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DOI 10.1007/s11239-011-0558-9
R. D. Lopes (&)
Duke Clinical Research Institute, Duke University Medical
Center, Box 3850, 2400 Pratt Street, Room 0311, Terrace Level,
Durham, NC 27705, USA
e-mail: renato.lopes@duke.edu
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P2Y12 receptor that mediates ADP-induced platelet activation and aggregation has become a favored target for the
inhibition of platelet aggregation. The most classic antagonist of the platelet P2Y12 receptor is ticlopidine. However,
its clinical use has been limited by a high incidence of toxic
effects, a delayed onset of action, and high inter-individual
variability in pharmacological response [7]. Therefore,
ticlopidine has been largely superseded by a newer thienopyridine, clopidogrel, which possesses similar efficacy
with lower toxicity. Currently, clopidogrel is the most
widely used P2Y12 inhibitor. Despite its proven efficacy,
safety, and advantages over ticlopidine, clopidogrel has its
own drawbacks including limited potency and high interpatient variability in pharmacological response. These
limitations have led to the search for alternative P2Y12
inhibitors.
The pharmacodynamics and pharmacokinetics of the
current P2Y12 inhibitors are shown in Table 1. Clopidogrel
and prasugrel are thienopyridine prodrugs acting on the
P2Y12 receptor by almost identical active metabolites
which irreversibly bind to the receptor. Slow and variable
active metabolite generation leads to clopidogrel having a
slow onset of action and wide inter-individual variability in
the pharmacodynamic response [8]. Compared with aspirin
alone, clopidogrel provides an approximate 20% reduction
in MI and a substantial reduction in stent thrombosis in
patients with ACS, as shown in the CURE trial [9]. The
clopidogrel benefit was consistent across most subgroups
and at all levels of patient risk. Importantly, the benefit that
emerged early (within the first 24 h of starting therapy) was
sustained up to 9 months.
The thienopyridine prasugrel has a more efficient active
metabolite generation than clopidogrel with a rapid onset
of action, more pronounced platelet inhibition, and no
clinically important variability in response. In the
TRITON-TIMI 38 trial, these features lead to an approximate 20% reduction in MI and a 52% reduction in stent
thrombosis during a 15 month follow-up period. In this
study, 13,608 patients with ACS were randomized in a
double-blind fashion to receive prasugrel or clopidogrel in
association with a planned percutaneous coronary intervention (PCI) procedure [10]. Of the patients treated with
prasugrel, 2.4% experienced at least 1 TIMI major bleeding
event unrelated to coronary artery bypass graft surgery
compared with 1.8% treated with clopidogrel (hazard ratio
1.32; P = 0.03). Based on this study, prasugrel was
approved and is available for patients with ACS. In patients
with ACS undergoing PCI, prasugrel is most effective in
ST-segment elevation MI, younger patients (\75 years of
age), those with a body weight [60 kg, and those with no
history of previous stroke. Patients with diabetes and those
who have received a stent also benefit more from prasugrel.
Ticagrelor, the first reversibly binding oral P2Y12
receptor antagonist, does not require metabolic activation,
has a rapid onset of action, and can disassociate from the
receptor permitting restoration of platelet function without
the need for production of new platelets. In pharmacodynamic studies, ticagrelor has demonstrated greater, more
rapid, and more consistent ADP-induced platelet inhibition
as compared with clopidogrel and more rapid offset of
action following cessation of therapy. In the PLATO study,
18,624 patients with ACS were randomized within 24 h
after symptom onset to receive ticagrelor or clopidogrel.
The results showed a 16% relative reduction of the composite of cardiovascular death, MI, and stroke, a 22%
reduction in total mortality, and a 23% reduction in stent
thrombosis. Ticagrelor was not associated with any
increase in overall bleeding, but there were more nonprocedural bleeding events with ticagrelor during longterm treatment [11]. Because of the unfavorable results of
Clopidogrel
Drug class
Thienopyridine
Cyclopentyl
Direct competitor of
triazolopyrimidine P2Y12 receptor
Chemical
activity
Prodrug
Prodrug
Direct acting
Reversibility
Irreversible
Irreversible
Irreversible
Reversible
Reversible
Reversible
Route of
administration
Oral
Oral
Oral
IV
Oral
Oral or IV
Time to peak
effect
500 mg 5 days
300 mg 6 h
1h
Several
min
120240 min
Drug elimination
half-life
7.27.6 h
3.7 h
59 min
12 h
\1 h for IV use; 12 h
for oral use
510 days
510 days
1h
24 h
12 h for IV use; 24 h
for oral use
Duration of action
Prasugrel
Prodrug
Cangrelor
Direct
acting
Ticagrelor
Elinogrel
Direct acting
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R. D. Lopes
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