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n engl j med 361;11 nejm.org september 10, 2009 104

5

The new england
journal of medicine
established in 1812 september 10, 2009 vol. 361 no. 11

Ticagrelor versus Clopidogrel in Patients with Acute
Coronary Syndromes

Lars Wallentin, M.D., Ph.D., Richard C. Becker, M.D., Andrzej Budaj, M.D., Ph.D., Christopher P. Cannon, M.D.,
Håkan Emanuelsson, M.D., Ph.D., Claes Held, M.D., Ph.D., Jay Horrow, M.D., Steen Husted, M.D., D.Sc.,

Stefan James, M.D., Ph.D., Hugo Katus, M.D., Kenneth W. Mahaffey, M.D., Benjamin M. Scirica, M.D., M.P.H.,
Allan Skene, Ph.D., Philippe Gabriel Steg, M.D., Robert F. Storey, M.D., D.M., and Robert A. Harrington, M.D.,

for the PLATO Investigators*

A b s t r a c t

From the Uppsala Clinical Research Cen-
ter, Uppsala, Sweden (L.W., C.H., S.J.);
Duke Clinical Research Institute, Durham,
NC (R.C.B., K.W.M., R.A.H.); Grochowski
Hospital, Warsaw, Poland (A.B.); Throm-
bolysis in Myocardial Infarction Study
Group, Brigham and Women’s Hospital,
Boston (C.P.C., B.M.S.); AstraZeneca Re-
search and Development, Mölndal, Swe-
den (H.E.), and Wilmington, DE ( J.H.);
Århus University Hospital, Århus, Den-
mark (S.H.); Universitätsklinikum Heidel-
berg, Heidelberg, Germany (H.K.); World-
wide Clinical Trials U.K., Nottingham,
United Kingdom (A.S.); INSERM Unité
698, Assistance Publique–Hôpitaux de
Paris and Université Paris 7, Paris (P.G.S.);
and the University of Sheffield, Sheffield,
United Kingdom (R.F.S.). Address reprint
requests to Dr. Wallentin at Uppsala
Clinical Research Center, University Hos-
pital, 75185 Uppsala, Sweden, or at lars.
wallentin@ucr.uu.se.

*The Study of Platelet Inhibition and Pa-
tient Outcomes (PLATO) investigators
are listed in the Appendix and the Sup-
plementary Appendix, available with the
full text of this article at NEJM.org.

This article (10.1056/NEJMoa0904327) was
published on August 30, 2009, at NEJM.
org.

N Engl J Med 2009;361:1045-57.
Copyright © 2009 Massachusetts Medical Society.

Background
Ticagrelor is an oral, reversible, direct-acting inhibitor of the adenosine diphos-
phate receptor P2Y12 that has a more rapid onset and more pronounced platelet
inhibition than clopidogrel.

Methods
In this multicenter, double-blind, randomized trial, we compared ticagrelor (180-mg
loading dose, 90 mg twice daily thereafter) and clopidogrel (300-to-600-mg loading
dose, 75 mg daily thereafter) for the prevention of cardiovascular events in 18,624
patients admitted to the hospital with an acute coronary syndrome, with or without
ST-segment elevation.

Results
At 12 months, the primary end point — a composite of death from vascular causes,
myocardial infarction, or stroke — had occurred in 9.8% of patients receiving ti-
cagrelor as compared with 11.7% of those receiving clopidogrel (hazard ratio, 0.84;
95% confidence interval [CI], 0.77 to 0.92; P<0.001). Predefined hierarchical testing of secondary end points showed significant differences in the rates of other com- posite end points, as well as myocardial infarction alone (5.8% in the ticagrelor group vs. 6.9% in the clopidogrel group, P = 0.005) and death from vascular causes (4.0% vs. 5.1%, P = 0.001) but not stroke alone (1.5% vs. 1.3%, P = 0.22). The rate of death from any cause was also reduced with ticagrelor (4.5%, vs. 5.9% with clopid- ogrel; P<0.001). No significant difference in the rates of major bleeding was found between the ticagrelor and clopidogrel groups (11.6% and 11.2%, respectively; P = 0.43), but ticagrelor was associated with a higher rate of major bleeding not re- lated to coronary-artery bypass grafting (4.5% vs. 3.8%, P = 0.03), including more instances of fatal intracranial bleeding and fewer of fatal bleeding of other types.

Conclusions
In patients who have an acute coronary syndrome with or without ST-segment eleva-
tion, treatment with ticagrelor as compared with clopidogrel significantly reduced
the rate of death from vascular causes, myocardial infarction, or stroke without an
increase in the rate of overall major bleeding but with an increase in the rate of non–
procedure-related bleeding. (ClinicalTrials.gov number, NCT00391872.

)

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In patients who have acute coronary syndromes with or without ST-segment eleva-tion, current clinical practice guidelines1-4
recommend dual antiplatelet treatment with aspi-
rin and clopidogrel. The efficacy of clopidogrel is
hampered by the slow and variable transforma-
tion of the prodrug to the active metabolite,
modest and variable platelet inhibition,5,6 an in-
creased risk of bleeding,7,8 and an increased risk
of stent thrombosis and myocardial infarction in
patients with a poor response.9 As compared with
clopidogrel, prasugrel, another thienopyridine
prodrug, has a more consistent and pronounced
inhibitory effect on platelets,5,6 resulting in a
lower risk of myocardial infarction and stent
thrombosis, but is associated with a higher risk
of major bleeding in patients with an acute coro-
nary syndrome who are undergoing percutane-
ous coronary intervention (PCI).

10

Ticagrelor, a reversible and direct-acting oral
antagonist of the adenosine diphosphate recep-
tor P2Y12, provides faster, greater, and more con-
sistent P2Y12 inhibition than clopidogrel.11,12 In
a dose-guiding trial, there was no significant
difference in the rate of bleeding with the use of
ticagrelor at a dose of 90 mg or 180 mg twice
daily and the rate with the use of clopidogrel at
a dose of 75 mg daily. However, dose-related epi-
sodes of dyspnea and ventricular pauses on Holter
monitoring, which occurred more frequently with
ticagrelor, led to the selection of the dose of 90 mg
twice daily for further studies.13 We conducted
the Study of Platelet Inhibition and Patient Out-
comes (PLATO) to determine whether ticagrelor
is superior to clopidogrel for the prevention of
vascular events and death in a broad population
of patients presenting with an acute coronary
syndrome.

M e t h o d s

Study Design

PLATO was a multicenter, randomized, double-
blind trial. The details of the design have been
published previously.14 The executive and opera-
tions committee, consisting of both academic
members and representatives of the sponsor, Astra-
Zeneca, designed and oversaw the conduct of the
trial. An independent data and safety monitoring
board monitored the trial and had access to the
unblinded data. The sponsor coordinated the data
management. Statistical analysis was performed
by Worldwide Clinical Trials, a contract research

organization, in collaboration with investigators
at the academic centers and the sponsor, all of
whom had full access to the final study data. The
manuscript was drafted by the chairs of the ex-
ecutive and operations committee, who were aca-
demic authors and who vouch for the accuracy
and completeness of the reported data. The study
design was approved by the appropriate national
and institutional regulatory authorities and ethics
committees, and all participants provided writ-
ten informed consent.

Study Patients

Patients were eligible for enrollment if they were
hospitalized for an acute coronary syndrome, with
or without ST-segment elevation, with an onset
of symptoms during the previous 24 hours. For
patients who had an acute coronary syndrome
without ST-segment elevation, at least two of the
following three criteria had to be met: ST-seg-
ment changes on electrocardiography, indicating
ischemia; a positive test of a biomarker, indicat-
ing myocardial necrosis; or one of several risk
factors (age ≥60 years; previous myocardial infarc-
tion or coronary-artery bypass grafting [CABG];
coronary artery disease with stenosis of ≥50% in
at least two vessels; previous ischemic stroke,
transient ischemic attack, carotid stenosis of at
least 50%, or cerebral revascularization; diabetes
mellitus; peripheral arterial disease; or chronic
renal dysfunction, defined as a creatinine clear-
ance of <60 ml per minute per 1.73 m2 of body- surface area). For patients who had an acute coronary syndrome with ST-segment elevation, the following two inclusion criteria had to be met: persistent ST-segment elevation of at least 0.1 mV in at least two contiguous leads or a new left bundle-branch block, and the intention to per- form primary PCI. Major exclusion criteria were any contraindication against the use of clopido- grel, fibrinolytic therapy within 24 hours before randomization, a need for oral anticoagulation therapy, an increased risk of bradycardia, and concomitant therapy with a strong cytochrome P-450 3A inhibitor or inducer.

Study Treatment

Patients were randomly assigned to receive tica-
grelor or clopidogrel, administered in a double-
blind, double-dummy fashion. Ticagrelor was
given in a loading dose of 180 mg followed by a
dose of 90 mg twice daily. Patients in the clopid-
ogrel group who had not received an open-label

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n engl j med 361;11 nejm.org september 10, 2009 1047

loading dose and had not been taking clopidogrel
for at least 5 days before randomization received
a 300-mg loading dose followed by a dose of 75
mg daily. Others in the clopidogrel group contin-
ued to receive a maintenance dose of 75 mg daily.
Patients undergoing PCI after randomization re-
ceived, in a blind fashion, an additional dose of
their study drug at the time of PCI: 300 mg of clo-
pid ogrel, at the investigator’s discretion, or 90 mg
of ticagrelor for patients who were undergoing
PCI more than 24 hours after randomization. In
patients undergoing CABG, it was recommended
that the study drug be withheld — in the clopid-
ogrel group, for 5 days, and in the ticagrelor
group, for 24 to 72 hours. All patients received
acetylsalicylic acid (aspirin) at a dose of 75 to
100 mg daily unless they could not tolerate the
drug. For those who had not previously been re-
ceiving aspirin, 325 mg was the preferred load-
ing dose; 325 mg was also permitted as the daily
dose for 6 months after stent placement.

Outpatient visits were scheduled at 1, 3, 6, 9,
and 12 months, with a safety follow-up visit
1 month after the end of treatment. The ran-
domized treatment was scheduled to continue
for 12 months, but patients left the study at their
6- or 9-month visit if the targeted number of
1780 primary end-point events had occurred by
that time. Initially, patients were to be assessed
by means of Holter monitoring for 7 days after
randomization, until a repeat assessment at
1 month had been obtained for 2000 of the en-
rolled patients.

End Points

Death from vascular causes was defined as death
from cardiovascular causes or cerebrovascular
causes and any death without another known
cause. Myocardial infarction was defined in ac-
cordance with the universal definition proposed
in 2007.14,15 Evaluation for stent thrombosis was
performed according to the Academic Research
Consortium criteria.16 Stroke was defined as focal
loss of neurologic function caused by an ischemic
or hemorrhagic event, with residual symptoms
lasting at least 24 hours or leading to death.

We defined major life-threatening bleeding as
fatal bleeding, intracranial bleeding, intrapericar-
dial bleeding with cardiac tamponade, hypo-
volemic shock or severe hypotension due to bleed-
ing and requiring pressors or surgery, a decline in
the hemoglobin level of 5.0 g per deciliter or
more, or the need for transfusion of at least

4 units of red cells. We defined other major
bleeding as bleeding that led to clinically signifi-
cant disability (e.g., intraocular bleeding with
permanent vision loss) or bleeding either associ-
ated with a drop in the hemoglobin level of at
least 3.0 g per deciliter but less than 5.0 g per
deciliter or requiring transfusion of 2 to 3 units
of red cells. We defined minor bleeding as any
bleeding requiring medical intervention but not
meeting the criteria for major bleeding.

An independent central adjudication commit-
tee adjudicated all suspected primary and sec-
ondary efficacy end points as well as major and
minor bleeding events.

Statistical Analysis

The primary efficacy variable was the time to the
first occurrence of composite of death from vas-
cular causes, myocardial infarction, or stroke.
We estimated that 1780 such events would be re-
quired to achieve 90% power to detect a relative
risk reduction of 13.5% in the rate of the primary
end point in the ticagrelor group as compared
with the clopidogrel group, given an event rate of
11% in the clopidogrel group at 12 months. Cox
proportional-hazards models were used to ana-
lyze the data on primary and secondary end
points. All patients who had been randomly as-
signed to a treatment group were included in the
intention-to-treat analyses.

The principal secondary efficacy end point was
the primary efficacy variable studied in the sub-
group of patients for whom invasive management
was planned at randomization. Additional sec-
ondary end points (analyzed for the entire study
population) were the composite of death from any
cause, myocardial infarction, or stroke; the com-
posite of death from vascular causes, myocardial
infarction, stroke, severe recurrent cardiac isch-
emia, recurrent cardiac ischemia, transient isch-
emic attack, or other arterial thrombotic events;
myocardial infarction alone; death from cardio-
vascular causes alone; stroke alone; and death
from any cause.

To address the issue of multiple testing, a
hierarchical test sequence was planned. The sec-
ondary composite efficacy end points were test-
ed individually, in the order in which they are
listed above, until the first nonsignificant differ-
ence was found between the two treatment groups.
Other treatment comparisons were examined in
an exploratory manner. No multiplicity adjust-
ment was made to the confidence intervals for

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n engl j med 361;11 nejm.org september 10, 2009104

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Table 1. Baseline Characteristics of the Patients, According to Treatment Group.*

Characteristic Ticagrelor Group Clopidogrel

Group

Median age — yr 62.0 62.0

Age ≥75 yr — no./total no. (%) 1396/9333 (15.0) 1482/9291 (16.0)

Female sex — no./total no. (%) 2655/9333 (28.4) 2633/9291 (28.3)

Median body weight — kg (range) 80.0 (28–174) 80.0 (29–180)

Body weight <60 kg — no./total no. (%) 652/9333 (7.0) 660/9291 (7.1)

BMI — median (range)† 27 (13–68) 27 (13–70)

Race — no./total no. (%)‡

White 8566/9332 (91.8) 8511/9291 (91.6)

Black 115/9332 (1.2) 114/9291 (1.2)

Asian 542/9332 (5.8) 554/9291 (6.0)

Other 109/9332 (1.2) 112/9291 (1.2)

Cardiovascular risk factor — no./total no. (%)

Habitual smoker 3360/9333 (36.0) 3318/9291 (35.7)

Hypertension 6139/9333 (65.8) 6044/9291 (65.1)

Dyslipidemia 4347/9333 (46.6) 4342/9291 (46.7)

Diabetes mellitus 2326/9333 (24.9) 2336/9291 (25.1)

Other medical history — no./total no. (%)

MI 1900/9333 (20.4) 1924/9291 (20.7)

Percutaneous coronary intervention 1272/9333 (13.6) 1220/9291 (13.1)

Coronary-artery bypass grafting 532/9333 (5.7) 574/9291 (6.2)

Congestive heart failure 513/9333 (5.5) 537/9291 (5.8)

Nonhemorrhagic stroke 353/9333 (3.8) 369/9291 (4.0)

Peripheral arterial disease 566/9333 (6.1) 578/9291 (6.2)

Chronic renal disease 379/9333 (4.1) 406/9291 (4.4)

History of dyspnea 1412/9333 (15.1) 1358/9291 (14.6)

Chronic obstructive pulmonary disease 555/9333 (5.9) 530/9291 (5.7)

Asthma 267/9333 (2.9) 265/9291 (2.9)

Gout 272/9333 (2.9) 262/9291 (2.8)

ECG findings at study entry — no./total no. (%)

Persistent ST-segment elevation 3497/9333 (37.5) 3511/9291 (37.8)

ST-segment depression 4730/9333 (50.7) 4756/9291 (51.2)

T-wave inversion 2970/9333 (31.8) 2975/9291 (32.0)

Positive troponin I test at study entry — no./total no. (%) 7965/9333 (85.3) 7999/9291 (86.1)

Final diagnosis of ACS — no./total no. (%)

ST-elevation MI 3496/9333 (37.5) 3530/9291 (38.0)

Non–ST-elevation MI 4005/9333 (42.9) 3950/9291 (42.5)

Unstable angina 1549/9333 (16.6) 1563/9291 (16.8)

Other diagnosis or missing data§ 283/9333 (3.0) 248/9291 (2.7)

Risk factors for ST-elevation MI — no./total no. (%)

Killip class >2 25/3496 (0.7) 41/3530 (1.2)

TIMI risk score ≥3 1584/3496 (45.3) 1553/3530 (44.0)

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n engl j med 361;11 nejm.org september 10, 2009 1049

the hazard ratios for the ticagrelor group as
compared with the clopidogrel group.

The consistency of treatment effects over
time was assessed by determining the relative
risk ratios for the periods from randomization
to 30 days and from 31 to 360 days. Another
predefined objective was to compare the two
treatment groups with respect to the occurrence
of stent thrombosis. The primary safety end point
was the first occurrence of any major bleeding
event. Additional safety end points included mi-
nor bleeding, dyspnea, bradyarrhythmia, any other
clinical adverse event, and results of laboratory
safety tests. The consistency of effects on effi-
cacy and safety end points was explored in 25
prespecified subgroups and 8 post hoc sub-
groups, without adjustment for multiple com-
parisons.

R e s u l t s

Study Patients and Study Drugs

We recruited 18,624 patients from 862 centers in
43 countries from October 2006 through July
2008. The follow-up period ended in February
2009, when information on vital status was avail-
able for all patients except five. The two treat-
ment groups were well balanced with regard to
all baseline characteristics (Table 1) and non-
study medications and procedures (Table 2).
Both groups started the study drug at a median
of 11.3 hours (interquartile range, 4.8 to 19.8)
after the start of chest pain. In the clopidogrel
group, taking into account both open-label and

randomized treatment, 79.1% of patients received
at least 300 mg, and 19.6% at least 600 mg, of
clopidogrel between the time of the index event
and up to 24 hours after randomization. Prema-
ture discontinuation of the study drug was slight-
ly more common in the tica grelor group than in
the clopidogrel group (in 23.4% of patients vs.
21.5%). The overall rate of adherence to the study
drug, as assessed by the site investigators, was
82.8%, and the median duration of exposure to
the study drug was 277 days (interquartile range,
179 to 365).

Efficacy

The primary end point occurred significantly less
often in the ticagrelor group than in the clopid-
ogrel group (in 9.8% of patients vs. 11.7% at 12
months; hazard ratio, 0.84; 95% confidence in-
terval [CI], 0.77 to 0.92; P<0.001) (Table 3 and Fig. 1). The difference in treatment effect was apparent within the first 30 days of therapy and persisted throughout the study period. As shown in Table 3 (and Fig. 1 in the Supplementary Ap- pendix, available with the full text of this article at NEJM.org), the hierarchical testing of second- ary end points showed significant reductions in the ticagrelor group, as compared with the clopid- ogrel group, with respect to the rates of the com- posite end point of death from any cause, myo- cardial infarction, or stroke (10.2% vs. 12.3%, P<0.001); the composite end point of death from vascular causes, myocardial infarction, stroke, severe recurrent ischemia, recurrent ischemia, transient ischemic attack, or other arterial throm-

Table 1. (Continued.)

Characteristic Ticagrelor Group Clopidogrel Group

Risk factors for non–ST-elevation MI — no./total no. (%)¶

Positive troponin I test 4418/5554 (79.5) 4455/5513 (80.8)

ST-segment depression >0.1 mV 3141/5554 (56.6) 3182/5513 (57.7)

TIMI risk score ≥5 1112/5554 (20.0) 1170/5513 (21.2)

* A positive result on testing for troponin I consisted of a troponin I level of 0.08 μg or more per liter for the first sample
taken, as measured at the central laboratory with the use of the Advia Centaur TnI-Ultra Immunoassay (Siemens). ACS
denotes acute coronary syndrome, ECG electrocardiographic, MI myocardial infarction, and TIMI Thrombolysis in
Myocardial Infarction.

† The body-mass index (BMI) is the weight in kilograms divided by the square of the height in meters.
‡ Race was self-reported. “Asian” does not include Indian or Southwest Asian ancestry.
§ This category includes patients with unspecified ACS or no ACS.
¶ Risk factors for non–ST-elevation MI were ascertained for patients with a final ACS diagnosis of non–ST-elevation MI or

unstable angina.

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n engl j med 361;11 nejm.org september 10, 200910

50

Table 2. Randomized Treatment, Other Treatments, and Procedures, According to Treatment Group.*

Characteristic
Ticagrelor Group

(N = 9333)
Clopidogrel Group

(N = 9291) P Value†

Start of randomized treatment

Patients receiving treatment — no. (%) 9235 (98.9) 9186 (98.9)

Time after start of chest pain — hr 0.89

Median 11.3 11.3

IQR 4.8–19.8 4.8–19.8

Time after start of hospitalization — hr 0.75

Median 4.9 5.3

IQR 1.3–18.8 1.4–15.8

Premature discontinuation of study drug — no. (%) 2186 (23.4) 1999 (21.5) 0.00

2

Because of adverse event 690 (7.4) 556 (6.0) <0.001

Because of patient’s unwillingness to continue 946 (10.1) 859 (9.2) 0.0

4

Other reason 550 (5.9) 584 (6.3) 0.27

Adherence to study drug — no. (%)‡ 7724 (82.8) 7697 (82.8) 0.89

Exposure to study drug — days 0.11

Median 277 277

IQR 177–365 181–365

Clopidogrel administered in hospital before randomization —
no. (%)

4293 (46.0) 4282 (46.1) 0.91

Clopidogrel dose given (as study drug or not) within 24 hours before
or after randomization — no. (%)

0.65

No loading dose, or missing information 4937 (52.9) 94 (1.0)

300–375 mg 1921 (20.6) 5528 (59.5)

600–675 mg 1282 (13.7) 1822 (19.6)

Other dose 697 (7.5) 1339 (14.4)

Same dose as that given before index event§ 496 (5.3) 508 (5.5)

Antithrombotic treatment in hospital — no. (%)

Aspirin

Before randomization 8827 (94.6) 8755 (94.2) 0.31

After randomization 9092 (97.4) 9056 (97.5) 0.85

Unfractionated heparin 5304 (56.8) 5233 (56.3) 0.49

Low-molecular-weight heparin 4813 (51.6) 4706 (50.7) 0.21

Fondaparinux 251 (2.7) 246 (2.6) 0.89

Bivalirudin 188 (2.0) 183 (2.0) 0.83

Glycoprotein IIb/IIIa inhibitor 2468 (26.4) 2487 (26.8) 0.62

Other medication administered in hospital or at discharge — no. (%)

Organic nitrate 7181 (76.9) 7088 (76.3) 0.

30

Beta-blocker 8339 (89.3) 8336 (89.7) 0.42

ACE inhibitor 7090 (76.0) 6986 (75.2) 0.22

Angiotensin-II–receptor blocker 1143 (12.2) 1125 (12.1) 0.79

Cholesterol-lowering drug (statin) 8373 (89.7) 8289 (89.2) 0.27

Calcium-channel inhibitor 2769 (29.7) 2789 (30.0) 0.61

Proton-pump inhibitor 4233 (45.4) 4128 (44.4) 0.21

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Tic agr el or vs. Cl opidogr el in Acu te Corona r y S y ndromes

n engl j med 361;11 nejm.org september 10, 2009 1051

botic events (14.6% vs. 16.7%, P<0.001); myocar- dial infarction alone (5.8% vs. 6.9%, P = 0.005); and death due to vascular causes (4.0% vs. 5.1%, P = 0.001). This pattern was also reflected in a reduction in the rate of death from any cause with ticagrelor (4.5%, vs. 5.9% with clopidogrel; P<0.001). The rate of stroke did not differ sig- nificantly between the two treatment groups, al- though there were more hemorrhagic strokes with ticagrelor than with clopidogrel (23 [0.2%] vs. 13 [0.1%], nominal P = 0.10). Concerning our first secondary objective of ascertaining the ef- fect in patients for whom invasive treatment was planned, the rate of the primary end point was also lower with ticagrelor (8.9%, vs. 10.6% with clopidogrel; P = 0.003). Among patients who re- ceived a stent during the study, the rate of defi-

nite stent thrombosis was lower in the ticagrelor
group than in the clopidogrel group (1.3% vs.
1.9%, P = 0.009).

The results regarding the primary end point
did not show significant heterogeneity in analy-
ses of the 33 subgroups, with three exceptions
(Fig. 2 in the Supplementary Appendix). The ben-
efit of ticagrelor appeared to be attenuated in
patients weighing less than the median weight
for their sex (P = 0.04 for the interaction), those not
taking lipid-lowering drugs at randomization
(P = 0.04 for the interaction), and those enrolled
in North America (P = 0.045 for the interaction).

Bleeding

The ticagrelor and clopidogrel groups did not dif-
fer significantly with regard to the rates of major

Table 2. (Continued.)

Characteristic
Ticagrelor Group
(N = 9333)
Clopidogrel Group
(N = 9291) P Value†

Invasive procedure performed during index hospitalization — no. (%)

Planned invasive treatment 6732 (72.1) 6676 (71.9) 0.68

Coronary angiography 7599 (81.4) 7571 (81.5) 0.91

PCI

During index hospitalization 5687 (60.9) 5676 (61.1) 0.83

Within 24 hours after randomization 4560 (48.9) 4546 (48.9) 0.93

Cardiac surgery 398 (4.3) 434 (4.7) 0.19

Invasive procedure performed during study — no. (%)

PCI 5978 (64.1) 5999 (64.6) 0.46

Stenting 5640 (60.4) 5649 (60.8) 0.61

With bare-metal stent only 3921 (42.0) 3892 (41.9) 0.87

With ≥1 drug-eluting stent 1719 (18.4) 1757 (18.9) 0.

40

CABG 931 (10.0) 968 (10.4) 0.32

Time from first dose of study drug to PCI — hr 0.78

Patients with ST-elevation MI

Median 0.25 0.25

IQR 0.05–0.75 0.05–0.72

Patients with non–ST-elevation MI

Median 3.93 3.65

IQR 0.48–46.9 0.45–50.8

* ACE denotes angiotensin-converting enzyme, CABG coronary-artery bypass grafting, IQR interquartile range, and PCI
percutaneous coronary intervention.

† P values were calculated with the use of Fisher’s exact test.
‡ Adherence to the study drug was defined as use of more than 80% of the study medication during each interval be-

tween visits, as assessed by the site investigator.
§ Patients who had been receiving clopidogrel before the study were not eligible for a loading dose of the drug at study

entry.

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n engl j med 361;11 nejm.org september 10, 20091052

bleeding as defined in the trial (11.6% and 11.2%,
respectively; P = 0.43) (Fig. 2 and Table 4). There
was also no significant difference in the rates of
major bleeding according to the Thrombolysis in
Myocardial Infarction (TIMI) criteria (7.9% with
ticagrelor and 7.7% with clopidogrel, P = 0.57) or
fatal or life-threatening bleeding (5.8% in both
groups, P = 0.70). The absence of a significant dif-

ference in major bleeding according to the trial
definition was consistent among all subgroups,
without significant heterogeneity, except with re-
gard to the body-mass index (P = 0.05 for interac-
tion) (Fig. 4 in the Supplementary Appendix). The
two treatment groups did not differ significantly
in the rates of CABG-related major bleeding or
bleeding requiring transfusion of red cells. How-

Table 3. Major Efficacy End Points at 12 Months.*

End Point
Ticagrelor

Group
Clopidogrel

Group

Hazard Ratio for
Ticagrelor Group

(95% CI) P Value†

Primary end point: death from vascular causes, MI, or stroke
— no./total no. (%)

864/9333 (9.8) 1014/9291 (11.7) 0.84 (0.77–0.92) <0.001‡

Secondary end points — no./total no. (%)

Death from any cause, MI, or stroke 901/9333 (10.2) 1065/9291 (12.3) 0.84 (0.77–0.92) <0.001‡

Death from vascular causes, MI, stroke, severe recurrent
ischemia, recurrent ischemia, TIA, or other arterial
thrombotic event

1290/9333 (14.6) 1456/9291 (16.7) 0.88 (0.81–0.95) <0.001‡

MI 504/9333 (5.8) 593/9291 (6.9) 0.84 (0.75–0.95) 0.005‡

Death from vascular causes 353/9333 (4.0) 442/9291 (5.1) 0.79 (0.69–0.91) 0.001‡

Stroke 125/9333 (1.5) 106/9291 (1.3) 1.17 (0.91–1.52) 0.22

Ischemic 96/9333 (1.1) 91/9291 (1.1) 0.74

Hemorrhagic 23/9333 (0.2) 13/9291 (0.1) 0.10

Unknown 10/9333 (0.1) 2/9291 (0.02) 0.04

Other events — no./total no. (%)

Death from any cause 399/9333 (4.5) 506/9291 (5.9) 0.78 (0.69–0.89) <0.001

Death from causes other than vascular causes 46/9333 (0.5) 64/9291 (0.8) 0.71 (0.49–1.04) 0.08

Severe recurrent ischemia 302/9333 (3.5) 345/9291 (4.0) 0.87 (0.74–1.01) 0.08

Recurrent ischemia 500/9333 (5.8) 536/9291 (6.2) 0.93 (0.82–1.05) 0.22

TIA 18/9333 (0.2) 23/9291 (0.3) 0.78 (0.42–1.44) 0.42

Other arterial thrombotic event 19/9333 (0.2) 31/9291 (0.4) 0.61 (0.34–1.08) 0.09

Death from vascular causes, MI, stroke — no./total no. (%)

Invasive treatment planned§ 569/6732 (8.9) 668/6676 (10.6) 0.84 (0.75–0.94) 0.003‡

Event rate, days 1–30 443/9333 (4.8) 502/9291 (5.4) 0.88 (0.77–1.00) 0.045

Event rate, days 31–360¶ 413/8763 (5.3) 510/8688 (6.6) 0.80 (0.70–0.91) <0.001

Stent thrombosis — no. of patients who received a stent/
total no. (%)

Definite 71/5640 (1.3) 106/5649 (1.9) 0.67 (0.50–0.91) 0.009

Probable or definite 118/5640 (2.2) 158/5649 (2.9) 0.75 (0.59–0.95) 0.02

Possible, probable, or definite 155/5640 (2.9) 202/5649 (3.8) 0.77 (0.62–0.95) 0.01

* The percentages are Kaplan–Meier estimates of the rate of the end point at 12 months. Patients could have had more than one type of end
point. Death from vascular causes included fatal bleeding. Only traumatic fatal bleeding was excluded from the category of death from vas-
cular causes. MI denotes myocardial infarction, and TIA transient ischemic attack.

† P values were calculated by means of Cox regression analysis.
‡ Statistical significance was confirmed in the hierarchical testing sequence applied to the secondary composite efficacy end points.
§ A plan for invasive or noninvasive (medical) management was declared before randomization.
¶ Patients with any primary event during the first 30 days were excluded.

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Tic agr el or vs. Cl opidogr el in Acu te Corona r y S y ndromes

n engl j med 361;11 nejm.org september 10, 2009 1053

ever, in the ticagrelor group, there was a higher
rate of non–CABG-related major bleeding ac-
cording to the study criteria (4.5% vs. 3.8%,
P = 0.03) and the TIMI criteria (2.8% vs. 2.2%,
P = 0.03) (Fig. 3 in the Supplementary Appendix).
With ticagrelor as compared with clopidogrel,
there were more episodes of intracranial bleed-
ing (26 [0.3%] vs. 14 [0.2%], P = 0.06), including
fatal intracranial bleeding (11 [0.1%] vs. 1 [0.01%],
P = 0.02). However, there were fewer episodes of
other types of fatal bleeding in the ticagrelor
group (9 [0.1%], vs. 21 [0.3%] in the clopidogrel
group; P = 0.03) (Table 4).

Other Adverse Events

Dyspnea was more common in the ticagrelor
group than in the clopidogrel group (in 13.8% of
patients vs. 7.8%) (Table 4). Few patients discon-
tinued the study drug because of dyspnea (0.9%
of patients in the ticagrelor group and 0.1% in
the clopidogrel group).

Holter monitoring was performed for a me-
dian of 6 days during the first week in 2866
patients and was repeated at 30 days in 1991
patients. There was a higher incidence of ven-
tricular pauses in the first week, but not at day 30,
in the ticagrelor group than in the clopidogrel
group (Table 4). Pauses were rarely associated
with symptoms; the two treatment groups did
not differ significantly with respect to the inci-
dence of syncope or pacemaker implantation
(Table 4).

Discontinuation of the study drug due to ad-
verse events occurred more frequently with ti-
cagrelor than with clopidogrel (in 7.4% of pa-
tients vs. 6.0%, P<0.001) (Table 2). The levels of creatinine and uric acid increased slightly more during the treatment period with ticagrelor than with clopidogrel (Table 4).

D i s c u s s i o n

PLATO shows that treatment with ticagrelor as
compared with clopidogrel in patients with acute
coronary syndromes significantly reduced the
rate of death from vascular causes, myocardial
infarction, or stroke. A similar benefit was seen
for the individual components of death from vas-
cular causes and myocardial infarction, but not
for stroke. The beneficial effects of ticagrelor
were achieved without a significant increase in
the rate of major bleeding.

The benefits of ticagrelor over clopidogrel

were seen in patients who had an acute coronary
syndrome with or without ST-segment elevation.
Previous trials have shown benefits of clopidogrel
in the same clinical settings.8,17-19 The advantages
were seen regardless of whether patients had re-
ceived appropriate initiation of treatment with the

Hazard ratio, 0.84 (95% CI, 0.77–0.92)

22p3

P<0.001

100

C
u

m
u

la
ti

ve
I

n
ci

d
en

ce
o

f
P

ri
m

ar
y

E
n

d
P

o
in

t
(%

)

90

70

60

10

20

30
40

80

50

0
0 2 4 6 8 1210

Months

10
8
2
4

12

6
0
0 2 4 6 8 1210

Clopidogrel

Ticagrelor

No. at Risk
Ticagrelor
Clopidogrel

9333
9291

8628
8521

8460
8362

8219
8124

6743
6650

5161
5096

4147
4047

AUTHOR:

FIGURE:

JOB:

4-C
H/T

RETAKE

SIZE

ICM

CASE

EMail Line
H/T
Combo

Revised

AUTHOR, PLEASE NOTE:
Figure has been redrawn and type has been reset.

Please check carefully.

REG F

Enon

1st

2nd

3rd

Wallentin

1 of 2

09-10-09

ARTIST: ts

36111 ISSUE:

Figure 1. Cumulative Kaplan–Meier Estimates of the Time to the First
Adjudicated Occurrence of the Primary Efficacy End Point.

The primary end point — a composite of death from vascular causes, myo-
cardial infarction, or stroke — occurred significantly less often in the ti-
cagrelor group than in the clopidogrel group (9.8% vs. 11.7% at 12 months;
hazard ratio, 0.84; 95% confidence interval, 0.77 to 0.92; P<0.001).

22p3
100
C
u
m
u
la
ti
ve
I
n
ci
d
en
ce
o

f
M

aj
o

r
B

le
ed

in
g

(%
)

90
70
60
10
20
30
40
80
50
0
0 2 4 6 8 1210
Months

P=0.43

10
5

15

0
0 2 4 6 8 1210
Clopidogrel
Ticagrelor
No. at Risk
Ticagrelor
Clopidogrel

9235
9186

7246
7305

6826
6930

6545
6670

5129
5209

3783
3841

3433
3479

AUTHOR:
FIGURE:
JOB:
4-C
H/T
RETAKE
SIZE
ICM
CASE
EMail Line
H/T
Combo
Revised
AUTHOR, PLEASE NOTE:
Figure has been redrawn and type has been reset.
Please check carefully.
REG F
Enon
1st

2nd
3rd

Wallentin

2 of 2

09-10-09
ARTIST: ts
36111 ISSUE:

Figure 2. Cumulative Kaplan–Meier Estimates of the Time to the First Major
Bleeding End Point, According to the Study Criteria.

The time was estimated from the first dose of the study drug in the safety
population. The hazard ratio for major bleeding, defined according to the
study criteria, for the ticagrelor group as compared with the clopidogrel
group was 1.04 (95% confidence interval, 0.95 to 1.13).

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T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e

n engl j med 361;11 nejm.org september 10, 20091054

currently recommended higher loading dose of
clopidogrel and regardless of whether invasive or
noninvasive management was planned.20-25 The
treatment effects were the same in the short term
(days 0 to 30) and in the longer term (days 31 to

360). This duration of treatment benefit has also
been shown with clopidogrel.26 Thus, ticagrelor
appears to expand on the previously demonstrat-
ed benefits of clopidogrel across the spectrum of
acute coronary syndromes.

Table 4. Safety of the Study Drugs.*

End Point
Ticagrelor
Group
Clopidogrel
Group

Hazard or Odds
Ratio for Ticagrelor
Group (95% CI)† P Value

Primary safety end points — no./total no. (%)

Major bleeding, study criteria 961/9235 (11.6) 929/9186 (11.2) 1.04 (0.95–1.13) 0.43

Major bleeding, TIMI criteria‡ 657/9235 (7.9) 638/9186 (7.7) 1.03 (0.93–1.15) 0.57

Bleeding requiring red-cell transfusion 818/9235 (8.9) 809/9186 (8.9) 1.00 (0.91–1.11) 0.96

Life-threatening or fatal bleeding, study criteria 491/9235 (5.8) 480/9186 (5.8) 1.03 (0.90–1.16) 0.70

Fatal bleeding 20/9235 (0.3) 23/9186 (0.3) 0.87 (0.48–1.59) 0.66

Nonintracranial fatal bleeding 9/9235 (0.1) 21/9186 (0.3) 0.03

Intracranial bleeding 26/9235 (0.3) 14/9186 (0.2) 1.87 (0.98–3.58) 0.06

Fatal 11/9235 (0.1) 1/9186 (0.01) 0.02

Nonfatal 15/9235 (0.2) 13/9186 (0.2) 0.69

Secondary safety end points — no./total no. (%)

Non–CABG-related major bleeding, study criteria 362/9235 (4.5) 306/9186 (3.8) 1.19 (1.02–1.38) 0.03

Non–CABG-related major bleeding, TIMI criteria 221/9235 (2.8) 177/9186 (2.2) 1.25 (1.03, 1.53) 0.03

CABG-related major bleeding, study criteria 619/9235 (7.4) 654/9186 (7.9) 0.95 (0.85–1.06) 0.32

CABG-related major bleeding, TIMI criteria 446/9235 (5.3) 476/9186 (5.8) 0.94 (0.82–1.07) 0.32

Major or minor bleeding, study criteria 1339/9235 (16.1) 1215/9186 (14.6) 1.11 (1.03–1.20) 0.008

Major or minor bleeding, TIMI criteria‡ 946/9235 (11.4) 906/9186 (10.9) 1.05 (0.96–1.15) 0.33

Dyspnea — no./total no. (%)

Any 1270/9235 (13.8) 721/9186 (7.8) 1.84 (1.68–2.02) <0.001

Requiring discontinuation of study treatment 79/9235 (0.9) 13/9186 (0.1) 6.12 (3.41–11.01) <0.001

Bradycardia — no./total no. (%)

Pacemaker insertion 82/9235 (0.9) 79/9186 (0.9) 0.87

Syncope 100/9235 (1.1) 76/9186 (0.8) 0.08

Bradycardia 409/9235 (4.4) 372/9186 (4.0) 0.21

Heart block 67/9235 (0.7) 66/9186 (0.7) 1.00

Holter monitoring — no./total no. (%)

First week

Ventricular pauses ≥3 sec 84/1451 (5.8) 51/1415 (3.6) 0.01

Ventricular pauses ≥5 sec 29/1451 (2.0) 17/1415 (1.2) 0.10

At 30 days

Ventricular pauses ≥3 sec 21/985 (2.1) 17/1006 (1.7) 0.52

Ventricular pauses ≥5 sec 8/985 (0.8) 6/1006 (0.6) 0.60

Neoplasm arising during treatment — no. of patients/
total no. (%)

Any 132/9235 (1.4) 155/9186 (1.7) 0.17

Malignant 115/9235 (1.2) 121/9186 (1.3) 0.69

Benign 18/9235 (0.2) 35/9186 (0.4) 0.02

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Tic agr el or vs. Cl opidogr el in Acu te Corona r y S y ndromes

n engl j med 361;11 nejm.org september 10, 2009 1055

The incremental reduction in the risk of coro-
nary thrombotic events (i.e., myocardial infarc-
tion and stent thrombosis) through more-intense
P2Y12 inhibition with ticagrelor is consistent with
similar effects of prasugrel.10 As noted above, the
benefits with ticagrelor were seen regardless of
whether invasive or noninvasive management was
planned; this issue has not been investigated with
other P2Y12 inhibitors. Treatment with ticagrelor
was also associated with an absolute reduction of
1.4 percentage points and a relative reduction of
22% in the rate of death from any cause at 1 year.
This survival benefit from more-intense platelet
inhibition with ticagrelor is consistent with reduc-
tions in the mortality rate obtained by means of
platelet inhibition with aspirin in patients who
had an acute coronary syndrome27,28 and with
clopidogrel in patients who had myocardial in-
farction with ST-segment elevation.22 In contrast,
other contemporary trials involving patients with
an acute coronary syndrome have not shown sig-
nificant reductions in the mortality rate with the
use of clopidogrel,8 prasugrel,10 or glycoprotein
IIb/IIIa inhibitors.29 The improved survival rate
with ticagrelor might be due to the decrease in
the risk of thrombotic events without a concomi-
tant increase in the risk of major bleeding, as seen
with other antithrombotic treatments in patients
with an acute coronary syndrome.30-32

Since P2Y12 inhibition with ticagrelor is revers-

ible, the antiplatelet effect dissipates more rapidly
than with the thienopyridines, which are irrevers-
ible P2Y12 inhibitors. Therefore, less procedure-
related bleeding might be expected. Although
the rates of major bleeding were not lower with
ticagrelor than with clopidogrel, the more-intense
platelet inhibition with ticagrelor was not asso-
ciated with an increase in the rate of any major
bleeding. In contrast to the experience with
prasugrel,10 which is also a more effective plate-
let inhibitor than clopidogrel but is irreversible,
there was no increased risk of CABG-related
bleeding with ticagrelor. As with prasugrel,10
non–procedure-related bleeding (spontaneous
bleeding), including gastrointestinal and intrac-
ranial bleeding, was more common with ticagre-
lor than with clopidogrel. Although the rare
episodes of intracranial bleeding were often fa-
tal, the rates of nonintracranial fatal bleeding,
death from vascular causes, and death from any
other cause were lower in the ticagrelor group
than in the clopidogrel group, resulting in an
overall reduction in the mortality rate with ti-
cagrelor.

Dyspnea occurred more frequently with ti-
cagrelor than with clopidogrel.13 Most episodes
lasted less than a week. Discontinuation of the
study drug because of dyspnea occurred in 0.9%
of patients in the ticagrelor group. Holter moni-
toring detected more ventricular pauses during

Table 4. (Continued.)

End Point
Ticagrelor
Group
Clopidogrel
Group
Hazard or Odds
Ratio for Ticagrelor
Group (95% CI)† P Value

Increase in serum uric acid from baseline value — %

At 1 mo 14±46 7±44 <0.001

At 12 mo 15±52 7±31 <0.001

1 Mo after end of treatment 7±43 8±48 0.56

Increase in serum creatinine from baseline value — %

At 1 mo 10±22 8±21 <0.001

At 12 mo 11±22 9±22 <0.001

1 Mo after end of treatment 10±22 10±22 0.59

* Plus–minus values are means ±SD. Data are shown for patients who received at least one dose of the study drug for events occurring up
to 7 days after permanent discontinuation of the study drug. The percentages for the primary and secondary safety end points are Kaplan–
Meier estimates of the rate of the end point at 12 months. Patients could have more than one type of end point. CABG denotes coronary-
artery bypass grafting.

† Hazard ratios are shown for all safety end points except bleeding requiring red-cell transfusion, for which odds ratios are shown. P values
for the odds ratios were calculated with the use of Fisher’s exact test.

‡ Major bleeding and major or minor bleeding according to Thrombolysis in Myocardial Infarction (TIMI) criteria refer to nonadjudicated
events analyzed with the use of a statistically programmed analysis in accordance with previously used definitions.10

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T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e

n engl j med 361;11 nejm.org september 10, 20091056

the first week in the ticagrelor group than in the
clopidogrel group,13 but such episodes were in-
frequent at 30 days and were rarely associated
with symptoms. There were no significant differ-
ences in the rates of clinical manifestations of
bradyarrhythmia between the two treatment
groups.

The superiority of ticagrelor over clopidogrel
with regard to the primary end point, as well as
the similarity in rates of major bleeding, was
consistent in 62 of 66 subgroups; the differences
were significant in the remaining 4 subgroups
(P<0.05 for heterogeneity). These findings may have been due to chance, given the large number of tests performed. The difference in results be- tween patients enrolled in North America and those enrolled elsewhere raises the questions of whether geographic differences between popula- tions of patients or practice patterns influenced the effects of the randomized treatments, although no apparent explanations have been found.

In conclusion, in patients who had an acute
coronary syndrome with or without ST-segment
elevation, treatment with ticagrelor, as compared
with clopidogrel, significantly reduced the rate
of death from vascular causes, myocardial infarc-
tion, or stroke, without an increase in the rate of
overall major bleeding but with an increase in
the rate of non–procedure-related bleeding.

Supported by AstraZeneca.
Dr. Wallentin reports receiving consulting fees from Regado

Biosciences and Athera Biotechnologies; lecture fees from Boeh-
ringer Ingelheim, AstraZeneca, and Eli Lilly, and grant support
from Astra Zeneca, Boehringer Ingelheim, Bristol-Myers Squibb,
GlaxoSmithKline, and Schering-Plough; Dr. Becker, consulting
fees from Regado Biosciences, AstraZeneca, Eli Lilly, and Bristol-

Myers Squibb and grant support from Momenta Pharmaceuticals,
the Medicines Company, and Bristol-Myers Squibb; Dr. Budaj,
consulting fees from Sanofi-Aventis and Eli Lilly and lecture fees
from Sanofi-Aventis, Boehringer Ingelheim, AstraZeneca, and
GlaxoSmithKline. Dr. Cannon reports having equity ownership
in Automedics Medical Systems and receiving grant support
from Accumetrics, AstraZeneca, Bristol-Myers Squibb, Sanofi-
Aventis, GlaxoSmithKline, Merck, Intekrin Therapeutics, Schering-
Plough, Novartis, and Takeda. Drs. Emanuelsson and Horrow
report being employees of AstraZeneca and having equity owner-
ship in AstraZeneca; Dr. Horrow also reports receiving lecture
fees from the Pharmaceutical Education and Research Institute.
Dr. Husted reports receiving consulting fees from AstraZeneca,
Sanofi-Aventis, and Eli Lilly and lecture fees from AstraZeneca,
Sanofi-Aventis, and Bristol-Myers Squibb; Dr. Katus, consulting
and lecture fees from AstraZeneca; Dr. Mahaffey, consulting
fees from AstraZeneca, Bristol-Myers Squibb, Johnson and John-
son, Eli Lilly, Pfizer, and Schering-Plough, lecture fees from Bayer,
Bristol-Myers Squibb, Daichii Sankyo, Eli Lilly, and Sanofi-
Aventis, and grant support from AstraZeneca, Portola Pharma-
ceuticals, Schering-Plough, the Medicines Company, Johnson
and Johnson, Eli Lilly, and Bayer; Dr. Scirica, consulting fees from
AstraZeneca, Cogentus Pharmaceuticals, and Novartis, lecture
fees from Eli Lilly, Daiichi Sankyo, and Sanofi-Aventis, and
grant support from Astra Zeneca, Daiichi Sankyo, and Novartis.
Dr. Steg reports receiving consulting fees from AstraZeneca,
Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Endotis
Pharma, GlaxoSmithKline, Medtronic, Merck Sharp and Dohme,
Nycomed, Servier, the Medicines Company, Daiichi Sankyo, and
Sanofi-Aventis, lecture fees from the Medicines Company,
Servier, Menarini, Pierre Fabre, Boehringer Ingelheim, Bristol-
Myers Squibb, Glaxo Smith Kline, Medtronic, Nycomed, and
Sanofi-Aventis, and grant support from Sanofi-Aventis and hav-
ing equity ownership in Aterovax. Dr. Storey reports receiving
consulting fees from AstraZeneca, Eli Lilly, Daiichi Sankyo,
Teva, and Schering-Plough, lecture fees from Eli Lilly, Daiichi
Sankyo, and AstraZeneca, and grant support from AstraZeneca,
Eli Lilly, Daiichi Sankyo, and Schering-Plough; and Dr. Har-
rington, consulting fees from Bristol-Myers Squibb, Sanofi-
Aventis, Portola Pharmaceuticals, Schering-Plough, and Astra-
Zeneca, lecture fees from Schering-Plough, Bristol-Myers Squibb,
Sanofi-Aventis, and Eli Lilly, and grant support from Millenium
Pharmaceuticals, Schering-Plough, the Medicines Company,
Portola Pharmaceuticals, Astra Zeneca, and Bristol-Myers
Squibb. No other potential conflict of interest relevant to this
article was reported.

appendix
Members of select PLATO committees are as follows (with principal investigators at participating centers and members of other com-
mittees listed in the Supplementary Appendix): Executive Committee — Sweden: L. Wallentin (cochair), S. James, I. Ekman; H. Emanuels-
son, A. Freij, M. Thorsen; United States: R.A. Harrington (cochair), R. Becker, C. Cannon, J. Horrow; Denmark: S. Husted; Germany: H.
Katus; U.K.: A. Skene (statistician), R.F. Storey; France: P.G. Steg; Steering Committee — Italy: D. Ardissino; Australia: P. Aylward; Philip-
pines: N. Babilonia; France: J.-P. Bassand; Poland: A. Budaj; Georgia: Z. Chapichadze; Belgium: M.J. Claeys; South Africa: P. Commerford; the
Netherlands: J.H. Cornel, F. Verheugt; Slovak Republic: T. Duris; China: R. Gao; Mexico: G.C. Armando; Germany: E. Giannitsis; United States:
P. Gurbel, R. Harrington, N. Kleiman, M. Sabatine, D. Weaver; Spain: M. Heras; Denmark: S. Husted; Sweden: S. James; Hungary: M.
Keltai; Norway: F. Kontny; Greece: D. Kremastinos; Finland: R. Lassila; Israel: B.S. Lewis; Spain: J.L. Sendon; Hong Kong: C. Man Yu; Austria:
G. Maurer; Switzerland: B. Meier; Portugal: J. Morais; Brazil: J. Nicolau; Ukraine: A. Nikolaevich Parkhomenko; Turkey: A. Oto; India: P. Pais;
Argentina: E. Paolasso; Bulgaria: D. Raev; Malaysia: D.S. Robaayah Zambahari; Russia: M. Ruda; Indonesia: A. Santoso; South Korea: K.-B.
Seung; Singapore: L. Soo Teik; Czech Republic: J. Spinar; Thailand: P. Sritara; United Kingdom: R. Storey; Canada: P. Théroux; Romania: M.
Vintila; Taiwan: D.W. Wu; Data Monitoring Committee — United States: J.L. Anderson (chair), D. DeMets (statistician); the Netherlands: M.
Simoons; United Kingdom: R. Wilcox; Belgium: F. Van de Werf.

References

Anderson JL, Adams CD, Antman EM, 1.
et al. ACC/AHA 2007 guidelines for the
management of patients with unstable
angina/non ST-elevation myocardial in-

farction: a report of the American College
of Cardiology/American Heart Associa-
tion Task Force on Practice Guidelines
(Writing Committee to Revise the 2002

Guidelines for the Management of Pa-
tients With Unstable Angina/Non ST-Ele-
vation Myocardial Infarction): developed
in collaboration with the American Col-

The New England Journal of Medicine
Downloaded from nejm.org on January 8, 2021. For personal use only. No other uses without permission.
Copyright © 2009 Massachusetts Medical Society. All rights reserved.

Tic agr el or vs. Cl opidogr el in Acu te Corona r y S y ndromes

n engl j med 361;11 nejm.org september 10, 2009 1057

lege of Emergency Physicians, the Society
for Cardiovascular Angiography and In-
terventions, and the Society of Thoracic
Surgeons: endorsed by the American As-
sociation of Cardiovascular and Pulmo-
nary Rehabilitation and the Society for
Academic Emergency Medicine. Circula-
tion 2007;116(7):e148-e304. [Erratum, Cir-
culation 2008;117(9):e180.]

Antman EM, Anbe DT, Armstrong 2.
PW, et al. ACC/AHA guidelines for the
management of patients with ST-elevation
myocardial infarction — executive sum-
mary: a report of the American College of
Cardiology/American Heart Association
Task Force on Practice Guidelines (Writ-
ing Committee to Revise the 1999 Guide-
lines for the Management of Patients
With Acute Myocardial Infarction). Circu-
lation 2004;110:588-636. [Erratum, Cir-
culation 2005;111:2013.]

Bassand JP, Hamm CW, Ardissino D, 3.
et al. Guidelines for the diagnosis and
treatment of non-ST-segment elevation
acute coronary syndromes. Eur Heart J
2007;28:1598-660.

Van de Werf F, Bax J, Betriu A, et al. 4.
Management of acute myocardial infarc-
tion in patients presenting with persistent
ST-segment elevation: the Task Force on
the Management of ST-Segment Elevation
Acute Myocardial Infarction of the Euro-
pean Society of Cardiology. Eur Heart J
2008;29:2909-45.

Jernberg T, Payne CD, Winters KJ, et 5.
al. Prasugrel achieves greater inhibition
of platelet aggregation and a lower rate of
non-responders compared with clopid-
ogrel in aspirin-treated patients with sta-
ble coronary artery disease. Eur Heart J
2006;27:1166-73.

Wallentin L, Varenhorst C, James S, et 6.
al. Prasugrel achieves greater and faster
P2Y12receptor-mediated platelet inhibi-
tion than clopidogrel due to more effi-
cient generation of its active metabolite in
aspirin-treated patients with coronary ar-
tery disease. Eur Heart J 2008;29:21-30.

Fox KA, Mehta SR, Peters R, et al. 7.
Benefits and risks of the combination of
clopidogrel and aspirin in patients under-
going surgical revascularization for non-
ST-elevation acute coronary syndrome:
the Clopidogrel in Unstable angina to
prevent Recurrent ischemic Events (CURE)
Trial. Circulation 2004;110:1202-8.

Yusuf S, Zhao F, Mehta SR, Chrolav-8.
icius S, Tognoni G, Fox KK. Effects of
clopidogrel in addition to aspirin in pa-
tients with acute coronary syndromes
without ST-segment elevation. N Engl J
Med 2001;345:494-502. [Errata, N Engl J
Med 2001;345:1506, 1716.]

Kuliczkowski W, Witkowski A, Polon-9.
ski L, et al. Interindividual variability in
the response to oral antiplatelet drugs: a
position paper of the Working Group on
antiplatelet drugs resistance appointed by
the Section of Cardiovascular Interven-
tions of the Polish Cardiac Society, en-

dorsed by the Working Group on Throm-
bosis of the European Society of Cardiology.
Eur Heart J 2009;30:426-35.

Wiviott SD, Braunwald E, McCabe CH, 10.
et al. Prasugrel versus clopidogrel in pa-
tients with acute coronary syndromes.
N Engl J Med 2007;357:2001-15.

Storey RF, Husted S, Harrington RA, 11.
et al. Inhibition of platelet aggregation by
AZD6140, a reversible oral P2Y12 receptor
antagonist, compared with clopidogrel in
patients with acute coronary syndromes.
J Am Coll Cardiol 2007;50:1852-6.

Husted S, Emanuelsson H, Heptin-12.
stall S, Sandset PM, Wickens M, Peters G.
Pharmacodynamics, pharmacokinetics,
and safety of the oral reversible P2Y12 an-
tagonist AZD6140 with aspirin in patients
with atherosclerosis: a double-blind com-
parison to clopidogrel with aspirin. Eur
Heart J 2006;27:1038-47.

Cannon CP, Husted S, Harrington RA, 13.
et al. Safety, tolerability, and initial effi-
cacy of AZD6140, the first reversible oral
adenosine diphosphate receptor antago-
nist, compared with clopidogrel, in pa-
tients with non-ST-segment elevation
acute coronary syndrome: primary results
of the DISPERSE-2 trial. J Am Coll Cardiol
2007;50:1844-51. [Erratum, J Am Coll
Cardiol 2007;50:2196.]

James S, Akerblom A, Cannon CP, et 14.
al. Comparison of ticagrelor, the first re-
versible oral P2Y(12) receptor antagonist,
with clopidogrel in patients with acute
coronary syndromes: rationale, design, and
baseline characteristics of the PLATelet
inhibition and patient Outcomes (PLATO)
trial. Am Heart J 2009;157:599-605.

Thygesen K, Alpert JS, White HD, et 15.
al. Universal definition of myocardial in-
farction. Circulation 2007;116:2634-53.

Cutlip DE, Windecker S, Mehran R, et 16.
al. Clinical end points in coronary stent
trials: a case for standardized definitions.
Circulation 2007;115:2344-51.

Mehta SR, Yusuf S, Peters RJ, et al. 17.
Effects of pretreatment with clopidogrel
and aspirin followed by long-term therapy
in patients undergoing percutaneous cor-
onary intervention: the PCI-CURE study.
Lancet 2001;358:527-33.

Sabatine MS, Cannon CP, Gibson CM, 18.
et al. Addition of clopidogrel to aspirin
and fibrinolytic therapy for myocardial
infarction with ST-segment elevation.
N Engl J Med 2005;352:1179-89.

Chen ZM, Jiang LX, Chen YP, et al. Ad-19.
dition of clopidogrel to aspirin in 45,852
patients with acute myocardial infarction:
randomised placebo-controlled trial. Lan-
cet 2005;366:1607-21.

Mehta SR, Yusuf S, Peters RJ, et al. 20.
Effects of pretreatment with clopidogrel
and aspirin followed by long-term therapy
in patients undergoing percutaneous cor-
onary intervention: the PCI-CURE study.
Lancet 2001;358:527-33.

Sabatine MS, Cannon CP, Gibson CM, 21.
et al. Effect of clopidogrel pretreatment

before percutaneous coronary interven-
tion in patients with ST-elevation myocar-
dial infarction treated with fibrinolytics:
the PCI-CLARITY study. JAMA 2005;294:
1224-32.

Bonello L, Camoin-Jau L, Armero S, et 22.
al. Tailored clopidogrel loading dose ac-
cording to platelet reactivity monitoring
to prevent acute and subacute stent throm-
bosis. Am J Cardiol 2009;103:5-10.

Collet JP, Silvain J, Landivier A, et al. 23.
Dose effect of clopidogrel reloading in
patients already on 75-mg maintenance
dose: the Reload with Clopidogrel Before
Coronary Angioplasty in Subjects Treated
Long Term with Dual Antiplatelet Therapy
(RELOAD) study. Circulation 2008;118:
1225-33.

Lotrionte M, Biondi-Zoccai GG, Agos-24.
toni P, et al. Meta-analysis appraising
high clopidogrel loading in patients under-
going percutaneous coronary interven-
tion. Am J Cardiol 2007;100:1199-206.

Montalescot G, Sideris G, Meuleman 25.
C, et al. A randomized comparison of
high clopidogrel loading doses in patients
with non-ST-segment elevation acute coro-
nary syndromes: the ALBION (Assessment
of the Best Loading Dose of Clopidogrel
to Blunt Platelet Activation, Inflammation
and Ongoing Necrosis) trial. J Am Coll
Cardiol 2006;48:931-8.

Yusuf S, Mehta SR, Zhao F, et al. Early 26.
and late effects of clopidogrel in patients
with acute coronary syndromes. Circula-
tion 2003;107:966-72.

ISIS-2 (Second International Study of 27.
Infarct Survival) Collaborative Group.
Randomised trial of intravenous strepto-
kinase, oral aspirin, both, or neither
among 17,187 cases of suspected acute
myocardial infarction: ISIS-2. Lancet
1988;2:349-60.

Antithrombotic Trialists’ Collabora-28.
tion. Collaborative meta-analysis of ran-
domised trials of antiplatelet therapy for
prevention of death, myocardial infarc-
tion, and stroke in high risk patients. BMJ
2002;324:71-86. [Erratum, BMJ 2002;324:
141.]

Boersma E, Harrington RA, Moliterno 29.
DJ, et al. Platelet glycoprotein IIb/IIIa in-
hibitors in acute coronary syndromes: a
meta-analysis of all major randomised
clinical trials. Lancet 2002;359:189-98.
[Erratum, Lancet 2002;359:2120.]

Yusuf S, Mehta SR, Chrolavicius S, et 30.
al. Effects of fondaparinux, on mortality
and reinfarction in patients with acute ST-
segment elevation myocardial infarction:
the OASIS-6 randomized trial. JAMA 2006;
295:1519-30.

Idem.31. Comparison of fondaparinux and
enoxaparin in acute coronary syndromes.
N Engl J Med 2006;354:1464-76.

Stone GW, Witzenbichler B, Guagliu-32.
mi G, et al. Bivalirudin during primary
PCI in acute myocardial infarction. N Engl
J Med 2008;358:2218-30.
Copyright © 2009 Massachusetts Medical Society.

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Copyright © 2009 Massachusetts Medical Society. All rights reserved.

Group#

Student Names

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Journal Assessment
Journal Title
Affiliation
Types of Articles
Target Audience
Types of Authors
Article Review Type
Journal Prestige
Overall Impression
Introduction
Title Authors
Funding Disclosure
Study Importance Study Purpose
Methods
Study Design
Participants, Recruitment, Intervention				·
Primary Outcome Secondary Outcomes
Statistics -Sample Size -Randomization -Blinding Tests Performed
Results
Baseline data
Primary Efficacy and Safety Outcomes	Below is an example table: Outcomes Group 1 Group 2 Group 3 NNT
Secondary Outcomes
Author’s Discussion & Conclusion
Discussion
Conclusion
My Evaluation & Conclusion
Evaluation	Strengths Limitations
My Conclusion
Application to patient care