Hindawi Publishing Corporation
Advances in Hematology
Volume 2010, Article ID 595934, 7 pages
CurrentConceptsonAntiplatelet Therapy:Focuson theNovel
L.Testa,1G.G.L.Biondi Zoccai,2M. Valgimigli,3R. A.Latini,1S.Pizzocri,1S.Lanotte,1
1Interventional Cardiology Department, St. Ambrogio Clinical Institute, 20149, Milan, Italy
2Institute of Cardiology, Ospedale “Le Molinette”, University of Turin, 10124, Turin, Italy
3Department of Cardiology, Arcispedale S. Anna, University of Ferrara, 44100, Ferrara, Italy
4Department of Cardiology, Royal North Shore Hospital, North Shore Heart Research Group, Kolling Institute,
University of Sydney, Sydney NSW 2065, Australia
Correspondence should be addressed to R. Bhindi, firstname.lastname@example.org
Received 23 March 2010; Accepted 16 August 2010
Academic Editor: David Varon
Copyright © 2010 L. Testa et al. This is an open access article distributed under the Creative Commons Attribution License, which
permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Thienopyridines are a class of drug targeting the platelet adenosine diphosphate (ADP) 2 receptor. They significantly reduce
platelet activity and are therefore clinically beneficial in settings where platelet activation is a key pathophysiological feature,
particularly myocardial infarction. Ticlopidine, the firstof the class introduced to clinical practice, was soonchallenged and almost
completely replaced by clopidogrel for its better tolerability. More recently, prasugrel and ticagrelor have been shown to provide
a more powerful antiplatelet action compared to clopidogrel but at a cost of higher risk of bleeding complications. Cangrelor,
a molecule very similar to ticagrelor, is currently being evaluated against clopidogrel. Considering the key balance of ischemic
protection and bleeding risk, this paper discusses the background to the development of prasugrel, ticagrelor, and cangrelor and
aims to characterise their risk-benefit profile and possible implementation in daily practice.
Ticlopidine, clopidogrel, and more recently prasugrel, con-
stitute the class of drugs called thienopyridines which is
characterized by the selective targeting of the adenosine
diphosphate (ADP) 2 receptor on the surface of platelets.
which may have critical clinical benefits in settings where
platelet activation is a key pathophysiological feature such
as in myocardial infarction. Historically, ticlopidine was the
first member of this class. However, its not insignificant, risk
of neutropenia and thrombotic thrombocytopenic purpura
led to its predominant replacement by clopidogrel in routine
clinical practice .
Thienopyridines play a key role in the cardiovascular
with stable angina (SA), acute coronary syndromes (ACSs),
and/or those undergoing percutaneous coronary interven-
tion (PCI). In these settings they reduce the restenosis rate,
the risk of thrombosis and major adverse cardiac events
[2, 3]. Perhaps clopidogrel administration alone is advisable
when there is contraindication to or aspirin intolerance
. In acute myocardial infarction, for patients who have
undergone diagnostic cardiac catheterization and for whom
PCI is planned, clopidogrel should be started and continued
for at least 1 month after bare metal stent implantation
and for several months after drug-eluting stent implantation
up to 12 months in patients who are not at high risk for
bleeding . In patients with unstable angina, clopidogrel
should be started on admission and administered for at
least 1 month, and, according to many experts, up to 9
months . Overall, for those patient treated with PCI the
coadministration of aspirin (permanently) and clopidogrel
is mandatory. Following a bare metal or a drug eluting
coronary stent implantation, clopidogrel is administered for
at least 1 month and 1 year, respectively .
On the basis of ex vivo platelet function tests [8–12], it
has been recently reported that up to 34% of patients show a
2 Advances in Hematology
Figure 1: Biochemical structures of thienopyridine and nonthienopirydine antiplatelet agents.
suboptimal antiplateletresponse toclopidogrel (“clopidogrel
nonresponders”) and, according to some pivotal studies [13–
15], these individuals should be considered as having a
higher risk of adverse clinical events in acute as well as
chronic coronary artery disease. This evidence drove the
A new thienopyridine agent Prasugrel (Effient, Eli Lilly,
Indianapolis, IN) , and two cyclopentyl triazolo pyrim-
idines agents, ticagrelor (Brilinta, AstraZeneca, Wilmington,
DL) , and cangrelor (Cangrelor, The Medicines Com-
pany, Parsippany, NJ) [18, 19] have been introduced, aimed
at overcoming the drawbacks of their predecessors such as
variable antiplatelet efficacy and risk of side effects. Only the
first has received approval from the FDA and the EMEA .
This paper will elucidate the evolution and possible
clinical application of these novel antiplatelet agents.
Like other members of the thienopyridine class (Figure 1),
Prasugrel is a prodrug absorbed via the gut and is hydrolysed
into a thiolactibe (R-95913) via esterases in the gut wall,
liver, and plasma. This is then oxidised into the active
thiol metabolite R-138727 by the cytochrome p450 system,
mainly through the CYP3A and CYP2B6 isoenzymes. The
latter irreversibly binds the G-protein linked P2Y12 ADP
receptors on the platelet surface. An important difference
between the metabolism of prasugrel and clopidogrel is that
a significant portion of the administered dose of clopidogrel
is deactivated in the early stages of its metabolism, resulting
in less availability of the active metabolite.
Ticagrelor (AZD6140) is the first member of a new
class of orally active antiplatelet agents not requiring
metabolic activation. Ticagrelor is essentially an adenosine-
triphosphate (ATP) derivate (see Figure 1). Like the thien-
opyridine class of drugs, it inhibits the P2Y12ADP-receptor,
however, this inhibitory linkage is completely reversible.
Like ticagrelor, cangrelor has been derived from ATP
(see Figure 1) and, at present, it can be administered only
intravenously. After infusion, it reversibly binds the P2Y12
receptor with high affinity without requiring a metabolic
The key pharmacodynamic and pharmacokinetic features
of the new antiplatelets agents are summarised in Table 1.
Studies in several animal models show that orally adminis-
tered prasugrel is completely absorbed from the gut and then
rapidly metabolised in the liver to the active thiol metabolite
has a stereoselective effect and exerts a more potent and
dose-dependent inhibition of platelet activity compared to
ticlopidine and clopidogrel. Time from ingestion to the
maximal concentration of the active metabolite is about 30
minutes. Mean elimination half-life of the active metabolite
is 3.7 hours. Like other thienopyridines, the metabolites of
prasugrel are excreted via the kidney [21–28].
Advances in Hematology3
Table 1: Main pharmacodynamic/pharmacokinetic features of novel antiplatelet agents.
TicagrelorOral NoYesYes 6–12Kidney
CangrelorIntravenousNo NoYes2.6–3.3 Kidney
Ticagrelor, the first studied member of the class of
cyclopentyl triazolo pyrimidines, has been obtained by the
beta-gamma-methylene substitution of the ester linkage in
the triphosphate group of ATP. In contrast to natural ATP
which is rapidly inactivated by soluble nucleotidases, it is
relatively resistant to enzymatic degradation. Moreover, it
does not require any metabolic activation although an active
metabolite has been identified with quite similar features
and antiplatelet capacity thus participating in the overall
antiplatelet effect. Peak plasma level of ticagrelor is reached
after 1.5–3 hours and the half-life is 6–12 hours, depending
on the dose [29, 30] and more than 70% is excreted via the
In animal models, cangrelor inhibits ex vivo ADP-
induced platelet aggregation without prolonging the bleed-
ing times perhaps showing a fast restoration of platelet
reactivity at the end of the infusion. It rapidly reaches the
steady state concentration with a half-life of 2.6–3.3 minutes
[31, 32] and it is excreted via the kidney.
4.1. Prasugrel. Prasugrel has been extensively investigated in
several phase II studies consistently showing that concen-
tration of the active prasugrel metabolite are higher, both
acutely and after 2 weeks of treatment, than the active
clopidogrel metabolite thus supporting the hypothesis that
the observed differences in pharmacodynamic effects could
respective metabolites [33, 34].
The Joint Utilisation of Medications to Block Platelets
Optimally (JUMBO-TIMI 26) study reported an equivalent
risk of major bleeding events compared to clopidogrel thus
providing important safety data which facilitated further
evaluation of efficacy of prasugrel [35, 36].
The large phase 3 Trial to Assess Improvement in Ther-
apeutic Outcomes by Optimizing Platelet Inhibition with
TIMI) 38 trial  was a double-blinded study that ran-
domised 13608 patients with acute coronary syndromes
to aspirin and prasugrel (60mg loading dose followed by
10mg daily) or aspirin and clopidogrel (300mg loading
dose followed by 75mg daily). The composite endpoint
of cardiovascular death/myocardial infarction/stroke was
significantly reduced in the prasugrel group, largely driven
by a lower rate of nonfatal myocardial infarction. No benefit
in terms of mortality was observed while a significant
increase in bleeding complications in the prasugrel group
was reported. According to subgroup analyses, patients
with diabetes mellitus, myocardial infarction, or complex
coronary lesions benefited most from prasugrel treatment.
On the other hand, elderly patients, patients with a low body
weight (<60kg) or a previous history of stroke or transient
ischemic attacks did not benefit .
In a recently published substudy (TRITON TIMI 38
substudy) which included 12844 patients undergoing coro-
nary stent implantation (bare metal or drug eluting stent),
prasugrel was associated with a significantly reduced risk
of ischemic events and stent thrombosis, compared to
acute phase (within 3 days) and from the third day till the
end of followup have been compared. Of note, the loading
as well as the maintenance dose of prasugrel were superior
to clopidogrel for the reduction of ischemic events .
Moreover, the excess of bleeding in the former group was
related to the maintenance dose only. Recently, it has been
shown that Prasugrel is able to provide a net benefit over
clopidogrel particularly in patients with diabetes mellitus,
that is, a reduction of ischemic events not counterbalanced
by an increased risk of major bleedings .
Prasugrel has also been shown to be superior to clopido-
grel in the setting of ST elevation myocardial infarction with
a durable benefit up to 15 months .
On a pharmacodynamic/pharmacologic basis such a
superiority might be explained by the absence of any
interaction of the common functional cytochrome P450
genetic variants with drug metabolite levels and inhibition
of platelet aggregation .
We have recently showed, by means of an explorative
meta-analysis, that prasugrel compared to clopidogrel is
associated with a one-third higher risk and a two-fold higher
risk of major and minor bleedings, respectively .
4.2. Ticagrelor. The Dose Confirmation Study assessing
antiplatelet Effects of AZD6140 versus clopidogRel in non-
ST segment Elevation myocardial infarction (DISPERSE-
2) study  enrolled 990 patients admitted with non-
ST elevation acute coronary syndromes. Patients were allo-
cated, in a randomised fashion, to 300mg loading dose of
clopidogrel followed by 75mg daily for 3 months versus
ticagrelor 90mg twice daily for 3 months or 180mg twice
daily for 3 months. Twenty-five percent of the patients were
diabetic while a diagnosis of previous myocardial infarction
4 Advances in Hematology
was present in about 24% of the cases. With respect to the
primary endpoint, the cumulative rate of major and minor
bleedings, no significant differences were found between
the two doses of ticagrelor versus clopidogrel while a trend
in favour of ticagrelor was seen according to the risk of
The Platelet Inhibition and Patient Outcomes (PLATO)
trial  was a large multicenter randomised controlled
trials that randomised more than 18000 patients with
ST elevation as well as non-ST-elevation acute coronary
syndromes. Patients were allocated to either clopidogrel
300mg (600mg in 19.6% of the cases) loading, then 75mg
daily for 9 months or ticagrelor 180mg loading, then 90mg
twice daily for 9 months. Twenty-five percent of the patients
were diabetic while a diagnosis of previous myocardial
infarction was present in about 21% of the cases. Ticagrelor
was associated with a significantly lower risk of the primary
endpoint (composite of cardiovascular death, myocardial
infarction, or stroke) while no differences were seen in the
rates of major bleeding.
4.3. Cangrelor. The CHAMPION PCI study  was a ran-
domized, double-blind, double-dummy, active-control trial
comparing cangrelor with 600mg of clopidogrel in patients
with acute coronary syndromes undergoing PCI. Within 30
minutes of PCI, all patients received either cangrelor (in an
intravenous bolus of 30µg per kilogram of body weight and
an intravenous infusion of 4µg per kilogram per minute)
or a placebo bolus and infusion. Patients received 600mg
of clopidogrel (in four 150-mg capsules) or placebo at the
time of infusion. To allow the transition from intravenous
cangrelor to oral clopidogrel, patients received another four
placebo in patients receiving clopidogrel) at the discontinua-
tion of the study drug infusion.
At 48 hours as well as at 30 days, cangrelor was not supe-
rior to clopidogrel with respect to the primary composite
endpoint (death from any cause, myocardial infarction, or
ischemia-driven revascularization) while, with respect to the
risk of major haemorrhage, cangrelor was associated with a
non statistically significantly higher risk.
In the CHAMPION PLATFORM , patients under-
went randomization according to a double-blind, placebo-
controlled, double-dummy design to receive either cangrelor
(bolus of 30µg per kilogram of body weight followed by
infusion of 4µg per kilogram per minute) or a placebo
bolus and infusion “for the duration of the PCI procedure”,
with a minimum infusion duration of 2 hours and a
maximum of 4 hours. Patients in the cangrelor group
received 600mg of clopidogrel after the end of the cangrelor
infusion, and those in the placebo group received 600mg
of clopidogrel at the end of the procedure. Cangrelor
was not superior to placebo in reducing the primary
endpoint (death, myocardial infarction, or ischemia-driven
revascularization at 48 hours). The prespecified secondary
endpoints of stent thrombosis and death were lower in the
cangrelor group, with no significant increase in the rate of
These two trials have been conducted and published in
parallel. Of note, at the 70% interim analysis, the interim-
was low. However, in the absence of safety concerns, the
executive committee and sponsor elected to continue the
CHAMPION PCI trial until the CHAMPION PLATFORM
underwent its 70% interim analysis. At that time, the
interim-analysis review committee and the data and safety
monitoring board reported that the estimated conditional
power in CHAMPION PLATFORM was also low and
recommended discontinuation of enrolment into both trials.
Overall, these two trials do not support the imple-
mentation of cangrelor in routine practice, however, a
third trial (BRIDGE: Maintenance of Platelet inihiBition
With cangRelor After dIscontinuation of ThienopyriDines
in Patients Undergoing surgery, http://clinicaltrials.gov/ct2/
show/NCT00767507) is still ongoing aiming at investigating
the possible protective role of cangrelor in patients who
discontinue antiplatelet agents waiting for heart surgery.
more potent and reliable in its antiplatelet effect, when
administered in combination with aspirin to patients with
ACS undergoing PCI, prasugrel reduced both ischemic coro-
nary events and the incidence of coronary stent thrombosis
compared with the combination of aspirin and clopidogrel.
More powerful antiplatelet activity comes at a cost of
higher risk of major bleeding, thus an accurate selection
of those patients with a favourable risk/benefit profile is
mandatory. This selection is even more important when
considering that it has been compared against clopidogrel
in an unselected population with respect to clopidogrel
responsiveness. The assessment of the latter would imply
a consensus over the right tool to measure the residual
platelet activity and the exact timing. Moreover, in order
to standardise the bleeding risk it should be consensually
adopted one of the several bleeding risk score currently
Prasugrel has already received approval from EMEA
and FDA  and it is clearly a very promising drug but,
consistent with any other new tool, a reasonable enthusiasm
should always be balanced with objective analyses.
Ticagrelor was associated with a much higher incidence
of dyspnea as compared with clopidogrel in PLATO (14.2%
of patients versus 9.2%; P < 0.001), something that had
However, most episodes lasted less than a week and dis-
continuation of the study drug because of dyspnea occurred
in 0.9% of patients in the ticagrelor group. In terms of other
side effects, Holter monitoring did detect more frequent
ventricular pauses during the first week in the ticagrelor
group than in the clopidogrel group, but such episodes
were infrequent at 30 days and were rarely associated with
symptoms. There were no significant differences in the rates
of clinical manifestations of bradyarrhythmia between the
two treatment groups.
Advances in Hematology5
Ticagrelor has been defined as a prospective “blockbuster
drug”: in 2009, clopidogrel was the second-biggest-selling
drug in the world, with global revenues of more than $8
billion although generic versions of clopidogrel are already
available in Europe and are expected to appear in the US
within a few years. Considering the high number of patients
“clopidogrel nonresponders”, these people likely represent
the initial target for newer antiplatelet drugs.
The potential availability of three agents, clopidogrel,
prasugrel, and ticagrelor, for antagonizing platelet ADP
receptors would probably give a real chance to tailor
A specific setting in which ticagrelor may be preferred
could be in patients whose coronary anatomy is unknown
and for whom a CABG procedure is deemed probable. And
if patients who are receiving clopidogrel or prasugrel need
elective surgery, it would seem reasonable to switch them
to ticagrelor five to seven days before surgery because of its
reversible platelet inhibition.
However, like prasugrel, the use of ticagrelor should
probably be avoided in those with a history of stroke or
transient ischemic attack and in those with a high risk of
bleeding. Given concerns over dyspnea, ticagrelor should
also be avoided in those with chronic obstructive pulmonary
disease, bradyarrhythmias unprotected by pacemakers or a
history of syncope.
Lastly, for all remaining patients with ACS, either
ticagrelor or prasugrel might be the right option.
While waiting for specifically designed trials, data from
indirect comparison of prasugrel and ticagrelor showed that
similar efficacy and safety have to be acknowledged, but
prasugrel appeared more protective from coronary stent
thrombosis, while causing more bleedings .
The introduction of generic clopidogrel will probably make
clinical decision making even more complicated. In the
world of multiple new antiplatelet agents, considering both
the need for ischemic protection and the hazard of bleeding
will be crucial.
Dr. L. Testa has received honoraria for lectures from Abbott.
Dr. G. G. L. B. Zoccai has lectured for Astra Zeneca, Bristol
Myers Squibb, Sanofi-Aventis; he has consulted for Astra
Zeneca; he has received research grants from Daiichi Sankyo,
Eli Lilly. Dr. M. Valgimigli has received honoraria for lec-
tures/advisory board from Abbott, Cordis, Daiichi Sankyo,
Eli Lilly, Iroko, Medtronic, Merck, and The Medicines
Company, and research grants from Eli Lilly and Iroko.
 A. Kastrati, A. Sch¨ omig, and E. Sch¨ omig, “Are we making
efficient use of clopidogrel?” European Heart Journal, vol. 25,
no. 6, pp. 454–456, 2004.
 S. Yusuf, F. Zhao, S. R. Mehta, S. Chrolavicius, G. Tognoni,
and K. K. Fox, “Effects of clopidogrel in addition to aspirin in
patients with acute coronary syndromes without ST-segment
elevation,” New England Journal of Medicine, vol. 345, no. 7,
pp. 494–502, 2001.
 M. Gent, “A randomised, blinded, trial of clopidogrel versus
aspirin in patients at risk of ischaemic events (CAPRIE),”
Lancet, vol. 348, no. 9038, pp. 1329–1339, 1996.
 K. Fox, M. A. Alonso Garcia, D. Ardissino et al., “Guidelines
on the management of stable angina pectoris: executive
summary—the Task Force on the Management of Stable
Angina Pectoris of the European Society of Cardiology,”
European Heart Journal, vol. 27, no. 11, pp. 1341–1381, 2006.
 ACC/AHA, Guidelines for the Management of Patients With
ST-Elevation Myocardial Infarction A Report of the American
College of Cardiology/American Heart Association Task Force
on Practice Guidelines (Committee to Revise the 1999 Guide-
lines for the Management of Patients With Acute Myocardial
Infarction) Developed in Collaboration With the Canadian
Cardiovascular Society, 2008, http://www.cardiosource.com/.
 ACC/AHA, Guideline Update for the Management of Patients
With Unstable Angina and Non–ST-Segment Elevation
Myocardial Infarction A Report of the American College of
Cardiology/American Heart Association Task Force on Prac-
tice Guidelines (Committee on the Management of Patients
With Unstable Angina), http://ww.cardiosource.com/.
 S. C. Smith Jr., T. E. Feldman, J. W. Hirshfeld Jr. et al.,
“ACC/AHA/SCAI 2005 guideline update for percutaneous
coronary intervention—summary article: a Report of the
American College of Cardiology/American Heart Association
Task Force on Practice Guidelines (ACC/AHA/SCAI Writing
Committee to Update the 2001 Guidelines for Percutaneous
Coronary Intervention),” Catheterization and Cardiovascular
Interventions, vol. 67, no. 1, pp. 87–112, 2006.
myth or reality?” Journal of the American College of Cardiology,
vol. 50, no. 4, pp. 296–298, 2007.
 M. O’Donoghue and S. D. Wiviott, “Clopidogrel response
variability and future therapies: clopidogrel: does one size fit
all?” Circulation, vol. 114, no. 22, pp. e600–e606, 2006.
 S. Matetzky, B. Shenkman, V. Guetta et al., “Clopidogrel
resistance is associated with increased risk of recurrent
atherothrombotic events in patients with acute myocardial
infarction,” Circulation, vol. 109, no. 25, pp. 3171–3175, 2004.
 K. P. Bliden, J. DiChiara, U. S. Tantry, A. K. Bassi, S.
K. Chaganti, and P. A. Gurbel, “Increased risk in patients
with high platelet aggregation receiving chronic clopidogrel
therapy undergoing percutaneous coronary intervention: is
the current antiplatelet therapy adequate?” Journal of the
American College of Cardiology, vol. 49, no. 6, pp. 657–666,
 T. Geisler, H. Langer, M. Wydymus et al., “Low response to
clopidogrel is associated with cardiovascular outcome after
coronary stent implantation,” European Heart Journal, vol. 27,
no. 20, pp. 2420–2425, 2006.
 J.-P. Collet, J.-S. Hulot, A. Pena et al., “Cytochrome P450 2C19
myocardial infarction: a cohort study,” The Lancet, vol. 373,
no. 9660, pp. 309–317, 2009.
 T. Simon, C. Verstuyft, M. Mary-Krause et al., “French reg-
istry of acute ST-elevation and non-ST-elevation myocardial
infarction (FAST-MI) investigators. Genetic determinants of
response to clopidogrel and cardiovascular events,” The New
6Advances in Hematology
 J. L. Mega, S. L. Close, S. D. Wiviott et al., “Cytochrome P-450
polymorphisms and response to clopidogrel,” New England
Journal of Medicine, vol. 360, no. 4, pp. 354–362, 2009.
 S. D. Wiviott, E. Braunwald, C. H. McCabe et al., “Prasugrel
New England Journal of Medicine, vol. 357, no. 20, pp. 2001–
 L. Wallentin, R. C. Becker, A. Budaj et al., “Ticagrelor versus
clopidogrel in patients with acute coronary syndromes,” New
England Journal of Medicine, vol. 361, no. 11, pp. 1045–1057,
 D. L. Bhatt, A. M. Lincoff, C. M. Gibson et al., “CHAMPION
PLATFORM Investigators. Intravenous platelet blockade with
cangrelor during PCI,” The New England Journal of Medicine,
vol. 361, no. 24, pp. 2381–2329, 2009.
 R. A. Harrington, G. W. Stone, S. McNulty et al., “Platelet
inhibition with cangrelor in patients undergoing PCI,” The
New England Journal of Medicine, vol. 36, no. 24, pp. 2318–
 L. Testa, R. Bhindi, W. J. van Gaal et al., “What is the
risk of intensifying platelet inhibition beyond clopidogrel?
A systematic review and a critical appraisal of the role of
Prasugrel,” International Journal of Medicine. In press.
 J. A. Jakubowski, K. J. Winters, H. Naganuma, and L. Wal-
review of preclinical and clinical studies and the mechanistic
basis for its distinct antiplatelet profile,” Cardiovascular Drug
Reviews, vol. 25, no. 4, pp. 357–374, 2007.
 K. Hagihara, A. Kurihara, K. Kawai et al., “Absorption,
distribution and excretion of the new thienopyridine agent
prasugrel in rats,” Xenobiotica, vol. 37, no. 7, pp. 788–801,
 R. L. Smith, T. A. Gillespie, T. J. Rash, A. Kurihara, and N. A.
Farid, “Disposition and metabolic fate of prasugrel in mice,
rats, and dogs,” Xenobiotica, vol. 37, no. 8, pp. 884–901, 2007.
 Y. Niitsu, A. Sugidachi, T. Ogawa et al., “Repeat oral dosing of
prasugrel, a novel P2Y12 receptor inhibitor, results in cumu-
lative and potent antiplatelet and antithrombotic activity in
579, no. 1–3, pp. 276–282, 2008.
 A. Sugidachi, F. Asai, K. Yoneda et al., “Antiplatelet action
of R-99224, an active metabolite of a novel thienopyridine-
type Gi-linked P2T antagonist, CS-747,” British Journal of
Pharmacology, vol. 132, no. 1, pp. 47–54, 2001.
 A. L. Frelinger III, J. A. Jakubowski, Y. F. Li et al., “The active
metabolite of prasugrel inhibits ADP-stimulated thrombo-
inflammatory markers of platelet activation: Influence of
other blood cells, calcium, and aspirin,” Thrombosis and
Haemostasis, vol. 98, no. 1, pp. 192–200, 2007.
 A. L. Frelinger, J. A. Jakubowski, Y. Li et al., “The active
metabolite of prasugrel inhibits adenosine diphosphate- and
collagen-stimulated platelet procoagulant activities,” Journal
of Thrombosis and Haemostasis, vol. 6, no. 2, pp. 359–365,
 M. Hasegawa, A. Sugidachi, T. Ogawa, T. Isobe, J. A.
Jakubowski, and F. Asai, “Stereoselective inhibition of human
platelet aggregation by R-138727, the active metabolite of CS-
747 (Prasugrel, LY640315), a novel P2Y12 receptor inhibitor,”
Thrombosis and Haemostasis, vol. 94, no. 3, pp. 593–598, 2005.
 J. J. J. Van Giezen and R. G. Humphries, “Preclinical and clini-
cal studies with selective reversible direct P2Y 12 antagonists,”
 U. S. Tantry, K. P. Bliden, and P. A. Gurbel, “AZD6140,” Expert
Opinion on Investigational Drugs, vol. 16, no. 2, pp. 225–229,
 M. A. Nassim, J. B. Sanderson, C. Clarke et al., “Investigation
of the novel P2T receptor antagonist AR-C69931MX on ex
vivo adenosine diphosphate-induced platelet aggregation and
bleeding time in healthy volunteers,” Journal of the American
College of Cardiology, vol. 33, no. 2, supplement A, p. 255A,
 A. H. Ingall, J. Dixon, A. Bailey et al., “Antagonists of the
platelet P(2T) receptor: A novel approach to antithrombotic
therapy,” Journal of Medicinal Chemistry, vol. 42, no. 2, pp.
 L.Wallentin, C.Varenhorst,S.Jamesetal.,“Prasugrelachieves
greater and faster P2Y12receptor-mediated platelet inhibition
than clopidogrel due to more efficient generation of its active
metabolite in aspirin-treated patients with coronary artery
disease,” European Heart Journal, vol. 29, no. 1, pp. 21–30,
 S. D. Wiviott, D. Trenk, A. L. Frelinger et al., “PRINCIPLE-
TIMI 44 Investigators. Prasugrel compared with high loading-
and maintenance-dose clopidogrel in patients with planned
percutaneous coronary intervention: the Prasugrel in Com-
parison to Clopidogrel for Inhibition of Platelet Activation
and Aggregation-Thrombolysis in Myocardial Infarction 44
trial,” Circulation, vol. 116, pp. 2923–2932, 2007.
 S. D. Wiviott, E. M. Antman, K. J. Winters et al., “Random-
ized comparison of prasugrel (CS-747, LY640315), a novel
thienopyridine P2Y12 antagonist, with clopidogrel in percu-
taneous coronary intervention: results of the Joint Utilization
of Medications to Block Platelets Optimally (JUMBO)-TIMI
26 trial,” Circulation, vol. 111, no. 25, pp. 3366–3373, 2005.
 V. L. Serebruany, M. G. Midei, H. Meilman, A. I. Malinin,
and D. R. Lowry, “Platelet inhibition with prasugrel (CS-747)
compared with clopidogrel in patients undergoing coronary
stenting: The subset from the JUMBO study,” Postgraduate
Medical Journal, vol. 82, no. 968, pp. 404–410, 2006.
 S. D. Wiviott, E. Braunwald, and C. H. McCabe, “TRITON-
TIMI 38 Investigators. Prasugrel versus clopidogrel in patients
with acute coronary syndromes,” The New England Journal of
Medicine, vol. 357, pp. 2001–2015, 2007.
 S. D. Wiviott, E. Braunwald, C. H. McCabe et al., “Intensive
oral antiplatelet therapy for reduction of ischaemic events
including stent thrombosis in patients with acute coronary
syndromes treated with percutaneous coronary intervention
and stenting in the TRITON-TIMI 38 trial: a subanalysis of a
randomised trial,” The Lancet, vol. 371, no. 9621, pp. 1353–
 E. M. Antman, S. D. Wiviott, S. A. Murphy et al., “Early and
late benefits of prasugrel in patients with acute coronary syn-
dromes undergoing percutaneous coronary intervention. A
TRITON-TIMI 38 (trial to assess improvement in therapeutic
outcomes by optimizing platelet inhibitioN with prasugrel-
thrombolysisinmyocardial infarction)analysis,” Journalofthe
American College of Cardiology, vol. 51, no. 21, pp. 2028–2033,
 S. D. Wiviott, E. Braunwald, D. J. Angiolillo et al., “TRITON-
TIMI 38 Investigators. Greater clinical benefit of more
intensive oral antiplatelet therapy with prasugrel in patients
with diabetes mellitus in the trial to assess improvement
in therapeutic outcomes by optimizing platelet inhibition
with prasugrel-thrombolysis in myocardial infarction 38,”
Circulation. In press.
Advances in Hematology7
 G. Montalescot, S. D. Wiviott, E. Braunwald et al., “Prasugrel
compared with clopidogrel in patients undergoing percu-
taneous coronary intervention for ST-elevation myocardial
infarction (TRITON-TIMI 38): double-blind, randomised
controlled trial,” The Lancet, vol. 373, no. 9665, pp. 723–731,
 J. L. Mega, S. L. Close, S. D. Wiviott et al., “Cytochrome P450
genetic polymorphisms and the response to prasugrel rela-
tionship to pharmacokinetic, pharmacodynamic, and clinical
outcomes,” Circulation, vol. 119, no. 19, pp. 2553–2560, 2009.
 C. P. Cannon, S. Husted, R. A. Harrington et al., “Safety,
tolerability, and initial efficacy of AZD6140, the first reversible
oral adenosine diphosphate receptor antagonist, compared
with clopidogrel, in patients with non-ST-segment elevation
acute coronary syndrome. primary results of the DISPERSE-2
trial,” Journal of the AmericanCollege of Cardiology, vol. 50, no.
19, pp. 1844–1851, 2007.
 S. Subherwal, R. G. Bach, and A. Y. Chen, “The CRUSADE
bleeding score to assess baseline risk of major bleeding in
non-ST-segment elevation myocardial infarction,” Journal of
American College of Cardiology, vol. 51, supplement A, pp.
 M. Moscucci, K. A. A. Fox, C. P. Cannon et al., “Predictors
of major bleeding in acute coronary syndromes: the Global
Registry of Acute Coronary Events (GRACE),” European Heart
Journal, vol. 24, no. 20, pp. 1815–1823, 2003.
 E. Nikolsky, R. Mehran, G. Dangas et al., “Development and
validation of a prognostic risk score for major bleeding in
patients undergoing percutaneous coronary intervention via
pp. 1936–1945, 2007.
 S. K. Mehta, A. D. Frutkin, J. B. Lindsey et al., “Bleeding in
patients undergoing percutaneous coronary intervention: the
development of a clinical risk algorithm from the national
ventions, vol. 2, no. 3, pp. 222–229, 2009.
 G. Biondi Zoccai, M. Lotrionte, A. Abbate et al., “Is prasugrel
superior to ticagrelor For the treatment of patients with
acute coronary syndromes? evidence from a 32,893-patient
adjusted indirect comparison meta-analysis,” in Proceedings
of the Cardiovascular Revascularization Therapy Conference,
Washington, DC, USA, February 2010.