The n e w e ng l a n d j o u r na l of
original article
The authors affiliations are listed in the
Appendix. Address reprint requests to Dr.
Bhatt at VA Boston Healthcare System,
1400 VFW Pkwy., Boston, MA 02132, or at
dlbhattmd@post.harvard.edu.
*Investigators in the Cangrelor versus
Standard Therapy to Achieve Optimal
Management of Platelet Inhibition
(CHAMPION) PLATFORM trial are listed
in the Supplementary Appendix, avail-
able with the full text of this article at
NEJM.org.
This article (10.1056/NEJMoa0908629) was
published on November 15, 2009, and up-
dated on December 9, 2009, at NEJM.org.
N Engl J Med 2009;361:2330-41.
Copyright 2009 Massachusetts Medical Society.
2330
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m e dic i n e
Intravenous Platelet Blockade
with Cangrelor during PCI
Deepak L. Bhatt, M.D., M.P.H., A. Michael Lincoff, M.D.,
C. Michael Gibson, M.D., Gregg W. Stone, M.D., Steven McNulty, M.S.,
Gilles Montalescot, M.D., Ph.D., Neal S. Kleiman, M.D., Shaun G. Goodman, M.D.,
Harvey D. White, D.Sc., Kenneth W. Mahaffey, M.D., Charles V. Pollack, Jr., M.D.,
Steven V. Manoukian, M.D., Petr Widimsky, M.D., Dr.Sc.,
Derek P. Chew, M.B., B.S., M.P.H., Fernando Cura, M.D., Ivan Manukov, M.D.,
Frantisek Tousek, M.D., M. Zubair Jafar, M.D., Jaspal Arneja, M.D.,
Simona Skerjanec, Pharm.D., and Robert A. Harrington, M.D.,
for the CHAMPION PLATFORM Investigators*
A bs t r ac t
Background
Intravenous cangrelor, a rapid-acting, reversible adenosine diphosphate (ADP) recep-
tor antagonist, might reduce ischemic events during percutaneous coronary interven-
tion (PCI).
Methods
In this double-blind, placebo-controlled study, we randomly assigned 5362 patients
who had not been treated with clopidogrel to receive either cangrelor or placebo at
the time of PCI, followed by 600 mg of clopidogrel. The primary end point was a
composite of death, myocardial infarction, or ischemia-driven revascularization at
48 hours. Enrollment was stopped when an interim analysis concluded that the
trial would be unlikely to show superiority for the primary end point.
Results
The primary end point occurred in 185 of 2654 patients receiving cangrelor (7.0%)
and in 210 of 2641 patients receiving placebo (8.0%) (odds ratio in the cangrelor
group, 0.87; 95% confidence interval [CI], 0.71 to 1.07; P=0.17) (modified intention-
to-treat population adjusted for missing data). In the cangrelor group, as compared
with the placebo group, two prespecified secondary end points were significantly
reduced at 48 hours: the rate of stent thrombosis, from 0.6% to 0.2% (odds ratio, 0.31;
95% CI, 0.11 to 0.85; P=0.02), and the rate of death from any cause, from 0.7% to
0.2% (odds ratio, 0.33; 95% CI, 0.13 to 0.83; P=0.02). There was no significant differ-
ence in the rate of blood transfusion (1.0% in the cangrelor group and 0.6% in the
placebo group, P=0.13), though major bleeding on one scale was increased in the
cangrelor group, from 3.5% to 5.5% (P<0.001), because of more groin hematomas.
Conclusions
The use of periprocedural cangrelor during PCI was not superior to placebo in re-
ducing the primary end point. The prespecified secondary end points of stent
thrombosis and death were lower in the cangrelor group, with no significant in-
crease in the rate of transfusion. Further study of intravenous ADP blockade with
cangrelor may be warranted. (ClinicalTrials.gov number, NCT00385138.)
n engl j med 361;24 nejm.org december 10, 2009
 Intr avenous Platelet Block ade with Cangrelor during PCI

B
lockade of the platelet adenosine
diphosphate (ADP) receptor has been dem- 5301 Patients requiring PCI (with or
onstrated to improve cardiovascular out- without stent, excluding STEMI)
underwent randomization
comes in patients undergoing percutaneous cor-
onary intervention (PCI).1-5 In patients undergoing
coronary stenting, ticlopidine given with aspirin
was found to decrease the risk of stent thrombo-
sis and other important ischemic complications, 2656 Received cangrelor, 30 g/kg 2645 Received placebo, 30 g/kg
as compared with aspirin alone or aspirin plus bolus and 2654 received 4 g/kg/min bolus and 4 g/kg/min infusion
infusion for 2 hr or the duration of for 2 hr or the duration of the
warfarin.6 Ticlopidine was ultimately replaced by the procedure, whichever was longer procedure, whichever was longer
clopidogrel as the ADP-receptor blocker of choice
because of the drugs improved profile for side
effects and adverse events.7
Despite its efficacy, clopidogrel has a delayed 2627 Received 600-mg placebo 2620 Received 600-mg clopidogrel
capsules immediately after capsules immediately after
onset of action, even when given with a loading procedure procedure
dose; it also does not provide complete ADP-recep-
tor inhibition and has substantial variability among
patients.8 Even in the contemporary era, the vex-
2620 Received 600-mg clopidogrel 2607 Received 600-mg placebo
ing problem of acute stent thrombosis has not capsules immediately after infusion capsules immediately after infusion
been eliminated.9,10 Moreover, many physicians
refrain from administering clopidogrel before ob-
taining angiographic definition of the coronary
anatomy, since this irreversible platelet inhibitor 48 hr after randomization 48 hr after randomization
2654 Included in modified 2641 Included in modified
has been associated with an increased risk of intention-to-treat analysis intention-to-treat analysis
perioperative bleeding if coronary-artery bypass 2662 Included in safety analysis 2650 Included in safety analysis
2691 Included in intention-to- 2664 Included in intention-to-
grafting (CABG) is required rather than PCI. In treat analysis treat analysis
addition, more potent oral ADP-receptor blockers
have been tested and found to reduce ischemic
outcomes even further but also increase the rate
of bleeding.11-15 Therefore, an even more potent
intravenous agent with fast onset and fast offset Follow-up analysis
of action might provide a desirable combination Primary and secondary end points at 30 days
Death at 6 mo and 1 yr
of protection from ischemia without an excessive
risk of bleeding.
Cangrelor (the Medicines Company) is an ade- Figure 1. Enrollment and Outcomes in the Modified Intention-to-Treat
Population.AUTHOR: Bhatt RETAKE: 1st
nosine triphosphate analogue that reversibly binds 2nd
All patientsFIGURE:
who underwent randomization, received at least one dose of a
to and inhibits the P2Y12 ADP receptor. It has a 1 of 2 3rd
study drug, and underwent the index percutaneous coronary Revised intervention
half-life of 3 to 6 minutes and, when given as a ARTIST: MRL
(PCI) were included in the modified intention-to-treat population. All effi-
SIZE
bolus plus infusion, quickly and consistently in- cacy analyses TYPE:
of the primary and secondary end points were performed in
Line Combo 4-C H/T
hibits platelets to a high degree, with normaliza- this population. The safety population included all patients who received
AUTHOR, PLEASE NOTE: 4 col
tion of platelet function within 60 minutes after at least one dose of a study drug. Intention-to-treat analyses
22p3 were also re-
Figure has been redrawn and type has been reset.
ported. STEMI denotes ST-segment elevation myocardial infarction.
discontinuation. In the Cangrelor versus Standard Please check carefully.
Therapy to Achieve Optimal Management of JOB: 36124 ISSUE: 12-10-09
Platelet Inhibition (CHAMPION) PLATFORM trial,
which we report here, we examined the efficacy with the use of 600 mg of clopidogrel given at the
of cangrelor versus placebo administered to pa- start of the PCI procedure, are also reported in
tients during PCI, with patients in the placebo this issue of the Journal.
group subsequently receiving a loading dose of
600 mg of clopidogrel at the end of the revascu- Me thods
larization procedure and patients in the cangrelor
group receiving 600 mg of clopidogrel at the end Patients
of the infusion. The results of the CHAMPION A total of 5362 patients who provided consent
PCI trial,16 which compared the use of cangrelor were enrolled at 218 sites in 18 countries from

n engl j med 361;24 nejm.org december 10, 2009 2331

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 2332
Table 1. Baseline Characteristics of the Patients, According to Study Population.*

Characteristic Modified Intention-to-Treat Population Intention-to-Treat Population Safety Population

Cangrelor (N=2656) Placebo (N=2645) Cangrelor (N=2693) Placebo (N=2669) Cangrelor (N=2662) Placebo (N=2650)
Median age (interquartile range) yr 63.0 (54.0 71.0) 63.0 (54.0 71.0) 63.0 (54.071.0) 63.0 (54.071.0) 63.0 (54.0 71.0) 63.0 (54.0 71.0)
Sex no. (%)
Male 1909 (71.9) 1863 (70.4) 1938 (72.0) 1877 (70.3) 1915 (71.9) 1866 (70.4)
Female 747 (28.1) 782 (29.6) 755 (28.0) 792 (29.7) 747 (28.1) 784 (29.6)
Race or ethnic group no. (%)
White 2015 (75.9) 2006 (75.8) 2039 (75.7) 2024 (75.8) 2017 (75.8) 2009 (75.8)
Asian 475 (17.9) 473 (17.9) 482 (17.9) 476 (17.8) 477 (17.9) 474 (17.9)
The

Black 75 (2.8) 72 (2.7) 80 (3.0) 73 (2.7) 76 (2.9) 73 (2.8)

Hispanic 74 (2.8) 84 (3.2) 75 (2.8) 85 (3.2) 75 (2.8) 84 (3.2)
Other 8 (0.3) 5 (0.2) 8 (0.3) 5 (0.2) 8 (0.3) 5 (0.2)
Missing data 9 (0.3) 5 (0.2) 9 (0.3) 6 (0.2) 9 (0.3) 5 (0.2)
Median weight (interquartile range) kg 80.0 (70.0 92.0) 80.0 (70.0 92.0) 80.0 (70.0 92.0) 80.0 (70.0 92.0) 80.0 (70.0 92.0) 80.0 (70.0 92.0)
Median height (interquartile range) cm 170.0 (163.0176.0) 170.0 (163.0176.0) 170.0 (163.0176.0) 170.0 (163.0176.0) 170.0 (163.0176.0) 170.0 (163.0176.0)
Stable angina no. (%) 139 (5.2) 140 (5.3) 145 (5.4) 142 (5.3) 138 (5.2) 141 (5.3)
Unstable angina no. (%) 939 (35.4) 909 (34.4) 949 (35.2) 918 (34.4) 940 (35.3) 911 (34.4)
Myocardial infarction without ST-segment 1578 (59.4) 1596 (60.3) 1599 (59.4) 1609 (60.3) 1584 (59.5) 1598 (60.3)
elevation no. (%)
n e w e ng l a n d j o u r na l
of

Medical history no./total no. (%)

Diabetes mellitus 812/2655 (30.6) 862/2642 (32.6) 828/2692 (30.8) 868/2666 (32.6) 815/2661 (30.6) 862/2647 (32.6)
Current smoker 842/2639 (31.9) 799/2628 (30.4) 850/2675 (31.8) 806/2651 (30.4) 845/2645 (31.9) 799/2633 (30.3)

n engl j med 361;24 nejm.org december 10, 2009

Hypertension 1972/2647 (74.5) 1962/2633 (74.5) 1994/2684 (74.3) 1979/2656 (74.5) 1974/2653 (74.4) 1966/2638 (74.5)
m e dic i n e

Hyperlipidemia 1324/2472 (53.6) 1332/2472 (53.9) 1342/2508 (53.5) 1347/2494 (54.0) 1325/2477 (53.5) 1335/2477 (53.9)
Stroke or transient ischemic attack 159/2644 (6.0) 158/2639 (6.0) 162/2681 (6.0) 160/2662 (6.0) 160/2650 (6.0) 158/2644 (6.0)
Family history of coronary artery disease 902/2489 (36.2) 890/2479 (35.9) 918/2525 (36.4) 901/2502 (36.0) 907/2495 (36.4) 891/2484 (35.9)
Myocardial infarction 640/2642 (24.2) 679/2636 (25.8) 645/2678 (24.1) 683/2659 (25.7) 641/2648 (24.2) 680/2641 (25.7)
PTCA or PCI 374/2645 (14.1) 409/2637 (15.5) 381/2682 (14.2) 411/2659 (15.5) 377/2651 (14.2) 409/2642 (15.5)
CABG 199/2655 (7.5) 221/2644 (8.4) 203/2692 (7.5) 223/2667 (8.4) 200/2661 (7.5) 221/2649 (8.3)
Congestive heart failure 206/2644 (7.8) 191/2641 (7.2) 210/2681 (7.8) 192/2664 (7.2) 208/2650 (7.8) 191/2646 (7.2)
Peripheral artery disease 122/2604 (4.7) 142/2598 (5.5) 126/2641 (4.8) 143/2619 (5.5) 124/2610 (4.8) 142/2603 (5.5)

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 Periprocedural medications no./total no.
(%)
Bivalirudin 559/2656 (21.0) 555/2644 (21.0) 565/2692 (21.0) 561/2666 (21.0) 561/2662 (21.1) 556/2649 (21.0)
Unfractionated heparin 1699/2656 (64.0) 1695/2644 (64.1) 1714/2692 (63.7) 1709/2666 (64.1) 1701/2662 (63.9) 1699/2649 (64.1)
Low-molecular-weight heparin 481/2654 (18.1) 497/2645 (18.8) 487/2690 (18.1) 501/2667 (18.8) 484/2660 (18.2) 497/2650 (18.8)
Glycoprotein IIb/IIIa 241/2653 (9.1) 244/2642 (9.2) 245/2689 (9.1) 247/2664 (9.3) 242/2659 (9.1) 244/2647 (9.2)
No. of target vessels no./total no. (%)
1 2218/2654 (83.6) 2201/2643 (83.3) 2231/2667 (83.7) 2211/2653 (83.3) 2217/2653 (83.6) 2202/2644 (83.3)
2 414/2654 (15.6) 412/2643 (15.6) 414/2667 (15.5) 412/2653 (15.5) 414/2653 (15.6) 412/2644 (15.6)
3 19/2654 (0.7) 29/2643 (1.1) 19/2667 (0.7) 29/2653 (1.1) 19/2653 (0.7) 29/2644 (1.1)
Missing data 3/2654 (0.1) 1/2643 (<0.1) 3/2667 (0.1) 1/2653 (<0.1) 3/2653 (0.1) 1/2644 (<0.1)
Type of stent no./total no. (%)
Drug-eluting 1033/2654 (38.9) 1021/2643 (38.6) 1037/2667 (38.9) 1023/2653 (38.6) 1032/2653 (38.9) 1022/2644 (38.7)
Nondrug-eluting 1509/2654 (56.9) 1510/2643 (57.1) 1514/2667 (56.8) 1515/2653 (57.1) 1509/2653 (56.9) 1510/2644 (57.1)
No stent or other 112/2654 (4.2) 112/2643 (4.2) 116/2667 (4.3) 115/2667 (4.3) 112/2653 (4.2) 111/2644 (4.2)
Angiographic complication (site reported)
no. (%)
Threatened abrupt closure 10 (0.4) 9 (0.3) 10 (0.4) 9 (0.3) 10 (0.4) 9 (0.3)
Unsuccessful procedure 81 (3.1) 95 (3.6) 84 (3.1) 97 (3.7) 81 (3.1) 95 (3.6)
Abrupt vessel closure 13 (0.5) 16 (0.6) 13 (0.5) 16 (0.6) 13 (0.5) 16 (0.6)
New thrombus or suspected thrombus 14 (0.5) 15 (0.6) 14 (0.5) 15 (0.6) 14 (0.5) 15 (0.6)

n engl j med 361;24 nejm.org december 10, 2009

Acute stent thrombosis 1 (<0.1) 5 (0.2) 1 (<0.1) 5 (0.2) 1 (<0.1) 5 (0.2)
Need for urgent CABG 5 (0.2) 3 (0.1) 5 (0.2) 4 (0.2) 5 (0.2) 3 (0.1)
Intravenous study drug administered 2656 (100.0) 2645 (100.0) 2663 (98.9) 2649 (99.3) 2662 (100.0) 2650 (100.0)
no. (%)
Intr avenous Platelet Block ade with Cangrelor during PCI

Bolus administered no. (%) 2656 (100.0) 2645 (100.0) 2663 (98.9) 2649 (99.3) 2662 (100.0) 2650 (100.0)
Infusion administered no. (%) 2654 (99.9) 2645 (100.0) 2659 (98.7) 2649 (99.3) 2658 (99.8) 2650 (100.0)
Median duration of infusion (interquartile 2.1 (2.02.3) 2.1 (2.02.3) 2.1 (2.02.3) 2.1 (2.02.3) 2.1 (2.02.3) 2.1 (2.02.3)
range) hr
Oral study drug administered no. (%) 2629 (99.0) 2625 (99.2) 2630 (97.7) 2626 (98.4) 2629 (98.8) 2627 (99.1)

* Percentages may not total 100 because of rounding. CABG denotes coronary-artery bypass grafting, PCI percutaneous coronary intervention, and PTCA percutaneous transluminal coronary
angioplasty.
Race or ethnic group was self-reported.
Data on unsuccessful procedures were available for 2653 patients in the placebo group in the intention-to-treat population, for 2654 patients in the cangrelor group in the modified inten-

Downloaded from www.nejm.org on December 16, 2009 . Copyright 2009 Massachusetts Medical Society. All rights reserved.
tion-to-treat population, and for 2653 patients in the cangrelor group in the safety population.

2333
 The n e w e ng l a n d j o u r na l
October 2006 through May 2009. Patients under-
went randomization according to a double-blind,
placebo-controlled, double-dummy design to re-
ceive either cangrelor (in a bolus of 30 g per
kilogram of body weight and an infusion of 4 g
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 can-
grelor group received 600 mg of clopidogrel after
the end of the cangrelor infusion, and those in
the placebo group received 600 mg of clopidogrel
at the end of the procedure (Fig. 1).
Inclusion criteria for the trial were an age of
at least 18 years, diagnostic coronary angiogra-
phy revealing at least one atherosclerotic lesion
amenable to PCI with or without stent implanta-
tion, and evidence of either myocardial infarction
without ST-segment elevation or unstable angina.
Patients with stable angina were initially eligible
at the beginning of the trial before a protocol
amendment. The diagnosis of nonST-segment
elevation myocardial infarction required a level
of troponin I or troponin T that was higher than
the upper limit of the normal range within 24
hours before randomization (or if troponin re-
sults were unavailable at that time, a level of
creatine kinasemyocardial band [CK-MB] isoen-
zyme that was higher than the upper limit of the
normal range). The diagnosis of unstable angina
required ischemic chest discomfort occurring at
rest and lasting for at least 10 minutes within 24
hours before randomization and dynamic electro-
cardiographic changes; an age of 65 years or older
or the presence of diabetes mellitus (or both) was
also required. All patients provided written in-
formed consent.
Exclusion criteria included the use of any
thienopyridine in the previous 7 days, a planned
staged PCI procedure in which the second stage
would occur within 30 days after the first proce-
dure, discharge planned within 12 hours after
PCI, the occurrence of myocardial infarction with
ST-segment elevation within 48 hours before ran-
domization, known or suspected pregnancy, lac-
tation, increased bleeding risk (the occurrence of
ischemic stroke within the previous year or any
previous hemorrhagic stroke), intracranial tumor,
cerebral arteriovenous malformation, intracranial
aneurysm, trauma or major surgery (including
CABG) within the previous month, current war-
farin use, active bleeding, a known international
2334 n engl j med 361;24 nejm.org december 10, 2009
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of m e dic i n e
normalized ratio of more than 1.5, a past or pres-
ent bleeding disorder, a platelet count of less
than 100,000 per cubic millimeter, severe hyper-
tension (systolic blood pressure, >180 mm Hg; or
diastolic blood pressure, >110 mm Hg), or the
use of fibrinolytic therapy or a glycoprotein IIb/
IIIa inhibitor in the 12 hours preceding random-
ization.
Primary and Secondary End Points
The primary efficacy end point was a composite of
death, myocardial infarction, or ischemia-driven
revascularization 48 hours after PCI. The prima-
ry analysis was performed on a modified inten-
tion-to-treat population. Confirmatory analyses
were performed on an intention-to-treat popula-
tion. Secondary end points included the individ-
ual rates of death, myocardial infarction, new
Q-wave myocardial infarction, ischemia-driven
revascularization, abrupt vessel closure, or stroke
at 48 hours. Rates of death at 30 days and 1 year
were also recorded. The clinical events commit-
tee adjudicated the rates of myocardial infarction,
Q-wave myocardial infarction, ischemia-driven
revascularization, stent thromboses, and stroke
(ischemic or hemorrhagic). The definition of stent
thrombosis was similar to the Academic Re-
search Consortiums definition of definite stent
thrombosis.
After review of the prespecified analyses, we
examined two exploratory end points that were
less reliant on the measurement of periprocedural
biomarkers. The exploratory end points, which
were composed of prespecified and adjudicated
end points, were a composite of death, Q-wave
myocardial infarction, or ischemia-driven revas-
cularization and a composite of death, Q-wave
myocardial infarction, or stent thrombosis. We
compared the rates of bleeding and adverse events
at 48 hours and examined several bleeding end
points. None of these events were prespecified as
a primary bleeding end point, since we wanted
to discern a bleeding effect if present and pro-
vide full disclosure of such bleeding. The defini-
tions of all these end points were consistent with
those used in the CHAMPION PCI trial.16
The statistical group at the Duke Clinical
Research Institute (DCRI) received regular trans-
fers of data from the sponsor. The DCRI was re-
sponsible for coordinating activities and analyses
for the independent data and safety monitoring
committee and an interim analysis review com-
 Intr avenous Platelet Block ade with Cangrelor during PCI

Table 2. Major End Points at 48 Hours, According to Study Population.*

Odds Ratio
Population and End Point Cangrelor Placebo (95% CI) P Value
no. (%)
Modified intention-to-treat population
No. of patients evaluated 2654 2641
Adjudicated end points
Death, myocardial infarction, or ischemia-driven revascularization 185 (7.0) 210 (8.0) 0.87 (0.711.07) 0.17
(primary end point)
Myocardial infarction 177 (6.7) 191 (7.2) 0.92 (0.741.13) 0.42
Ischemia-driven revascularization 19 (0.7) 24 (0.9) 0.79 (0.431.44) 0.44
Death from any cause 6 (0.2) 18 (0.7) 0.33 (0.130.83) 0.02
Stroke 7 (0.3) 5 (0.2) 1.39 (0.444.40) 0.57
Stent thrombosis 5 (0.2) 16 (0.6) 0.31 (0.110.85) 0.02
Q-wave myocardial infarction 4 (0.2) 8 (0.3) 0.50 (0.151.65) 0.25
Exploratory end points
Death, Q-wave myocardial infarction, or ischemia-driven revascular- 23 (0.9) 41 (1.6) 0.55 (0.330.93) 0.02
ization
Death, Q-wave myocardial infarction, or stent thrombosis 13 (0.5) 34 (1.3) 0.38 (0.200.72) 0.003
Intention-to-treat population
No. of patients evaluated 2691 2664
Adjudicated end points
Death, myocardial infarction, or ischemia-driven revascularization 187 (6.9) 213 (8.0) 0.86 (0.701.05) 0.15
Myocardial infarction 177 (6.6) 192 (7.2) 0.91 (0.731.12) 0.36
Ischemia-driven revascularization 19 (0.7) 26 (1.0) 0.72 (0.401.31) 0.28
Death from any cause 8 (0.3) 19 (0.7) 0.42 (0.180.95) 0.04
Stroke 7 (0.3) 6 (0.2) 1.16 (0.393.44) 0.80
Stent thrombosis 5 (0.2) 16 (0.6) 0.31 (0.110.84) 0.02
Q-wave myocardial infarction 4 (0.1) 9 (0.3) 0.44 (0.141.43) 0.17
Exploratory end points
Death, Q-wave myocardial infarction, or ischemia-driven revascular- 25 (0.9) 44 (1.7) 0.56 (0.340.92) 0.02
ization
Death, Q-wave myocardial infarction, or stent thrombosis 15 (0.6) 36 (1.4) 0.41 (0.220.75) 0.004
Safety population
No. of patients evaluated 2660 2646
Adjudicated end points
Death, myocardial infarction, or ischemia-driven revascularization 185 (7.0) 212 (8.0) 0.86 (0.701.05) 0.14
Myocardial infarction 176 (6.6) 193 (7.3) 0.90 (0.731.11) 0.33
Ischemia-driven revascularization 19 (0.7) 25 (0.9) 0.75 (0.411.37) 0.36
Death from any cause 7 (0.3) 18 (0.7) 0.39 (0.160.92) 0.03
Stroke 7 (0.3) 5 (0.2) 1.39 (0.444.40) 0.57
Stent thrombosis 5 (0.2) 16 (0.6) 0.31 (0.110.85) 0.02
Q-wave myocardial infarction 4 (0.2) 9 (0.3) 0.44 (0.141.44) 0.17
Exploratory end points
Death, Q-wave myocardial infarction, or ischemia-driven revascular- 24 (0.9) 42 (1.6) 0.56 (0.340.94) 0.03
ization
Death, Q-wave myocardial infarction, or stent thrombosis 14 (0.5) 35 (1.3) 0.40 (0.210.74) 0.003

* Data were missing for two patients in the cangrelor group and three in the placebo group in the modified intention-to-treat population, for
two patients in the cangrelor group and five in the placebo group in the intention-to-treat population, and for two patients in the cangrelor
group and four in the placebo group in the safety population.

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 The n e w e ng l a n d j o u r na l
mittee. At the conclusion of the trial, the full data-
base was transferred to the DCRI for the primary
and secondary analyses. These analyses were per-
formed independently but in collaboration with
the sponsor. One of the trials principal academic
investigators prepared the first draft of the manu-
script, which was then reviewed and edited by
the executive committee and selected members
of the steering committee and site investigators.
The sponsor had the right to review but not ap-
prove the final manuscript. The trials principal
investigators accept full responsibility for the ac-
curacy and completeness of the reported analyses
and interpretations of the data.
Statistical Analysis
All efficacy analyses were performed in the mod-
ified intention-to-treat population, which consist-
ed of all patients who underwent randomization,
received at least one dose of a study drug, and
underwent the index PCI. All safety-related anal-
yses were performed on the safety population,
which included all patients who received at least
one dose of a study drug. Patients in the safety
analyses were assigned to a study group on the
basis of the treatment they actually received, not
as randomized. Intention-to-treat analyses are also
presented for full disclosure of results. The be-
tween-group comparison of the primary end point
was performed by calculating an odds ratio with
accompanying 95% confidence intervals with the
use of logistic regression. Logistic regression was
also used to analyze the majority of the remain-
ing secondary end points. All reported P values
are two-sided, with a P value of less than 0.05
considered to indicate statistical significance.
The trial had a power of 85% to detect a 25%
relative reduction in the primary end point, on the
assumption that the event would occur in 7.7%
of patients in the placebo group, with a projected
sample size of 6400 patients. While the trial was
under way and the results were still blinded, an
adaptive design was prospectively implemented.17
This design allowed for early termination for ei-
ther lack of efficacy or superiority of the primary
end point, for a sample-size increase in the entire
trial population, or for a sample-size increase in
specified subgroups.17 After a second interim
analysis, trial enrollment was terminated because
the review committee decided that the trial was
unlikely to show the superiority of cangrelor.
2336 n engl j med 361;24 nejm.org december 10, 2009
Downloaded from www.nejm.org on December 16, 2009 . Copyright 2009 Massachusetts Medical Society. All rights reserved.
of m e dic i n e
Figure 2 (facing page). KaplanMeier Curves for the
Rate of the Primary End Point, Stent Thrombosis,
and Death.
Panel A shows the rate of the primary efficacy end
point a composite of death, myocardial infarction,
or ischemia-driven revascularization at 48 hours after
percutaneous coronary intervention (PCI) in the
cangrelor group and the placebo group. Panel B shows
the rate of stent thrombosis at 48 hours (at left) and
at 35 days (at right) after PCI. Panel C shows the rate
of death at 48 hours (left) and 35 days (right). In Pan-
els B and C, which both show landmark analyses of
the KaplanMeier curves, the value at day 2 has been
reset to zero in the right-hand panels. In all three pan-
els, data are shown for the end points at 305 days,
as specified in the protocol.
R e sult s
Patients
A total of 5362 patients were included in the in-
tention-to-treat population; 61 of these patients
did not receive a study drug or undergo PCI,
which left 5301 patients in the primary modified
intention-to-treat population (Fig. 1 in the Sup-
plementary Appendix, available with the full text
of this article at NEJM.org). Baseline characteris-
tics were well matched in the two study groups
(Table 1). The majority of patients (59.8%) had
received the diagnosis of myocardial infarction
without ST-segment elevation. During PCI, unfrac-
tionated heparin was the most frequently used
antithrombin agent (in 63.9% of patients), and
glycoprotein IIb/IIIa inhibitors were used spar-
ingly (in 9.2% of patients). Drug-eluting stents
were used less often than bare-metal stents (in
38.7% of patients vs. 56.9% of patients). The time
from hospital admission to PCI was short (me-
dian, 7.9 hours; interquartile range, 3.3 to 24.1).
Primary End Point
The primary end point occurred in 185 of 2654
patients receiving cangrelor (7.0%) and in 210 of
2641 patients receiving placebo (8.0%) (odds ra-
tio in the cangrelor group, 0.87; 95% confidence
interval [CI], 0.71 to 1.07; P=0.17) (Table 2 and
Fig. 2A). (Data were missing for two patients in the
cangrelor group and four in the placebo group.)
There was no significant between-group differ-
ence in the overall rate of myocardial infarction,
Q-wave myocardial infarction, or ischemia-driven
revascularization.
 Intr avenous Platelet Block ade with Cangrelor during PCI

A Primary End Point 9.6%

10
Placebo
9
8 8.9%
Cangrelor
7

Event Rate (%)

6
5
4
3
2
1 P=0.25
0
01 5 10 15 20 25 30 35
Days
No. at Risk
Cangrelor 2656 2459 2446 2439 2435 2434 2399 545
Placebo 2645 2422 2404 2396 2393 2388 2365 539

B Stent Thrombosis
0.7 0.7
0.61%
0.6 Placebo 0.6

0.5 0.5 0.46%

Placebo
Event Rate (%)

0.4 0.4 0.38%

0.3 0.3 Cangrelor

0.2 0.19% 0.2

Cangrelor
0.1 0.1
P=0.02 P=0.65
0.0 0.0
0 12 24 36 48 2 5 10 15 20 25 30 35
Hours Days
No. at Risk
Cangrelor 2656 2648 2646 2645 2644 2644 2634 2624 2619 2617 2616 2582 569
Placebo 2645 2624 2618 2617 2614 2614 2603 2589 2581 2579 2577 2551 559

C Death
1.2 1.2
1.10%
1.0 P=0.02 1.0 P=0.97

1.10%
Event Rate (%)

0.8 0.8 Placebo

0.68%
0.6 0.6 Cangrelor
Placebo
0.4 0.4
0.23%
0.2 Cangrelor 0.2

0.0 0.0
0 12 24 36 48 2 5 10 15 20 25 30 35
Hours Days
No. at Risk
Cangrelor 2656 2652 2651 2649 2648 2648 2642 2634 2629 2627 2626 2614 1685
Placebo 2645 2635 2629 2627 2623 2623 2617 2604 2599 2596 2595 2586 1667

AUTHOR: Bhatt RETAKE: 1st

2nd
FIGURE: 2 of 2 3rd
Revised
ARTIST: MRL
SIZE
6 col 2337
nTYPE:
engl j med
Line 361;24 nejm.org
Combo 4-C december
H/T 10, 2009
33p9
AUTHOR, PLEASE NOTE:
Figure has been
Downloaded from www.nejm.org on December redrawn
16, 2009 and type hasbeen
. Copyright 2009reset.
Massachusetts Medical Society. All rights reserved.
Please check carefully.

JOB: 36124 ISSUE: 12-10-09

 The n e w e ng l a n d j o u r na l
The rate of stent thrombosis at 48 hours was
significantly lower in the cangrelor group (0.2%)
than in the placebo group (0.6%) (5 vs. 16 pa-
tients) (odds ratio, 0.31; 95% CI, 0.11 to 0.85;
P=0.02), and the difference was still significant
at 30 days (Fig. 2B, and Table 1 in the Supplemen-
tary Appendix). The rate of death at 48 hours was
significantly lower in the cangrelor group (0.2%)
than in the placebo group (0.7%) (6 vs. 18 patients)
(odds ratio, 0.33; 95% CI, 0.13 to 0.83; P=0.02),
though at 30 days, this difference was no longer
significant (Fig. 2C, and Table 1 in the Supplemen-
tary Appendix).
Somewhat counterintuitively, in the subgroup
of 1659 patients who did not have an elevation
in the troponin level at baseline, the primary end
point was reduced in the cangrelor group (4.6%),
as compared with the placebo group (7.2%)
(odds ratio, 0.62; 95% CI, 0.41 to 0.95; P=0.03).
Therefore, exploratory analyses were performed
in the overall study population to evaluate the fol-
lowing two composite clinical end points: death,
Q-wave myocardial infarction, or stent thrombo-
sis; and death, Q-wave myocardial infarction, or
ischemia-driven revascularization. These end
points were significantly reduced in the cangre-
lor group (Table 2).
Bleeding
According to the criteria for major or minor
bleeding in the Thrombolysis in Myocardial In-
farction (TIMI) study or of severe or moderate
bleeding in the Global Utilization of Streptokinase
and Tissue Plasminogen Activator for Occluded
Coronary Arteries (GUSTO) study, the rates of
bleeding did not differ significantly between the
two groups. However, according to criteria for
major and minor bleeding of the Acute Catheter-
ization and Urgent Intervention Triage Strategy
(ACUITY) trial and the criteria for mild bleeding
in the GUSTO trial, the rates of bleeding were sig-
nificantly higher in the cangrelor group (Table 3).
The difference in major bleeding according to the
ACUITY criteria was due to an excess of groin he-
matomas but not in more serious forms of bleed-
ing in the cangrelor group. The rates of red-cell
transfusion were not significantly different (0.9%
in the cangrelor group vs. 0.6% in the placebo
group, P=0.12). Notably, among patients who were
at increased risk for bleeding, such as the elderly
and those who had a history of stroke or transient
ischemic attack, the rate of transfusion was not
2338 n engl j med 361;24 nejm.org december 10, 2009
Downloaded from www.nejm.org on December 16, 2009 . Copyright 2009 Massachusetts Medical Society. All rights reserved.
of m e dic i n e
significantly higher in the cangrelor group than
in the placebo group (Fig. 2 in the Supplementary
Appendix). There was no significant difference in
the rate of arrhythmia in the cangrelor group, as
compared with the placebo group (2.3% vs. 2.4%,
P=0.77). There was a higher incidence of dyspnea
in the cangrelor group (1.4%) than in the placebo
group (0.5%), with 37 patients and 14 patients, re-
spectively (P=0.002) (for details on adverse events,
see Table 2 in the Supplementary Appendix).
Discussion
Cangrelor was not superior to placebo in reduc-
ing the composite of death, myocardial infarc-
tion, or ischemia-driven revascularization at 48
hours after PCI, the primary end point of this
study. However, important prespecified second-
ary end points, which are considered exploratory,
including rates of stent thrombosis and death from
any cause, were significantly reduced in the can-
grelor group at 48 hours. Given the mechanism
of action of cangrelor, these reductions in impor-
tant clinical outcomes are plausible.
In light of a recent trial of another reversible
ADP-receptor antagonist (the oral agent ticagrelor),
the potential mechanistic benefits of cangrelor
seem even more likely to affect important ische
mic outcomes.14 The Study of Platelet Inhibition
and Patient Outcomes (PLATO) (ClinicalTrials.gov
number, NCT00391872) showed a significant
reduction in mortality among patients receiving
ticagrelor, as compared with those receiving clopi-
dogrel, with 6 to 12 months of therapy.14 Al-
though a periprocedural infusion of cangrelor
would not be expected to have as profound a re-
duction in mortality against an active control
(600 mg of clopidogrel, as was administered in
the CHAMPION PCI trial), it is conceivable that
such benefits might be apparent as compared with
administering placebo, as was done in our study.
Our study raises questions about the appro-
priate definition for and prognostic use of peripro-
cedural myocardial infarction in patients enter-
ing a study with raised biomarkers at baseline.
In such patients short times from admission to
PCI prevent a clear delineation between myocar-
dial infarction that occurred before randomiza-
tion and myocardial infarction that occurred after
randomization. In addition, although the inclu-
sion of periprocedural myocardial infarction as
an end point is useful to increase the number of
 Intr avenous Platelet Block ade with Cangrelor during PCI

Table 3. Bleeding Events at 48 Hours (Safety Population).

Cangrelor Placebo Odds Ratio

Event (N=2662) (N=2650) (95% CI) P Value
no. (%)
Access-site bleeding requiring radiologic 8 (0.3) 10 (0.4) 0.80 (0.312.02) 0.63
or surgical intervention
Hematoma at puncture site
5 cm 115 (4.3) 71 (2.7) 1.64 (1.212.22) 0.001
<5 cm 150 (5.6) 119 (4.5) 1.27 (0.991.63) 0.06
Intracranial hemorrhage 2 (0.1) 1 (<0.1) 1.99 (0.1821.98) 0.57
Intraocular hemorrhage 0 0
Bleeding requiring surgery 1 (<0.1) 1 (<0.1) 1.00 (0.0615.92) 1.00
Retroperitoneal hemorrhage 2 (0.1) 1 (<0.1) 1.99 (0.1821.98) 0.57
Ecchymosis 95 (3.6) 57 (2.2) 1.68 (1.212.35) 0.002
Epistaxis 6 (0.2) 12 (0.5) 0.50 (0.191.33) 0.16
Oozing at puncture site 125 (4.7) 91 (3.4) 1.39 (1.051.83) 0.02
Thrombocytopenia 2 (0.1) 3 (0.1) 0.66 (0.113.97) 0.65
Hemodynamic compromise 7 (0.3) 5 (0.2) 1.40 (0.444.40) 0.57
Transfusion
Any blood 26 (1.0) 16 (0.6) 1.62 (0.873.03) 0.13
Platelet 4 (0.2) 2 (0.1) 1.99 (0.3710.89) 0.43
Red-cell 25 (0.9) 15 (0.6) 1.67 (0.883.17) 0.12
Drop in hemoglobin or hematocrit* 33 (1.2) 35 (1.3) 0.94 (0.581.51) 0.79
Category of bleeding
ACUITY criteria
Minor bleeding 320 (12.0) 246 (9.3) 1.34 (1.121.59) 0.001
Major bleeding 147 (5.5) 93 (3.5) 1.61 (1.232.10) <0.001
GUSTO criteria
Mild bleeding 427 (16.0) 310 (11.7) 1.44 (1.231.69) <0.001
Moderate bleeding 20 (0.8) 13 (0.5) 1.54 (0.763.09) 0.23
Severe or life-threatening bleeding 9 (0.3) 6 (0.2) 1.50 (0.534.21) 0.45
TIMI criteria
Minor bleeding 22 (0.8) 16 (0.6) 1.37 (0.722.62) 0.34
Major bleeding 4 (0.2) 9 (0.3) 0.44 (0.141.44) 0.17

* A drop in hemoglobin or hematocrit was defined as a decrease of at least 3 g per deciliter in hemoglobin or a 9% de-
crease in hematocrit after treatment, as compared with baseline, as reported by investigators.
The bleeding options under each criterion are not mutually exclusive. For example, a patient may have had both major
and minor bleeding on the basis of criteria from the Acute Catheterization and Urgent Intervention Triage Strategy
(ACUITY) trial if more than one bleeding episode occurred. Each patient was counted only once for each criterion level,
regardless of the number of bleeding events that were identified under each criterion. Listed bleeding events include
bleeding associated with coronary-artery bypass grafting. GUSTO denotes Global Utilization of Streptokinase and
Tissue Plasminogen Activator for Occluded Coronary Arteries, and TIMI Thrombolysis in Myocardial Infarction.

events in clinical trials, its clinical relevance con- trial) except in the subgroup of patients with a
tinues to be widely debated.18-21 Our results do negative troponin test at baseline but do show an
not show an effect of cangrelor on periproce- effect of cangrelor on more important outcomes
dural myocardial infarction (as defined in this (e.g., stent thrombosis and death). These find-

n engl j med 361;24 nejm.org december 10, 2009 2339

Downloaded from www.nejm.org on December 16, 2009 . Copyright 2009 Massachusetts Medical Society. All rights reserved.
 The n e w e ng l a n d j o u r na l of m e dic i n e

ings should lead to further research on the most
appropriate end points for clinical trials involv-
ing patients with acute coronary syndromes and
positive biomarkers at baseline who undergo PCI.
Taken together, the two CHAMPION trials
may provide insight into the optimal timing of
periprocedural antiplatelet blockade with clopid
ogrel. In the examination of secondary compos-
ite end points, there was a more robust effect in
the CHAMPION PLATFORM trial (600 mg of
clopidogrel at the end of the procedure) than in
the CHAMPION PCI trial (600 mg of clopidogrel
at the beginning of the procedure). Therefore, if
one contrasts the results of the two CHAMPION
trials, it appears that the 600 mg loading dose
of clopidogrel may provide incremental benefit
when given at the start of the procedure versus
only at the end, though this conclusion remains
speculative. However, even when clopidogrel is
given at the start of the procedure, the additional
antiplatelet blockade conferred by cangrelor may
provide clinical benefit, as suggested by the reduc-
tion in secondary end points in the CHAMPION
PCI trial and by the results of the platelet sub-
study in the two CHAMPION trials.16
Cangrelor did not cause more major or minor
bleeding on the basis of GUSTO and TIMI crite-
ria.22,23 However, it did cause more bleeding on
the basis of the more sensitive ACUITY criteria
for major bleeding and GUSTO criteria for mild
bleeding, as one might expect for a potent anti-
platelet agent, as compared with placebo.24 Re-
assuringly, there was no significant increase in
the rate of blood transfusion in the cangrelor
group, as compared with the placebo group, and
the excess in major bleeding on the basis of
ACUITY criteria was because of an increased num-
ber of groin hematomas in the cangrelor group.
The occurrence of transient dyspnea is intriguing,
given a similar observation in the PLATO trial.14
Perhaps this effect reflects the similar mecha-
nisms of action of cangrelor and ticagrelor, which
are both reversible platelet ADP-receptor antago-
nists that may act through other adenosine-depen-
dent pathways as well.
The early termination of this study does de-
crease its statistical power. The primary end
point of this trial was negative; therefore, any
additional end points, even prespecified ones,
should be interpreted with caution but may serve
to generate hypotheses for future investigations.
The definition of periprocedural myocardial in-
farction that was used in this trial may not have
been a good end point to detect an effect of can-
grelor for patients who had an elevated troponin
level at baseline and had rapid times to PCI.
In conclusion, although the use of cangrelor
in our study did not result in a significant reduc-
tion in the primary end point of death, myocar-
dial infarction, or ischemia-driven revasculariza-
tion in patients undergoing PCI, in exploratory
analyses the rates of important prespecified sec-
ondary end points of stent thrombosis and death
were reduced. Given the rapid effect on platelet
inhibition seen in the CHAMPION platelet sub-
study, the reductions in these secondary end points
are biologically plausible.
Supported by the Medicines Company.
Financial and other disclosures provided by the authors are
available with the full text of this article at NEJM.org.
We thank Penny Hodgson and Elizabeth Cook of the Duke
Clinical Research Institute for their editorial support; and Med-
icines Company employees Jayne Prats and Meredith Todd for
their assistance in constructing figures and appendices and Bo
Gao for his collaboration on statistical analyses.

Appendix
The affiliations of the authors are as follows: the VA (Veterans Affairs) Boston Healthcare System and Brigham and Womens Hospital
(D.L.B.) and Beth Israel Deaconess Medical Center (C.M.G.) all in Boston; Cleveland Clinic, Cleveland (A.M.L.); Columbia Univer-
sity Medical Center and the Cardiovascular Research Foundation, New York (G.W.S.); Interventional Cardiology and Cardiac Research,
Hudson Valley Heart Center, Poughkeepsie, NY (M.Z.J.); Duke Clinical Research Institute, Duke University Medical Center, Durham, NC
(S.M., K.W.M., R.A.H.); Institut de Cardiologie, PitiSalptrire Hospital, Paris (G.M.); Methodist DeBakey Heart Center, Methodist
Hospital, Houston (N.S.K.); Terrence Donnelly Heart Centre, Division of Cardiology, St. Michaels Hospital and the Canadian Heart
Research Centre, Toronto (S.G.G.); Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, New Zealand (H.D.W.);
Pennsylvania Hospital, University of Pennsylvania, Philadelphia (C.V.P.); Sarah Cannon Research Institute and Hospital Corporation of
America, Nashville (S.V.M.); Third Faculty of Medicine, Charles University, Prague, Czech Republic (P.W.); Flinders University/Flinders
Medical Centre, Adelaide, SA, Australia (D.P.C.); the Department of Interventional Cardiology, Instituto Cardiovascular de Buenos Aires,
Buenos Aires (F.C.); Clinic of Invasive Cardiology, St. Georges University Hospital, Plovdiv, Bulgaria (I.M.); Regional Hospital, esk
Budjovice, Czech Republic (F.T.); Arneja Heart Institute, Nagpur, Maharashtra, India (J.A.); and the Medicines Company, Parsippany,
NJ (S.S.).

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