Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

Drug Therapy of Cardiovascular Diseases
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It is vital that for clopidogrel, there is no specific guidance for responding to
genotype test results. For poor CYP2C19 metabolizers, one of the options is to
increase the dose of clopidogrel to a 600 mg loading dose followed by 150 mg once
daily. Platelet response is improved in poor metabolizers, but there are no data on
outcomes. Experts argue that there are no definitive data on other choices, such as
switching to prasugrel (Effient), specifically in clopidogrel nonresponders. Like clopidogrel,
prasugrel is a prodrug that is converted to an active metabolite. However, it is
converted mainly by CYP3A4 and CYP2B6 instead of CYP2C19. 25
Clinical Application
Guided by the replicated findings of CYP2C19*2 as a determinant of clopidogrel
response in patients undergoing percutaneous coronary intervention for atherosclerotic
heart disease, the FDA approved new labeling of clopidogrel in March 2010.
This includes a boxed warning alerting physicians to the genetic findings and suggests
alternative antiplatelet therapy in CYP2C19*2 homozygotes. 26 These may
include prasugrel and ticagrelor, which are not markedly affected by the CYP2C19
genotype. 27 The idea of increasing the clopidogrel dose has also been evaluated, but
not specifically in CYP2C19*2 homozygotes. 28
ASPIRIN
Aspirin is widely used for the prophylaxis of cardiovascular events in patients with
cardiovascular risk factors or established atherosclerotic disease. Aspirin undergoes
polymorphic metabolism. Among the enzymes involved in aspirin biodisposition,
a major role is played by the enzymes UDP-glucuronosyltransferase (UGT) 1A6,
CYP2C9, and the xenobiotic/medium chain fatty acid:CoA ligase ACSM2, although
other UGTs and ACSMs enzymes may significantly contribute to aspirin metabolism.
UGT1A6, CYP2C9, and ACSM2 are polymorphic, as well as PTGS1 and PTGS2,
the genes coding for the enzymes cyclooxygenases COX1 and COX2, respectively.
The genes associated with response to aspirin also include several platelet glycoproteins
(GPIIb-IIIa, GPVI, GPIa, and GPIb). 29,30
The mechanism of action of aspirin is by irreversibly inactivating cyclooxygenase-1
(COX-1), so that the conversion of arachidonic acid to prostaglandin G2/H2, along with
TXA2, is inhibited. The inhibition of TXA2 production leads to a lower expression of
glycoprotein (GP) IIb/IIIa, causing an inhibition of platelet activation and aggregation.
Aspirin has been proven to have efficacy in the secondary and primary prevention of
CVD. However, serious vascular events still occur in patients despite the use of aspirin.
A reduced ability of aspirin to inhibit platelet aggregation has been associated with an
increased risk of adverse events. 31 A substantial number of patients experience recurrent
events. Such aspirin resistance is generally defined as failure of aspirin to produce
an expected biological response: for example, inhibition of platelet aggregation or of
thromboxane A2 synthesis. While its etiology is not evident, genetic factors are likely
to play their part. Aspirin’s ability to suppress platelet function varies widely among
individuals, and lesser suppression of platelet function is associated with increased
risk of myocardial infarction, stroke, and cardiovascular death. 31 Platelet response