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

• Published in: Clinical research in cardiology 2009-09, Vol.98 (9), p.533-540
• Main Authors: Neubauer, Horst, Krüger, Jan Christopher, Lask, Sebastian, Endres, Heinz G, Pepinghege, Fenena, Engelhardt, Andreas, Bulut, Daniel, Mügge, Andreas
• Format: Article
• Language: English
• Subjects: Adult; Cardiology; Cross-Over Studies; Dose-Response Relationship, Drug; Female; Flow cytometry; Humans; Male; Medicine; Medicine & Public Health; Middle Aged; Original Paper; Platelet Activation - drug effects; Platelet Aggregation - drug effects; Platelet Aggregation Inhibitors - administration & dosage; Ticlopidine - administration & dosage; Ticlopidine - analogs & derivatives; Treatment Outcome; Young Adult
• ISSN: 1861-0684; 1861-0692
• DOI: 10.1007/s00392-009-0033-1

Background 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. Methods 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). Results 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 a