Effects of Ticagrelor Versus Prasugrel on Coronary Microcirculation in Patients Undergoing Elective Percutaneous Coronary Intervention: Results of the PROtecting MICROcirculation During Coronary Angioplasty (PROMICRO)-3 Randomised Study
Condition: Coronary Artery Disease
MeSH terms: Coronary Artery Disease
Study type: Interventional
Phase: Phase 4

Summary: 
      Besides being at least as effective as prasugrel in inhibiting platelet aggregation,
      ticagrelor has been shown to have additional properties potentially affecting coronary
      microcirculation. We sought to compare the effects of ticagrelor and prasugrel on absolute
      coronary blood flow (Q) and microvascular resistance (R) in patients with stable coronary
      artery disease (CAD) undergoing elective percutaneous coronary intervention (PCI).

      The PROMICRO-3 study shows that in patients with stable CAD undergoing PCI pre-treatment with
      a loading dose of ticagrelor compared with prasugrel improves post-procedural coronary flow
      and microvascular function and seems to reduce the related myocardial injury.
    

Detailed description: 
      Patient population We enrolled patients naïve to platelet P2Y12 receptor inhibitors with
      stable CAD referred to elective percutaneous coronary intervention (PCI) of an isolated,
      functionally significant (as confirmed by a fractional flow reserve [FFR] <0.80) stenosis
      located in the proximal two-thirds of a major coronary artery.

      Study protocol Patients were randomly assigned to receive loading doses of either ticagrelor
      (180 mg) or prasugrel (60 mg) at least 12 hours before intervention. Assignment to one of the
      two treatments was determined by a computer-based randomization system and randomization
      assignment for each patient was kept in a sealed envelope. At least 12 hours before PCI
      (average 13.8±1.1), a study nurse not involved in the procedure was responsible of opening
      the sealed envelope and administering study drugs according to treatment allocation. Both the
      patient and the catheterization laboratory team (operator and scrubbed nurse) were blinded to
      the assigned treatment. The PCI procedures were performed by standard technique. In all
      cases, balloon pre-dilatation was performed before stent implantation.

      Adjunctive medications All patients were administered a 500-mg loading dose of aspirin the
      day before the procedure. In the catheterization laboratory, all patients received a
      weight-adjusted intravenous heparin bolus (100 IU/kg) in order to maintain activated clotting
      time between 250 and 300 seconds. Patients randomized to the prasugrel group received
      clopidogrel 75 mg once daily as of the day after the PCI, whereas patients randomized to the
      ticagrelor group received a 600-mg loading dose the day after PCI, and a 75-mg maintenance
      dose as of the next day.8

      Coronary physiology indexes Coronary physiology indexes were measured in each patient before
      and after PCI. Briefly, an intracoronary pressure/temperature sensor-tipped guide wire
      (PressureWire X, Abbott, IL) was advanced through the guiding catheter in the distal segment
      of the target coronary artery. A dedicated monorail catheter (RayFlow, Hexacath, Paris,
      France), allowing the infusion of saline through 4 outer side holes and the measurement of
      temperature by the guidewire through 2 inner side holes, was then advanced over the
      guidewire. The tip of the infusion catheter was placed in the first centimeter of the
      coronary artery, and the catheter was connected to an infusion pump (Medrad Stellant; Medrad
      Inc, Warrendale, PA), and saline at room temperature infused at a pre-specified flow rate
      (Qi, 20 mL/min for the left anterior descending [LAD] and left circumflex artery [LCx] and 15
      mL/min for the right coronary artery [RCA]), resulting in a hyperaemic state similar to that
      produced by adenosine. The temperature of the saline/blood mixture (T) and the distal
      coronary pressure (Pd) were measured after achieving a steady state. Aortic pressure (Pa) was
      measured through the guiding catheter. Fractional flow reserve (FFR) was calculated as Pd/Pa
      during hyperaemia. The temperature of the infused saline (Ti) was measured after pulling the
      temperature sensor of the guidewire back into the infusion catheter. Pressure tracings and
      temperatures were simultaneously analysed by a dedicated console equipped with software that
      automatically calculates physiology indexes (Coroventis Coroflow, Uppsala, Sweden). Q was
      calculated as 1.08 x (Ti/T) x Qi, and expressed in ml/min. Following the Ohm's law, R was
      calculated as Pd/Q, and expressed as mm Hg/L/min, or Wood units.

      Platelet function analysis Platelet reactivity was measured before study drug assignment and
      at the time of PCI using the VerifyNow P2Y12 assay (Accumetrics, San Diego, California). The
      VerifyNow P2Y12 assay is a validated optical turbidimetric point-of-care assay specifically
      assessing the effects of P2Y12 receptor inhibitors:12 the results are reported as P2Y12
      reaction units (PRU), and the lower the PRU value, the higher the platelet aggregation
      inhibition.

      Peri-procedural myocardial injury High sensitivity Troponin I (hs-TnI; Roche Diagnostics,
      Mannheim, Germany) was determined in blood samples taken before, 8 and 24 hours after the
      intervention. Peak post-PCI hs-TnI levels were considered for the analysis.

      Statistical analysis At the time the study was conceived, no published data were available on
      this topic. However, an estimate of Q values was assumed from preliminary data collected at
      our Institution.10 Expecting a 20% reduction in post-PCI R with ticagrelor compared with
      prasugrel (320±75 vs 400±85 mmHg/l/min), a total of at least 23 patients per group were
      needed to achieve 90% power at a 2-sided alpha of 0.05 to detect the anticipated difference.
      Therefore, we aimed at enrolling a total of 50 patients (25 per group). Continuous variables
      are expressed as mean ± SD or as median [25th, 75th percentile], as appropriate. Categorical
      variables are reported as frequencies and percentages. Normal distribution was tested with
      the Shapiro-Wilk W test. Comparisons between continuous variables were performed using the
      Student t test or Mann-Whitney test. These tests were corrected for repeated measures where
      appropriate. Repeated measures 2-way analysis of variance (ANOVA) was used to assess the
      effect interaction between treatment and time on continuous variables. Comparisons between
      categorical variables were evaluated using the Fisher exact test or the Pearson chi-square
      test, as appropriate. Correlations between continuous variables were assessed using the
      Spearman correlation test. Statistical analysis was performed using STATA/IC 14 (STATA Corp.,
      College Station, Texas) and p values <0.05 (two tailed) were considered significant.
    

Intervention name(s): Ticagrelor; Prasugrel
Intervention type(s): Drug; Drug
Intervention description(s): Patient treated with 180 mg ticagrelor 12 hours before the procedure; Patient treated with 60 mg prasugrel 12 hours before the procedure
Other intervention name(s): Ticagrelor 180 mg; Pasugrel 60 mg
Intervention MeSH terms: Ticagrelor; Prasugrel Hydrochloride
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Patients were randomly assigned to receive loading doses of either ticagrelor (180 mg) or prasugrel (60 mg) at least 12 hours before intervention. Assignment to one of the two treatments was determined by a computer-based randomization system.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Other
Keywords: Coronary Flow; Coronary Resistances; Platelet Reactivity