Factors contributing to clopidogrel resistance

Factors contributing to clopidogrel resistance or variability in response to clopidogrel

Factors contributing to clopidogrel resistance: Genetic factors responsible for variability in clinical response to clopidogrel (clopidogrel resistance) include polymorphisms of CYP (Cytochrome P), GPIa (Glycoprotein Ia), P2Y₁₂ and GPIIIa (Glycoprotein IIIa).

It may be noted that antiplatelet therapy is the cornerstone for treatment of patients with acute coronary syndrome and those undergoing percutaneous coronary interventions. Dual antiplatelet therapy (DAPT) with aspirin and clopidogrel reduces major adverse cardiovascular events (MACE). But despite having DAPT, MACE do occur, indicating resistance and other patient and procedure related factors. These of course have become lesser with the newer agent ticagrelor.

Clinical factors which contribute to a variable response to clopidogrel may be poor compliance, lower doses, poor absorption, drug-drug interactions involving CYP3A4, acute coronary syndrome, diabetes mellitus/insulin resistance and elevated body mass index.

Cellular factors which may cause clopidogrel resistance may be accelerated platelet turnover, reduced CYP3A metabolic activity, increased ADP exposure, upregulation of the P2Y₁₂ pathway, upregulation of the P2Y₁ pathway and upregulation of P2Y–independent pathways (collagen, epinephrine, TX₂ or thromboxane A₂, thrombin) [1].

Reference

1. Dominick J Angiolillo, Antonio Fernandez-Ortiz, Esther Bernardo, Fernando Alfonso, Carlos Macaya, Theodore A Bass, Marco A Costa. Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives. J Am Coll Cardiol. 2007 Apr 10;49(14):1505-16.