Trimetazidine as an Adjunct to Enhance Clopidogrel Response.
Condition: Platelet Dysfunction Due to Drugs
Study type: Interventional
Phase: Phase 2

Summary: 
      Hypothesis:

      Trimetazidine improves Clopidogrel response in patients.

      • The investigators postulate that the inhibition of platelet aggregation in response to
      Clopidogrel may be accentuated by Trimetazidine, i.e. Trimetazidine enhances Clopidogrel
      response.

      Null Hypothesis:

      There is no difference in Clopidogrel response in patients with stable coronary artery
      disease with adjunctive Trimetazidine.
    

Detailed description: 
      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

      Trimetazidine prevents a decrease in intracellular ATP levels, thereby ensuring the proper
      functioning of ionic pumps and transmembrane sodium-potassium flow whilst maintaining
      cellular homeostasis (8). It is also known that ATP acts as an antagonist of the effects of
      ADP at P2Y1 and P2Y12 receptors (9,10) and that high concentrations can inhibit ADP-induced
      platelet aggregation (11,12). The drug is suitable for initial use as monotherapy in patients
      with angina pectoris and because of its different mechanism of action as adjunctive therapy
      in those with symptoms not sufficiently controlled by nitrates, beta blockers or calcium
      channel antagonists. Multicenter trials of Trimetazidine by a European collaborative working
      group have demonstrated that the antianginal efficacy of Trimetazidine is equivalent to that
      of propranolol but does not reduce cardiac rate-pressure product or coronary blood flow (13).
      The 2013 European Society of Cardiology (ESC) guidelines take into consideration the
      possibility of using Trimetazidine as treatment for stable coronary artery disease-however,
      this is a IIb recommendation (14). The current recommendations do not consider this treatment
      in other cardiovascular diseases such as chronic heart failure (15) or acute coronary
      syndromes (16,17). The role of Trimetazidine in other coronary conditions has yet to be
      clearly established (18).

      Trimetazidine has been treated as a drug with a high safety and tolerability profile (19). It
      has been generally very well tolerated in clinical trials and usually only isolated cases of
      adverse events (ADRs-adverse drug reactions) were observed during treatment (mainly
      gastrointestinal disturbances e.g. vomiting, nausea) (7). Some other very rare and reversible
      adverse effects have also been described such as thrombocytopenia, agranulocytosis and liver
      dysfunction (20). Other minor adverse effects e.g. headache were also reported. Most of them
      were not considered to be directly related to Trimetazidine (20). However, some recently
      reported ADRs require careful evaluation in longer follow-up. The main identified serious ADR
      is connected to Parkinson's syndrome and related symptoms such as tremor (21). It is worth
      emphasizing that extrapyramidal symptoms reported in patients receiving Trimetazidine have a
      very low prevalence (incidence of 0.36/100,000 person-years) and are generally reversible
      after drug withdrawal.

      The investigators postulate that the inhibition of platelet aggregation in response to
      Clopidogrel may be accentuated by Trimetazidine, i.e. Trimetazidine enhances Clopidogrel
      response.
    

Intervention name(s): Trimetazidine
Intervention type(s): Drug
Intervention description(s): 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).
Other intervention name(s): Vasteral MR, Laboratoires Servier, France
Intervention MeSH terms: Trimetazidine
Intervention model: Single Group Assignment
Intervention model description: The study will be of a prospective, randomized, controlled, sequential trial design.
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: platelet inhibition; platelet reactivity; clopidogrel; trimetazidine