Fixed-dose vs. Phenotype-based PrAsugrel Dose to MATCH Therapeutic Zone in Asians With Acute Coronary Syndrome
Condition: Acute Coronary Syndrome; Platelet Thrombus; Bleeding
MeSH terms: Acute Coronary Syndrome; Syndrome
Study type: Interventional
Phase: Phase 4

Summary: 
      The purpose of this study is to determine whether the fixed-dose (prasugrel 10 mg/d vs. 5
      mg/d) vs. phenotype (platlet function test by VerifyNow P2Y12 assay)-based prasugrel dose
      adjustment can match therapeutic zone of platelet reactivity in PCI-treated Asians with acute
      coronary syndrome
    

Detailed description: 
      The combination of clopidogrel and aspirin has been the mainstay treatment strategy to
      prevent ischemic events in a wide spectrum of patients with high-risk coronary artery
      disease. Multiple lines of evidence have demonstrated that patients who are poor responders
      or who have high on-clopidogrel platelet reactivity (HPR) to adenosine diphosphate (ADP) are
      at increased risk of post-percutaneous coronary intervention (PCI) ischemic event occurrence.
      A consensus paper suggested the cutoffs of HPR determined by various platelet function tests
      to be used for personalized antiplatelet therapy. In addition, several clinical studies have
      reported that patients with low on-treatment platelet reactivity (LPR) can be related with
      increased risk of serious bleeding following PCI.

      Although multiple coronary risk factors can influence the response to clopidogrel, the
      cytochrome P450 (CYP) 2C19 loss-of-function allele is a major component in determining the
      level of platelet reactivity and the prevalence of HPR during clopidogrel treatment. There
      are multiple CYP2C19 alleles associated with loss-of-function (*2-*8), and interethnic
      differences in loss-of-function allele carriage exist (Table 1).4 Approximately 30% of
      Caucasians are the CYP2C19 loss-of-function allele carriers with vast majority carry the *2
      allele. However, ~ 65% of East Asians carry the CYP2C19 loss-of-function allele; ~50% carry
      the *2 allele and the rest carry the *3 allele. Furthermore, the influence of the CYP2C19*3
      allele on the antiplatelet response to clopidogrel seems greater compared with the CYP2C19*2
      allele.6 It has been suggested that the high prevalence of CYP2C19 loss-of-function allele
      carriage in East Asians may explain the higher prevalence of HPR during clopidogrel treatment
      (at least 40% during standard-dose administration).

      However, despite the higher prevalence of HPR, numerous prospective clinical studies and
      registry data have shown that East Asians have similar or even lower rates of post-PCI
      ischemic event occurrence during clopidogrel therapy compared with Caucasians- the "East
      Asian paradox". Intriguingly, studies in PCI-treated East Asians have reported higher HPR
      cutoffs compared with HPR cutoffs obtained from the Western population (252.5-288 vs. 208-235
      P2Y12 reaction units [PRU] by the VerifyNow P2Y12 assay). The level and relative contribution
      of HPR to post-stenting ischemic event occurrence in East Asians may differ from the Western
      population.

      Even though East Asians have shown the low level of platelet inhibition during clopidogrel
      treatment, accompanying risk of post-PCI serious bleeding in East Asians was highest compared
      with other races in the CHSRISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic
      Stabilization, Management, and Avoidance) study.16 Moreover, the suggested cutoff of LPR in
      PCI-treated Koreans appeared higher compared with that in Caucasians (e.g. VASP-P index 30%
      vs. 17%). Taken together, East Asians may have an intrinsically reduced risk of arterial
      thrombosis leading to an increased therapeutic zone of platelet reactivity to ADP compared
      with Caucasians (the increased cutoffs of LPR and HPR).

      # Are there ethnic differences in thrombogenecity? Arterial thrombosis is platelet rich and
      superimposed on ruptured and inflamed atherosclerotic lesions.18 However, experimental
      studies suggest that arterial and venous thrombosis are finely regulated processes involving
      a highly complex interplay between platelets and other blood cells, soluble plasma proteins,
      and the vessel wall.18,19 The convincing associations of arterial thrombosis to coagulation
      system and inflammation have been repeatedly demonstrated in multiple clinical trials:
      fibrinogen, factor V Leiden (G1691A) and prothrombin G20210A gene mutations, high-sensitivity
      C-reactive protein (CRP) and so on.

      To date, there is no definite evidence to suggest that differences in intrinsic platelet
      function exist between races. However, there are numerous data suggesting inter-ethnic
      differences in coagulation, fibrinolytic activity, and inflammation. Several population-based
      clinical trials have reported different incidences of venous thromboembolism (VTE) across
      races.23,24 In most studies, patients of Asian descent appear to have a lower rate of VTE
      than other races. Prevalence of arterial thrombosis also has been shown to increase in black
      race compared with non-black race. This disparity between the races has been partially
      explained by genetic risk factors.24 In the Multi-ethnic Study of Atherosclerosis (MESA)
      study evaluating multiple hemostatic factors and plasma endothelial activation markers in
      individuals living in the USA, African Americans generally had the most thrombogenic and
      dysfunctional endothelial profile, followed by Hispanics and Caucasians with similar levels,
      and finally East Asians. A growing body of evidence has demonstrated different levels of
      inflammation between the races, in which East Asians appear to have the lowest level of
      inflammation.

      In summary, East Asians appear to have a less prothrombotic state compared with African
      Americans and Caucasians. The latter observation may explain why the East Asian population
      has a lower risk of ischemic event occurrence and a higher propensity for bleeding during
      clopidogrel treatment after PCI.

      # Future direction of "ethnicity/phenotype-based antiplatelet therapy" Two large-scale,
      prospective clinical trials (Trial to Assess Improvement in Therapeutic Outcomes by
      Optimizing Platelet Inhibition With Prasugrel-TIMI 38 [TRITON-TIMI 38] and PLATelet
      Inhibition and Patient Outcomes [PLATO])30,31 evaluating the clinical efficacy and safety of
      potent P2Y12 receptor inhibitors (prasugrel and ticagrelor) in ACS patients demonstrated the
      superiority of strong platelet inhibition to prevent the occurrence of ischemic events
      compared with clopidogrel treatment. However, the recent "real world" clinical data from
      Western population have shown that ACS patients with LPR (about 30% of total cohort) have the
      increased risk of serious bleeding (e.g. 15.5% of TIMI minor plus major bleeding during
      1-year prasugrel treatment). In the era of potent P2Y12 receptor inhibitors, the concept of
      LPR and overcoming the risk of bleeding may be the emerging target in the field of platelet
      research.

      Because PLATO and TRITON TIMI-38 enrolled a limited number of Asians (~3% of total cohort),
      it is difficult to draw reliable conclusions regarding whether these potent P2Y12 receptor
      inhibitors will provide similar benefits in East Asians compared with other races.
      Aforementioned, East Asians may have an intrinsically reduced risk of arterial thrombosis
      leading to an increased therapeutic zone of platelet reactivity compared with Caucasians.
      Like most cardiovascular drugs, marked interethnic differences in pharmacokinetics and
      pharmacodynamics of prasugrel exist. Exposure of the active metabolite and platelet
      inhibition during prasugrel treatment was higher in East Asians including Chinese, Japanese,
      and Korean populations compared with Caucasians even after adjustment for body weight. In a
      recent pharmacodynamic study including stented Koreans, a 10 mg/d of prasugrel achieved the
      lowest level of PRU compared with 5 mg/d of prasugrel and 75 mg/d of clopidogrel (80.1 ± 45.9
      vs.163.1 ± 61.2 vs. 214.0 ± 69.1, p < 0.001). About two thirds of 10 mg/d prasugrel group met
      the criteria of LPR (≤ 94 PRU), which can support that 10 mg/d of prasugrel is so strong to
      increase the risk of serious bleeding in most of East Asians.

      Taken together, the optimal dosage of antiplatelet regimens and the inhibitory level of the
      target pathway may differ between the races. In East Asians with less thrombogenicity,
      excessive inhibition of platelet function by potent P2Y12 receptor inhibitors may markedly
      increase the risk of serious bleeding without protection against post-PCI ischemic event
      occurrence. Therefore, dedicated investigations in East Asians are required before we can
      apply Western recommendations for novel antiplatelet therapy in the former population. It is
      a time to consider the paradigm shift from "one size fits all" to "ethnicity/phenotype-based
      antiplatelet therapy". We designed the A-MATCH study to cover this unmet need to guarantee
      clinical efficacy and safety in East Asians with less thrombogenicity.
    

Intervention name(s): Prasugrel
Intervention type(s): Drug
Intervention description(s): For fixed-dose group, patients will receive prasugrel 10 or 5 mg/d for 1 month Irrespective of platelet function test.
Intervention MeSH terms: Prasugrel Hydrochloride
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Acute Coronary Syndrome, Asians, platelet, prasugrel