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Vascular Health and Risk Management 2010:6 419–429
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Open Access Full Text Article
Novel antiplatelet agents in the prevention
of cardiovascular complications – focus
on ticagrelor
Margaret M Marczewski1
Marek Postula1,2
Dariusz Kosior1
11st Chair and Department of
Cardiology, Central University
Hospital, Medical University of
Warsaw, Warsaw, Poland; 2Department
of Experimental and Clinical
Pha rma col ogy, Medical Univer sit y
of Warsaw, Warsaw, Poland
Correspondence: Marek Postula
Department of Experimental and Clinical
Pharmacology, Medical University of
Warsaw, 26/28 Krakowskie Przedmieście
St, 00-927 Warsaw, Poland
Tel +48 22 826 2116
Fax +48 22 826 2116
Email mpostula@amwaw.edu.pl
Abstract: Atherothrombosis, thrombus formation as a result of atherosclerotic plaque
rupture, is a major modern health problem, often underlying coronary artery disease, stroke,
and peripheral arterial disease. After the treatment of an acute thrombotic episode, long-term
therapy is warranted as a secondary prophylaxis of such events and their complications. Because
of the importance of platelets’ involvement in the initiation and propagation of thrombosis,
antiplatelet drugs have come to the forefront of atherothrombotic disease treatment. Dual
antiplatelet therapy of aspirin plus clopidogrel – the current standard – has its benefits, but
it also has its limitations with regard to its pharmacologic properties and adverse effects. For
these reasons, within the last decade or so, the investigation of novel antiplatelet agents has
prospered. Here, we review the main pathways through which platelets participate in acute
thrombosis and the interruption of these pathways by using novel antiplatelet agents, including
P2Y12 receptor antagonists (the recently approved prasugrel, the probable next-in-line
ticagrelor, and others). The need for a more individualized patient therapy is evident; although
most of the aforementioned pharmaceuticals have the potential to contribute to this, their
clinical utility remains to be seen.
Keywords: antiplatelet therapy, antagonist, P2Y12 receptor, ADP receptor
Different classes of platelet-inhibiting drugs
Platelets have an established role in the pathogenesis of atherosclerosis-related
diseases, including coronary artery disease (CAD), acute coronary syndromes
(ACSs), and stroke. Rupture of an atherosclerotic plaque promotes the activation
of platelets and initiates the coagulation cascade. Activation of platelets and their
subsequent aggregation, which is amplified by various pathways, lead to thrombus
formation at the site of vascular injury. Tissue hypoxia and irreversible damage in
conditions such as myocardial infarction (MI) and ischemic stroke are rather due
to an acute thrombus formed atop a ruptured atherosclerotic plaque than due to the
stenosis caused by atherosclerosis.1 Thus, antiplatelet agents have been used in acute
conditions of arterial thrombosis and as part of secondary prophylaxis to prevent
recurrent thromboembolic episodes.
Acetylsalicylic acid (aspirin) was the first antiplatelet agent, which irreversibly
inhibits the cyclooxygenase 1 enzyme in the arachidonic acid pathway through
acetylation, thereby preventing the conversion of arachidonic acid into thromboxane
A2 (TXA2) – a potent vasoconstrictor and platelet activator.2 Despite being used as a
drug for more than 100 years, aspirin continues to play a dominant role in the treatment
of cardiovascular diseases (CVDs) because of its ease of use and cost-effectiveness.
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Marczewski et al
Long-term aspirin therapy brings about a 20%–25% odds
reduction in the risks of subsequent MI, stroke, or vascular death
among intermediate- to high-risk patients with atherothrombotic
disease.3,4 However, its relatively low potency [producing only
a partial inhibition of platelet aggregation (IPA)], some patients’
resistance to aspirin, and its gastrointestinal toxicity prompted
the search for more potent, more consistent, and more specific
platelet-inhibiting agents.1–3
Currently, two classes of antiplatelet drugs are used
alongside aspirin. Clopidogrel, a thienopyridine adenosine
diphosphate (ADP) receptor antagonist, on the basis of a
12,562-patient study, CURE (Clopidogrel in Unstable angina
to prevent Recurrent Events) trial in 2001, has become a
standard part of dual antiplatelet therapy with aspirin, which
is used for a longer term after an acute MI.5 Glycoprotein
IIb/IIIa (GP IIb/IIIa) antagonists, such as abciximab, are
used in high-risk patients before percutaneous coronary
intervention (PCI).3 The limitations of clopidogrel – its
delayed onset of action, interpatient variability in response
to clopidogrel (including some patients’ outright resistance
to it), and the irreversibility of its action – have encouraged
the investigation of novel antiplatelet agents with satisfactory
safety profiles and adequate efficacy.3,6,7
The process of platelet activation and aggregation involves
multiple signaling molecules and their receptors, therefore
allowing for many therapeutic targets. First, platelets adhere
to the subendothelial proteins (ie, von Willebrand factor
and collagens) exposed at sites of vascular injury. This is
followed by intracellular signaling, with platelet activation
and secretion of further mediators, which amplify and sustain
the initial platelet response.8 In particular, activated platelets
release ADP, serotonin, and calcium via degranulation, as
well as synthesize thromboxane from arachidonic acid;
thrombin, another key substance, is locally generated
through the coagulation cascade.9,10 Platelet activation is
propagated through blood-soluble agonists acting upon
their respective platelet receptors: ADP via P2Y1 and P2Y12,
thrombin via protease-activated receptor 1 (PAR1) and
PAR4, and thromboxane via the thromboxane/prostanoid
(TP) receptor.11 The final common pathway for all these auto-
crine and paracrine activation signals is GP IIb/IIIa-mediated
platelet aggregation. Thus, in both physiologic hemostasis
and pathologic states, platelets are recruited into the mass of
a platelet – fibrin thrombus.9–11
The various classes of antiplatelet drugs act synergistically
through complementary yet independent mechanisms,
preventing platelet aggregation and thus acute thrombus
formation. Currently available drugs and those under
investigation target the thromboxane-induced (ie, aspirin and
terutroban), ADP-induced (such as ticlopidine, clopidogrel,
and prasugrel), and thrombin-induced (eg, SCH 530348
and E5555) pathways of platelet activation and their final
common pathway of GP IIb/IIIa (abciximab, eptifibatide, and
tirofiban)-induced platelet aggregation.11–14 The processes of
platelet adhesion, activation, and aggregation along with the
targets of platelet-inhibiting drugs are shown in Figure 1.
All antiplatelet drugs, in addition to inhibiting acute
arterial thrombosis, have the danger of interfering with the
physiologic role of platelets in hemostasis. Thus, the range
of adverse effects, particularly bleeding, is a major factor
in evaluating the utility of the available and upcoming
antiplatelet drugs and their combination regimens. In
addition to the safety profile and drug efficacy, other factors
to be taken into account when choosing from the available
and developing antiplatelet drugs include the specificity to
platelets, route of administration, reversibility of action,
the onset of action, peak of effect, and its duration or
wearing-off time (offset).
Blockade of ADP receptors
of subtype P2Y12 – from the
molecular level to the clinical
utility of thienopyridines
The key role of ADP in the processes of platelet aggregation and
thrombus formation has led to the development of antiplatelet
drugs targeting the P2Y12 receptor. Activated platelets release
ADP from their dense granules, which functions as a soluble
positive feedback mediator that binds to the receptors (P2Y1
and P2Y12) on the platelets’ surface. Both these purinoreceptors
belong to the group of G-protein-coupled receptors, with P2Y1
being coupled to Gq and P2Y12 to Gi; thus, each subtype of
ADP receptor has a distinct intracellular signaling pathway.9,10
Stimulation of the P2Y1 receptor and its Gq protein mobilizes
intracellular calcium and triggers a change in the platelet shape
and rapidly reversible aggregation.15 A signal through the
P2Y12 receptor and its Gi protein results in reduced levels of
cyclic adenosine monphosphate, amplification of the platelet
response, stabilization of the resulting aggregates, and secre-
tion of further mediators from the granules.16 Although the
coactivation of both purinoreceptors is necessary for normal
ADP-induced aggregation, P2Y12 is considered the major
platelet ADP receptor, and because of its more restricted
expression, it has become an attractive therapeutic target of
antithrombotic agents.9,13,17
The thienopyridine class of antiplatelets (ticlopidine,
clopidogrel, and prasugrel) selectively and irreversibly
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421
Novel mechanisms of action of antiplatelet agents
inhibits the P2Y12 purinoreceptor throughout the lifespan of
the platelet. Although currently clopidogrel is the dominant
member, its modest platelet inhibition, delayed onset of
action, and significant interpatient variability in response to
clopidogrel (including some patients’ nonresponsiveness to
the drug) paved the way for more potent and stable drugs.18
Ticlopidine had been discovered before clopidogrel, but has
been eclipsed because of its adverse hematologic side effects,
including neutropenia and thrombotic thrombocytopenic
purpura.3 The opposite is true of the third-generation
thienopyridine, prasugrel – previously known as CS-747,
LY-640315 – which has been approved by the United States
Food and Drug Administration recently and has found a
place in the latest recommendations of British and American
institutions.19,20
All the orally administered thienopyridines are prodrugs,
which require biotransformation into their active metabolites
by fixed sets of hepatic cytochrome P450 (CYP) enzymes, in
particular, the CYP3A4 isozyme. In contrast to clopidogrel’s
esterase inactivation and two-step CYP-dependent activation,
prasugrel has a more efficient and simpler metabolism,
which requires only one reaction by the liver enzymes
to yield its active metabolite.21,22 This difference in the
metabolism of these thienopyridines translates clinically
into different patient responses and drug interactions with
these antiplatelet agents. Certain common genetic variants of
CYP2C19 resulted in decreased levels of clopidogrel’s active
metabolite, resulting in a lower platelet inhibition and most
importantly a higher rate of major adverse cardiovascular
events; on the other hand, prasugrel’s pharmacology and
clinical efficacy were not found to be affected by CYP
polymorphisms or by the concomitant use of CYP-inhibitory
drugs. Other advantages of prasugrel include a faster onset
of action and an approximately tenfold higher potency than
clopidogrel.22–27
Prasugrel has been shown to be of particular benefit in
patients with diabetes, especially those on insulin (30%
relative risk reduction [RRR] in cardiovascular death, MI,
or stroke [P , 0.001] and 37% RRR, respectively). Another
look at the TRITON-TIMI 38 data with respect to diabetes
status showed the reduction by prasugrel of the composite
of CV death, MI and stroke noted in non-diabetic subjects
(n = 10,462, 9.2% vs 10.6%, P = 0.02), was even more
significant in those with diabetes mellitus (n = 3,146, 12.2%
vs 17.0%, P , 0.001), especially those treated with insulin
(n = 776, 14.3% vs 22.2%, P = 0.009).14,28 On the other
hand, its dose should be adjusted for low-weight patients
(,60 kg), and it should be rather avoided in the elderly
($75 years) and in those with a history of stroke or transient
ischemic attack because of an increased bleeding risk.29 Such
recommendations are largely based on the results of the
Phase 3 TRITON-TIMI 38 (TRial to assess Improvement
A) ADHESION
PLATELET
B) ACTIVATION C) AGGREGATION
PLATELET
collagen
ADP
P2Y2
P2Y1
PAR4
PAR1
Thrombin
α granule
AACOXTXA2
TP
Fibrinogen
GP IIb/IIa
GP IIb/IIa
vWF
endothelial
cell
TXA2
SCH 530348
E5555
ASA
NCX4016
terutroban
thienopyridines:
ticlopidine
clopidogrel
prasugrel
abciximab
eptifibatide
tirofiban
non-thienopyridines:
thrombin receptor
antagonists
ADP receptor
antagonists
GP IIb/IIa
antagonists
ticagrelor
cangrelor
elinogrel - PRT060128
BX667
BX048
Figure 1 Scheme of platelet adhesion, activation, and aggregation processes – showing the key players and sites of action of antiplatelet agents. Drugs at various stages of
investigation appear in parentheses.
Abbreviations: AA, arachidonic acid; ADP, adenosine diphosphate; ASA, aspirin; COX, cyclooxygenase; GP, glycoprotein; PAR, protease-activated receptor; PR, thromboxane/
prostanoid receptor; TXA2, thromboxane; vWF, von Willebrand Factor.
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Marczewski et al
in Therapeutic Outcomes by optimizing platelet inhibition
with prasugrel – Thrombolysis In Myocardial Infarction 38)
on 13,608 patients with ACS undergoing planned PCI.30 It
demonstrated the composite rate of death, MI, or stroke to
be reduced by 19% and the rate of stent thrombosis to be
halved in patients receiving prasugrel compared with those
receiving clopidogrel. Although prasugrel had an increased
efficacy, it also increased the risk of bleeding, especially in
the aforementioned groups, including life-threatening hemor-
rhage and fatal bleeding.14,30
Although prasugrel is still under investigation, it has
already found an official place in antiplatelet therapy through
support from American and British institutions. In October
2009, the United Kingdom’s National Institute for Health
and Clinical Excellence recommended a limited use of
prasugrel, in combination with aspirin, in three specific but
sizeable subgroups of patients with ACS undergoing PCI:
those undergoing immediate primary PCI for myocardial
infarction with ST elevation (STEMI), those who had stent
thrombosis during clopidogrel treatment, and those with
diabetes mellitus.20 In November 2009, the American Col-
lege of Cardiology, the American Heart Association, and the
Society for Cardiovascular Angiography and Interventions
jointly released guidelines for the use of prasugrel in patients
with STEMI once the coronary anatomy is known and PCI
is planned.19
Ticagrelor – an overview of its
pharmacologic and clinical proles
Novel nonthienopyridine platelet P2Y12 receptor antago-
nists, including ticagrelor, cangrelor, and elinogrel, are also
being investigated. These are direct and reversible P2Y12
antagonists with various formulations but with rapid onsets
and short durations of action. Among these, ticagrelor has
come the furthest, having undergone a Phase 3 clinical
trial.31 As a prototype drug from the novel cyclopentyl-
triazolopyrimidine class of antiplatelets, ticagrelor (previ-
ously known as AZD6140) is chemically distinct from the
thienopyridines and can reversibly inhibit the P2Y12 ADP
receptor. It is highly selective and very specific for the P2Y12
receptor, and it exhibits a greater, more consistent IPA than
clopidogrel.32 Like the thienopyridines, ticagrelor is also
administered orally, but because of its direct action, ie, not
requiring metabolic activation, ticagrelor has a rapid onset,
peaking within 2–4 hours of dosing.33 The metabolism of
ticagrelor yields an active molecule (AR-C124910XX) that
has similar P2Y12-blocking activity as its parent molecule.
Ticagrelor’s plasma half-life is approximately 12 hours,
which corresponds to twice-daily dosing. In contrast to
clopidogrel and prasugrel, which should be discontinued
approximately 5 days before the restoration of normal
platelet-mediated hemostasis, ticagrelor’s short duration of
action and an offset of action in 1–2 days preclude the need
for delaying surgical intervention, such as coronary artery
bypass grafting (CABG). On the other hand, this potential
advantage also carries the risk of increased thrombotic events
if patients miss a ticagrelor dose.14,18,19 The pharmacologic
properties of some currently used and investigational anti-
platelet drugs are shown in Table 1.
Several Phase 2 clinical trials have been conducted using
ticagrelor, the first reversibly binding oral P2Y12 receptor
antagonist (Table 2). In an initial Phase 2a parallel-group
safety and efficacy trial (DISPERSE), 200 patients with
atherosclerosis were randomized to receive either ticagrelor
(doses of 50, 100, or 200 mg twice daily, or 400 mg once
daily) or clopidogrel (75 mg once daily) for 28 days, in addi-
tion to 75–100 mg of aspirin per day. Measuring the IPA
showed that the three higher doses of ticagrelor (ie, 100 and
200 mg twice daily and 400 mg once daily) provide a nearly
complete inhibition of ADP-induced platelet aggregation
after the initial dosing. Although investigators write that
in general ticagrelor was well tolerated, there was a higher
incidence of bleeding with the three higher doses, mostly
of mild to moderate severity, and there were also reports of
dyspnea.36
This trial was followed by the Phase 2b Dose confIrma-
tion Study assessing anti-Platelet Effects of AZD6140 vs
clopidogRel in non-ST-segment Elevation acute coronary
syndromes (DISPERSE-2) trial.37 In this trial, 990 patients
with non-ST-segment elevation ACS were randomized to
receive any one of the following dosage: ticagrelor 90 mg
twice daily, ticagrelor 180 mg twice daily, or clopidogrel
300 mg loading dose plus 75 mg once daily for up to 12
weeks. This study showed no difference in major bleeding but
an increase in minor bleeding at the higher dose of ticagrelor,
with encouraging – although not statistically significant –
results on the secondary end point of MI.37 For the possible
advantage of ticagrelor’s reversible inhibition, there was only
a numerically lower rate of bleeding (again nonsignificant) in
ticagrelor-treated patients undergoing CABG between 1 and
5 days after stopping ticagrelor, which would be consistent
with the recovery of platelet function. Another analysis of
the DISPERSE-2 data compared the antiplatelet effects of
ticagrelor with those of clopidogrel and assessed the effects
of ticagrelor on clopidogrel-pretreated patients.39 It demon-
strated that ticagrelor treatment resulted in further IPA in
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Novel mechanisms of action of antiplatelet agents
Table 1 Pharmacologic properties and adverse effects of a selection of antiplatelet agents
Drug Action Aggregation
to ADP
Route of
administration
Metabolism Time to
peak effect
Offset of
action
Adverse effects
Clopidogrel
300 mg
IRR ∼30% Oral Esterase inactivation
and two-step hepatic
CYP-dependent
activation
∼4 hours ∼5 days Bleeding (major and
minor), interpatient
variability, and
dyspnea in
approximately
8% of patients34
Prasugrel
60 mg
IRR 75%–80% Oral Esterase activation
and one-step CYP-
dependent activation
(liver or gut)
1–2 hours ∼5 days Bleeding (major and
minor) and dyspnea in
approximately
5% of patients30
Ticagrelor R 75%–80% Oral None required 1–2 hours 1–2 days Bleeding, dyspnea in
approximately
14% of patients,
and ventricular pauses31
Cangrelor
4 μg/kg/min
R.90% Intravenous None required Minutes 20 minutes Bleeding (minor) and
dyspnea in
approximately
1% of patients35
Elinogrel
40 mg
R Oral/intravenous None required 20 minutes ∼1 day No increase in bleeding
SCH 530348 R (.90% to
TRAP)
Oral None required With
LD: hours;
without
LD: days
Weeks No increase in bleeding
Abbreviations: ADP, adenosine diphosphate; CYP, cytochrome P450; IRR, irreversible; LD, loading dose; R, reversible; TRAP, thrombin receptor antagonist peptide.
patients already receiving clopidogrel, including those with
the highest platelet aggregation response.
On the basis of previous dose-confirmation trials, the
Phase 3 PLATO (PLATelet inhibition and patient Outcomes)
trial was conducted to compare ticagrelor and clopidogrel
with respect to their efficacy in preventing cardiovascular
events and safety.31 In this trial, 18,624 patients with ACS
(both with and without ST-segment elevation), in addition
to the aspirin therapy, received loading doses of ticagrelor
180 mg or clopidogrel 300 mg (with an additional 300 mg
clopidogrel at PCI) and then ticagrelor 90 mg twice daily or
clopidogrel 75 mg once daily for 6–12 months. As compared
to treatment with clopidogrel, ticagrelor was found to
significantly reduce the rate of death from vascular causes,
MI, or stroke (primary end point: 11.7% vs 9.8%; P , 0.001),
without an increase in the rate of overall major bleeding.31
These findings are noteworthy in that ticagrelor is the first
investigational antiplatelet to demonstrate a reduction in
cardiovascular death when compared with clopidogrel in
patients with ACS. Ticagrelor reduced the risk of cardio-
vascular events early on, and this benefit over clopidogrel
increased over time. Among the subset of patients who
received a stent during the study, a 38% RRR of definite
stent thrombosis was achieved with ticagrelor (1.0% vs 1.6%;
P = 0.003).40 Patients weighing less than the median weight
for their sex, those who were not on lipid-lowering drugs at
randomization, and those from North America were found
to attain fewer benefits from ticagrelor treatment.31 Although
there was no increased risk of CABG-related bleeding, the
PLATO investigators did find an increase in the rate of
non-procedure-related bleeding (clopidogrel 3.8% vs ticagre-
lor 4.5%; P = 0.03), including more instances of fatal intrac-
ranial bleeding but fewer instances of fatal bleeding of other
types.31 The summation of major and minor bleeding events
also showed an increase with ticagrelor when compared
with clopidogrel (ticagrelor 16.1% vs clopidogrel 14.6%;
P = 0.008).40 In addition to the bleeding tendency, in line with
the findings of Phase 2 trials, ticagrelor was associated with
more ventricular pauses in the first week (ticagrelor 5.8% vs
clopidogrel 3.6%; P = 0.01), but not at day 30, and with more
reports of dyspnea (ticagrelor 13.8% vs clopidogrel 7.8%;
P , 0.001).31 The former occurred without clinical conse-
quences for the patient, whereas the latter was responsible
for 1 in 100 ticagrelor-treated patients stopping treatment.41
Thus, dyspnea was clinically limiting in around 1% of
ticagrelor-treated patients. This rare but clinically meaning-
ful and recurring finding awaits authoritative assessment and
explanation. Given the large database of the PLATO trial,
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Marczewski et al
analyses continue to be made of the findings. A subanalysis
of patients with STEMI (PLATO STEMI) also showed that
compared with clopidogrel treatment, ticagrelor treatment
reduced cardiovascular events for up to a year (11.0% vs
9.3%; P = 0.02), a difference driven mainly by a statisti-
cally significant reduction in MIs (6.1% vs 4.7%; P = 0.01),
without an increase in major bleeding.42
In the meantime, results of further Phase 2 trials of
ticagrelor were released. The ONSET/OFFSET study
(n = 123) was designed to assess the rates of onset and offset
of the antiplatelet effects of ticagrelor versus clopidogrel
taken for 6 weeks by patients with stable CAD receiving
aspirin therapy.38 Using the same dosing scheme as that used
in PLATO trial, it showed that ticagrelor achieved faster
onset (41% IPA vs 8% at 30 minutes; P , 0.0001), greater
IPA, and faster offset in comparison with clopidogrel. The
RESPOND trial, through a two-way crossover, investigated
the antiplatelet effect of ticagrelor in 98 patients with stable
CAD, which included both clopidogrel responders and
clopidogrel nonresponders.43,44 The importance of this issue
is reflected in reports estimating the frequency of clopidogrel
nonresponders at about 10% and low responders at about
20%.44 Among patients identified as clopidogrel responders,
switching from clopidogrel to ticagrelor resulted in a mean
IPA increase of 26%, whereas switching from ticagrelor to
clopidogrel resulted in a mean IPA decrease of 24%.45 Thus,
the RESPOND trial found that patients could be switched
from ticagrelor treatment to clopidogrel treatment without
the interruption of antiplatelet effect. It was concluded that
clopidogrel nonresponders and responders exhibit superior
platelet inhibition during ticagrelor therapy. However, the
RESPOND trial findings also demonstrated that because of
the variability of the clopidogrel response, identification of
clopidogrel nonresponders is difficult.41 Finally, research has
shown ticagrelor to produce platelet inhibition, regardless
of the genotypic variations in the three genes that had been
associated with the variability in platelet reactivity.39
All these trials underline the potential of ticagrelor to
achieve a rapid and sustained antiplatelet effect, which
could be reversed and could overcome nonresponsiveness
and interpatient variability to clopidogrel, thus addressing
the main limitations of clopidogrel therapy.3 Nonetheless,
Table 2 Ticagrelor: results of clinical trials
Phase Clinical trial Patients Dosage Results
Phase 2 DISPERSE36 200 patients
with atherosclerosis
Randomization to ticagrelor
(doses of 50, 100, or 200 mg
TD, or 400 mg OD) or
clopidogrel (75 mg OD),
on top of aspirin (75–100 mg OD),
for 28 days
Ticagrelor TD produced a more rapid
and greater IPA than clopidogrel
(90% vs 60%)
DISPERSE-237 990 patients
with non-ST-segment
elevation ACS
Randomization to ticagrelor
(90 or 180 mg TD) or
clopidogrel (75 mg OD),
on top of aspirin
(75 and 100 mg OD),
for up to 12 weeks
No difference was observed in the total
bleeding rate between 90-mg
ticagrelor-treated, 180-mg
ticagrelor-treated, and clopidogrel-
treated groups (9.8%, 8.0%, and 8.1%,
respectively)
ONSET/OFFSET38 123 patients
with stable CAD
Randomization to ticagrelor
(90 mg TD), clopidogrel
(75 mg OD), or placebo,
on top of aspirin (75–100 mg OD),
for 6 weeks
Ticagrelor achieved more rapid and
greater platelet inhibition than high-LD
clopidogrel .50% IPA (98% vs 31%,
P , 0.0001) and .70% IPA (90% vs
16%, P , 0.0001) at 2-h post-LD; this
was sustained during the maintenance
phase and was faster in offset after
drug discontinuation
Phase 3 PLATO31 18,624 patients
with ACS
Randomization to LDs of
ticagrelor (180 mg) or
clopidogrel (300 mg; with an
additional 300 mg clopidogrel at
PCI), then ticagrelor (90 mg TD)
or clopidogrel (75 mg OD), on
top of aspirin (75–100 mg OD),
for 6–12 months
Compared with clopidogrel treatment,
ticagrelor treatment was found to
signicantly reduce the rate of death
from vascular causes, MI, or stroke
(primary end point: 11.7% vs 9.8%,
P , 0.001), without an increase in
the rate of overall major bleeding
Abbreviations: ACS, acute coronary syndrome; CAD, coronary artery disease; IPA, inhibition of platelet aggregation; LD, loading dose; MI, myocardial infarction; OD, once
daily; PCI, percutaneous coronary intervention; TD, twice daily.
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Novel mechanisms of action of antiplatelet agents
its adverse effects such as dyspnea and bradycardia, its
relationship with patient weight, and the lack of its benefit in
North American patients require further investigation before
ticagrelor may advance further toward a place in antiplatelet
therapy guidelines.31
Other antiplatelet drugs in research
and development and their clinical
potential
Cangrelor, another novel reversible P2Y12 antagonist, is a
chemically modified version of ticagrelor, which can be
administered parenterally. It acts rapidly, producing profound
platelet inhibition within 15 minutes of initiating infusion
when compared with the 1- to 2-hour time frame for prasugrel
and ticagrelor. This intravenous (iv) adenosine triphosphate
analog has a plasma half-life of 5–9 minutes and is highly
reversible, so the platelet function returns to the baseline
level of activation 20 minutes after the discontinuation of
cangrelor.14,46,47 Because of such a rapid offset, cangrelor
was foreseen as a drug for the catheterization laboratory;
like GP IIb/IIIa antagonists, it has to be started right before
a PCI procedure and stopped immediately after it, while
other antiplatelets would provide long-term protection
from then onward.46,48 Phase 2 safety trials did not note
any deaths or serious events attributed to cangrelor.46,47
CHAMPION-PCI (A Clinical Trial Comparing Cangrelor
to Clopidogrel in Subjects Who Require Percutaneous
Coronary Intervention), a prospective Phase 3 trial of 9,000
patients with unstable angina, MI, or ACS awaiting PCI,
aimed to compare the efficacy of cangrelor with that of
clopidogrel in subjects requiring PCI.49 On the other hand,
the CHAMPION PLATFORM (A Clinical Trial Comparing
Treatment With Cangrelor [in Combination With Usual
Care] to Usual Care, in Subjects Who Require Percutaneous
Coronary Intervention), a trial on 6400 patients requiring
PCI, planned to test the potential superiority of cangrelor
(combined with usual care) over the placebo, as measured by
a composite of all-cause mortality, MI, and ischemia-driven
revascularization.50 Both studies have been terminated due to
insufficient evidence of cangrelor’s clinical efficacy.51
Although no Phase 3 data are available, another Phase 2
study is in progress, with the purpose of demonstrating that
patients receiving cangrelor infusion before CABG have an
acceptable safety profile and can undergo surgery without
excessive perioperative bleeding. This maintenance of
platelet inihiBition with cangRelor after dIscontinuation of
thienopyriDines in patients undergoing surGEry (BRIDGE)
trial plans to follow up 220 patients undergoing nonemergent
CABG, who had already received a thienopyridine antiplatelet
drug, and foresees completion in July 2010.52
Elinogrel (also known as PRT060128), the next addition
to the reversible, direct-acting nonthienopyridine P2Y12
receptor antagonists, is unique in that it can be administered
both orally and intravenously.53 This allows for an immedi-
ate and reversible effect of high-level platelet inhibition,
preferable in acute conditions, and an easy transition to
reversible platelet inhibition in the chronic setting.54 Its
simplified administration covers the full spectrum of care,
from acute onset to chronic care, and its reversibility allows
for surgery without significant delay. Thus far, elinogrel has
undergone Phase 2A ERASE MI (Early Rapid ReversAl of
platelet thromboSis with intravenous Elinogrel before PCI
to optimize reperfusion in acute Myocardial Infarction) pilot
trial.55 In this safety and efficacy dose-escalation trial, 70
patients with STEMI undergoing primary PCI were random-
ized to an iv bolus of placebo versus elinogrel (at doses of
10, 20, 40, and 60 mg), in addition to standard treatment,
prior to angiography. There appeared to be no difference
between the placebo and elinogrel (at doses of 10, 20, 40,
and 60 mg) with respect to the incidence of the infrequent
bleeding events. Neither were there any differences in serious
adverse events, laboratory values, and corrected thrombolysis
in MI (TIMI) frame count, nor was any ST resolution between
elinogrel and placebo.56 Although the dose-confirmation
phase was not started, as the trial was prematurely terminated
for administrative reasons, the ERASE MI findings provide
preliminary support for the use of elinogrel as an adjunctive
therapy in primary PCI for STEMI. Meanwhile, the results
of elinogrel’s Phase 2b INNOVATE-PCI (A randomized,
double-blind, active-controlled trial to evaluate intravenous
and oral PRT060128, a selective and reversible P2Y12
inhibitor, vs clopidogrel, as a novel antiplatelet therapy in
patients undergoing nonurgent PCI) are awaited. In this trial,
800 patients, who were randomized to the clopidogrel control
or to one of three experimental regimens of elinogrel (80-mg
bolus administered intravenously prior to PCI, followed by
twice-daily oral dosing of 50, 100, or 150 mg), are being
studied prior to nonurgent PCI and in the 60-day chronic
treatment phase.57 INNOVATE-PCI is designed not to exam-
ine a prespecified endpoint, but rather to explore a number
of analyses to understand the clinical efficacy, biological
activity, tolerability, and safety of elinogrel.
Two more investigational nonthienopyridine P2Y12
antagonists, BX 667 and its active metabolite BX 048, are in
the early stages of clinical development. Thus far, they have
undergone animal trials, performed on rat and dog models,
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Marczewski et al
and pharmacodynamic and pharmacokinetic studies.58,59 They
are hoped to be useful in safely decreasing cardiovascular
events in patients undergoing PCI.
Besides the great variety of new ADP receptor antago-
nists, a new class of antiplatelet agents targeting the potent
thrombin-induced activation of platelets is emerging. The
first member of these thrombin receptor antagonists (TRAs)
SCH 530348 and the second member E5555 antagonize the
platelet PAR1. This receptor found in platelets and smooth
muscle cells possesses a high affinity to thrombin and
via coupling to Gp/Gi proteins, mediates the activation of
these cells by thrombin.11 The safety and efficacy of SCH
530348 have already been tested in various Phase 2 trials,
including the TRA-PCI study, and two Phase 3 trials are
presently being conducted.60 The TRA 2(°)P-TIMI 50 trial
(Thrombin Receptor Antagonist in Secondary Prevention
of Atherothrombotic Ischemic Events) on approximately
19,500 patients with atherosclerotic disease (prior MI or
stroke or with existing peripheral arterial disease), in the
course of at least 1-year follow-up, compares the safety
and efficacy of SCH 530348 against the existing standard
of care (aspirin and clopidogrel) in preventing MI, stroke,
and urgent coronary revascularization and in assessing its
bleeding risk.61 On the other hand, the TRA-CER (Thrombin
Receptor Antagonist for Clinical Event Reduction in Acute
Coronary Syndrome) study is designed to compare the
efficacy of a combination of SCH 530348 and the existing
standard of care (eg, aspirin and clopidogrel) with that of the
existing standard of care alone in preventing MI and stroke
in patients with ACS.62 By following up approximately
10,000 patients with non-STEMI for a minimum of 1 year,
the study will also assess the bleeding risk of both treatment
variants (ie, a combination of SCH 530348 and the existing
standard of care, and the existing standard of care alone). The
results of these large-scale trials, planned to be completed
in September 2010 and July 2011, respectively, are eagerly
awaited. The other member of the TRA group, E5555, is
currently being evaluated in two Phase 2 trials, LANCE-
LOT (Lessons from Antagonizing the Cellular Effects Of
Thrombin) trials 201 and 202.63,64 In each trial, approximately
600 patients with CAD will be followed up in order to assess
E5555’s safety and efficacy in inhibiting platelet aggregation
and endovascular inflammatory processes and to measure the
incidence of major adverse cardiovascular events.
There are also new up-and-coming drugs interfer-
ing with the thromboxane pathway, upon which aspirin
acts. NCX 4016 (nitroaspirin) is a nitric oxide-releasing
aspirin that combines all the benefits of aspirin with those
of nitric oxide.65 NCX 4016, with its antithrombotic,
antiatherogenic, and vasodilatory properties, is known to be
strongly cardioprotective. Also being evaluated is S18886
(terutroban), a TXA2 receptor inhibitor, currently undergo-
ing the PERFORM (Prevention of Cerebrovascular and
Cardiovascular Events of Ischemic Origin with Terutroban
in Patients with a History of Ischemic Stroke or Transient
Ischemic Attack) study in patients with recent stroke or
transient ischemic attack.12,66 This Phase 2 trial is designed to
compare this specific TP receptor antagonist with aspirin in
reducing the incidence of cerebrovascular and cardiovascular
events.67 Terutroban may be of particular interest because
studies in a murine model have shown the inhibition of the
TXA2 receptor to decrease atherosclerosis progression.68
Moreover, novel antithrombotic compounds discovered
inhibit thrombin while antagonizing GP IIb/IIIa. The future
of such dual-function pharmaceuticals in CVDs remains to be
seen. The same is true for PR-15, the investigational platelet
GP VI adhesion antagonist, and the drugs targeting platelet
endothelial aggregation receptor 1.69,70
Conclusions and future research
Given the pathologic process of intraarterial platelet activation
underlying CVDs, it is clear that antiplatelet therapeutic
options are needed for treating CVDs and preventing their
complications. Significant progress has already been made in
the field of antiplatelet therapy, as it aims to inhibit platelet
aggregation and acute thrombus formation, while preventing
intolerable bleeding. There exists a growing spectrum of
drugs modifying these pathologic processes, which continues
to expand in the hopes of overcoming the limitations of
current standard treatment. Novel platelet-inhibiting drugs
act through diverse mechanisms, mostly interfering with
ADP-induced platelet aggregation, but also targeting the
TXA2 pathway and thrombin-induced signaling.11–13 In con-
trast to the available GP IIb/IIIa antagonists, which block the
final common pathway of platelet aggregation, the possibility
emerges of disrupting initial mechanisms of adhesion by
targeting GP IV, a key receptor for collagen.69 As combina-
tion regimens are often required to achieve sufficient platelet
inhibition, new approaches to old mechanisms are explored,
such as the combination of nitric oxide and aspirin in the
investigational agent NCX 4016.65
As our understanding of the complex molecular and
genetic bases of atherothrombotic disease expands, modern
medicine moves toward more individualized patient treatment.
The growing stock of antiplatelet drugs at our disposal
can help us treat the full spectrum of and various stages
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427
Novel mechanisms of action of antiplatelet agents
in atherothrombotic manifestations of atherosclerosis while
catering to the needs and risk factors of specific patients. This is
slowly becoming a reality, for example, prasugrel is especially
useful in patients with high risk of ischemic events as in those
with diabetes mellitus.19,28,29 Ticagrelor is possibly a useful
agent before CABG, as its more potent platelet inhibition did
not increase CABG-related bleeding, although its side effects
such as dyspnea and ventricular pauses could additionally
limit its patient base.31 On the other hand, both prasugrel
and ticagrelor seem less liable to decreased patient response
because of genetic polymorphism of receptors and enzymes;
thus, these agents potentially provide platelet inhibition in
patients who are clopidogrel nonresponders.22,38,39 Elinogrel,
even though it has not entered Phase 3 trials, is encouraging
because of its simplified administration scheme, allowing for
a smooth transition from acute to chronic treatment.
Progress with respect to the potency of platelet inhibition
has also brought increased bleeding tendency. To shift the
balance from causing excess bleeding toward preventing
vascular occlusion, dose adjustments are necessary in
low-weight patients for drugs such as prasugrel and
ticagrelor.29,31 As age is another factor found to increase bleed-
ing, elderly patients still await a registered drug to address
their needs. In contrast to the studies on clopidogrel and pra-
sugrel, ticagrelor, besides its stronger platelet inhibition, did
not increase the risk of major bleeding; thus, it may become
an antiplatelet option for older patients, although it may not be
possible for those with respiratory problems or symptomatic
bradycardia.30,31,34 Also, with regard to bleeding, the group of
thrombin receptor inhibitors is particularly promising, as it
is hypothesized that the pathway they block may play a role
only in pathologic thrombosis, leaving physiologic hemosta-
sis intact. Such an advantage with respect to bleeding risk is
also evidenced by animal studies, showing a decrease in the
progression of atherosclerosis.11,68
Dyspnea, another clinically relevant adverse effect,
was found to occur in up to 5%, 8%, 14%, and 1% of
patients receiving prasugrel, clopidogrel, ticagrelor, and
cangrelor, respectively.30,31,34,35 An analysis by Serebruany
et al71 considered the pathophysiology of the respiratory
distress and platelet inhibition. The authors found dyspnea
to be a very rare complication, mostly caused by underlying
diseases – cardiac, respiratory, or allergic – and concomitant
medications (high-dose angiotensin-converting enzyme
inhibitors) rather than by the antiplatelet therapy itself. It was
suggested that especially reversible agents (like ticagrelor)
could lead to the development of mild, asymptomatic
thrombotic thrombocytopenic purpura, fluid retention,
and dyspnea. Another proposed hypothesis is that certain
antiplatelets may be metabolized to adenosine (ticagrelor’s
molecular structure has components almost identical to those
of adenosine), which is an established bronchoprovocator.
Although the true reason for the statistically significant
increase in dyspnea – particularly with ticagrelor – remains to
be uncovered, it is clear that further studies should follow up
this finding to assess its clinical significance in the long-term
care of patients with atherothrombotic disease.71
In summary, the abundant novel antiplatelet agents, with
their higher potencies, higher platelet specificities, various
drug formulations, possible reversibility, less variability in
patient response, more rapid onsets and offsets of action,
and short time to peak, along with their attempts for better
safety, hold high potential. Some are in advanced stages of
development with assuring outcomes, and further clinical
evaluation is needed to determine which of them will find a
place within standard antiplatelet therapy.
Disclosures
The authors report no conflicts of interest. The authors alone
are responsible for the content and writing of this paper.
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