Salts of Clopidogrel: Investigation to ENsure Clinical Equivalence
Condition: Acute Coronary Syndrome; Coronary Artery Disease; Ischemic Stroke; Peripheral Artery Disease; Carotid Artery Disease; Atrial Fibrillation
MeSH terms: Ischemic Stroke; Carotid Artery Diseases; Atrial Fibrillation; Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Acute Coronary Syndrome; Peripheral Arterial Disease
Study type: Observational

Summary: 
      Clopidogrel besylate (CB) is not differentiated relative to the orignal clopidogrel hydrogen
      sulfate (CHS) in the pharmacokinetics and in antiplatelet potency in healthy volunteers. In
      addition,CB exhibits similar pharmacodynamic properties compared to CHS in patients with a
      history of acute coronary syndrome (ACS) and in patients with ACS undergoing percutaneous
      coronary intervention (PCI). However, there is a lack of data on the clinical efficacy and
      safety of this salt to the original salt in patients with cardiovascular disease. The aim of
      this study is to investigate the clinical efficacy and safety of CB in relation to that of
      CHS in patients eligible to receive clopidogrel.
    

Detailed description: 
      It is now well documented that platelets play an important role in the pathogenesis of acute
      coronary syndromes. This phenomenon has significantly strengthened the position of
      antiplatelet drugs in treatment, and prevention of these syndromes. In terms of
      administration, antiplatelet drugs are divided into two categories, the oral and intravenous
      medications. Of these, oral medications are the choice for long-term or prophylactic
      treatment of patients with acute coronary syndrome. Among them, is clopidogrel, which
      together with aspirin is now the cornerstone of antiplatelet therapy. Indeed, clopidogrel is
      a widely used antiplatelet drug. It is second in sales worldwide after atorvastatin and has
      been prescribed to more than 100 million patients worldwide. Clopidogrel can be used as
      monotherapy or in combination with aspirin. The efficacy in reducing ischemic events in
      patients with ACS has been shown in more than 15 major clinical studies involving more than
      200,000 patients. These studies also proved the safety of clopidogrel to the bleeding
      complications (only 1-2% per year).Clopidogrel is a second generation thienopyridine that
      inhibits the binding of ADP to purinergic receptors of platelet membrane. The ADP activates
      platelets through different receptors coupled to G-proteins. The main receptor for platelet
      activation by ADP is P2Y12, associated with the adenyl cyclase and cause deactivation of the
      resulting reduction in the levels of c-AMP. The identification of this receptor led to the
      complete elucidation of the mechanism of action of clopidogrel, which proved to be an
      irreversible antagonist P2Y12.

      Clopidogrel is a prodrug that, once granted, is absorbed in the intestine by a process in
      which an important role is played by the protein carrier ABCB1/MDR1. Then clopidogrel is
      converted in the liver to the pharmacologically active metabolite by the action of cytochrome
      P450 (CYP450) and mainly isoform CYP2C19 and isoforms CYP3A4, CYP3A5, CYP1A2, CYP2B6 and
      CYP2C9. It should be noted that 85% of clopidogrel absorbed, hydrolyzed by esterases in the
      intestinal mucosa and blood to form biologically inactive products while only 15% of the
      administered drug is converted to its active metabolite, which is a potent, irreversible,
      selective inhibitor of receptor P2Y12 ADP resulting in the inhibition of the activation of
      receptor GPIIb / IIIa and thereby preventing platelet aggregation.

      Currently, clopidogrel generic forms are available in the market. Indeed, in 2010 and after
      10 years of circulation of the original formulation (clopidogrel bisulfate) under the trade
      names Plavix or Iscover, released new generic formulations of clopidogrel (generic) due to
      expiration of the period of exclusive marketing using the original formulation. Main
      difference of generic forms of clopidogrel to the original formulation (clopidogrel
      bisulfate) is pharmacochemical recommendation salt of clopidogrel, which in the case of
      generic formulations is benzenesulfonic (besylate) or hydrochloride salt. Generic
      formulations of clopidogrel have received marketing approval from the health authorities of
      the European Union. Bioequivalence comparative studies of clopidogrel generic formulations in
      healthy volunteers for generic clopidogrel bisulfate, clopidogrel besylate and clopidogrel
      hydrochloride have proven same pharmacodynamic and pharmacokinetic profile. Considering the
      wide variability of platelet response to clopidogrel treatment and the high incidence of
      atherothrombotic events in clopidogrel hyporesponsive patients, studies comparing the
      pharmacodynamic properties of various generic clopidogrel formulations with those of original
      clopidogrel bisulfate in CAD patients are essential.

      Therefore, given the numerous generic clopidogrel salts that are commercially available
      today, it is of importance to note that any clinical data or research results arising from
      the use of these formulations in patients with cardiovascular disease should be related to
      the specific product used and not generally to the generic clopidogrel.

      Our group has performed two prospective pharmacodynamic studies comparing the antiplatelet
      effectiveness of clopidogrel besylate with that of clopidogrel bisulfate in patients with a
      history of an ACS, and in ACS patients undergoing PCI. In both studies we showed
      pharmacodynamic bioequivalence in all platelet function tests performed.

      There is a strong need of conducting further clinical studies with adequate number of
      patients with each clopidogrel generic formulation commercially available in order to confirm
      its therapeutic equivalence with the innovator product.
    

Observational model: Other
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Suitable for the study will be every patient eligible to receive clopidogrel based on the
        international guidelines. In particular, in the study will participate patients with an
        acute coronary syndrome (ACS) or having a stable coronary artery disease (CAD). Patients
        who have experienced an acute ischemic stroke or a transient ischemic attack (TIA) during
        the previous 6 months or having a history of peripheral artery disease (PAD) or carotid
        artery disease, will be also eligible for enrollment. Finally, patients with atrial
        fibrillation (AF) who will refuse or will not be eligible to use of any oral anticoagulant
        will be included in the study. The study will include at least 1,500 patients (at least 750
        will receive clopidogrel hydrogen sulfate and at least 750 clopidogrel besylate).
      
Keywords: clopidogrel besylate; clopidogrel hydrogen sulfate; Generic clopidogrel; Coronary Artery Disease