Pharmacogenetic Approach to Anti-platelet Therapy for the Treatment of ST-segment Elevation Myocardial Infarction (STEMI)
Condition: STEMI
MeSH terms: Myocardial Infarction; ST Elevation Myocardial Infarction; Infarction
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      The objective of the RAPID STEMI study is to evaluate the feasibility, efficacy, and safety
      of a pharmacogenetic approach to anti-platelet therapy for the treatment of ST-segment
      elevation myocardial infarction (STEMI) patients following percutaneous coronary intervention
      (PCI) using point-of-care genetic testing for the CYP2C19*2, *17, and ABCB1 3435 C>T alleles.
    

Detailed description: 
      Dual anti-platelet therapy following percutaneous coronary intervention (PCI) for the
      treatment of STEMI has traditionally consisted of aspirin and clopidogrel. Despite this
      treatment approach, a substantial portion of patients experience recurrent adverse
      cardiovascular events including death, myocardial infarction, and stent thrombosis. This
      persistent vulnerability has been associated with inadequate platelet inhibition in response
      to clopidogrel administration, a phenomenon referred to as high on-treatment platelet
      reactivity. Although multiple variables have been implicated in altered clopidogrel response,
      mounting evidence has suggested a crucial role for common genetic variants including:
      CYP2C19*2, *17, and ABCB1 3435 C>T alleles.

      Presence of the CYP2C19*2 allele has been associated with a 1.5- to 6-fold increased risk of
      cardiovascular death, myocardial infarction, and stent thrombosis following PCI in patients
      treated with clopidogrel. These findings, recently bolstered by 2 separate meta-analyses, led
      the American Food and Drug Administration to issue a boxed warning for clopidogrel stating
      that poor metabolizers may not receive the full benefit of the drug. The ABCB1 3435 TT
      genotype has also been linked with increased adverse cardiovascular events in individuals
      treated with clopidogrel following PCI for an acute coronary syndrome. In contrast, the
      CYP2C19*17 gain-of-function allele appears to enhance the activity of clopidogrel and has
      been associated with reduced ischemic events but increased bleeding.

      As a result of these findings, experts have begun to advocate for routine genotyping in the
      context of PCI. A personalized approach to dual anti-platelet therapy following PCI is
      feasible given the presence of treatment alternatives such as prasugrel that are capable of
      overcoming clopidogrel resistance. Selective administration of prasugrel to patients at
      increased risk of clopidogrel resistance has the potential to successfully minimize adverse
      ischemic events, while simultaneously minimizing associated bleeding events and health care
      costs. A prospective pharmacogenomic approach to anti-platelet therapy has been previously
      hampered by limited access and the time-delay associated with genetic testing. The
      development of point-of-care genetic testing for the CYP2C19*2, *17, and ABCB1 3435 C>T
      alleles that requires minimal training to perform carries the potential to overcome these
      obstacles and may facilitate the incorporation of pharmacogenetic strategies into routine
      clinical practice.

      Patients receiving PCI in the context of STEMI will undergo point-of-care genetic testing for
      the CYP2C19*2, *17, and ABCB1 3435 C>T alleles. CYP2C19*2 carriers and individuals homozygous
      for the ABCB1 3435 T allele will subsequently be randomized to prasugrel 10mg daily for 1
      month or clopidogrel 150mg daily for 1 week followed by 75mg daily. The remaining individuals
      without an at-risk genotype will receive standard therapy with clopidogrel. At the end of the
      1 month period, efficacy of the treatment strategies will be evaluated using VerifyNow
      platelet function testing. The effect of the CYP2C19*17 allele will be prospectively
      evaluated during the treatment period.
    

Intervention name(s): Point-of-Care Genetic Testing; Prasugrel
Intervention type(s): Genetic; Drug
Intervention description(s): Point-of-Care Genetic Testing for Genetic Variants Linked to Adverse Outcomes with Clopidogrel (CYP2C19*2 & ABCB1 3435 TT); Treatment of STEMI patients carrying at least one high risk genetic variant with prasugrel 10mg daily.
Other intervention name(s): Spartan RX; Effient
Intervention MeSH terms: Prasugrel Hydrochloride
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary purpose: Treatment
Keywords: STEMI; Pharmacogenetics; Prasugrel; Clopidogrel; Percutaneous Coronary Intervention