Summary
Background
The salt linked to the clopidogrel molecule in generic preparations is suspected to affect its clinical efficacy. There is a lack of information about inhibition of platelet reactivity by generic preparations.
Aims
To compare the effect of original clopidogrel (clopidogrel bisulphate [Plavix ® ]), generic clopidogrel preparations (clopidogrel hydrochloride [Clopidogrel-Mepha ® ]; clopidogrel besylate [Clopidogrel Sandoz ® ]) and prasugrel (Efient ® ) on platelet reactivity in patients with coronary artery disease.
Methods
Patients with coronary artery disease treated with stents received, in a random sequence, original clopidogrel bisulphate, clopidogrel hydrochloride and clopidogrel besylate. Platelet function was assessed with the Multiplate analyser after an initial loading dose (600 mg) and at day 10 after each treatment period. Prasugrel was given for another 10 days. An adenosine diphosphate (ADP) test value < 46 antiaggregation units (U) was defined as therapeutic platelet inhibition.
Results
Sixty patients (mean age 69 ± 10 years; 50 men) were randomized. Original clopidogrel bisulphate, clopidogrel hydrochloride and clopidogrel besylate provided similar inhibition of platelet reactivity with values of 31 ± 25, 33 ± 28 and 28 ± 23 U, respectively ( P not significant). Prasugrel provided better inhibition of platelet function (10 ± 11 vs. 31 ± 25 U for clopidogrel bisulphate; P < 0.001). An ADP test value > 46 U was measured in 11 patients (18%) with clopidogrel bisulphate, 13 (22%) with clopidogrel besylate and 13 (22%) with clopidogrel hydrochloride compared with only one (2%) with prasugrel.
Conclusion
Generic clopidogrel preparations provided similar inhibition of platelet reactivity to original clopidogrel bisulphate, although prasugrel was more efficient.
Résumé
Objectifs
Le but de cette étude est de comparer l’effet sur l’agrégation plaquettaire de la molécule originale de clopidogrel (clopidogrel bisulfate [Plavix ® ]) aux molécules génériques (clopidogrel besylate [clopidogrel Sandoz ® ] et clopidogrel hydrochloride [clopidogrel-Mepha ® ]) et au prasugrel (Efient ® ).
Historique
On suspecte que le sel utilisé pour lier la molécule de clopidogrel pourrait changer l’efficacité du médicament et par là même avoir un impact sur son activité d’antiagrégant plaquettaires. Aucune information n’est actuellement disponible.
Méthode
Des patients avec maladie coronaire traités par angioplastie et mise en place de stent ont été inclus dans cette étude. Ils ont reçu de manière randomisée les trois molécules de clopidogrel, à savoir le clopidogrel bisulfate (Plavix ® ), le clopidogrel hydrochloride (Clopidogrel-Mepha ® ) et le clopidogrel besylate (Clopidogrel Sandoz ® ) pour une durée de dix jours chacune. Après cette période de 30 jours les malades étaient placés sous prasugrel pour une nouvelle période de dix jours. L’agrégation plaquettaire a été mesurée après la dose de charge (600 mg) et après chaque intervalle de traitement de dix jours. Un appareil de type Multiplate Analyzer a été utilisé pour évaluer la fonction plaquettaire. Une valeur d’ADP inférieure à 46 U représentait une antiagrégation plaquettaire efficace.
Résultats
Soixante patients (50 hommes) avec un âge moyen de 69 ± 10 ans ont été inclus. Il n’y avait pas de différence significative de l’activité antiagrégante entre les trois préparations de clopidogrel, le clopidogrel bisulfate, le clopidogrel hydrochloride et le clopidogrel besylate avec des valeurs d’ADP de, respectivement, 31 ± 25 U, 33 ± 28 et 28 ± 23 U ( p = NS). Le prasugrel est significativement plus efficace que l’ensemble des clopidogrel ; 10 ± 11 U vs. 31 ± 25 U. Une valeur d’ADP supérieure à 46 U a été observée chez 11 malades avec le clopidogrel bisulfate (19,6 %), 12 malades (21,1 %) avec le clopidogrel besylate et 13 malades (23,2 %) avec le clopidogrel hydrochloride. Seul un patient (2,3 %) avec le prasugrel avait une valeur d’ADP supérieure à 46 U.
Conclusion
Le niveau d’antiagrégation plaquettaire obtenu avec les préparations génériques de clopidogrel est comparable à celui obtenu avec la forme originale alors que le prasugrel est plus efficace.
Background
Dual antiplatelet therapy with aspirin and thienopyridine is essential after coronary intervention and stent placement . The level of on-treatment platelet reactivity is associated with long-term adverse cardiovascular events after percutaneous coronary intervention (PCI) . The efficacy of such treatment is largely influenced by interindividual variability in the pharmacodynamic response to clopidogrel . In addition, clopidogrel recently became generic; several commercial preparations are now available in which clopidogrel is linked to a salt that might change its clinical efficacy. None of these generic preparations has been validated other then by pharmacodynamic tests. In this prospective trial, we use a platelet function test to compare, in routine clinical practice, platelet reactivity after randomized administration of two new generic clopidogrel preparations (clopidogrel besylate [Clopidogrel Sandoz ® ] and clopidogrel hydrochloride [Clopidogrel-Mepha ® ]) and the original preparation (clopidogrel bisulphate [Plavix ® ]).
Methods
Patient selection and study design
Consecutive patients with ischaemic heart disease undergoing PCI with stent implantation were considered for enrolment in this trial. PCI was performed using standard techniques by the femoral or radial route. Exclusion criteria were: cardiogenic shock; pregnancy; intolerance to aspirin, thienopyridine or contrast media; poor compliance; active bleeding; inability to give informed consent; anaemia; thrombocytopenia; moderate-to-severe renal failure (defined as creatinine clearance of 30 to 60 mL/min and < 30 mL/min, respectively); planned surgery; or inability to have follow-up information. Patients already treated with thienopyridines were equally excluded. All patients gave their written informed consent and the protocol was approved by the hospital’s ethical committee. The control group was composed of 50 healthy medication-free adults. The subjects in the control group did not receive any antiplatelet therapy. The rationale behind having a control group was to confirm the validity of the platelet aggregation test.
This was a single-blind randomized trial with complete crossover ( Fig. 1 ). The primary endpoint was therapeutic antiaggregation defined as a value of < 46 antiaggregation units (U) on whole blood platelet function testing. Randomization was achieved with envelopes, the patients being assigned to one of the three clopidogrel groups for 10 days, then crossed over to another clopidogrel molecule, as shown in Fig. 1 .
Percutaneous coronary intervention and antiplatelet therapy management
At the time of PCI, all patients received 500 mg of aspirin in addition to either unfractionated or low-molecular-weight heparin. A loading dose (600 mg) of clopidogrel was given at the end of the procedure. The clopidogrel molecule was chosen at random between original clopidogrel bisulphate, clopidogrel hydrochloride or clopidogrel besylate. After treatment initiation, the clopidogrel preparation was given for 10 days at a dose of 75 mg/day. At days 10 and 20, the clopidogrel molecule was changed to a new molecule, so that after 30 days all patients had received all clopidogrel preparations for 10 days. After this initial 30-day period, a loading dose (60 mg) of prasugrel was given, followed by a maintenance dose of 10 mg/day for 10 days. After these 40 days, the patient was left for 1 year on the drug that provided the lowest platelet reactivity.
Platelet reactivity assessment
Platelet reactivity testing of clopidogrel and prasugrel was performed using the Multiplate analyser (Dynabyte, Munich, Germany). This method has been approved for human use by the United States Food and Drug Administration. The assay is made up of two distinct silver electrode sensors. The changes in the electrodes’ impedance after platelet adhesion is detected by the sensor and allows aggregation units to be calculated. The variables evaluated are: maximal aggregation, velocity (steepness of the curve) and area under the curve (AUC, AU min), calculated from the mean values of the two curves. The final result is expressed in units (U), with 1 U defined as 10 AU min. Platelet reactivity was assessed 6 hours after the loading dose of clopidogrel and every 10 days at the time of the switch of the clopidogrel preparation. Efficient platelet inhibition was defined as an adenosine diphosphate (ADP) test value < 46 U. Patients with values > 46 U received a loading dose of another clopidogrel preparation on the same day, with repeated platelet function measurement after 6 hours.
For the trial, the operator determining platelet reactivity was blinded to the treatment arm, patient characteristics and biomarkers.
Statistical analyses
We performed a power analysis that concluded the inclusion of 60 patients at resistance rates of 15% for original clopidogrel and 40% for the generic clopidogrel preparations would yield a statistical power of 88% at a significance level of alpha equal to 0.05 for a two-tailed analysis. The power analysis was performed for proportions of paired samples.
Continuous variables are presented as mean ± standard deviation and after confirmation of a normal distribution (QQ plot). To compare antiaggregation units achieved with the different clopidogrel preparations, the paired t test was employed. Categorical variables are presented as numbers and percentages. We considered a P value < 0.05 as significant. SPSS software, version 18 (SPSS Inc., Chicago, IL, USA) was used for statistical analyses.
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