R, Goldenberg I, Novikov I, Pres H, Savion N, Varon D, Hod H (2004) Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation 109:3171–3175PubMedCrossRefGoogle Scholar
  12. 12.
    Wenaweser P, Dörffler-Melly J, Imboden K, Windecker S, Togni M, Meier B, Haeberli A, Hess OM (2005) Stent thrombosis is associated with an impaired response to antiplatelet therapy. J Am Coll Cardiol 45:1748–1752PubMedCrossRefGoogle Scholar
  13. 13.
    Geisler T, Langer H, Wydymus M, Göhring K, Zürn C, Bigalke B, Stellos K, May AE, Gawaz M (2006) Low response to clopidogrel is associated with cardiovascular outcome after coronary stent implantation. Eur Heart J 27:2420–2425PubMedCrossRefGoogle Scholar
  14. 14.
    Hochholzer W, Trenk D, Bestehorn HP, Fischer B, Valina CM, Ferenc M, Gick M, Caputo A, Büttner HJ, Neumann FJ (2006) Impact of the degree of peri-interventional platelet inhibition after loading with clopidogrel on early clinical outcome of elective coronary stent placement. J Am Coll Cardiol 48:1742–1750PubMedCrossRefGoogle Scholar
  15. 15.
    Buonamici P, Marcucci R, Migliorini A, Gensini GF, Santini A, Paniccia R, Moschi G, Gori AM, Abbate R, Antoniucci D (2007) Impact of platelet reactivity after clopidogrel administration on drug-eluting stent thrombosis. J Am Coll Cardiol 49:2312–2317PubMedCrossRefGoogle Scholar
  16. 16.
    Patti G, Nusca A, Mangiacapra F, Gatto L, D’Ambrosio A, Di Sciascio G (2008) Point-of-care measurement of clopidogrel responsiveness predicts clinical outcome in patients undergoing percutaneous coronary intervention results of the ARMYDA-PRO (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty-Platelet Reactivity Predicts Outcome) study. J Am Coll Cardiol 52:1128–1133PubMedCrossRefGoogle Scholar
  17. 17.
    Marcucci R, Gori AM, Paniccia R, Giusti B, Valente S, Giglioli C, Buonamici P, Antoniucci D, Abbate R, Gensini GF (2009) Cardiovascular death and nonfatal myocardial infarction in acute coronary syndrome patients receiving coronary stenting are predicted by residual platelet reactivity to ADP detected by a point-of-care assay. A 12-month follow-up. Circulation 119:237–242PubMedCrossRefGoogle Scholar
  18. 18.
    Carlsson J, von Wagenheim B, Linder R, Anwari TM, Qvist J, Petersson I, Magounakis T, Lagerqvist B (2007) Is late stent thrombosis in drug-eluting stents a real clinical issue? A single-center experience and review of the literature. Clin Res Cardiol 96:86–93PubMedCrossRefGoogle Scholar
  19. 19.
    CAPRIE Steering Committee (1996) A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 348:1329–1339CrossRefGoogle Scholar
  20. 20.
    Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK, Clopidogrel in unstable angina to prevent recurrent events trial investigators (2001) Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. New Engl J Med 345:494–502PubMedCrossRefGoogle Scholar
  21. 21.
    Steinhubl SR, Berger PB, Mann JT 3rd, Fry ET, DeLago A, Wilmer C, Topol EJ, for the CREDO Investigators (2002) Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA 288:2411–2420PubMedCrossRefGoogle Scholar
  22. 22.
    Sabatine MS, Cannon CP, Gibson CM, López-Sendón JL, Montalescot G, Theroux P, Claeys MJ, Cools F, Hill KA, Skene AM, McCabe CH, Braunwald E, CLARITY-TIMI 28 Investigators (2005) Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med 352:1179–1189PubMedCrossRefGoogle Scholar
  23. 23.
    Bhatt DL, Topol EJ, Clopidogrel for High Atherothrombotic Risk, Ischemic Stabilization, Management, Avoidance Executive Committee (2004) Clopidogrel added to aspirin versus aspirin alone in secondary prevention and high-risk primary prevention: rationale and design of the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial. Am Heart J 148:263–268PubMedCrossRefGoogle Scholar
  24. 24.
    Chen ZM, Jiang LX, Chen YP, Xie JX, Pan HC, Peto R, Collins R, Liu LS, COMMIT (ClOpidogrel, Metoprolol in Myocardial Infarction Trial) collaborative group (2005) Addition of clopidogrel to aspirin in 45, 852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet 366:1607–1621PubMedCrossRefGoogle Scholar
  25. 25.
  26. 26.
    Silber S, Borggrefe M, Böhm M, Hoffmeister HM, Dietz R, Ertl G, Heusch G (2008) Drug-eluting coronary stents and drug eluting balloon catheters: summary of the position papers of the DGK. Clin Res Cardiol 97:548–563PubMedCrossRefGoogle Scholar
  27. 27.
    Michelson AD, Barnard MR, Krueger LA, Frelinger AL 3rd, Furman MI (2000) Evaluation of platelet function by flow cytometry. Methods 21:259–270PubMedCrossRefGoogle Scholar
  28. 28.
    Neubauer H, Günesdogan B, Hanefeld C, Spiecker M, Mügge A (2003) Lipophilic statins interfere with the inhibitory effects of clopidogrel on platelet function—a flow cytometry study. Eur Heart J 24:1744–1749PubMedCrossRefGoogle Scholar
  29. 29.
    Weber AA, Adamzik M, Bachmann HS, Görlinger K, Grandoch M, Leineweber K, Müller-Beißenhirtz H, Wenzel F, Naber C (2008) Methods to evaluate the pharmacology of oral antiplatelet drugs. Herz 33:287–296PubMedCrossRefGoogle Scholar
  30. 30.
    Ivandic BT, Schlick P, Staritz P, Kurz K, Katus HA, Giannitsis E (2006) Determination of clopidogrel resistance by whole blood platelet aggregometry and inhibitors of the P2Y12 receptor. Clin Chem 52:383–388PubMedCrossRefGoogle Scholar
  31. 31.
    Neubauer H, Lask S, Engelhardt A, Mügge A (2008) How to optimise clopidogrel therapy? Reducing the low-response incidence by aggregometry-guided therapy modification. Thromb Haemost 99:357–362PubMedGoogle Scholar
  32. 32.
    Brandt JT, Payne CD, Wiviott SD, Weerakkody G, Farid NA, Small DS, Jakubowski JA, Naganuma H, Winters KJ (2007) A comparison of prasugrel and clopidogrel loading doses on platelet function: magnitude of platelet inhibition is related to active metabolite formation. Am Heart J 153:66.e9-16Google Scholar
  33. 33.
  34. 34.
    Poole-Wilson PA, Swedberg K, Cleland JG, Di Lenarda A, Hanrath P, Komajda M, Lubsen J, Lutiger B, Metra M, Remme WJ, Torp-Pedersen C, Scherhag A, Skene AM (2003) Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomised controlled trial. Lancet 362:7–13PubMedCrossRefGoogle Scholar
  35. 35.
    Hjalmarson A, Goldstein S, Fagerberg B, Wedel H, Waagstein F, Kjekshus J, Wikstrand J, El Allaf D, Vitovec J, Aldershvile J, Halinen M, Dietz R, Neuhaus KL, Janosi A, Thorgeirsson G, Dunselman PH, Gullestad L, Kuch J, Herlitz J, Rickenbacher P, Ball S, Gottlieb S, Deedwania P (2000) Effects of controlled-release metoprolol on total mortality, hospitalizations, and wellbeing in patients with heart failure: the Metoprolol CR/XL Randomized Intervention Trial in congestive heart failure (MERIT-HF). MERIT-HF Study Group. JAMA 283:1295–1302PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Horst Neubauer
    • 1
  • Jan Christopher Krüger
    • 1
  • Sebastian Lask
    • 1
  • Heinz G. Endres
    • 2
  • Fenena Pepinghege
    • 1
  • Andreas Engelhardt
    • 1
  • Daniel Bulut
    • 1
  • Andreas Mügge
    • 1
  1. 1.Cardiovascular Center, St. Josef HospitalRuhr University BochumBochumGermany
  2. 2.Department of Medical Informatics, Biometry and EpidemiologyRuhr University BochumBochumGermany

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