Trimetazidine as an Adjunct to Enhance Clopidogrel Response: The TRACER Study.

Rationale and Background:

Dual antiplatelet therapy with Aspirin and Clopidogrel represents the standard of care for the prevention of recurrent ischemic events in patients undergoing percutaneous coronary intervention (PCI). For more than 10 years, dual antiplatelet therapy with Aspirin and Clopidogrel has remained the cornerstone of treatment for patients with acute coronary syndrome (ACS). However, some patients have impaired Clopidogrel response and thus persist with high on-treatment platelet reactivity (HOT-PR) resulting in an increased risk of atherothrombotic events (1). This can be attributed to several factors such as genetic polymorphisms regulating the activity of the cytochrome P450 (CYP) 2C19 enzyme, which is key in metabolizing Clopidogrel into its active metabolite (2,3). The boxed warning added to the Clopidogrel label underscoring the potential risk of adverse cardiovascular outcomes among patients with a "poor metabolizer" genotype and advocating the use of other antiplatelet medications or alternative dosing strategies for these patients (4) has led to investigations of treatment options associated with more optimal platelet inhibition. These include increasing Clopidogrel dosing, adding a third antiplatelet agent (e.g. Cilostazol) and switching to a novel generation P2Y12 inhibitor (e.g. Prasugrel or Ticagrelor). The novel oral P2Y purinoceptor 12 (P2Y12) receptor inhibitors Prasugrel and Ticagrelor were approved by the FDA for clinical use in 2009 and 2011 respectively (5).

Activation of P2Y12 inhibits AC, causing a decrease in cAMP and VASP-P levels and activation of P2Y1 causes an increase in intracellular Ca2+ levels. These changes promote platelet aggregation by altering the ligand-binding properties of the GP IIb/IIIa receptor. Inhibition of the P2Y12 receptor therefore, suppresses platelet activation (5).

Trimetazidine is a clinically effective antianginal agent that has no negative inotropic or vasodilator properties (6). It is presently clinically used throughout Europe and in >80 countries worldwide. It is a cytoprotective drug that normalizes metabolic disturbances in low-flow ischemia via several-not yet fully understood-mechanisms of action (7). The best-known mechanism of action is its capacity to inhibit β-oxidation of free fatty acid (FFA) (7). The main cytoprotective mechanisms (7) are outlined in the following table:

FFA breakdown inhibition and glucose breakdown stimulation Reduction in the amount of oxygen necessary for ATP production Reduction in the cellular accumulation of lactic acid and H+ Reduction in the cellular accumulation of Na+ and Ca2+ Reduction in ATP losses for maintaining ion homeostasis Reduction of adverse effects of overloading cells with calcium Anti-radical effect Reduction of granulocyte infiltration to the ischaemic and reperfused area of the myocardium Cardiomyocyte apoptosis inhibition