PERS PE C T IV E
for both drug-eluting and bare- elevation myocardial infarction.
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
Downloaded from www.nejm.org at ASSISTANCE PUBLIQUE HOPITAUX P on September 5, 2009 .
Copyright © 2009 Massachusetts Medical Society. All rights reserved.
No other potential conflict of interest rele-
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
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-
PE R S PE C T IV E Weighing Benefits and Risks — The FDA’s Review of Prasugrel

tions, including both those detect-
ed clinically and those detected
solely through the measurement
of cardiac enzymes; most of the
latter occurred during the index
hospitalization. The results from
the two strata, taken from the ap-
proved label, are shown in the
table, along with the overall re-
sults.
Prasugrel reduced end-point
events but was associated with a
relative increase in the risk of
bleeding of approximately 30%.
The frequencies of major or minor
bleeding, as assessed according
to the Thrombolysis in Myocar-
dial Infarction (TIMI) definitions
(i.e., overt bleeding with a de-
crease in hemoglobin level of at
least 3 g per deciliter or intracra-
nial hemorrhage), that was not
related to coronary-artery bypass
grafting (CABG) were 4.5% with
prasugrel and 3.4% with clopid-
ogrel. Fatal hemorrhage occurred
infrequently but was more com-
mon with prasugrel than with
clopidogrel (0.3% vs. 0.1%).
In weighing the risks and
benefits, the FDA review team
noted that the components of
the primary end point represent-
ed irreversible tissue damage and
concluded that the benefit of pre-
venting such events is generally

Patients with Outcome Events in TRITON–TIMI 38.*

Relative Risk Reduction

Patient Group at Presentation Treatment Group (95% CI)† P Value

Prasugrel Clopidogrel
%
Unstable angina and non–ST-segment-­elevation
myocardial infarction
No. of patients 5044 5030
End-point event (% of patients)
Cardiovascular death, nonfatal myocardial infarction, 9.3 11.2 18.0 (7.3 to 27.4) 0.002
or nonfatal stroke
Cardiovascular death 1.8   1.8 2.1 (−30.9 to 26.8) 0.89
Nonfatal myocardial infarction 7.1   9.2 23.9 (12.7 to 33.7) <0.001
Nonfatal stroke 0.8   0.8 2.1 (−51.3 to 36.7) 0.92
ST-segment-elevation myocardial infarction
No. of patients 1769 1765
End-point event (% of patients)
Cardiovascular death, nonfatal myocardial infarction, 9.8 12.2 20.7 (3.2 to 35.1) 0.02
or nonfatal stroke
Cardiovascular death 2.4   3.3 26.2 (−9.4 to 50.3) 0.13
Nonfatal myocardial infarction 6.7   8.8 25.4 (5.2 to 41.2) 0.02
Nonfatal stroke 1.2   1.1 −9.7 (−104 to 41.0) 0.77
Overall
No. of patients 6813 6795
End-point event (% of patients)
Cardiovascular death, nonfatal myocardial infarction, 9.4 11.5 18.8 (9.8 to 26.8) <0.001
or nonfatal stroke
Cardiovascular death 2.0   2.2 11.4 (−11.8 to 29.9) 0.31
Nonfatal myocardial infarction 7.0   9.1 24.3 (14.7 to 32.8) <0.001
Nonfatal stroke 0.9   0.9 −1.6 (−45.1 to 28.8) 0.93

* Death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke was the primary composite end point. CI de-
notes confidence interval, and TRITON –TIMI Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet
Inhibition with Prasugrel –Thrombolysis in Myocardial Infarction.
† The relative risk was assessed by means of a Kaplan –Meier analysis. Relative risk reduction was calculated as (1 − hazard ratio) × 100%.
Negative values indicate an increase in the relative risk.

n engl j med 361;10  nejm.org  september 3, 2009 943

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Copyright © 2009 Massachusetts Medical Society. All rights reserved.
PERS PE C T IV E
worth the risk of bleeding events
that have no irreversible conse-
quences. Clearly, bleeding events
may have serious consequences,
but most of those that led to ir-
reversible harm (e.g., intracranial
hemorrhage) were included in the
primary end point, and there
were few fatal bleeding events.
For each 1000 patients who were
given prasugrel instead of clopid-
ogrel, 24 end-point events were
prevented — 21 nonfatal myo-
cardial infarctions and 3 cardio-
vascular deaths. (The rate of
stroke was essentially the same
with either drug.) The cost was
10 excess major or minor bleed-
ing events, 2 of which were fatal.
There were also 19 excess mini-
mal bleeding events (i.e., overt
bleeding with a decrease in hemo­
globin level of less than 3 g per
deciliter). There was no signifi-
cant difference in overall mortal-
ity, although there was a trend
in favor of prasugrel (a reduc-
tion of approximately 1 death per
1000 patients: 3 fewer deaths
from cardiovascular causes as
balanced against 2 excess deaths
due to bleeding). Not all observ-
ers agree that the treatment ef-
fect was important, since many
of the excess myocardial infarc-
tions in the clopidogrel group
were not manifested clinically but
were merely “enzyme leaks” that
were detected during routine
monitoring in the peri-interven-
tional period. The agency and
the advisory committee conclud-
ed, however, that such enzyme
elevations indicate tissue damage
and that such damage has serious
long-term consequences. More-
over, there was also a significant
reduction in the rate of nonfatal
myocardial infarctions that oc-
curred after the peri-interven-
tional period.4
944 n engl j med 361;10  nejm.org  september 3, 2009
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Copyright © 2009 Massachusetts Medical Society. All rights reserved.
Weighing Benefits and Risks — The FDA’s Review of Prasugrel
In some subgroups, bleeding
was more common or more seri-
ous with prasugrel than with
clopidogrel. Patients who received
prasugrel and underwent CABG
were at higher risk for bleeding;
the frequencies of major or mi-
nor bleeding were 14.1% with
prasugrel and 4.5% with clopid-
ogrel. Among patients 75 years
of age or older, fatal hemorrhage
occurred in 9 of 891 patients in
the prasugrel group (1.0%) ver-
sus 1 of 894 patients in the clo-
pidogrel group (0.1%). However,
older patients in two subgroups
at particularly high risk (patients
with diabetes and patients with
a prior myocardial infarction) ap-
peared to benefit substantially
from prasugrel, and these data
are included in the label.
Concerns regarding bleeding
led to several risk-mitigation strat-
egies: a boxed warning under-
scores the increased risk for pa-
tients 75 years of age or older
and for patients undergoing ur-
gent CABG; a statement in the
label emphasizes that choosing
a therapy requires balancing the
reduction in the risk of throm-
botic events against the bleeding
risk; a medication guide warns
patients about bleeding; and the
manufacturer has a postmarket-
ing requirement to investigate
the ability of platelet transfusion
to reverse prasugrel-induced plate-
let inhibition, as a potential treat-
ment for uncontrolled bleeding.
Excess neoplasms were report-
ed in the study’s prasugrel group.
The frequency of newly diag-
nosed cancers was 1.6% in the
prasugrel group versus 1.2% in
the clopidogrel group (relative
risk, 1.29; 95% confidence inter-
val, 0.96 to 1.72). Several factors
were weighed in considering
whether prasugrel was causally
related to the higher rate of tu-
mors. It was difficult to concep-
tualize a mechanism through
which prasugrel could initiate or
stimulate nonspecific tumor de-
velopment. Given the relatively
brief duration of the study (15
months) and the early emergence
of many of the tumors, it was
not thought that induction of new
tumors could plausibly explain
the increase. Moreover, studies in
animals of the carcinogenicity of
prasugrel were negative. The FDA
therefore focused on the possi-
ble stimulation by prasugrel of
existing tumors. We asked the
sponsor to undertake tumor-pro-
gression studies to assess the
effects of prasugrel and its me-
tabolites in human colon, lung,
and prostate tumor-cell lines
grown in vitro and in congeni-
tally immunodeficient “nude”
mice in vivo. These studies were
negative. To our knowledge, the
only products that are thought
to stimulate tumor development
are the erythropoietins, which,
unlike prasugrel, are growth fac-
tors. Finally, given the observa-
tional nature of safety analyses,
the fact that numerous compari-
sons were performed without sta-
tistical correction, and the lack of
prespecified hypotheses, as well
as the marginal statistical sup-
port for the finding, the possi-
bility of a false positive finding
seemed high. We concluded that
causality was unlikely; the advi-
sory committee agreed. The im-
balance is described in the adverse-
reactions section of prasugrel’s
label but is not emphasized as
a warning. The sponsors have a
postmarketing requirement to
collect baseline and subsequent
data on cancer in a large, ongo-
ing clinical trial.
The agency also faced a drug-
PE R S PE C T IV E
formulation issue during the
­review process. As the TRITON–
TIMI study was nearing comple-
tion, the sponsors discovered a
reaction within the tablets that
caused conversion of the drug
from its salt form to a base form,
with somewhat lower bioavail-
ability in a high-pH gastric envi-
ronment — for instance, when
the drug was administered with
proton-pump inhibitors. This re-
action was considered extensively,
but it was concluded that salt-to-
base conversion, although unde-
sirable, had no clinically impor-
tant effect on the performance
of prasugrel.1,2
The principal advantage of pra-
sugrel over clopidogrel appears to
be the prevention of nonfatal myo-
cardial infarctions, many of which
n engl j med 361;10  nejm.org  september 3, 2009
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Weighing Benefits and Risks — The FDA’s Review of Prasugrel
would not have immediate overt
clinical consequences. The cost of
this prevention is excess bleeding
— an important adverse effect,
but one that is transient and does
not result in increases in strokes
or deaths. Ultimately, deciding
which drug is preferable will be a
matter of individual clinical judg-
ment. The FDA made sure that
prasugrel’s label clearly articulates
the balance between efficacy and
risk — a balance that physicians
will need to assess carefully when
choosing treatment for individual
patients.
No potential conflict of interest relevant
to this article was reported.
From the Office of New Drugs, Center for
Drug Evaluation and Research, Food and
Drug Administration, Silver Spring, MD.
1. Food and Drug Administration. FDA ap-
proved drug products. (Accessed August 13,
2009, at http://www.accessdata.fda.gov/
scripts/cder/drugsatfda/index.cfm?fuseaction
=Search.Label_ApprovalHistory#apphist.)
2. Food and Drug Administration Center for
Drug Evaluation and Research Cardiovascu-
lar and Renal Drugs Advisory Committee.
Prasugrel for reduction of cardiovascular
events in patients with acute coronary syn-
drome (ACS). (Accessed August 13, 2009, at
http://www.fda.gov/downloads/Advisory
Committees/CommitteesMeetingMaterials/
Drugs/CardiovascularandRenalDrugsAdvisory
Committee/UCM136141.pdf.)
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. Antman EM, Wiviott SD, Murphy SA, et
al. Early and late benefits of prasugrel in pa-
tients with acute coronary syndromes under-
going percutaneous coronary intervention: a
TRITON-TIMI 38 (TRial to Assess Improve-
ment in Therapeutic Outcomes by Optimiz-
ing Platelet InhibitioN with Prasugrel-Throm-
bolysis In Myocardial Infarction) analysis.
J Am Coll Cardiol 2008;51:2028-33.
Copyright © 2009 Massachusetts Medical Society.
945