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Optimizing platelet inhibition
J.J.J. van Giezen*
Department of BioScience, AstraZeneca R&D, Mölndal, Sweden
* Corresponding author. Tel: +46 31 70 64 942; fax: +46 31 77 63 700. E-mail address: hans.vangiezen{at}astrazeneca.com
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Abstract
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The platelet P2Y
12 receptor plays a critical role in sustaining
ADP-mediated platelet aggregation. Drawbacks of the thienopyridine
clopidogrel, a prodrug of an irreversible P2Y
12 antagonist,
include the need for two-step metabolism to its active form
and partial hydrolysis to its inactive metabolite. Both contribute
to high variability in the degree of platelet inhibition and
the irreversibility of binding complicates both acute and planned
invasive treatments when rapid offset of antiplatelet activity
is desired. Novel P2Y
12 antagonists include the thienopyridine
prasugrel and the selective, direct, reversible antagonists
cangrelor (iv) and AZD6140 (oral). Prasugrel, also an irreversible
antagonist, requires only one-step metabolism to active form
and achieves greater inhibition of platelet aggregation (IPA)
than clopidogrel. Recently published data indicate that this
translates into improved efficacy. Like clopidogrel, prasugrel
relies on new platelet generation for offset of effect. The
direct reversible antagonists bind directly to the receptor,
and the degree of IPA closely follows plasma drug concentrations.
In addition to permitting more rapid offset of effect and greater
and more consistent IPA than clopidogrel, direct reversible
antagonists may exert additional beneficial effects via blockade
of P2Y
12 in vascular smooth muscle cells. Reversible antagonists
also appear to exhibit a wider therapeutic window, showing reduced
bleeding time prolongation per given degree of antithrombotic
effect in experimental models. Ongoing large-scale Phase 3 clinical
trials are examining cangrelor in patients with acute coronary
syndromes (ACS) also undergoing percutaneous coronary intervention
(PCI) and AZD6140 in ACS patients being treated with medical
therapy, PCI, or coronary artery bypass grafting.
Key Words: AZD6140 • Clopidogrel • Cangrelor • Platelets • Prasugrel • P2Y12 antagonists
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Introduction
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Improved understanding of the important role of ADP in sustaining
platelet aggregation has made inhibition of the P2Y
12 ADP receptor
on platelets a major target of antithrombotic drug development
efforts. The therapeutic benefits of P2Y
12 inhibition were first
observed with the early thienopyridine ticlopidine. In the last
decade, ticlopidine has been largely replaced by clopidogrel,
which, like ticlopidine, is a prodrug of an irreversible P2Y
12 antagonist. Major trials with clopidogrel have confirmed that
P2Y
12 inhibition is associated with reduced thrombotic events
in the clinical setting.
1–3 Drawbacks of clopidogrel include
the need for CYP3A4-dependent metabolism to its active form
and partial hydrolysis to inactive form, factors that likely
account for the variability in measured inhibition of platelet
aggregation (IPA) after treatment. Moreover, irreversible P2Y
12 binding complicates invasive medical treatment when fast offset
of antiplatelet effects is desired. Current efforts in drug
development have focused on optimizing pharmacological characteristics
and clinical benefits of P2Y
12 antagonists.
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Chemical characteristics of novel P2Y12 antagonists
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Clopidogrel is metabolized via a two-step, CYP3A4-dependent
process, resulting in an active metabolite that includes a reactive
sulfhydryl group that can bind directly to a free cystein residue
in the P2Y
12 active site. A significant percentage of each administered
clopidogrel dose is, however, metabolized by esterases to an
inactive carboxylic acid derivative (
Figure 1).
4,5 In contrast,
the novel thienopyridine prasugrel is metabolized to its active
form via a one-step process that occurs following hydrolysis
by carboxyesterases to a thiolacetone.
4 Because metabolism of
prasugrel into an inactive carboxylic acid is prohibited by
the fact that the methyl-ester part of the molecule is replaced
by a stable cyclopropyl-ketone group, prasugrel administration
results in a higher concentration of active metabolite per dose
compared with clopidogrel. The pharmacodynamic properties of
prasugrel's active metabolite are very similar to those of clopidogrel's
active metabolite; it also binds irreversibly to the P2Y
12 receptor
via a reactive sulfhydryl group and has similar antiplatelet
activity.
6 Clinically, the improved metabolism of prasugrel
results in improved IPA at lower doses when compared with clopidogrel.
7
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Figure 1 Chemical characteristics of (A) clopidogrel and the novel thienopyridine prasugrel with their active metabolites; (B) the stable, selective oral P2Y12 antagonist, AZD6140; and (C) the reversible iv P2Y12 antagonist, cangrelor.
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Recognition that ATP competitively antagonizes ADP-induced platelet
aggregation, a discovery that actually led to identification
of the P2Y
12 receptor subtype, encouraged attempts to identify
ATP analogues that could act as direct and reversible inhibitors
of the P2Y
12 receptor.
5 ATP has poor stability and low potency
at P2 receptors. Cangrelor, an iv ATP analogue, shows increased
stability conferred by changes in the ATP phosphate chain; it
exhibits enhanced potency compared with ATP, with substitutions
on the purine ring conferring
1000-fold greater potency at P2Y
12.
Efforts to identify compounds suitable for oral administration led to identification of the first selective, stable non-phosphate P2Y12-receptor antagonist (AR-C109318XX).5 Refinement of this compound led to identification of the selective, stable, and reversible oral P2Y12 antagonist AZD6140, an agent that binds directly to the P2Y12 receptor without requiring metabolism to active form. AZD6140, together with cangrelor, represents a new class of antagonists, termed cyclopentyl-triazolo-pyrimidines, which differ from other ATP analogues. The structure of AZD6140 has crucial structural differences from ATP, including inclusion of a nitrogen atom in the purine-like moiety and omission of an oxygen atom in the sugar-like moiety of the molecule. Hence, AZD6140 and ATP differ significantly in their electrostatic properties; e.g. AZD6140 is lipophilic, whereas ATP is highly hydrophilic. As with cangrelor, AZD6140 has nanomolar affinity for the P2Y12 receptor and is highly selective vs. other P2 and P1 adenosine receptors.5
There are pre-clinical data to suggest that reversible antagonists may have beneficial effects on bleeding risk when compared with other antiplatelet agents, even at comparable levels of IPA and inhibition of thrombosis. In a model of cyclic flow reduction in dogs, both clopidogrel and the reversible P2Y12 antagonists had a significantly greater separation between antithrombotic effect and increase in bleeding time (i.e. therapeutic window) compared with orbofiban, a platelet glycoprotein (GP) IIb/IIIa inhibitor; AZD6140 and cangrelor showed trends towards greater separation than did clopidogrel.5 At 90% antithrombotic effect, there was a 120% increase in bleeding times with clopidogrel vs. a 40% increase for AZD6140 (Figure 2A). This improved separation was confirmed in a rat model of combined arterial thrombosis and bleeding time measurements8 and was maintained when aspirin was administered concomitantly (unpublished data). These data appear to be consistent with the clinical studies of AZD6140 in stable patients (DISPERSE)9 and in patients with ACS (DISPERSE2).10 Those trials have also shown that AZD6140 treatment indeed resulted in higher and more consistent IPA when compared with clopidogrel, without an increase in total bleeding. Furthermore, the pre-clinical studies suggest a direct correlation between ex vivo measured IPA and antithrombotic effect. In the canine model, although no antithrombotic effect is seen at IPA levels up to 35%, there seems to be a roughly linear correlation at higher levels of IPA, with full antithrombotic effect occurring at maximum IPA (Figure 2B). These results raise the question of whether such a threshold level of IPA exists in humans. Although no data on the association between IPA levels and clinical outcomes are currently available from large-scale trials, there are several smaller studies that provide evidence for such a threshold level. For example, it has been reported that suboptimal platelet inhibition after treatment with clopidogrel may be associated with increased stent thrombosis or ischaemic events after percutaneous coronary intervention (PCI).11,12
The TRITON trial, investigating whether higher levels of IPA
obtained with prasugrel vs. clopidogrel in patients with planned
PCI and known cardiovascular anatomy resulted in a reduction
in clinical outcomes, has recently been published.
13 It showed
that the higher levels of IPA obtained with the tested dose
of prasugrel
14 indeed resulted in an overall 19% reduction in
the primary efficacy endpoint of the combined incidence of cardiovascular
death, non-fatal myocardial infarction (MI), and non-fatal stroke.
This strengthens the hypothesis that increased IPA levels result
in a reduction in cardiovascular events.
Cangrelor and AZD6140 are currently being evaluated in large Phase 3 clinical trials to further validate the hypothesis that higher IPA leads to increased clinical benefits and to investigate whether reversible inhibition indeed translates into an improved bleeding- related safety profile. Cangrelor is being investigated in patients scheduled to undergo PCI (the CHAMPION PCI and CHAMPION PLATFORM trials), and AZD6140 in all ACS patients who are medically managed or scheduled to undergo PCI or CABG (the PLATO trial).
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Differences between reversible antagonists and irreversible thienopyridines
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Reversible P2Y
12 blockade may offer benefits beyond increased
IPA. When an antagonist binds irreversibly, it remains bound
to the receptor even if plasma drug levels decline, which in
effect means that platelets are inhibited for the remainder
of their life span. In the case of clopidogrel and other thienopyridines,
the active metabolite likely prevents ADP from binding to the
receptor and may cause structural changes (
Figure 3).
15 With
reversible binding, the receptor becomes fully functional again
once plasma levels of the antagonist decline sufficiently to
minimize the inhibitory effect on platelet aggregation. The
reversible inhibitor AZD6140 may bind independently of ADP since
compounds from the same chemical class could not prevent binding
of
3H-ADP.
15 Thus, it appears that ADP may still be able to
bind to the P2Y
12 receptor under appropriate physiological conditions
even in the presence of AZD6140. However, subsequent signalling
is prevented since AZD6140 appears to keep the receptor ‘locked’
in an inactive state during the transient ADP ‘burst’
following platelet activation. Because AZD6140 binds reversibly
to the P2Y
12 receptor, the inhibitory effect is directly dependent
on the concentration of available drug in the plasma. This permits
relatively rapid offset of effect when drug levels are reduced.
This would, in turn, allow antiplatelet therapy to be withdrawn
closer to the time of surgery when compared with an irreversible
inhibitor. Thus, reversibility may potentially translate into
a reduced period of risk for thrombosis that exists during the
recommended 5-day washout while on clopidogrel.
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Figure 3 (A) Inhibition of thrombosis, inhibition of ADP-induced (10 µM) platelet aggregation (IPA), and fold-increase in tongue bleeding time in the cyclic flow reduction (CFR) model for clopidogrel (left) and AZD6140 (right). Dotted lines indicate ‘therapeutic window’, calculated as dose inducing a 3.5-fold increase in bleeding time divided by dose inhibiting 50% of CFRs (BT3.5/CFR ID50). Thus, AZD6140 exhibits a wider therapeutic window—i.e. greater separation between antithrombotic effect and increase in bleeding. For example, AZD6140 is associated with reduced bleeding time compared with clopidogrel at the dose of each achieving 90% reduction in thrombosis. (B) Combined data from the CFR model of thrombosis in the femoral artery of anaesthetized dogs. Data show that after a threshold of 30% inhibition of ADP-induced (10 µM) platelet aggregation, there is an approximately linear relationship between degree of antithrombotic effect and percentage of IPA for clopidogrel, the platelet GPIIb/IIIa inhibitor orbofiban, the iv reversible P2Y12 antagonist cangrelor, and the oral reversible P2Y12 antagonist AZD6140. Data are from 5 to 6 animals per treatment group and are mean ± SEM. Adapted from van Giezen and Humphries. Semin Thromb Hemost 2005;31:1844–1851 with permission.5
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Other pre-clinical studies suggest that reversible inhibitors
may also be distinguished from thienopyridines by their interactions
with non-platelet P2Y
12 receptors. P2Y
12 receptors are also
present in vascular smooth muscle cells (VSMCs) in higher concentrations
than other ADP receptors (P2Y
1 and P2Y
13) and are active in
stimulating contraction of human blood vessels.
16 In studies
of human arterial segments from patients undergoing coronary
bypass, Wihlborg
et al. showed that a stable form of ADP (2-MeSADP)
induced contraction in submaximally pre-contracted vessels,
revealing P2Y
12-mediated vasoconstriction. These contractions
were blocked by the selective reversible P2Y
12 antagonist AR-C67085
but not by the selective P2Y
1 antagonist MRS 2179, indicating
both that the contractions were predominantly P2Y
12-mediated
and that they could be inhibited by a selective reversible antagonist
(
Figure 4). However, 2-MeSADP-induced contraction was not inhibited
in vessel segments from patients who had been treated with clopidogrel.
In contrast,
in vitro addition of AZD6140 did inhibit the 2-MeSADP-induced
constriction in blood vessels from both control and clopidogrel-treated
mice.
17 It is believed that the active clopidogrel metabolite
binds with P2Y
12 receptors as platelets pass through the liver;
the very short half-life of the metabolite prevents sufficient
amounts of the inhibitor from reaching the systemic circulation
and acting on VSMC receptors. A systemically acting reversible
P2Y
12 antagonist may be able to reach and block these receptors
to inhibit P2Y
12-mediated vasoconstriction. The potential clinical
benefits of this effect may include reduction of thrombogenic
vasospasm and improvement in myocardial perfusion after thrombosis.
Indeed, such an effect has been observed in a canine thrombosis
model reported by Wang
et al.
18 In this study, treatment with
the selective P2Y
12 antagonist AR-C69931MX (cangrelor) in dogs
receiving tissue-type plasminogen activator and heparin after
thrombus formation resulted in reduced reocclusion and cyclic
flow variation and improved myocardial tissue flow compared
with placebo (
Figure 5). It is probable that inhibition of VSMC
P2Y
12 had contributed to this observed improvement in regional
blood flow.
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Figure 4 (A) Effect of the reversible P2Y12 antagonist AR-67085 and the reversible P2Y1 antagonist MRS 2179 on 2-MeSADP-induced contraction of internal mammary artery segments from patients undergoing coronary bypass surgery. Contractions are expressed as a percentage of initial contraction with 60 mmol/L K+. 2-MeSADP-mediated contractions were significantly reduced by AR-67085 (n = 5–10; P < 0.05), and there was no significant difference in response with or without MRS 2179 (n = 8–10). (B) Response to 2-MeSADP in segments from patients receiving clopidogrel and not receiving clopidogrel (n = 6–10) shows no effect of clopidogrel treatment on contraction. Wihlborg AK, et al. ADP receptor P2Y12 is expressed in vascular smooth muscle cells and stimulates contraction in human blood vessels. Arterioscler Thromb Vasc Biol 2004;24:1810–1825. Reproduced with permission from Lippincott, Williams and Wilkins.16
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Figure 5 Findings for myocardial regional blood flow in a canine coronary electrolytic injury thrombosis model in animals receiving tissue-type plasminogen activator (t-PA), heparin, and either the reversible P2Y12 antagonist AR-69931MX or placebo after thrombus formation (n = 10 in each group). Regional blood flow was significantly improved (P < 0.05) with AR-69931MX treatment. Wang K, et al. Blockade of the platelet P2Y12 receptor by AR-C69931MX sustains coronary artery recanalization and improves the myocardial tissue perfusion in a canine thrombosis model. Arterioscler Thromb Vasc Biol 2003;23:357–362. Reproduced with permission from Lippincott, Williams and Wilkins.18
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Pharmacokinetics and pharmacodynamics of reversibility/irreversibility
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As shown in
Figure 6, the active metabolite of clopidogrel is
no longer detectable in plasma
6 h after a 600 mg loading dose,
19 consistent with its short-half-life. Monitoring of IPA over
24 h during clopidogrel treatment of patients with atherosclerosis
in the DISPERSE study showed that during daily dosing IPA increases
from the pre-dose level of 50% to a peak of
65% at 4 h after
dosing, and then decreases again during the remainder of the
dosing interval.
9 This daily variability in IPA with clopidogrel
must be attributed to the generation of new platelets and their
entry into the circulation between 6 and 24 h after dosing when
no metabolite is being formed. Mean platelet survival is
10
days, and
10% of the platelet population is replaced daily in
an individual.
20 Given the brief presence of the clopidogrel
active metabolite in the circulation, it must follow that most
of the newly generated platelets are left uninhibited until
the next daily dose. Platelet kinetics also explain clopidogrel's
prolonged time to offset of effect, since the return of platelet
function depends on synthesis of a sufficient population of
new platelets in the absence of drug to replace the irreversibly
bound platelets. Similar restrictions likely apply to other
thienopyridines or other irreversible platelet inhibitors. Although
shortly after dosing, a greater peak plasma concentration of
the prasugrel active metabolite is observed compared with the
clopidogrel metabolite, plasma concentrations decline at approximately
the same rate thereafter (
Figure 7),
21 suggesting that, even
here, part of the newly generated platelets will remain uninhibited
between given doses. Therefore, prior to each new dose of a
thienopyridine, a mixed platelet population may exist comprising
those that are fully inhibited and others that are completely
uninhibited, resulting in variable IPA in individuals based
on the their unique ratios. The clinical relevance of this is
not known at this time.
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Figure 6 Plasma levels of clopidogrel (A) and active metabolite (B) in patient with adequate IPA after a clopidogrel 600 mg loading dose (control) and in patients with suboptimal IPA after loading dose (non-responder). The responder profile shows that levels of active metabolite are undetectable in plasma at around 6 h after dosing. Profiles in non-responders indicate failure to metabolize clopidogrel to its active metabolite as a cause of clopidogrel resistance, a common clinical phenomenon. Reprinted from Thromb Haemost, 93, von Beckerath N, et al. A patient with stent thrombosis, clopidogrel-resistance and failure to metabolize clopidogrel to its active metabolite, 789–791, 2005, with permission from Elsevier.19
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Figure 7 Plasma concentrations of prasugrel active metabolite after a 60 mg dose and clopidogrel active metabolite after a 300 mg dose, indicating that also for a prasugrel loading dose, the active metabolite only reaches significant plasma levels during the initial hours after dosing.21
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In contrast, daily observable variability in IPA with the direct
reversible antagonist AZD6140 is directly linked to changes
in plasma drug levels. As discussed by Husted
et al.,
9 pre-dose
IPA in DISPERSE patients receiving daily treatment with AZD6140
100 mg twice daily was
80%, increasing to
90% before declining
until administration of the next dose 12 h later. Because AZD6140
binds reversibly to the receptor and a dynamic equilibrium between
bound and unbound platelets is established, all circulating
platelets are exposed to drug until the next dose, though to
a slightly lesser extent. Whether this difference in kinetics
between thienopyridines and reversible inhibitors has clinical
consequence remains to be determined and the ongoing PLATO trial
will provide this data. It is worth noting that even when the
second daily dose of AZD6140 is missed, IPA at AZD6140 doses
greater than 50 mg is still maintained at levels above those
seen with clopidogrel 75 mg when both are measured at 24 h (
Figure 8).
9 By 48 h, however, plasma drug levels have declined markedly,
resulting in offset of IPA, and patients could potentially undergo
surgery sooner than if they were receiving thienopyridine therapy.
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Figure 8 Final extent IPA on Day 28 in patients receiving clopidogrel 75 mg once daily or AZD6140 100 mg twice daily in the DISPERSE trial, with no second dose of AZD6140 given on Day 28. IPA in AZD6140-treated patients remained above that for clopidogrel-treated patients over the entire 24 h dosing period. Reprinted from Husted S, et al. Pharmacodynamics, pharmacokinetics, and safety of the oral reversible P2Y12 antagonist AZD6140 with aspirin in patients with atherosclerosis: a double-blind comparison to clopidogrel with aspirin. 2006;27:1038–1047, with permission from Oxford Journals.9
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Summary
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Recently published data from the TRITON study with the new thienopyridine
prasugrel and ongoing Phase 3 clinical trials with the reversible
iv antagonist cangrelor and the reversible oral antagonist AZD6140
are examining whether platelet inhibition via P2Y
12-receptor
inhibition can be optimized to provide clinical benefits beyond
those achieved with current antiplatelet therapy. The TRITON-TIMI
38 trial examined whether the greater IPA achievable with prasugrel
translated into a superior risk:benefit profile vs. clopidogrel
in patients with ACS undergoing PCI. The results showed a clear
reduction in risk of ischaemic events. The effects of cangrelor
are being examined in the CHAMPION PCI trial (vs. clopidogrel)
and the CHAMPION PLATFORM trial (cangrelor plus usual care vs.
placebo plus usual care) in patients undergoing PCI. The PLATO
trial is examining whether treatment with the oral reversible
P2Y
12 antagonist AZD6140 can provide additional benefits without
increasing bleeding when compared with clopidogrel in ACS patients
treated with medical therapy, PCI, or CABG.
Conflict of interest: Dr. van Giezen is an employee of AstraZeneca.
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Funding
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Dr. van Giezen is an employee of AstraZeneca and conducts research
for AstraZeneca.
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References
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