PERS PE C T IV E
Prasugrel in Clinical Practice
Deepak L. Bhatt, M.D., M.P.H.
O n July 10, 2009, after an
18-month review, the Food
and Drug Administration (FDA)
approved the thienopyridine pra-
sugrel for use in patients with
unstable angina or myocardial
infarction who undergo percuta-
neous coronary intervention
(PCI). The new drug is the latest
addition to a class of agents that
inhibit the platelet adenosine
diphosphate (ADP) receptor, pre-
venting initial platelet activation
and consequent platelet aggre-
gation — a mechanism that has
represented a major advance in
the treatment of atherothrom-
botic diseases.1 Indeed, the use
of the thienopyridine ticlopidine
in combination with aspirin to
inhibit platelet aggregation facili-
tated the widespread use of cor-
onary-artery stenting. Because of
the potential for serious side ef-
fects such as neutropenia, ticlo-
pidine was quickly eclipsed by
clopidogrel, which had better he-
matologic safety and fewer gas-
trointestinal side effects. Clopid-
ogrel monotherapy was shown to
be somewhat superior to aspirin
monotherapy for preventing re-
current ischemic events in pa-
tients with recent myocardial
infarction, ischemic stroke, or
symptomatic peripheral arterial
disease, but because of its cost,
it did not replace aspirin, instead
becoming an alternative for pa-
tients who could not tolerate
­aspirin. Trials in patients with
acute coronary syndromes and
those undergoing coronary stent-
ing showed that the combination
of aspirin and clopidogrel was
superior to aspirin alone during
12 months of treatment.
The new member of the class,
940 n engl j med 361;10  nejm.org  september 3, 2009
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prasugrel, is more effective than
ticlopidine and clopidogrel at in-
hibiting the ADP receptor (see dia-
gram) — largely because it is
more efficiently metabolized, so
more active metabolite is deliv-
ered to the platelet. Therefore,
prasugrel prevents platelet activa-
tion to a greater degree than does
clopidogrel at current doses. In
theory, this greater ex vivo effect
should translate into a greater
reduction in ischemic events —
but it may also lead to more
bleeding.2 Both hypotheses were
verified in the Trial to Assess
Improvement in Therapeutic Out-
comes by Optimizing Platelet In-
hibition with Prasugrel–Throm-
bolysis in Myocardial Infarction
(TRITON–TIMI) 38 (ClinicalTrials.
gov number, NCT00097591).3
Moreover, the risk of bleeding
might be increased still further
with real-life use, and the FDA
has required that prasugrel’s la-
beling include a black-box warn-
ing about that risk.
Among 13,608 study patients
with unstable angina or myocar-
dial infarction who were under-
going planned PCI, prasugrel sig-
nificantly reduced the risks of
recurrent myocardial infarction
and stent thrombosis as com-
pared with clopidogrel. The ben-
efits were particularly sizable
among patients with diabetes or
ST-segment elevation. There ap-
peared to be continued benefit
over the 15 months of the trial.
This study pushes the stan-
dard for the appropriate duration
of dual-antiplatelet therapy for
acute coronary syndromes (cur-
rently 12 months) to at least 15
months. What is uncertain is
whether an indefinite duration
Prasugrel in Clinical Practice
of dual-antiplatelet therapy is war-
ranted after an acute coronary
syndrome. Questions of cost and
serious risk of bleeding must be
considered, but lifelong dual-
antiplatelet therapy may be ben-
eficial for patients with a previ-
ous acute coronary syndrome.
The future availability of generic
clopidogrel and ongoing trials
of other antiplatelet agents may
make such use more palatable.
Many practical questions re-
main. Although TRITON–TIMI
38 demonstrated a reduction in
the risk of myocardial infarction
and stent thrombosis, there was
an increase in major bleeding
events, including a small but
statistically significant excess of
fatal bleeding events (approxi-
mately 3 such events per 1000 pa-
tients treated). Three subgroups
appeared to be particularly prone
to serious bleeding: the elderly,
the underweight, and patients
with a previous stroke or tran-
sient ischemic attack. Although
studies of clopidogrel have iden-
tified polyvascular disease as a
predictor of benefit from dual-
antiplatelet therapy, in the small
subgroup of patients in this
study with a previous stroke or
transient ischemic attack, prasu-
grel significantly increased the
rate of intracranial hemorrhage.
Therefore, it would be best to
avoid prasugrel in such patients.
Regarding the observations in
the elderly and underweight, the
pharmacokinetic data suggest that
in patients who are 75 years of
age or older or who weigh less
than 60 kg, reducing the prasu-
grel dose would probably miti-
gate the bleeding risk. Instead
of the usual maintenance dose of
PE R S PE C T IV E Prasugrel in Clinical Practice

were having planned PCIs. A small

Prasugrel number of patients, however, went
O on to undergo coronary-artery
bypass grafting (CABG). Among
O
N these patients, the rate of major
bleeding in the prasugrel group
CH3 O
S F Rapid
absorption was more than four times that
after oral in the clopidogrel group (13.4%
ingestion vs. 3.2%). Cardiac surgeons who
have been reluctant to operate on
Hydrolysis by patients receiving clopidogrel will
esterases
probably find prasugrel even more
Liver
Oxidation by
objectionable. Thus, the strategy
cytochrome P-450 of administering prasugrel in the
emergency department to patients
ADP
with acute coronary syndromes
Active metabolite
will be viewed as problematic and
is untested, although an ongoing
trial is comparing prasugrel with
clopidogrel in the initial medical
Platelet ADP P2Y12 management of acute coronary
receptor syndromes. Until such data have
Platelet
activation decreased
been examined, early prasugrel
treatment without delineation of
the coronary anatomy by cardiac
Mechanism of Action of Prasugrel. catheterization should not be rou-
COLOR FIGURE
Prasugrel is a prodrug with rapid and almost complete absorption after oral ingestion
Draft 7 7/14/09 tine in patients with myocardial
of a loading dose. It is metabolized into its active form, which
Author
binds irreversibly to the
Bhatt infarction without ST-segment ele-
adenosine diphosphate (ADP) P2Y12 receptor on platelets Fig for
# their 1 lifespan, thereby
vation. The finding of increased
inhibiting their activation and decreasing subsequent platelet
Title aggregation.
Mechanism Hydrolysis
of action
by intestinal carboxylesterases and oxidation by intestinal and
Prasurgrel
hepatic cytochrome bleeding rates among patients
ME
P-450 enzymes convert prasugrel into its active metabolite. DE Prasugrel Curfman has a greater
undergoing CABG also raises
antiplatelet effect than clopidogrel because it is metabolized
ArtistmoreKnoper
efficiently. Genetic concern about potentially elevat-
polymorphisms affecting the cytochrome P-450 system mayFigure explain
AUTHOR some
PLEASEof the differ-
NOTE:
has been redrawn and type has been reset ed risks of bleeding from non-
ences in metabolism between prasugrel and clopidogrel. Please check carefully

Issue date 3/05/09

10 mg a day, 5 mg is recommend-
ed in patients who weigh less
than 60 kg. It is hoped that even
at lower doses, prasugrel will still
be more effective than clopido-
grel; confirmation may be forth-
coming from an ongoing phase
3 clinical trial. Prasugrel would
generally not be recommended
for patients 75 years of age or
older, though it might be con-
sidered if they were at high risk
because of diabetes or previous
myocardial infarction.
The option of using a lower
dose of prasugrel is appealing
— for example, for patients who
have frequent nuisance bleeding
when taking the higher dose.
Again, there is no direct evi-
dence that efficacy would be
maintained, nor that switching
to clopidogrel would be safer in
patients who have bleeding on
standard-dose prasugrel. These
questions are worthy of explora-
tion. There is a potential role for
point-of-care testing of platelet
function, and ongoing trials may
clarify whether assay-guided dose
determinations affect the rates
of ischemic events or the bleed-
ing risk.
Patients in TRITON–TIMI 38
CABG surgery that might occur
in patients who have received
prasugrel in the previous 7 days.
It will be important to accumu-
late registry data to examine the
rate of bleeding outside the care-
fully defined population of a
clinical trial.
Recent concerns regarding the
risk of thrombosis with drug-
eluting stents have captured the
attention of interventional cardi-
ologists,4 some of whom will un-
doubtedly want to use prasugrel
in patients undergoing complex
stenting procedures. In TRITON–
TIMI 38, the finding of an ap-
proximately 50% reduction in the
rate of stent thrombosis held true

n engl j med 361;10 nejm.org september 3, 2009 941

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PERS PE C T IV E
for both drug-eluting and bare-
metal stents. Reductions were
seen in both early and late stent
thrombosis. However, patients
with acute coronary syndromes
are at greater risk for stent throm-
bosis (and recurrent ischemic
events in general) than patients
undergoing elective PCI.5 Even
complex PCI carries a much low-
er risk of future thrombotic events
if the patient does not have an
acute coronary syndrome. There-
fore, we should be cautious about
recommending prasugrel routine-
ly after elective PCI.
Prasugrel represents an advance
in antiplatelet therapy for acute
coronary syndromes. TRITON–
TIMI 38 supports its use in pa-
tients with such syndromes when
there is a very high probability
of PCI, such as in myocardial in-
farction with ST-segment eleva-
tion or after coronary angiography
in patients with non–ST-segment
Weighing Benefits and Risks — The FDA’s Review of Prasugrel
Ellis F. Unger, M.D.
T he Food and Drug Adminis-
tration (FDA) approved pras-
ugrel on July 10, 2009. Developed
by Eli Lilly and Daiichi Sankyo,
prasugrel is a thienopyridine that
inhibits platelet aggregation. It
was approved for the reduction of
thrombotic cardiovascular events
in patients with acute coronary
syndrome (unstable angina or
myocardial infarction) who under­
go percutaneous coronary inter-
vention (PCI). The FDA grappled
with a number of complex issues
during the review process,1 and
the application was presented to
the Cardiovascular and Renal
Drugs Advisory Committee on
February 3, 2009.2
942 n engl j med 361;10  nejm.org  september 3, 2009
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Copyright © 2009 Massachusetts Medical Society. All rights reserved.
elevation myocardial infarction.
Use in the elderly should be
avoided except in high-risk situa-
tions. Lower maintenance doses
in the underweight appear to be
warranted, though prospective
confirmation of this strategy is
necessary. Routine prasugrel ad-
ministration in the emergency
department for myocardial in-
farction without ST-segment ele-
vation appears premature. Using
prasugrel in initial medical man-
agement for patients with acute
coronary syndromes is currently
not warranted but is under study.
Although routine use after com-
plex elective PCI is appealing,
this, too, should probably be
avoided until further study has
been completed.
Dr. Bhatt reports receiving honoraria,
speaker’s fees, and consulting fees from a
number of pharmaceutical companies, in-
cluding Eli Lilly, Daiichi Sankyo, Sanofi-
Aventis, and Bristol-Myers Squibb, and do-
nating them to nonprofit organizations.
The Trial to Assess Improve-
ment in Therapeutic Outcomes
by Optimizing Platelet Inhibition
with Prasugrel–Thrombolysis in
Myocardial Infarction (TRITON–
TIMI) 38 (ClinicalTrials.gov num-
ber, NCT00097591) provided the
principal evidence of prasugrel’s
effectiveness3 and tested the hy-
pothesis that prasugrel plus as-
pirin was more effective than
clopidogrel plus aspirin for the
treatment of patients with an
acute coronary syndrome who
were undergoing PCI. Randomiza-
tion was stratified according to
presentation, with one stratum
including patients with unstable
angina and non–ST-segment-ele-
Prasugrel in Clinical Practice
No other potential conflict of interest rele-
vant to this article was reported.
From the Department of Cardiology at the
Veterans Affairs (VA) Boston Healthcare
System and the integrated interventional
cardiovascular program at Brigham and
Women’s Hospital and the VA Boston
Healthcare System — both in Boston.
This article (10.1056/NEJMp0806848) was
published on July 15, 2009, at NEJM.org.
1. Meadows TA, Bhatt DL. Clinical aspects
of platelet inhibitors and thrombus forma-
tion. Circ Res 2007;100:1261-75.
2. Bhatt DL. Intensifying platelet inhibition
— navigating between Scylla and Charybdis.
N Engl J Med 2007;357:2078-81.
3. Wiviott SD, Braunwald E, McCabe CH, et
al. Prasugrel versus clopidogrel in patients
with acute coronary syndromes. N Engl J
Med 2007;357:2001-15.
4. Curfman GD, Morrissey S, Jarcho JA, Dra-
zen JM. Drug-eluting coronary stents —
promise and uncertainty. N Engl J Med
2007;356:1059-60.
5. Bavry AA, Bhatt DL. Appropriate use of
drug-eluting stents: balancing the reduction
in restenosis with the concern of late throm-
bosis. Lancet 2008;371:2134-43. [Erratum,
Lancet 2008;372:536.]
Copyright © 2009 Massachusetts Medical Society.
vation myocardial infarction and
the other including patients with
ST-segment-elevation myocardial
infarction. The primary compos-
ite end point included death from
cardiovascular causes, nonfatal
myocardial infarction, and non-
fatal stroke, as measured in an
analysis of time to first event. A
total of 13,608 patients were en-
rolled in the trial; the results
showed that 9.4% of patients had
an end-point event with prasug-
rel vs. 11.5% with clopidogrel,
P<0.001; this was an 18.8% reduc-
tion in the composite end point
overall. The difference was driven
primarily by a reduction in the
rate of nonfatal myocardial infarc-