J Thromb Thrombolysis (2011) 31:306309

DOI 10.1007/s11239-011-0558-9

Antiplatelet agents in cardiovascular disease

Renato D. Lopes

Published online: 13 February 2011

Springer Science+Business Media, LLC 2011

Abstract Despite improvements in the treatment of acute

coronary syndromes (ACS), cardiovascular disease remains
the leading cause of death in the United States. Antiplatelet
agents, such as aspirin and clopidogrel, play an important
role in the treatment of patients with ACS, particularly
those at high risk for whom treatment may yield the
greatest benefits. The main challenge in preventing and
managing ACS is to tailor treatment for each patient by
taking into consideration patient characteristics, comorbidities, underlying short- and long-term risk factors,
ischemic and bleeding risks, and expected individual
responses to different medications. Several new alternatives providing more rapid and consistent platelet inhibition than aspirin and clopidogrel have been introduced for
routine treatment of patients with ACS. These new treatments seem to provide additional benefits without a significant increase in the risk of bleeding, if used for the
appropriate patients. In this article, we review the new
antiplatelet agents being developed as well as their pharmacological characteristics, potential clinical indications,
and key interactions with other antithrombotic drugs.
Keywords Aspirin
Clopidogrel
Novel antiplatelet
agents
Platelet aggregation inhibition
Coronary artery
disease

Cardiovascular disease remains the leading cause of death

in the United States, despite improvements in the treatment

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

123

of acute coronary syndromes (ACS) [1]. Antiplatelet agents

play an important role in the treatment of patients with
ACS, particularly those at high risk for whom treatment
may yield the greatest benefits. Antiplatelet agents alter
platelet adhesion, activation, and aggregation, thereby
limiting the role of the platelet in propagating the thrombotic process. Currently, the most common antiplatelet
agents used in the treatment of ACS are aspirin, P2Y12
inhibitors (clopidogrel and prasugrel), and small-molecule
intravenous glycoprotein IIb/IIIa inhibitors.
New therapies currently being developed aim to prevent
further progression of thrombosis and atherosclerosis. The
main challenge in preventing and managing ACS is to tailor
treatment for each patient by taking into consideration
patient characteristics, comorbidities, underlying short- and
long-term risk factors, ischemic and bleeding risks, and
expected individual responses to different medications. This
ambitious new approach will likely place a substantial
burden on global health care resources and may ultimately
require prioritization among several treatment alternatives.
Platelet inhibition in the setting of ACS has been a key
pillar of treatment for the last 20 years [25]. Aspirin, of
which the primary antithrombotic mechanism is to inhibit
the biosynthesis of thromboxane (and platelet activation)
by inactivation of platelet cyclo-oxygenase-1, affords a
22% risk reduction for nonfatal myocardial infarction (MI)
[6]. However, aspirin is not very effective alone. It fails to
prevent most (around 75%) serious vascular events in
patients with symptomatic atherothrombosis [6]. Recurrent
vascular events in patients taking aspirin have many possible causes and aspirin resistance has emerged as a relevant issue in clinical practice. Thus, there was a need for
new antiplatelet agents.
Adenosine diphosphate (ADP)-induced platelet aggregation plays an important role in arterial thrombosis. The

Antiplatelet agents in cardiovascular disease

307

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

Table 1 Comparison of pharmacodynamics and pharmacokinetics of P2Y12 inhibitors

Ticlopidine

Clopidogrel

Drug class

Thienopyridine

Thienopyridine Thienopyridine ATP

analogue

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

Immediately after IV use;

4 h after oral use

Drug elimination
half-life

2436 h after a single

dose and up to 96 h
after 14 days of
repeated doses
510 days

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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308

ticagrelor in US patients (which were inconsistent with the

findings in most other countries), including worse outcomes such as major adverse coronary events, MI, and
stroke, this new and promising drug is still not approved to
be used in the US.
Elinogrel, a novel, potent, reversibly binding competitive P2Y12 receptor antagonist, useful both for intravenous
and oral administration is currently under evaluation. It has
potential advantages over thienopyridines, such as clopidogrel and prasugrel, because it is a direct-acting drug
(non-prodrug) with reversible platelet inhibition and competitive P2Y12 receptor binding. In particular, the reversible and competitive nature of P2Y12 receptor binding of
elinogrel could provide additional antithrombotic protection beyond that of aspirin alone with the potential for less
impact on bleeding. Elinogrel can offer a differentiating
antiplatelet action in the thrombotic milieu (low local ADP
concentration in a high-flow environment, and thus greater
platelet inhibition) against the hemostatic milieu (high
local ADP concentration in a lower-flow environment, and
thus less platelet inhibition), which may translate into the
clinical benefit of less bleeding while retaining its antithrombotic effect. In the phase II INNOVATE-PCI study,
pharmacodynamic assessments demonstrated that an
intravenous bolus of elinogrel followed by a twice daily
oral maintenance regimen up to 120 days provided greater
inhibition of platelet aggregation than a loading and
maintenance regimen of clopidogrel in 652 patients
undergoing non-urgent PCI. This greater pharmacodynamic effect of elinogrel, however, was not associated with
an excess of TIMI major or minor bleeding events during
either periprocedural or maintenance phases. Adverse
events were largely similar between elinogrel- and clopidogrel-treated patients in INNOVATE-PCI, except that
transient and mild episodes of dyspnea were more frequently reported in the elinogrel arm. The results of
INNOVATE-PCI clearly support further clinical evaluation
of elinogrel in target patient populations that will benefit
most from antiplatelet therapy.
Thrombin might be a good target for platelet inhibition
because it is the most potent activator of platelets during
the thrombosis process. As a result, a protease-activated
receptor 1 (PAR1) inhibitor, a member of a potentially new
class of drugs called thrombin receptor antagonists, is
under investigation. Pre-clinical and phase II studies suggest that consistent and high levels of PAR1 inhibition may
have a beneficial antithrombotic effect with a minimal
increase in bleeding. Phase III studies of the selective
PAR1 inhibitor vorapaxar are currently underway, both in
ACS and chronic coronary artery disease (CAD) [12, 13].
TRACER is a prospective, randomized, double-blind,
multicenter, phase III study that aims to enroll over 10,000
ACS patients. The objective of the study is to evaluate the

123

R. D. Lopes

efficacy and safety of vorapaxar compared with placebo in

addition to standard of care in patients with non-ST-segment elevation ACS. The primary study outcome is the
composite of cardiovascular death, MI, stroke, recurrent
ischemia with rehospitalization, and urgent coronary
revascularization. The TRA 2 P-TIMI 50 trial is a phase
III, randomized, double-blind, placebo-controlled, multinational clinical trial designed to evaluate the efficacy and
safety of vorapaxar during long-term treatment of patients
with established atherosclerotic disease receiving standard
therapy. The study aims to enroll up to 27,000 patients and
the primary study outcome is the composite of cardiovascular death, MI, stroke, and urgent coronary revascularization. Both studies will continue until a predetermined
minimum number of centrally adjudicated primary and key
secondary outcome events have occurred, and all subjects
have participated in the study for at least 1 year.
Finally, patients with CAD commonly have other
comorbidities, such as atrial fibrillation, that require the use
of oral anticoagulants in addition to antiplatelet agents. In
this setting, the use of triple therapy, currently defined as
aspirin plus clopidogrel and warfarin, is a medical dilemma
in clinical practice. The combination of oral anticoagulants
with 1 or 2 antiplatelet agents has been demonstrated to be
effective; however, there is a substantial increased risk of
bleeding [1416]. For patients with ACS and atrial fibrillation with a CHADS2 score C2, oral anticoagulation with
warfarin (goal international normalized ratio [INR]
2.02.5) in addition to low-dose aspirin (81 mg) and
clopidogrel should be used. In this case, clopidogrel should
be used for the shortest duration necessary (e.g., 4 weeks)
following bare metal stent placement. After clopidogrel is
stopped, low-dose aspirin and warfarin (INR 2.03.0)
should be continued long term. The atrial fibrillation
guidelines state that after clopidogrel is stopped, warfarin
can be continued as monotherapy. For patients with stable
CAD, atrial fibrillation, and no coronary stents, warfarin
monotherapy is also the best current treatment option. For
patients with atrial fibrillation and recent MI, combination
therapy with warfarin and low-dose aspirin should be used,
particularly if the patient is at low risk of bleeding.
In conclusion, several new alternatives providing more
rapid and consistent platelet inhibition than clopidogrel
have been introduced for the routine treatment of patients
with ACS. When used in the appropriate patients, these
new treatments seem to provide additional benefits without
an increase in the risk of bleeding. Within the next few
years, more treatment alternatives might be available to
further improve outcomes of the large population of
patients with ACS. The use of these new antiplatelet agents
in combination with other new oral anticoagulants should
provide important insights about the efficacy and safety of
triple therapy in patients with CAD and atrial fibrillation.

Antiplatelet agents in cardiovascular disease

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