The ImPact of Trimetazidine on MicrOcirculation After Stenting for Stable Coronary Artery Disease
Condition: Coronary Artery Disease; Microcirculation; Vascular Resistance
MeSH terms: Coronary Artery Disease; Myocardial Ischemia; Coronary Disease
Study type: Interventional
Phase: Phase 4

Summary: 
      The study should enrol 50 patients with stable coronary artery disease scheduled for elective
      percutaneous coronary intervention of single, de novo lesion of native coronary artery.
      Patients will be randomized to orally given trimetazidine on top of standard medical therapy
      for stable coronary artery disease versus standard therapy only. The randomization will begin
      48 hrs before intervention. Index of microcirculatory resistance (IMR) will be measured by
      thermodilution method using coronary pressure and temperature wire before and after stent
      implantation. Echocardiography will be performed before intervention and within 30 minutes
      after intervention. Patients will be followed clinically for a period of one year.
    

Detailed description: 
      The study is prospective, single blinded randomized study that will be performed in a single
      tertiary cardiovascular centre. The inclusion criteria for the study are the presence of the
      stable angina or positive stress test, Canadian Cardiovascular Society (CCS) class less than
      IV and an indication for percutaneous intervention of a single, de novo, native coronary
      artery lesion with diameter stenosis greater than 70%. Exclusion criteria are left
      ventricular systolic function (LVEF) less than 30%, acute coronary syndrome, a history of
      previous myocardial infarction in the territory supplied by the treated coronary artery,
      existence of the collateral circulation to another coronary artery supplied by the treated
      vessel, chronic total occlusion, significant bifurcation lesion, previous surgical
      revascularization, significant renal function impairment (GFR less than 60ml/min), allergy to
      any constituents of trimetazidine, aspirin and antiplatelet medications used after PCI,
      contrast agents, contraindication to adenosine use. The patient with disorders like Parkinson
      disease, parkinsonian symptoms, tremors, restless leg syndrome, and other related movement
      disorders will also be excluded from the study.

      Patients, who are trimetazidine naïve, will be randomly assigned to receive either
      trimetazidine plus previous medications (TMZ group) 48h before scheduled PCI or just previous
      medication (Control group). Paients that are TMZ naïve and randomized to TMZ group will be
      given loading of 70mg of TMZ on day 0. The PCI operator would not be aware if the patient
      receives TMZ. All patients will be pretreated before PCI with aspirin 100mg/day, Clopidogrel
      75mg/day seven days before the procedure. Patient will be asked to sign informed consent form
      before entering the study and the study protocol was approved by Ethics committee of Clinical
      Hospital Center Zemun.

      Patients will undergo PCI intervention on day 2. Before PCI patients will receive heparin 80
      - 100 IU/kg iv. PCI procedure has to be performed with angioplasty balloon predilation of the
      treated lesion to avoid influence of direct stenting on IMR measurement. The stenting will be
      performed according to operator's preference. The fractional flow reserve (FFR), coronary
      flow reserve (CFR) and IMR will be measured before and after PCI using coronary pressure - /
      thermistor - tipped wire (Radi Pressure Wire Certus, St Jude Medical, Uppsala, Sweden).
      Maximal hyperemia will be achieved using iv infusion of adenosine (140mcg/kg/min) during the
      procedure. The pressure wire will be advanced through 6F guiding catheter to position the
      pressure sensor at a point 10 mm distal to the distal end of the stenosis or the stent after
      PCI procedure. Three injections of 3ml normal saline at room temperature will be administered
      via guiding catheter at baseline before starting PCI procedure and at maximal hyperemia. The
      transit time will be measured as the time that elapses between the moment when one-half of
      the saline had been injected (defined as T0, and determined on the temperature curve from the
      shaft of the wire) and the moment when one-half of the saline had passed the sensor.
      Simultaneous recordings of mean aortic pressure (guiding catheter, Pa) and mean distal
      coronary pressure (distal pressure sensor, Pd) will also be obtained at baseline and during
      maximal hyperemia. FFR will be calculated by dividing the mean distal coronary pressure (Pd)
      by the mean aortic pressure (Pa) during maximal hyperemia. CFR will be calculated as a ratio
      of mean transit time at basal condition (Tbas) and after inducing hyperemia (Thyp). The IMR
      will be calculated using the following equation: IMR = Pa x Thyp [(Pd - Pw) / (Pa - Pw)],
      where Pw is the coronary wedge pressure. Pw will be measured as the distal coronary pressure
      Pd (from the distal pressure and temperature sensor) during complete balloon occlusion of the
      vessel with the angioplasty balloon during PCI.

      Coronary angiograms will be analyzed offline using a computer-assisted, automated
      edge-detection algorithm using dedicated software Axiom Sensis (Siemens, Erlangen, Germany)
      by an independent operator not involved in the study or PCI procedure. QCA of the lesion,
      TIMI coronary flow, TIMI myocardial blush and TIMI frame count before and after PCI will be
      assessed.

      Comprehensive echocardiogram with 2D-strain analysis will be done before and immediately
      after PCI procedure within 30 minutes after its end.

      After the procedure, the patients who had an uneventful PCI will stay in the hospital for 24
      h. Blood samples for Troponin I, creatin kinaze (CK) and CK-MB will be collected at 6, 12 and
      24 h after the procedure, and for C reactive protein (CRP) after 24h. Complications of the
      interventions will be documented in the patients study file. Periprocedural myocardial
      necrosis is defined as rise in troponin I level three times 99th percentile upper limit of
      reference range, according to definition of myocardial infarction for clinical trials on
      coronary interventions.

      After discharge from the hospital patients will be followed according to hospital protocol.
      Patients will be seen in an office visit 30 days and 6 months after baseline PCI procedure.
      At 12 months after baseline procedure patients' vital status will be assessed by telephone
      interview.

      Statistical analysis

      Continuous data will be summarized as the means ± SD. Categorical data will be summarized as
      counts and percentages. Unpaired t-tests will be used for comparing the continuous variables,
      if the distribution is normal, and Mann Whitney U test if the distribution is not normal.
      Chi-squared test and Fisher's exact test will be used for categorical vari¬ables.
      Multivariate logistic regression analysis will be performed to determine independent
      predictors of impaired IMR after PCI. Univariate analysis would be conducted first to
      identify potential factors for impaired IMR. The likelihood-ratio test will be used, and the
      variables with a p value < 0.2 would be included in the multivariate model. A p value of
      p<0.05 will be considered to be statistically significant. All statistical analyses will be
      performed with the PASWStatistics 18.0 statistical software (SPSS Inc, Chicago, Illinois,
      USA).

      Based on the previous studies it was estimated that study sample size needed for expected
      difference in IMR values of 9 to be obtained between study groups (power 80%) is around 40
      patients.
    

Intervention name(s): trimetazidine
Intervention type(s): Drug
Intervention description(s): After being randomized to Trimetazidin and cardiac medication vs. only cardiac medication, patient will undergo scheduled PCI of single, new, native coronary artery lesion using balloon predilatation and subsequent stenting.
Other intervention name(s): Vastarel MR; Preductal MR; Trimetacor
Intervention MeSH terms: Trimetazidine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Care Provider)
Primary purpose: Treatment
Keywords: trimetazidine; microcirculation; stenting; pressure wire