Drug Profile

Cangrelor: a review on
pharmacology and clinical
trial development
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Expert Rev. Cardiovasc. Ther. 11(10), 12791291 (2013)

Francesco Franchi,
Fabiana Rollini,
Ana Muniz-Lozano,
Jung Rae Cho and
Dominick J Angiolillo*
University of Florida College of
Medicine-Jacksonville, Jacksonville,
FL, USA
*Author for correspondence:
Tel.: +1 904 244 3933
Fax: +1 904 244 3102
For personal use only.
Dual antiplatelet therapy with aspirin and an oral ADP P2Y12 receptor antagonist is the
standard-of-care for the prevention of ischemic events in patients with acute coronary syndrome
or undergoing percutaneous coronary intervention (PCI). However, currently available ADP P2Y12
receptor antagonists have several limitations, such as interindividual response variability,
drugdrug interactions, slow onset/offset and only oral availability. Cangrelor is a reversible,
potent, intravenous, competitive inhibitor of the ADP P2Y12 receptor that rapidly achieves near
complete and predictable platelet inhibition. Along with reversible binding to the receptor
cangrelor also has a very short half-life (35 min), which in turn results in a rapid offset of action.
These properties make cangrelor a promising drug for clinical use in patients undergoing PCI or
patients waiting for major surgery but still require antiplatelet protection. This manuscript
provides an update of the current status of knowledge on cangrelor, focusing on its pharmacologic

dominick.angiolillo@jax.ufl.edu
properties and clinical trial development, including the BRIDGE and CHAMPION-PHOENIX trials.

KEYWORDS: acute coronary syndrome antiplatelet therapy cangrelor percutaneous coronary intervention
P2Y12 receptor antagonist

The platelet ADP P2Y12 receptor plays a key
role in platelet activation and aggregation proc-
esses [13]. The use of P2Y12 inhibitors has con-
sistently demonstrated to reduce the risk of
thrombotic recurrences in patients with acute
coronary syndrome (ACS) and undergoing per-
cutaneous coronary intervention (PCI) [48].
However, oral P2Y12 receptor inhibitors mostly
utilized in clinical practice (clopidogrel, prasu-
grel and ticagrelor) have several limitations [913].
Clopidogrel is a prodrug characterized by high
variability in absorption, delayed onset of
action, drugdrug interactions, incomplete
P2Y12 receptor inhibition and broad interindi-
vidual response variability [1416]. Importantly,
patients who persist with high platelet reactivity
despite clopidogrel therapy have an increased
risk of atherothrombotic recurrences, particu-
larly in the setting of PCI [17].
Prasugrel and ticagrelor have represented
important advancements to the field of oral
P2Y12 receptor inhibition as both drugs are
characterized by more prompt, potent and pre-
dictable antiplatelet effects and which have
resulted in greater clinical efficacy over clopi-
dogrel [7,8,18]. However, these drugs still present
limitations. These include a delayed antiplatelet
effect, particularly in the setting of ST-elevation
myocardial infarction (STEMI), a clinical set-
ting where immediate and potent platelet inhib-
itory effects are needed [19,20], as well as their
delayed offset of action requiring 5 (ticagrelor)
or 7 (prasugrel) days of withdrawal before con-
sidering patients for surgery according to prac-
tice guidelines [913,21,22]. Ultimately, current
P2Y12 inhibitors are only available orally and
cannot provide reliable inhibition in patients
hemodynamically unstable or who are unable to
swallow or rapidly absorb medication taken
orally, such as patients who are sedated, intu-
bated, in shock or those with nausea or vomit-
ing [23,24]. Considering all these limitations, the
clinical development of an intravenous P2Y12
receptor inhibitor with fast onset and offset of
action, potent effect and low interindividual
variability is needed.
Cangrelor (The Medicines Company, Parsip-
pany, NJ, USA) is a reversible ATP analog,
available for intravenous use, which directly and
reversibly binds to the P2Y12 receptor without
being metabolized. These pharmacologic prop-
erties allow achievement of high levels of

www.expert-reviews.com 10.1586/14779072.2013.837701
2013 Informa UK Ltd ISSN 1477-9072 1279

 Drug Profile iz-Lozano, Rae Cho & Angiolillo
Franchi, Rollini, Mun

presented in this article, which aims to

S
HN
provide an update on the latest clinical
trial data on cangrelor. However, a sum-
N
mary of preclinical and early phase clini-
N cal investigations is provided below.
4Na+
Preclinical studies have shown the effi-
O O O
O N
CF3 cacy of cangrelor to inhibit thrombus for-
N S mation and ADP-induced platelet
P P O
P aggregation in animal models and the
O O
O lower increase in bleeding time when

O
O
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Michigan University on 03/02/15

Cl compared with glycoprotein IIb/IIIa

Cl
HO inhibitors (GPIs) [30]. Cangrelor showed a
OH
dose-dependent effect on platelet inhibi-
tion in healthy volunteers at an infusion
Figure 1. Cangrelor (2-trifluoropropylthio, N-(2-(methylthio)ethyl)-b,
g-dichloromethylene ATP). rate of 0.14 mg/kg/min, rapidly achiev-
ing the steady-state plasmatic concentra-
tions. The half-life was very short
platelet inhibition with a rapid onset and offset of effect [25,26]. (2.6 min) with reversion of platelet inhibition after 20 min of
This manuscript provides an overview of the current status of infusion discontinuation [31]. Greater inhibition of ADP-
knowledge on cangrelor, focusing on its pharmacologic proper- induced platelet aggregation and less response variability with
ties and most recent clinical trial development. cangrelor than with clopidogrel were also demonstrated in
other Phase I investigations [32,33]. The safety and preliminary
Pharmacological properties efficacy results of cangrelor have been evaluated in several
Cangrelor is an intravenous ATP analog that blocks ADP- Phase II clinical investigations. A multicenter Phase II study
For personal use only.

induced platelet activation at the P2Y12 receptor. ADP targets performed in ACS patients (n = 39) showed a mean half-life of
P2Y1 and P2Y12 receptors; the P2Y12 receptor among other less than 5 min, a small volume of distribution and a dose-
functions, amplifies platelet responses mediated by other ago- dependent effect. The steady-state level of inhibition was
nists, such as dense granule release and p-selectin expression [27]. achieved within 30 min of onset of infusion and the propor-
ATP is rapidly metabolized by ectonucleotidases resulting in tions of patients with 100% inhibition of maximal platelet
less affinity to the P2Y1 and P2Y12 receptors [28,29]. The final aggregation induced by ADP 3 mmol/l at 24 h were 77% with
molecule of cangrelor (2-trifluoropropylthio, N-(2-(methylthio) 2 mg/kg/min and 86% with 4 mg/kg/min. All patients had >80%
ethyl)-b, g-dichloromethylene ATP) was modified from ATP inhibition of aggregation at rates of 2 and 4 mg/kg/min and 60%
and has a higher affinity and longer half-life because anhydride of the baseline platelet aggregation was recovered within 1 h after
groups were replaced with methylene groups and halogen. stopping infusion. Minor bleedings were observed in 56%
Addition of non-polar moieties and sulfide-linked chains con- patients, with no major bleeding and a poor correlation between
fers a higher antagonistic property for the P2Y12 receptor, and bleeding times and drug plasmatic concentrations [34].
its potency was increased by sixfold by changing from AR- The Safety, Tolerability and Effect on Patency in Acute
C67085 at the adenosine C2 position with 3,3,3-trifluoropro- Myocardial Infarction (STEP-AMI) trial studied the effect of
pylthio and N6 methylthioethyl groups (FIGURE 1) [25,26]. continuous infusion of cangrelor as adjunctive therapy to fibri-
These structural changes result in unique pharmacologic nolysis with alteplase in patients with STEMI (n = 92). The
advantages. Cangrelor has higher resistance to ectonucleotidases primary end point of thrombolysis in myocardial infarction
and affinity for the P2Y12 receptor, [29], and is directly active (TIMI)-3 flow at 60 min showed no difference between the
because it does not require hepatic conversion. Cangrelor combination of half-dose of alteplase plus cangrelor and full-
reaches steady-state concentrations within few minutes and is dose of alteplase, while cangrelor alone was significantly infe-
characterized by predictable plasma levels, due to its linear rior. However, in patients receiving combination therapy an
dose-dependent pharmacokinetic profile, which in turn leads to improvement in ST-segment resolution was noted, even if it
more stable pharmacodynamic effects. Moreover, it has a fast did not reach statistical significance. No difference was
offset of action with platelet aggregation returning to baseline observed between groups in major adverse clinical events and
levels within 3060 min, due to the reversible binding and the bleeding [35]. In a Phase II trial in patients undergoing elective
very short half-life (35 min) [25,26]. or urgent PCI cangrelor demonstrated similar 30-day incidence
of cardiac adverse events compared with abciximab (7.6 vs
Preclinical studies & early phase clinical investigations 5.3%; p = not significant). Platelet inhibition was similar dur-
Preclinical studies and early phase clinical investigations have ing the steady-state phase, but 1224 h after terminating infu-
already been extensively described in two prior reports in this sion, it persisted in the abciximab group while returned to
journal [25,26]. Therefore, details on these issues are not baseline in cangrelor-treated patients. Of note, no statistically

1280 Expert Rev. Cardiovasc. Ther. 11(10), (2013)

 A review on pharmacology & clinical trial development of cangrelor
significant differences in rates of bleeding were found when
comparing cangrelor either with placebo or abciximab [36].
Since diabetes mellitus (DM) is known to be associated with
impaired response to antiplatelet therapies [37], the pharmacody-
namic effect of cangrelor was compared in clopidogrel-nave
CAD patients (n = 103) with and without DM. After in vitro
incubation with 500 nmol/l of cangrelor, a significant reduc-
tion in vasodilator-stimulated phosphoprotein P2Y12 reactivity
index (VASP-PRI) was observed in the overall population
(80.6 14.0% relative reduction in PRI). Interestingly, this
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Michigan University on 03/02/15
reduction was consistent in DM and non-DM patients
(p < 0.0001 for both comparisons), with no difference in PRI
values between groups (16.1 12.3 vs 16.8 11.3;
p = 0.346). Moreover, the dose-dependent effect of cangrelor
was not influenced by DM status [38].
Drug interactions
A randomized study on healthy volunteers first showed a com-
petitive interaction between cangrelor and clopidogrel. Subjects
(n = 20) were randomized to receive clopidogrel (600 mg
loading dose) either simultaneously or immediately after can-
grelor administration (bolus of 30 mg/kg and 1-h infusion of
4 mg/kg/min). The expected levels of sustained platelet inhibi-
tion were only achieved by the group in which clopidogrel
For personal use only.
was administered after cangrelor infusion and post-infusion
platelet aggregation returned to baseline in subjects receiving
both drugs simultaneously. In fact, the very high affinity of
cangrelor to P2Y12 receptor prevents the active metabolite of
clopidogrel to bind to the receptor. Therefore, clopidogrel-
induced platelet inhibition is precluded if the P2Y12 receptor
is already inhibited by cangrelor [39]. Moreover, in vitro pre-
incubation of blood with cangrelor prior to addition of both
clopidogrel and prasugrel active metabolites reduced their
ability to inhibit platelet aggregation. By contrast, addition of
cangrelor after pre-incubation with active metabolites of clopi-
dogrel or prasugrel led to a sustained platelet inhibition [40].
Using an ex vivo canine model, no significant pharmacody-
namic interaction was observed between cangrelor and the
direct-acting P2Y12 receptor antagonist ticagrelor [41].
Overall, these observations underline the need of an appro-
priate transitioning strategy from cangrelor to oral P2Y12
receptor inhibitors. Thus far, ex vivo transitioning studies in
humans have only been performed from cangrelor to clopi-
dogrel in which clopidogrel should be administered only after
cangrelor infusion discontinuation [39]. Transitioning studies
from cangrelor to prasugrel or ticagrelor have yet to
be reported.
Cangrelor as bridging strategy for surgery: the BRIDGE
trial
The thienopyridines clopidogrel and prasugrel are irreversible
platelet inhibitors, with duration of effects corresponding to the
lifespan of a circulating platelet (710 days) and practice guide-
lines recommend stopping therapy for 5 and 7 days, respectively,
prior to surgery to minimize bleeding complications [913].
www.expert-reviews.com
Drug Profile
Ticagrelor is a non-thienopyridine which despite its reversible
binding activity to the P2Y12 receptor, still requires several
days to return to baseline platelet reactivity and should be
stopped for at least 5 days before surgery according to practice
guidelines [913]. This is indeed relevant because it is estimated
that about 520% of patients need to undergo some kind of
surgery within the year after stent implant or ACS diagno-
sis [42]. The risk of perioperative cardiac ischemic events, par-
ticularly stent thrombosis, is high in these patients, because
surgery has a prothrombotic effect and antiplatelet therapy is
often withdrawn in order to prevent bleeding complica-
tions [42]. Several approaches using currently available intrave-
nous antithrombotic drugs have been proposed for bridging
strategies. However, heparin or low molecular weight heparin
are generally not recommended, because such treatment is
associated with increased bleeding and they do not have anti-
platelet effects (unfractionated heparin can actually increase
platelet reactivity) [43,44]. GPIs, in particular the small mole-
cules tirofiban and eptifibatide, have been tested in some small
study because of their rapid onset of action, and consistent
platelet inhibitory effects [43,44]. Nevertheless, GPIs have a slow
offset of action, requiring 46 h to return to baseline platelet
function [45] and their prolonged administration in the setting
of bridging can increase the risk of bleeding. Therefore, can-
grelor has clear advantages over other strategies to be consid-
ered as a therapeutic option for bridging.
The role of cangrelor in patients on dual antiplatelet therapy
undergoing cardiac surgery was recently investigated in the
Bridging antiplatelet therapy with cangrelor in patients under-
going cardiac surgery (BRIDGE) trial [46]. This double-blind,
placebo-controlled, Phase II, multicenter trial enrolled patients
with ACS (n = 210) or treated with a coronary stent, receiving
a thienopyridine (at least 500 mg ticlopidine, 75 mg of clopi-
dogrel or 10 mg of prasugrel) within at least 72 h prior to ran-
domization and awaiting coronary artery bypass graft (CABG)
surgery. The trial consisted of two independent phases, with
the same eligibility criteria. Phase I aimed to identify the dose
of cangrelor achieving the desired antiplatelet effect. Patients
(n = 5) were administered escalating doses of cangrelor until
platelet reactivity inhibition was greater than 60% (measured
by VerifyNow P2Y12 testing) in 80% of daily samples. The
dose of 0.75 mg/kg/min met this pharmacodynamic efficacy
end point and was used in the randomized, double-blind,
placebo-controlled stage. Thus, in Phase II, patients were
randomized to receive cangrelor infusion (0.75 mg/kg/min) plus
standard-of-care or placebo infusion plus standard-of-care after
thienopyridine discontinuation. Infusion was continued
throughout the preoperative period up to 16 h before surgical
incision. CABG had to occur no sooner than 48 h but no lon-
ger than 7 days from randomization, at the discretion of the
investigator. The primary efficacy end point was the proportion
of patients with platelet reactivity of less than 240 P2Y12 reac-
tion units (PRU), measured by VerifyNow P2Y12 testing, for
all samples assessed during study drug infusion prior to surgery.
The main safety end point was excessive CABG surgery-related
1281
 Drug Profile iz-Lozano, Rae Cho & Angiolillo
Franchi, Rollini, Mun
A Cangrelor in patients undergoing PCI: Phase III studies
98.8%
100%
p < 0.0001
80%
RR: 5.2 (95% CI: 3.38.1)
60%
40%
19.0%
20%
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Michigan University on 03/02/15
0%
Cangrelor Placebo
B likelihood of achieving the primary end point. In CHAM-
15%
11.8%
p = 0.76 10.4%
10%
5%
For personal use only.
0%
Cangrelor Placebo
Figure 2. Primary efficacy and safety end point of the
BRIDGE trial. (A) Percent of patients with P2Y12 reaction units
<240 for all on-treatment samples. (B) Excessive coronary artery
bypass graft surgery-related bleeding.
Data taken from [46].
bleeding. The primary efficacy end point was significantly
higher in the cangrelor group than in the placebo group
(98.8 vs 19.0%; relative risk [RR]: 5.2; 95% CI: 3.38.1;
p < 0.001). After discontinuation of infusion prior to surgical
incision, PRU levels and the percentage of patients with platelet
reactivity lower than 240 PRU were similar between groups
(p = 0.21 and 0.31, respectively) (FIGURE 2 & TABLE 1). Study-
defined excessive CABG surgery-related bleeding were not sig-
nificantly different between groups (11.8% in the cangrelor
arm vs 10.4% in placebo arm; p = 0.76) (FIGURE 2). Pre-CABG-
surgery major-bleeding events were overall rare and similar
between both treatment groups; minor bleeding events were
numerically more frequent with cangrelor and driven by ecchy-
mosis at the site of venous puncture, which were performed
daily for pharmacodynamics assessments. Ischemic end points
prior to surgery were low (2.8% in the cangrelor arm and
4.0% in the placebo arm) even if the trial was not powered to
assess these differences. Despite the prolonged infusion, rates of
dyspnea, an undesired side effect of reversible P2Y12 receptors
inhibitors (oral and intravenous), were low (1.9% with cangre-
lor vs 1.0% with placebo, 3 events total) and there was no evi-
dence of abnormal laboratory values, including hepatic
enzymes [46] which had been observed with other parenteral
P2Y12 receptors inhibitors [47,48].
1282
CHAMPION-PCI & CHAMPION-PLATFORM
The efficacy of cangrelor in patients undergoing PCI, predomi-
nantly for ACS, was initially investigated in two parallel large
Phase III trials, the Platelet Inhibition with Cangrelor in
Patients Undergoing PCI (CHAMPION-PCI) trial [49] and the
Intravenous Platelet Blockade with Cangrelor during PCI
(CHAMPION-PLATFORM) trial (FIGURE 3) [50]. The primary
end point for both studies was a composite of death from any
cause, myocardial infarction (MI) and ischemia-driven revascu-
larization (IDR) at 48 h post-randomization. However, enroll-
ment was terminated earlier in response to a recommendation
from the interim analysis review committee because of the low
PION-PCI, 98% of patients (n = 8882) was enrolled, while
only 84% (n = 5364) in CHAMPION-PLATFORM. In both
trials, patients randomized to cangrelor received their loading
dose of clopidogrel after discontinuation of cangrelor infusion,
in order to avoid interaction between clopidogrel and cangre-
lor. Patients with STEMI and on prior clopidogrel therapy
were eligible for CHAMPION-PCI, but excluded from
CHAMPION-PLATFORM. The use of glycoprotein IIb/IIIa
was discouraged in both trials [49,50]. The design and pivotal
findings of both trials are summarized in FIGURE 3 & TABLE 1,
respectively.
In brief, in CHAMPION-PCI, patients were randomized
to the experimental arm, receiving a 30-mg/kg bolus dose of
cangrelor followed by a 4-mg/kg/min maintenance infusion
(administered within 30 min of the PCI start and continued
for a minimum of 2 h and no longer than 4 h), or to the
active control arm, receiving a 600-mg loading dose of clopi-
dogrel prior to the start of PCI [49]. At 48 h, cangrelor was
not superior to clopidogrel with respect to the primary com-
posite end point, which occurred in 7.5% of patients in the
cangrelor group and 7.1% of patients in the clopidogrel
group (odds ratio [OR]: 1.05; 95% CI: 0.881.24;
p = 0.59). Similarly, no differences were observed at 30 days.
The rate of major bleeding according to ACUITY (Acute
Catheterization and Urgent Intervention Triage Strategy) cri-
teria was higher with cangrelor (3.6 vs 2.9%; OR: 1.26; 95%
CI: 0.991.60; p = 0.06). However, using different bleeding
scores, the rate of major bleeding was not different between
cangrelor and clopidogrel. A secondary exploratory end point
of death from any cause, Q-wave MI, or IDR showed a
numerical reduction with cangrelor, which however was not
significant (0.6 vs 0.9%; OR: 0.67; 95% CI: 0.391.14;
p = 0.14). Stent thrombosis was also reduced in cangrelor
group but without statistical significance (0.2 vs 0.3%; OR:
0.63; 95% CI: 0.251.63; p = 0.34).
The CHAMPION-PLATFORM trial was designed to
explore if the efficacy of cangrelor (plus standard-of-care) was
superior to that of standard-of-care (clopidogrel 600 mg load-
ing dose followed by 75 mg/day maintenance dose) in patients
undergoing PCI [50]. Patients were randomized to receive can-
grelor (with a bolus of 30 mg/kg followed by a 4 mg/kg/min
Expert Rev. Cardiovasc. Ther. 11(10), (2013)
 Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Michigan University on 03/02/15
For personal use only.

Table 1. Pivotal clinical trials on cangrelor.

Study N (efficacy/safety Treatment Setting Major end point Outcomes Ref.
population) arms
BRIDGE 186/207 Cangrelor vs placebo ACS or post-PCI patients Patients with PRU < 240 [46]

www.expert-reviews.com
treated with a for all on-treatment samples 98.8 vs 19.0%; RR: 5.2
thienopyridine undergoing (3.38.0); p < 0.001
CABG surgery in the last sample 98.8 vs 31.0%; RR: 3.2
(2.34.4); p < 0.001
after infusion discontinuation 26.9 vs 20.0%; RR: 1.3
(0.82.4); p = 0.31
Excessive CABG-related 11.8 vs 10.4%; RR: 1.1
bleeding (0.52.5); p = 0.76
CHAMPION 7754/8739 Cangrelor + clopidogrel SA, NSTE-ACS, STEMI Death, MI, IDR 7.5 vs 7.1%; OR: 1.05 [49]
PCI vs undergoing PCI (patients (0.881.24); p = 0.59
clopidogrel on clopidogrel allowed) Stent thrombosis 0.2 vs 0.3%; OR: 0.63
(0.251.63); p = 0.34
GUSTO severe bleeding 0.2 vs 0.3%; OR: 0.91
(0.392.14); p = 0.82
ACUITY major bleeding 3.6 vs 2.9%; OR: 1.26
(0.991.60); p = 0.06
CHAMPION 5295/5312 Cangrelor + clopidogrel SA, NSTE-ACS undergoing Death, MI, IDR 7.0 vs 8.0%; OR: 0.87 [50]
PLATFORM vs PCI (patients on (0.711.07); p = 0.17
clopidogrel clopidogrel not allowed) Stent thrombosis 0.2 vs 0.6%; OR: 0.31
(0.110.85); p = 0.02
GUSTO severe bleeding 0.3 vs 0.2%; OR: 1.50
(0.534.21); p = 0.45
ACUITY major bleeding 5.5 vs 3.5%; OR: 1.61
(1.232.10); p < 0.001
CHAMPION 10942/11056 Cangrelor + clopidogrel SA, NSTE-ACS, STEMI Death, MI, IDR, ST 4.7 vs 5.9%; OR: 0.78 [55]
PHOENIX vs undergoing PCI (patients (0.660.93); p = 0.005
clopidogrel on clopidogrel not Stent thrombosis 0.8 vs 1.4%; OR: 0.62
allowed) (0.430.90); p = 0.01
GUSTO severe bleeding 0.2 vs 0.1%; OR: 1.50
A review on pharmacology & clinical trial development of cangrelor

(0.534.22); p = 0.44
ACUITY major bleeding 4.3 vs 2.5%; OR: 1.72
(1.392.13); p < 0.001

Primary efficacy end point.

Primary safety end point.

In the CHAMPION-PCI and CHAMPION PLATFORM trials there was no predefined primary safety end point.
ACUITY: Acute Catheterization and Urgent Intervention Triage Strategy; CABG: Coronary artery bypass graft; GUSTO: Global Use of Strategies to Open Occluded Coronary Arteries; IDR: Ischemia-driven revascularization;
MI: Myocardial infarction; NSTE-ACS: Non-ST-segment elevation acute coronary syndrome; OR: Odds ratio; PCI: Percutaneous coronary intervention; RR: Relative risk; SA: Stable angina; STEMI: ST-segment elevation myo-
cardial infarction; ST: Stent thrombosis.
Drug Profile

1283
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1284
Drug Profile

A B C
Patients who require PCI (SA, NSTE-ACS, STEMI) Patients who require PCI (SA, NSTE-ACS) Patients who require PCI (SA, NSTE-ACS, STEMI)
(patients on clopidogrel allowed) (patients on clopidogrel not allowed) (patients on clopidogrel not allowed)

1:1 randomization 1:1 randomization 1:1 randomization post angiography

Double blind, double dummy Double blind, double dummy Double blind, double dummy

Cangrelor Placebo Cangrelor

Cangrelor Clopidogrel Placebo
bolus (30 g/kg) & bolus & bolus (30 g/kg) &
bolus (30 g/kg) & capsules (600 mg) bolus & infusion
Franchi, Rollini, Mun

infusion (4 g/kg/min) infusion infusion (4 g/kg/min)

infusion (4 g/kg/min) +
+ Placebo
Placebo capsules bolus & infusion
Placebo capsules Clopidogrel 300 mg or 600 mg
Patients undergoing PCI (before or immediately after PCI) (before or immediately after PCI)*
Study drug infusion: for at least 2 hours or
the duration of the procedure, whichever is longer
Patients undergoing PCI Patients undergoing PCI
Study drug infusion: for at least 2 hours or Study drug infusion: for 24 hours or
the duration of the procedure, whichever was longer Placebo capsules Clopidogrel (600 mg) the duration of the procedure, whichever is longer
immediately immediately
after procedure after procedure
Clopidogrel capsules (600 mg) Placebo capsules
Clopidogrel (600 mg) Placebo capsules immediately post-infusion immediately post-infusion
at discontinuation at discontinuation Clopidogrel (600 mg) Placebo capsules
of infusion of infusion immediately immediately
after infusion after infusion
iz-Lozano, Rae Cho & Angiolillo

Aspirin 75-325 mg and clopidogrel 75 mg maintenance

Clopidogrel maintenance Clopidogrel maintenance dose (or other P2Y12inhibitor maintenance dose)

Figure 3. Study designs of the CHAMPION trials. (A) CHAMPION-PCI; (B) CHAMPION-PLATFORM; (C) CHAMPION PHOENIX.

At the discretion of the physician.
NSTE-ACS: Non-ST-segment elevation acute coronary syndrome; PCI: Percutaneous coronary intervention; SA: Stable angina; STEMI: ST-segment elevation myocardial
infarction.
Data taken from [49,50,55].

Expert Rev. Cardiovasc. Ther. 11(10), (2013)

 A review on pharmacology & clinical trial development of cangrelor
infusion), administered within 30 min before the procedure
and continued for 24 h) or a matching placebo bolus and
infusion. Differently from CHAMPION-PCI, in which
patients received clopidogrel loading before the procedure,
patients in the placebo group received a loading dose of
600 mg of clopidogrel at the end of the PCI. Cangrelor
showed no significant reduction in the incidence of the primary
end point compared with placebo (7 vs 8%; OR: 0.87; 95%
CI: 0.711.07; p = 0.17). However, at 48 h, the two prespeci-
fied adjudicated secondary end points of rate of stent thrombo-
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Michigan University on 03/02/15
sis and rate of death from any cause were significantly reduced
with the use of cangrelor (0.2 vs 0.6%; OR: 0.31; 95% CI:
0.110.85; p = 0.02 and 0.2 vs 0.7%; OR: 0.33; 95% CI:
0.130.83; p = 0.02, respectively). In addition, cangrelor signif-
icantly reduced the combined exploratory end points of death,
Q-wave MI or stent thrombosis (p = 0.003) and death, Q-
wave MI or IDR (p = 0.02). Major bleeding were increased in
the cangrelor group only with ACUITY criteria due to more
groin hematomas (5.5 vs 3.5%; p < 0.001). The incidence of
transient dyspnea associated with cangrelor use was overall low,
but significantly increased in both CHAMPION trials (1 vs
0.4%; p = 0.001 and 1.4 vs 0.5%; p = 0.002 in CHAMPION
PCI and PLATFORM, respectively).
A pre-defined prospectively designed platelet function sub-
For personal use only.
study of CHAMPION trials was performed in a selected
cohort of patients (n = 234) to provide insight into the phar-
macodynamic effects of cangrelor, particularly exploring if can-
grelor therapy may interfere with the inhibitory effects of
clopidogrel [51]. Pharmacodynamic assays included PRU
assessed by VerifyNow P2Y12 testing, platelet aggregation by
light transmittance (LTA) and markers of platelet activation
determined by flow cytometry. The primary end point was the
percentage of patients who achieved less than a 20% change in
PRU between baseline and 10 h after PCI. The difference in
the percent of patients who reached the primary end point in
the cangrelor arm (38.1%) compared with the clopidogrel arm
(25.3%) was not statistically significant (difference: 12.79%;
95% CI: -1.18%, 26.77%; p = 0.076). During infusion,
patients in cangrelor arm achieved significantly lower platelet
aggregation as measured by VerifyNow (median PRU: 93.5 vs
277.0; p < 0.001), which were paralleled by both LTA and
flow cytometry analyses. Moreover, cangrelor treatment signifi-
cantly reduced the prevalence of patients with high on-
treatment platelet reactivity (p < 0.01), defined as PRU >235.
Further, platelet reactivity measured after infusion discontinua-
tion was not significantly different between two groups, sug-
gesting that the pharmacodynamic effects of clopidogrel were
not attenuated by cangrelor. In addition, this observation con-
firmed the rapid recovery of platelet function after discontinua-
tion of cangrelor infusion.
In both CHAMPION trials, the primary end point was
driven by the occurrence of MI. However, MI is difficult to
evaluate post-PCI particularly when cardiac biomarkers are ele-
vated before the procedure and when the time from hospital
admission to PCI is short as in the CHAMPION trials
www.expert-reviews.com
Drug Profile
(6.3 [interquartile range 2.623.7 h in PCI] and 7.9 [interquar-
tile range 3.324.1 h] in PLATFORM). In fact, a benefit with
cangrelor was observed in prespecified secondary end points
not dependent on cardiac biomarkers, including death, Q-wave
MI, IDR or stent thrombosis. Moreover, in the CHAMPION-
PLATFORM subgroup of 1659 patients who did not have an
elevation in troponin levels at baseline, the primary end point
was significantly reduced in the cangrelor group compared with
the placebo group (4.6 vs 7.2%; p = 0.03). Considering all
these issues, a prespecified pooled analysis of data from
CHAMPION trials using the universal definition to define MI
to explore the effect of cangrelor on ischemic events was per-
formed [52]. The universal definition of MI [53] used in the
analysis defined MI associated with PCI as elevation of bio-
markers >three-times the 99thpercentile upper limit of normal
in patients with normal baseline or unknown baseline troponin
levels. If baseline troponin levels were abnormal, only Q-wave
MIs were included. Applying this definition 59.5% of events,
originally defined as MI, were removed from the analysis. The
authors showed that at 48 h cangrelor significantly reduced the
primary end point (3.1 vs 3.8%; OR: 0.82; 95% CI: 0.68
0.99; p = 0.037). At 30 days, the absolute difference in the pri-
mary end point was similar (0.6 vs 0.7%), but was no longer
statistically significant (p = 0.10).
CHAMPION PHOENIX
Given the hypothesis-generating data from the pooled analysis
of the CHAMPION-PCI and CHAMPION-PLATFORM tri-
als [52], CHAMPION PHOENIX trial was designed using a
new primary end point, including a more accurate definition of
MI, to evaluate if addition of cangrelor to clopidogrel stand-
ard-of-care in clopidogrel-nave patients undergoing PCI (for
stable angina, NSTE-ACS and STEMI) could reduce ischemic
complications related to PCI [54]. After angiography patients
(n = 11,145) were randomized to receive either cangrelor bolus
(30 mg/kg) followed by infusion (4 mg/kg/min) or clopidogrel
loading dose (300 or 600 mg as per institutional standard).
The bolus and infusion (cangrelor or matching placebo) had to
be administered as soon as possible after randomization but
only after completion of the initial angiography and not more
than 30 min before PCI. In patients with STEMI, infusion
was allowed to be administered as soon as possible after ran-
domization (before or immediately after angiography). The
infusion had to be continued for 24 h or until the conclusion
of the index PCI, whichever was longer. The loading dose of
clopidogrel (or matching placebo in the cangrelor arm) was
administered, as directed by the investigator, before or immedi-
ately after the PCI. At the end of the infusion, patients received
either 600 mg of clopidogrel in the cangrelor arm or matching
placebo in the control arm (FIGURE 3). All patients were adminis-
tered aspirin (75325 mg) indefinitely and clopidogrel 75 mg
maintenance dose for at least 48 h. GPIs therapy was allowed
only as rescue therapy during PCI. The primary efficacy end
point was a composite of death from any cause, MI (deter-
mined using the universal definition), IDR and stent
1285
 Drug Profile iz-Lozano, Rae Cho & Angiolillo
Franchi, Rollini, Mun

Table 2. Efficacy and safety major end point in CHAMPION PHOENIX trial.
Cangrelor Clopidogrel OR (95% CI) p-value
Efficacy end point
Patients (n) 5472 5470
Primary end point: all-cause 257 (4.7%) 322 (5.9%) 0.78 (0.660.93) 0.005
death, MI, IDR, ST
Stent thrombosis 46 (0.8%) 74 (1.4%) 0.62 (0.430.90) 0.01
MI 207 (3.8%) 255 (4.7%) 0.80 (0.670.97) 0.02
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Michigan University on 03/02/15

Q-wave MI 11 (0.2%) 18 (0.3%) 0.61 (0.291.29) 0.19

IDR 28 (0.5%) 38 (0.7%) 0.74 (0.451.20) 0.22

Cardiovascular death 18 (0.3%) 18 (0.3%) 1.00 (0.521.92) >0.999
Safety end point (non-CABG-related bleeding)
Patients (n) 5529 5527
GUSTO severe or 9 (0.2%) 6 (0.1%) 1.50 (0.534.22) 0.44
life-threatening#
GUSTO moderate 22 (0.4%) 13 (0.2%) 1.69 (0.853.37) 0.13
GUSTO severe or moderate 31 (0.6%) 19 (0.3%) 1.63 (0.922.90) 0.09
ACUITY major 235 (4.3%) 139 (2.5%) 1.72 (1.392.13) <0.001
For personal use only.

ACUITY major without 42 (0.8%) 26 (0.5%) 1.62 (0.992.64) 0.05

5 cm hematoma
TIMI major 5 (0.1%) 5 (0.1%) 1.00 (0.293.45) >0.999
Net adverse clinical events
Death, MI, IDR, ST or 264 (4.8%) 327 (6.0%) 0.80 (0.680.94) 0.008
GUSTO severe bleeding

Modified intention-to-treat population defined as patients receiving study treatment and undergoing PCI.

Safety population defined as patients exposed to study medication.

Cardiovascular death and all-cause death are equal.
#
Primary safety end point.
ACUITY: Acute Catheterization and Urgent Intervention Triage Strategy; CABG: Coronary artery bypass graft; CI: Confidence interval; GUSTO: Global Use of Strategies to
Open Occluded Coronary Arteries; IDR: Ischemia-driven revascularization; MI: Myocardial infarction; OR: Odds ratio; PCI: Percutaneous coronary intervention; ST: Stent
thrombosis; TIMI: Thrombolysis in myocardial infarction.
Data taken from [55].

thrombosis assessed at 48 h. The key secondary end point was
the incidence of stent thrombosis at 48 h (including definite
stent thrombosis and intra-procedural stent thrombosis). The
primary safety end point was severe bleeding not related to
coronary-artery bypass grafting, according to the Global Use of
Strategies to Open Occluded Coronary Arteries (GUSTO) cri-
teria, at 48 h. Several others bleeding definitions were also
applied. As specified by the protocol, the primary analysis was
adjusted for clopidogrel loading dose (as more than 15% of
patients received a 300 mg loading dose of clopidogrel) and for
baseline status of biomarkers (normal vs abnormal). The modi-
fied intention-to-treat population (consisting of patients who
underwent PCI and received the study drug) comprised
10,942 patients.
Addition of cangrelor to standard-of-care therapy signifi-
cantly reduced the primary efficacy end point on the basis of
the pre-specified logistic-regression analysis (4.7% in the
cangrelor group vs 5.9% in the clopidogrel group; adjusted OR
with cangrelor, 0.78; 95% CI: 0.660.93; p = 0.005) (TABLE 2),
with a number needed to treat to prevent one primary end
point event of 84 (95% CI: 49285) [55]. The result of the
crude analysis was similar (OR: 0.79; 95% CI: 0.670.93;
p = 0.006). The efficacy of cangrelor was primarily driven by a
reduction in the rate of MI (3.8 vs 4.7%; OR: 0.80; 95% CI:
0.670.97; p = 0.02). The rate of the key secondary efficacy
end point of stent thrombosis at 48 h was significantly reduced
in the cangrelor arm (0.8 vs 1.4%; OR: 0.62; 95% CI: 0.43
0.90; p = 0.01), in particular, intra-procedural stent thrombosis
(0.6 vs 1.0%). The reduction of the primary end point and of
the key secondary end point was persistent even at 30 days.
Importantly, the rate of severe bleeding was not significantly
increased by cangrelor with GUSTO criteria (0.16 vs 0.11%;
OR: 1.50; 95% CI: 0.534.22; p = 0.44), as well as with other
definitions of bleeding. However, the rate of major bleeding

1286 Expert Rev. Cardiovasc. Ther. 11(10), (2013)

 A review on pharmacology & clinical trial development of cangrelor
according to the more sensitive ACUITY criteria was signifi-
cantly higher in patients treated with cangrelor (4.3 vs 2.5%;
p < 0.001). This was primarily driven by more hematoma in
the site of vascular access, even due to the low rate of radial
access in both groups (~26%). In fact, after excluding hemato-
mas 5 cm, the difference between groups was no longer sig-
nificant (0.8 vs 0.5%; p = 0.05) [55].
The benefit with respect to the primary end point was
consistent across multiple pre-specified subgroups. In particu-
lar, the benefit with cangrelor was similar among patients
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Michigan University on 03/02/15
presenting with STEMI, NSTE-ACS or stable angina (p for
interaction = 0.98) and was independent from the dose of
clopidogrel loading (p for interaction = 0.62), stent type
(p for interaction = 0.79), timing of clopidogrel loading dose
(p for interaction = 0.99) and duration of study drug infu-
sion (p for interaction = 0.31). The only significant interac-
tion was the history of peripheral artery disease (p for
interaction = 0.003 in favor of patients with positive history),
which was most likely a play of chance finding. Moreover,
no significant difference in the rate of GUSTO severe or
moderate bleeding was shown in any subgroup. Combining
the primary efficacy end point and the primary safety end
point, the net rate of adverse clinical events was significantly
reduced by the use of cangrelor (4.8 vs 6.0%; OR: 0.80;
For personal use only.
95% CI: 0.680.94; p = 0.008). Patients treated with cangre-
lor experienced a higher rate of transient dyspnea (1.2 vs
0.3%; p < 0.001), but the rate of discontinuation of the
study drug due to adverse events was low and similar in both
groups (0.5 vs 0.4%). Overall, compared with clopidogrel
administered immediately before or after PCI, the use of can-
grelor significantly reduced the rate of peri-PCI events,
including stent thrombosis [55].
Conclusion
Cangrelor is an intravenous antagonist of the P2Y12 receptor
characterized by rapid, potent, predictable and reversible pla-
telet inhibition with rapid offset. These pharmacologic prop-
erties make cangrelor a desirable agent in various clinical
settings. These include cangrelor as a bridging therapy in
patients waiting for surgery but also need to maintain
adequate platelet blockade, as demonstrated in the BRIDGE
trial. In addition, cangrelor is an attractive strategy in
patients requiring PCI who have not been pre-treated with
an oral P2Y12 inhibitor, as shown by the clinical benefits in
the CHAMPION PHOENIX trial. Ultimately, cangrelor
may result as a treatment option for patients requiring P2Y12
receptor blockade but not able to assume oral medications,
such as patients who are sedated, intubated, in shock or those
with nausea or vomiting. Although cangrelor is still not
approved for clinical use, this is being evaluated by drug-
regulating agencies in the USA and Europe.
Expert commentary
Recent clinical trials have provided new pivotal insights on
the efficacy and safety of cangrelor. The safety and efficacy of
www.expert-reviews.com
Drug Profile
this intravenous P2Y12 receptor inhibitor has been shown in
several clinical settings, in particular as a bridging strategy in
patients treated with a thienopyridine requiring CABG as
well as in a wide population of patients undergoing PCI.
When used as a bridging strategy to CABG after thienopyri-
dine discontinuation, cangrelor (at an infusion dose of
0.75 mg/kg/min) achieves levels of platelet inhibition known
to be associated with a low risk of thrombotic events. More-
over, this effect is achieved without an increased risk of
bleeding before or during CABG, although with a numerical
increase in minor pre-CABG bleeding, and is independent of
prior thienopyridine dose and time of discontinuation. Can-
grelor has shown a consistent pharmacodynamic effect during
intravenous infusion with an extremely rapid offset after dis-
continuation prior to surgery. Importantly, the use of cangrelor
is not associated with increased incidence of adverse events
leading to drug discontinuation or laboratory abnormalities
despite extended dosing. Transient dyspnea, a common side
effect of reversible P2Y12 receptors inhibitors, is increased with
the use of cangrelor, even if the rate of this undesired effect is
overall very low, ranging between 1 and 2% in all trials. How-
ever, there are some limitations and observations that need to
be made. The BRIDGE trial was not powered to assess differ-
ences in ischemic and bleeding events and much larger sample
size would be warranted to this extent. However, it may be
argued that a larger trial, particularly to define safety, may not
be needed given the robust clinical data deriving from the
CHAMPION program comprising over 25,000 patients. More-
over, the BRIDGE trial assessed only patients undergoing
CABG, while in clinical practice most surgeries are non-car-
diac. However, this was performed in order to select a homoge-
nous patient population undergoing high-risk surgery (high risk
for bleeding and ischemic events). Even if this trial has enabled
a better understanding of the safety profile of cangrelor, more
heterogeneous patient populations undergoing non-cardiac sur-
gery are indeed warranted.
In the setting of adjunctive antiplatelet therapy in patients
who require PCI, the CHAMPION PHOENIX trial, which
was developed based on lesson learned from two large-scale
clinical trials which failed to meet their primary efficacy end
point, showed that intravenous ADP receptor antagonism
with cangrelor significantly reduced the composite of death,
MI, ischemia-driven revascularization or stent thrombosis at
48 h, with a significant 22% odds reduction. Even the key
secondary end point of stent thrombosis was significantly
reduced, with a 38% odds reduction. Moreover, the benefit
was sustained through 30 days and was achieved with no
excess in severe bleeding or transfusion (except for the very
sensitive ACUITY criteria, primarily driven by hematoma at
the site of vascular access) and with a low rate of adverse
events. Therefore, intravenous cangrelor may be an attractive
option across the full spectrum of PCI, including stable
angina, NSTEMI and STEMI. Despite these favorable data,
some limitations may emerge from the PHOENIX trial. First
of all, both 300 and 600 mg loading doses of clopidogrel
1287
 Drug Profile iz-Lozano, Rae Cho & Angiolillo
Franchi, Rollini, Mun

were allowed but, to date, a 600 mg loading dose is more
commonly used. However, in the three-quarters of patients
who received 600 mg, the benefit of cangrelor remained stat-
istically significant and was not attenuated. Second, even if it
is possible that the benefits observed with cangrelor would
have been attenuated with a longer duration of pretreatment,
the clopidogrel pretreatment was given on the table as is
consistent with many practices around the world and in par-
ticular in the USA. Furthermore, prospective randomized
clinical trials, namely CREDO and PRAGUE-8, did not find
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Michigan University on 03/02/15
Phase III clinical trial investigation powered for efficacy
showing improved outcomes in patients undergoing PCI
with a favorable safety profile, are indeed promising for its
approval. These findings add to trial data in the setting of
bridging patients to surgery. Even if the BRIDGE trial was
designed only in patients undergoing CABG, the use of can-
grelor may represent a valid antiplatelet treatment option for
bridging in patients undergoing non-cardiac surgery. In light
of this clinical problem, although a mega-trial in this clini-
cal setting is unlikely to be conducted, post-marketing regis-

a significant benefit for clopidogrel pretreatment [5,56].
Finally, the benefit seen with cangrelor may also have been
mitigated if prasugrel and ticagrelor had been used in the
control arm. However, to date, even oral pretreatment with
these more potent antiplatelet agents, while biologically
appealing and intuitive, remains unproven in prospective
randomized clinical trials. Further, recent pharmacodynamic
studies have shown that in the setting of patients with
STEMI undergoing primary PCI, prasugrel and ticagrelor
require at least to 2 h to exert antiplatelet effects, with ele-
vated rate of high-on treatment platelet reactivity during this
timeframe, exposing patients at increased risk of thrombotic
complications [19,20]. Abnormal intestinal absorption,
impaired metabolism, in addition to heightened platelet reac-
For personal use only.
tries are indeed anticipated. Further, a better understanding
on how to use cangrelor in patients treated with prasugrel
and ticagrelor is indeed warranted. Therefore, studies assess-
ing the pharmacodynamic effects of transitioning from can-
grelor to prasugrel or ticagrelor will provide important
insights given the uptake of these agents particularly in the
setting of ACS undergoing PCI. Indeed, clinical studies in
which cangrelor is utilized as part of treatment algorithms
together with novel agents, particularly in the setting of
STEMI undergoing primary PCI where novel agents have
delayed onset of action, will be of added value.
Financial & competing interests disclosure
DJ Angiolillo received payment as a consulting fee or honorarium from

tivity are all factors that contribute to these pharmacodynam-
ics findings even with the novel oral P2Y12 receptor
inhibitors. These findings highlight limitations of oral anti-
platelet therapies which are hampered by intestinal absorp-
tion. Indeed, cangrelor may be of particular value in this
setting given its immediate antiplatelet effects obtained
through intravenous administration.
Five-year view
Cangrelor is expected to be reviewed by the US FDA and the
EMA in 2013. Pending drug-regulating authority approval in
the USA and Europe, cangrelor still remains an investiga-
tional agent. However, the recent results from a large
Bristol-Myers Squibb, Sanofi-Aventis, Eli Lilly, Daiichi Sankyo, The
Medicines Company, AstraZeneca, Merck, Evolva, Abbott Vascular and
PLx Pharma, and for participation in review activities from Johnson &
Johnson, St. Jude and Sunovion. DJ Angiolillo has received institu-
tional payments for grants from Bristol-Myers Squibb, Sanofi-Aventis,
GlaxoSmithKline, Otsuka, Eli Lilly, Daiichi Sankyo, The Medicines
Company, AstraZenecaand Evolva. DJ Angiolillo has other financial
relationships with Esther and King Biomedical Research Grant. The
authors have no other relevant affiliations or financial involvement
with any organization or entity with a financial interest in or financial
conflict with the subject matter or materials discussed in the manuscript
apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.

Key issues
Dual antiplatelet therapy with aspirin and oral ADP P2Y12 receptor antagonists is currently the standard of care for prevention of
ischemic events in patients with acute coronary syndrome and undergoing percutaneous coronary intervention.
Despite the proven clinical benefit associated with currently available P2Y12 receptor inhibiting therapy, clopidogrel, prasugrel and
ticagrelor present several drawbacks, such slow onset of action, in particular in patients with ST-elevation myocardial infarction, slow off-
set and only oral availability.
Cangrelor is a direct, potent, reversible, competitive inhibitor of the P2Y12 receptor that rapidly achieves near complete inhibition of
ADP-induced platelet aggregation administered by intravenous infusion.
The BRIDGE trial showed cangrelor to be a feasible treatment option as a smooth and effective bridging strategy in patients on
thienopyridine therapy who require coronary artery bypass graft.
The results of the Phase III CHAMPION PHOENIX trial demonstrated the efficacy of cangrelor in addition to standard-of-care therapy in
the reduction of the peri-percutaneous coronary intervention ischemic complications in a wide spectrum of clinical settings.
Studies investigating the use of cangrelor in addition to prasugrel and ticagrelor as well as the transition between these new antiplatelet
agents are warranted.

1288 Expert Rev. Cardiovasc. Ther. 11(10), (2013)

 A review on pharmacology & clinical trial development of cangrelor
References
Papers of special note have been highlighted as:
of interest
of considerable interest
1 Storey RF, Newby LJ, Heptinstall S. Effects
of P2Y1 and P2Y12 receptor antagonists on
platelet aggregation induced by different
agonists in human whole blood. Platelets
12(7), 443447 (2001).
2 Gachet C. ADP receptors of platelets and
their inhibition. Thromb. Haemost. 86(1),
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Michigan University on 03/02/15
222232 (2001).
3 Angiolillo DJ, Ueno M, Goto S. Basic
principles of platelet biology and clinical
implications. Circ. J. 74(4), 597607
(2010).
4 Yusuf S, Zhao F, Mehta SR et al. The
clopidogrel in unstable angina to prevent
recurrent events trial investigators. effects of
clopidogrel in addition to aspirin in patients
with acute coronary syndromes without
ST-segment elevation. N. Engl. J. Med.
345(7), 494502 (2001).
5 Steinhubl SR, Berger PB, Mann JT 3rd
et al. CREDO Investigators. Clopidogrel for
the reduction of events during observation.
For personal use only.
Early and sustained dual oral antiplatelet
therapy following percutaneous coronary
intervention: a randomized controlled trial.
JAMA 288(19), 24112420 (2002).
6 Chen ZM, Jiang LX, Chen YP et al.
COMMIT (ClOpidogrel and Metoprolol in
Myocardial Infarction Trial) collaborative
group. Addition of clopidogrel to aspirin in
45,852 patients with acute myocardial
infarction: randomised placebo-controlled
trial. Lancet 366(9497), 16071621 (2005).
7 Wiviott SD, Braunwald E, McCabe CH
et al. Prasugrel versus clopidogrel in patients
with acute coronary syndromes. N. Engl. J.
Med 357(20), 20012015 (2007).
8 Wallentin L, Becker RC, Budaj A et al.
Ticagrelor versus clopidogrel in patients
with acute coronary syndromes. N. Engl. J.
Med. 361(11), 10451057 (2009)
9 Steg PG, James SK, Atar D et al. The Task
Force on the management of ST-segment
elevation acute myocardial infarction of the
European Society of Cardiology (ESC).
ESC Guidelines for the management of
acute myocardial infarction in patients
presenting with ST-segment elevation. Eur.
Heart J. 33(20), 25692619 (2012).
10 Hamm CW, Bassand JP, Agewall S et al.
ESC Committee for Practice Guidelines.
ESC Guidelines for the management of
acute coronary syndromes in patients
presenting without persistent ST-segment
elevation: The Task Force for the
www.expert-reviews.com
management of acute coronary syndromes
(ACS) in patients presenting without
persistent ST-segment elevation of the
European Society of Cardiology (ESC). Eur.
Heart J. 32(23), 29993054 (2011).
11 American College of Emergency Physicians;
Society for Cardiovascular Angiography and
Interventions; OGara PT, Kushner FG,
Ascheim DD et al. 2013 ACCF/
AHA guideline for the management of
ST-elevation myocardial infarction: a report
of the American College of Cardiology
Foundation/American Heart Association
Task Force on Practice Guidelines. J. Am.
Coll. Cardiol. 61(4), e78e140 (2013).
12 Jneid H, Anderson JL, Wright RS et al.
2012 ACCF/AHA focused update of the
guideline for the management of patients
with unstable angina/non-ST-elevation
myocardial infarction (updating the
2007 guideline and replacing the
2011 focused update): a report of the
American College of Cardiology
Foundation/American Heart Association
Task Force on Practice Guidelines. J. Am.
Coll. Cardiol. 60(7), 645681 (2012).
Levine GN, Bates ER, Blankenship JC et al.
13
ACCF/AHA/SCAI guideline for
percutaneous coronary intervention: a report
of the american college of cardiology
foundation/american heart association task
force on practice guidelines and the society
for cardiovascular angiography and
interventions. J. Am. Coll. Cardiol. 58(24),
e44e122 (2011).
14 Angiolillo DJ, Fernandez-Ortiz A,
Bernardo E et al. Variability in individual
responsiveness to clopidogrel: clinical
implications, management, and future
perspectives. J. Am. Coll. Cardiol. 49(14),
15051516 (2007).
15 Ferreiro JL, Angiolillo DJ. Clopidogrel
response variability: current status and
future directions. Thromb. Haemost. 102(1),
714 (2009).
16 Angiolillo DJ, Ferreiro JL. Platelet
adenosine diphosphate P2Y12 receptor
antagonism: benefits and limitations of
current treatment strategies and future
directions. Rev. Esp. Cardiol. 63(1), 6076
(2010).
17 Bonello L, Tantry US, Marcucci R et al.
Consensus and future directions on the
definition of high on-treatment platelet
reactivity to adenosine diphosphate. J. Am.
Coll. Cardiol. 56(12), 91933 (2010).
18 Ferreiro JL, Angiolillo DJ. New directions
in antiplatelet therapy. Circ. Cardiovasc.
Interv. 5(3), 43345 (2012).
Drug Profile
19 Alexopoulos D, Xanthopoulou I, Gkizas V
et al. Randomized assessment of ticagrelor
versus prasugrel antiplatelet effects in
patients with ST-segment-elevation
myocardial infarction. Circ. Cardiovasc.
Interv. 5(6), 797804 (2012).
Pharmacodynamic study assessing
limitations of novel P2Y12 antagonists in
ST-elevation myocardial infarction.
20 Parodi G, Valenti R, Bellandi B et al.
Comparison of prasugrel and ticagrelor
loading doses in st-segment elevation
myocardial infarction patients: rapid (rapid
activity of platelet inhibitor drugs) primary
pci study. J. Am. Coll. Cardiol. 61(15),
16011606 (2013).
21 Gurbel PA, Bliden KP, Butler K et al.
Randomized double-blind assessment of the
ONSET and OFFSET of the antiplatelet
effects of ticagrelor versus clopidogrel in
patients with stable coronary artery disease:
the ONSET/OFFSET study. Circulation
120(25), 25772585 (2009).
22 Price MJ, Walder JS, Baker BA et al.
Recovery of platelet function after
discontinuation of prasugrel or clopidogrel
maintenance dosing in aspirin-treated
patients with stable coronary disease: the
recovery trial. J. Am. Coll. Cardiol. 59(25),
23382343 (2012).
23 Osmancik P, Jirmar R, Hulikova K et al.
A comparison of the VASP index between
patients with hemodynamically complicated
and uncomplicated acute myocardial
infarction. Catheter Cardiovasc. Interv. 75(2),
158166 (2010).
24 Heestermans AA, van Werkum JW,
Taubert D et al. Impaired bioavailability of
clopidogrel in patients with a ST-segment
elevation myocardial infarction. Thromb.
Res. 122(6), 776781 (2008).
25 Ueno M, Ferreiro JL, Angiolillo DJ. Update
on the clinical development of cangrelor.
Expert Rev. Cardiovasc. Ther. 8(8),
10691077 (2010).
26 Ferreiro JL, Ueno M, Angiolillo DJ.
Cangrelor: a review on its mechanism of
action and clinical development. Expert Rev.
Cardiovasc Ther. 7(10), 1195201 (2009).
27 Dorsam RT, Kunapuli SP. Central role of
the P2Y12 receptor in platelet activation.
J. Clin. Invest. 113(3), 340345 (2004).
28 Hechler B, Vigne P, Leon C,
Breittmayer JP, Gachet C, Frelin C. ATP
derivatives are antagonists of the
P2Y1 receptor: similarities to the platelet
ADP receptor. Mol. Pharmacol. 53(4),
727733 (1998).
1289
 Drug Profile
Franchi, Rollini, Mun
29 Ingall AH, Dixon J, Bailey A et al.
Antagonists of the platelet P2T receptor:
a novel approach to antithrombotic therapy.
J. Med. Chem. 42(2), 213220 (1999).
30 van Giezen JJ, Humphries RG. Preclinical
and clinical studies with selective reversible
direct P2Y12 antagonists. Semin. Thromb.
Hemost. 31(2), 195204 (2005).
31 Nassim MA, Sanderson JB, Clarke C et al.
Investigation of the novel P2T receptor
antagonist AR-C69931MX on ex vivo
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Michigan University on 03/02/15
adenosine diphosphate-induced platelet
aggregation and bleeding time in healthy
volunteers. J. Am. Coll. Cardiol.
33(2 Suppl. A), A255 (1999).
Phase I trial assessing cangrelor
pharmacokinetic properties.
32 Javis GE, Nassim MA, Humphries RG
et al. The P2Y antagonist AR-C69931MX is
a more effective inhibitor of ADP-induced
platelet aggregation than clopidogrel. Blood
94(Suppl. 1), A22 (1999).
33 Aleil B, Ravanat C, Cazenave JP,
Rochoux G, Heitz A, Gachet C. Flow
cytometric analysis of intraplatelet VASP
For personal use only.
phosphorylation for the detection of
clopidogrel resistance in patients with
ischemic cardiovascular diseases. J. Thromb.
Haemost. 3(1), 8592 (2005).
34 Storey RF, Oldroyd KG, Wilcox RGOpen
multicentre study of the P2T receptor
antagonist AR-C69931MX assessing safety,
tolerability and activity in patients with
acute coronary syndrome. Thromb. Haemost.
85(3), 401407 (2001).
35 Greenbaum AB, Ohman EM, Gibson CM
et al. Preliminary experience with
intravenous P2Y12 platelet receptor
inhibition as an adjunct to reduced-dose
alteplase during acute myocardial infarction:
results of the Safety, Tolerability and Effect
on Patency in Acute Myocardial Infarction
(STEP-AMI) angiographic trial. Am. Heart
J. 154(4), 702709 (2007).
36 Greenbaum AB, Grines CL, Bittl JA et al.
Initial experience with an intravenous
P2Y12 platelet receptor antagonist in
patients undergoing percutaneous coronary
intervention: results from a 2-part, phase II,
multicenter, randomized, placebo- and
active-controlled trial. Am. Heart J. 151(3),
689.e1689.e10 (2006).
37 Ferreiro JL, Angiolillo DJ. Diabetes and
antiplatelet therapy in acute coronary
syndrome. Circulation 123(7), 798813
(2011).
38 Ferreiro JL, Ueno M, Tello-Montoliu A
et al. Effects of cangrelor in coronary artery
disease patients with and without diabetes
1290
iz-Lozano, Rae Cho & Angiolillo
mellitus: an in vitro pharmacodynamic
investigation. J. Thromb. Thrombolysis 35(2),
155164 (2013).
39 Steinhubl SR, Oh JJ, Oestreich JH,
Ferraris S, Charnigo R, Akers WS.
Transitioning patients from cangrelor to
clopidogrel: pharmacodynamic evidence of a
competitive effect. Thromb. Res. 121(4),
527534 (2008).
Pharmacodynamic study showing the
interaction between cangrelor and
clopidogrel when concomitantly
administered.
40 Dovlatova NL, Jakubowski JA, Sugidachi A,
Heptinstall S. The reversible P2Y antagonist
cangrelor influences the ability of the active
metabolites of clopidogrel and prasugrel to
produce irreversible inhibition of platelet
function. J. Thromb. Haemost. 6(7),
11531159 (2008).
41 Ravnefjord A, Weilitz J, Emanuelsson BM,
van Giezen JJ. Evaluation of ticagrelor
pharmacodynamic interactions with
reversibly binding or non-reversibly binding
P2Y12 antagonists in an ex-vivo canine
model. Thromb. Res. 130(4), 622628
(2012).
42 Brilakis ES, Banerjee S, Berger PB.
Perioperative management of patients with
coronary stents. J. Am. Coll. Cardiol.
49(22), 21452150 (2007).
43 Savonitto S, Caracciolo M, Cattaneo M,
DE Servi S. Management of patients with
recently implanted coronary stents on dual
antiplatelet therapy who need to undergo
major surgery. J. Thromb. Haemost. 9(11),
21332142 (2011).
44 Rossini R, Bramucci E, Castiglioni B et al.
Coronary stenting and surgery: perioperative
management of antiplatelet therapy in
patients undergoing surgery after coronary
stent implantation. G. Ital. Cardiol. (Rome).
13(78), 528551 (2012).
45 Bhatt DL, Topol EJ. Current role of
platelet glycoprotein IIb/IIIa inhibitors in
acute coronary syndromes. JAMA 284(12),
15491558 (2000).
46 Angiolillo DJ, Firstenberg MS, Price MJ
et al.; BRIDGE Investigators. Bridging
antiplatelet therapy with cangrelor in
patients undergoing cardiac surgery:
a randomized controlled trial. JAMA 307(3),
265274 (2012).
Phase II trial of cangrelor as bridging
strategy in patients on dual antiplatelet
therapy requiring major cardiac surgery.
47 Welsh RC, Rao SV, Zeymer U et al.
INNOVATE-PCI Investigators.
A randomized, double-blind,
active-controlled phase 2 trial to evaluate a
novel selective and reversible intravenous
and oral P2Y12 inhibitor elinogrel versus
clopidogrel in patients undergoing
nonurgent percutaneous coronary
intervention: the INNOVATE-PCI trial.
Circ. Cardiovasc. Interv. 5(3), 336346
(2012).
48 Ueno M, Rao SV, Angiolillo DJ. Elinogrel:
pharmacological principles, preclinical and
early phase clinical testing. Future Cardiol.
6(4), 445453 (2010).
49 Harrington RA, Stone GW, McNulty S
et al. Platelet Inhibition with Cangrelor in
Patients Undergoing PCI. N. Engl. J. Med.
361(24), 23182329 (2009).
Phase III trial of cangrelor evaluating the
efficacy of cangrelor in patients
undergoing percutaneous coronary
intervention (PCI).
50 Bhatt DL, Lincoff M, Gibson M et al.
Intravenous Platelet Blockade with
Cangrelor during PCI. N. Engl. J. Med.
361(24), 23302341 (2009).
Phase III trial of cangrelor evaluating the
efficacy of cangrelor in patients
undergoing PCI.
51 Angiolillo DJ, Schneider DJ, Bhatt DL
et al. Pharmacodynamic effects of cangrelor
and clopidogrel: the platelet function
substudy from the cangrelor versus standard
therapy to achieve optimal management of
platelet inhibition (CHAMPION) trials.
J. Thromb. Thrombolysis 34(1), 4455
(2012).
52 White HD, Chew DP, Dauerman HL et al.
Reduced immediate ischemic events with
cangrelor in PCI: a pooled analysis of the
CHAMPION trials using the universal
definition of myocardial infarction. Am.
Heart J. 163(2), 18290.e4 (2012).
Post hoc analysis of CHAMPION trials
showing the benefit of cangrelor
combining data of two major Phase III
trials and applying the universal
definition of myocardial infarction.
53 Thygesen K, Alpert JS, White HD et al.
Universal definition of myocardial
infarction. Circulation 116(22), 26342653
(2007).
54 Leonardi S, Mahaffey KW, White HD et al.
Rationale and design of the Cangrelor
versus standard therapy to achieve optimal
Management of Platelet InhibitiON
PHOENIX trial. Am. Heart J. 163(5),
768776.e2 (2012).
55 Bhatt DL, Stone GW, Mahaffey KW et al.
CHAMPION PHOENIX Investigators.
Expert Rev. Cardiovasc. Ther. 11(10), (2013)
 A review on pharmacology & clinical trial development of cangrelor
Effect of platelet inhibition with cangrelor
during PCI on ischemic events. N. Engl. J.
Med. 368(14), 13031313 (2013).
Phase III trial of cangrelor demonstrating
the efficacy and safety of cangrelor in a
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Michigan University on 03/02/15
For personal use only.
www.expert-reviews.com
wide spectrum of patients undergoing
PCI.
56 Widimsky P, Motovska Z, Simek S et al.
Clopidogrel pre-treatment in stable angina:
for all patients > 6 h before elective
coronary angiography or only for
Drug Profile
angiographically selected patients a few
minutes before PCI? A randomized
multicentre trial PRAGUE-8. Eur. Heart J.
29(12), 14951503 (2008).
1291