Impact of tailored anti-P2Y12 therapies in acute coronary syndromes

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Date: Apr. 2015
From: Pharmacogenomics(Vol. 16, Issue 5)
Publisher: Future Medicine Ltd.
Document Type: Report
Length: 5,071 words
Lexile Measure: 2190L

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Author(s): Fabian Stimpfle aff1 , Tobias Geisler [*] aff1

Keywords:

acute coronary syndrome; clopidogrel; point-of-care; prasugrel; ticagrelor

Pharmacodynamic & genetic variability of antiplatelet drugs

Clopidogrel

Clopidogrel has an increased pharmacodynamic variability depending on different factors including clinical risk factors (age, diabetes, renal failure, body mass index, smoking habit) [1 ] and genetic polymorphisms [2-4 ]. Variability of response to clopidogrel is associated with genetic variance in CYP450 enzyme activity, predominately CYP2C19, which is majorly involved in a two-step enzymatic conversion of clopidogrel into its biologically active thiol metabolite. CYP2C19 is genetically polymorphic. Subjects carrying loss-of-function alleles (e.g., CYP2C19*2, *3 ) reveal a slower and lower metabolization of clopidogrel leading to decreased levels of active metabolites and or decreased platelet aggregation inhibition following clopidogrel administration. In contrast, carriers of a CYP2C19*17 allele are fast metabolizers of clopidogrel [5 ]. Of note, there is a general overlap of exhibiting both (fast and slow metabolizer alleles) in the general population.

Prasugrel

Compared with clopidogrel, prasugrel appears to be superior regarding platelet inhibition due to a lower rate of high on-treatment platelet reactivity [6 ] and is associated with a significant reduction of major cardiovascular events at the costs of enhanced major bleeding risk in patients with acute coronary syndrome [7 ]. CYP450 enzymes do only contribute to one step of prasugrel bioactivation and CYP2C19 polymorphisms are less important for this metabolism [8 ]. A genetic substudy of the TRITON-TIMI-38 study showed that clinical efficacy of prasugrel was not reduced by CYP2C19*2 carrier status. However, a recent study suggests also an impact of CYP2C19*2 and *17 polymorphism on platelet response (genotyping was done using amplification refractory mutation system PCR in duplex reaction and vasodilator-stimulated phosphoprotein-P was used to measure platelet response) and bleeding risk in real world acute coronary syndrome (ACS) patients [9 ].

Ticagrelor

Ticagrelor, a cyclopentyl-triazolo-pyrimidine, was tested in the PLATO trial. In the initial analysis, ticagrelor was superior to clopidogrel treatment in patients with ACS (NSTE-ACS and ST elevation myocardial infarction) in terms of reducing the primary end point composite of death from vascular causes, myocardial infarction or stroke but was associated with increased risk of major bleeding not related to coronary artery bypass grafting (4.5 vs 3.8%, p = 0.03) [10 ]. Recently, inconsistencies were reported regarding the reduction of the primary end point at sites monitored by the drug maker compared with those sites that were monitored by an independent organization [11 ]. The steering committee of the PLATO trial recently published a response letter in the same journal to confirm the integrity of the overall results [ 12 ].

CYP2C19 does not seem to play a relevant role in drug metabolism of ticagrelor [13 ]. In a substudy of the PLATO trial, CYP2C19 genotypes showed no association with clinical benefits of ticagrelor over clopidogrel [14 ].

Despite the more intensified antiplatelet therapies with prasugrel and ticagrelor, there is a residual risk for post-ACS ischemic events of about 10% in clinical trials. A more amplified antiplatelet therapy is currently limited by the increased...

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Gale Document Number: GALE|A411315291