Ticagrelor Loading Dose Versus Clopidogrel Loading and Reloading With Ticagrelor.
Condition: Platelet Reactivity
Study type: Interventional
Phase: Phase 3

Summary: 
      In the PLATO substudy referring to patients presenting with an ST-elevation Myocardial
      Infarction(STEMI), out of the 4201 who received ticagrelor, 1326 had been pre-treated with a
      600mg clopidogrel loading dose (LD) within 24 hours prior to randomization. It is a logical
      assumption, that patients who are being reloaded with ticagrelor will demonstrate reduced
      platelet reactivity (PR) at 24 hours, in comparison to those who were initially loaded with
      ticagrelor, due to the synergistic antiplatelet effect. Single loading with ticagrelor
      though, will possibly be accompanied by a smaller bleeding potency compared to reloading with
      ticagrelor. Therefore, we assume that single loading with ticagrelor is non-inferior to
      reloading with ticagrelor, in terms of platelet reactivity.

      P2Y12 inhibitor naive patients with STEMI, they will be randomized immediately after coronary
      angiography (Hour 0) in receiving either Ticagrelor 180mg LD or Clopidogrel 600mg LD and 2
      hours later reloading with Ticagrelor 180mg, after written informed consent. PR will be
      measured, using the VerifyNow assay at randomization (Hour 0) and at 2, 4, 6 and 24 hours
      post randomization. In addition, a 12-lead ECG will be performed before randomization, 90 and
      180 minutes after the first balloon inflation, as well as on the exit day. Troponin I and
      CK-MB will be assessed at randomization and at hour 4, 12, 24, 48 and 72 after randomization.

      Non inferiority of Ticagrelor LD versus Ticagrelor re-LD would be accepted if the upper bound
      of the 2-sided 95% CI around the estimated LS mean difference (Ticagrelor LD minus Ticagrelor
      re-LD) in the primary end point (PR at 24 hours) would lie bellow Δ=35 PRU. This
      non-inferiority margin (Δ) represents the upper bound of the LS mean difference in PR between
      Ticagrelor and Prasugrel arm at 24 hours after LD in a pharmacodynamic study of 55 STEMI
      patients.

      Considering previous studies PR at 24 hours post randomization was estimated at 47±40 PRU and
      41±35 PRU for Ticagrelor only LD and Ticagrelor re-LD group respectively. To obtain 85%
      statistical power with a 2-sided alpha=0.05, approximately 32 patients in each treatment
      group (64 in total) would be needed to establish the primary hypothesis using the
      abovementioned non-inferiority margin of 35 PRU. Anticipating a 5% dropout rate, enrollment
      was set to at least 68 patients. The primary endpoint, as well as PR at all the other time
      points of the study will be analyzed separately via a mixed effect model with treatment as
      fixed effect, patient as a random intercept and PR at baseline as a covariate. Least squares
      estimates of the mean difference will be presented, with 95% confidence intervals and a
      two-sided p-value for the treatment effect. P values for secondary endpoints will be reported
      for two-tailed tests of superiority.
    


Intervention name(s): Clopidogrel and Ticagrelor; Ticagrelor
Intervention type(s): Drug; Drug
Intervention description(s): Clopidogrel 600mg loading dose followed by Ticagrelor 180mg loading dose; Ticagrelor 180mg loading dose
Intervention MeSH terms: Clopidogrel; Ticagrelor
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary purpose: Treatment
Keywords: platelet reactivity; ticagrelor loading dose; clopidogrel loading dose