Design and rationale for the Prevention of

Cardiovascular Events in Patients With Prior Heart

Attack Using Ticagrelor Compared to Placebo on a
Background of AspirinThrombolysis in Myocardial
Infarction 54 (PEGASUS-TIMI 54) trial
Marc P. Bonaca, MD, MPH,
a
Deepak L. Bhatt, MD, MPH,
a
Eugene Braunwald, MD,
a
Marc Cohen, MD,
b
Philippe Gabriel Steg, MD,
c
Robert F. Storey, MD,
d
Peter Held, MD, PhD,
e
Eva C. Jensen, MD, PhD,
e
and
Marc S. Sabatine, MD, MPH
a
Boston, MA; New York, NY; Paris, France; Sheffield, United Kingdom; and
Mlndal, Sweden
Background P2Y
12
receptor antagonist therapy is recommended in addition to ASA for up to 1 year after acute
coronary syndrome to reduce ischemic events. In contrast, the benefit of long-term dual antiplatelet therapy beyond 1 year
remains unclear. Ticagrelor is a potent, reversibly binding P2Y
12
receptor-antagonist that has been shown to be superior to
clopidogrel in patients with acute coronary syndromes for up to 1 year.
Study Design PEGASUS-TIMI 54 is a randomized, double-blind, placebo-controlled, multinational clinical trial
designed to evaluate the efficacy and safety of ticagrelor in addition to aspirin (75-150 mg) for the prevention of major adverse
cardiovascular events in patients with a history of myocardial infarction and risk factors. Patients with a history of spontaneous
myocardial infarction within 1 to 3 years are randomized in a 1:1:1 fashion to ticagrelor 90 mg twice daily, ticagrelor 60 mg
twice daily, or matching placebo, all with low dose ASA, until the end of the study. The primary endpoint is a composite of
cardiovascular death, myocardial infarction, or stroke. Recruitment began in October 2010 and completed in April 2013 with
a sample size of over 21,000 patients. The trial is planned to continue until the latest of either 1,360 adjudicated primary end
points are accrued or the last patient randomized has been followed for at least 12 months.
Conclusions PEGASUS-TIMI 54 is investigating whether the addition of intensive antiplatelet therapy with ticagrelor to
low-dose aspirin reduces major adverse cardiovascular events in high-risk patients with a history of myocardial infarction. (Am
Heart J 2014;167:437-444.e5.)
A key element in the pathobiology of acute coronary
events is the activated platelet.
1,2
Aspirin has been shown
to be effective at reducing the risk of ischemic events in
patients with prior myocardial infarction (MI).
3,4
The
addition of a P2Y
12
receptor antagonist to aspirin, so-
called dual antiplatelet therapy (DAPT), has been shown
to reduce further the risk of ischemic events in patients
presenting with an acute coronary syndrome (ACS).
5-7
The importance of more potent antiplatelet therapy in
this setting has been further illustrated as newer
generations of P2Y
12
receptor antagonists characterized
by greater potency and less variability have demonstrated
superior efficacy compared to clopidogrel.
8,9
The optimal duration of DAPT after MI, however, is not
known. Although landmark analyses demonstrate contin-
ued accrual of benefit beyond the immediate period
following the ACS,
9,10
the duration of the ACS trials were
only approximately 1 year.
5,8,9
A dedicated trial of long-
term P2Y
12
receptor blockade with clopidogrel on a
background of aspirin in a broad patient population with
atherosclerotic disease or risk factors did not show a
statistically significant benefit
11
although, in a post-hoc
From the
a
TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham
and Women's Hospital and Harvard Medical School, Boston, MA,
b
Cardiovascular
Division, Department of Medicine, Newark Beth Israel Medical Center, Mount Sinai School
of Medicine, New York, NY,
c
Universit Paris-Diderot, Sorbonne-Paris Cit, INSERM U-
698, Dpartement Hospitalo-Universitaire FIRE, Hpital Bichat, Paris, France,
d
Department
of Cardiovascular Science, University of Sheffield, Sheffield, United Kingdom, and
e
AstraZeneca, Mlndal, Sweden.
Clinical Trial Registration Information: URL: http://www.clinicaltrials.gov Registration
Number: NCT01225562.
Submitted August 23, 2013; accepted December 8, 2013.
Reprint requests: Marc P. Bonaca, MD, MPH, TIMI Study Group, Cardiovascular Division,
Brigham and Womens Hospital, 75 Francis Street, Boston, MA 02115.
E-mail: mbonaca@partners.org
0002-8703/$ - see front matter
2014, Mosby, Inc. All rights reserved.
http://dx.doi.org/10.1016/j.ahj.2013.12.020
analysis of patients with prior cardiovascular events, and
particularly prior MI, there was a significant reduction in
the incidence of ischemic complications.
12
Ticagrelor is a reversibly-binding, direct-acting, potent
P2Y
12
receptor antagonist that represents a distinct
chemical class from the thienopyridines.
13
Advantages
to this compound include that it is not a prodrug and
therefore does not require metabolic activation, a rapid
onset of antiplatelet effect (within 2 hours), low inter-
individual variability, and reversibility that results in a
faster offset of action when compared with thienopyr-
idines.
14-17
The PLATOtrial studied ticagrelor 90 mg twice
daily compared with clopidogrel 75 mg once daily in
addition to aspirin in patients presenting across the
spectrum of ACS.
9
The primary results of PLATO
demonstrated superiority of ticagrelor in reducing the
primary endpoint of vascular death, MI, or stroke (9.8% vs
11.7%, HR 0.84, 95% CI 0.77-0.92, P b .001) with an
acceptable risk benefit profile relative to clopidogrel
(PLATO major bleeding 11.6% vs. 11.2%, P = .43; TIMI
noncoronary artery bypass graft (CABG) major bleeding
2.8%vs. 2.2%, P = .03; intracranial bleeding (ICH) 0.3%vs.
0.2%, P = .06).
9
The reduction in ischemic events was
apparent within the first 30 days and persisted throughout
the duration of follow up.
9
An important finding with this
compound was a robust reduction in death from vascular
causes (HR 0.79, P = .001) and all cause mortality (HR
0.78, P b .001).
9
The PEGASUS-TIMI 54 trial is evaluating whether long-
term therapy with ticagrelor in addition to aspirin
reduces the risk of major adverse cardiovascular events
in stable patients with a history of MI in comparison with
placebo. In addition, PEGASUS-TIMI 54 is evaluating 2
intensities of antiplatelet therapy including the 90 mg
twice-daily dose of ticagrelor studied in PLATO as well as
a lower dose, 60 mg twice daily, to examine whether
slightly lower intensity in the chronic phase of long-term
therapy may optimize the balance of efficacy and
bleeding, as the risk of recurrent event diminishes over
time after an acute MI.
Study design and population
PEGASUS-TIMI 54 is a randomized, double-blind,
placebo-controlled multinational clinical trial designed
to evaluate the efficacy and safety of ticagrelor in addi-
tion to low dose aspirin for long-term treatment of
stable patients with a history of spontaneous MI. The
primary hypothesis is that the addition of ticagrelor to
standard therapy will reduce the incidence of major
adverse cardiovascular events during long-term follow-up
(Figure).
Study patients must have a history of a spontaneous MI
occurring 1 to 3 years prior to enrollment as well as at least
one additional high risk feature (see Table I). Of note, early
in the course of the study (within the first 6 months of
enrollment, b400 patients randomized), based on data
from other trials and registries (not involving ticagrelor)
that demonstrated an increased risk of intracranial
hemorrhage with more intensive antiplatelet therapy in
Figure
Trial Schema
Stable patients with history of MI 1-3 yrs prior
+ additional atherothrombosis risk factor* N ~ 21,000
Ticagrelor
90 mg bid
Placebo
RANDOMIZE
DOUBLE BLIND
Follow-up Visits
Q4 mos for 1
st
yr, then Q6 mos
Planned treatment with ASA 75 150 mg &
Standard background care
Primary Efficacy Endpoint: CV Death, MI, or Stroke
Primary Safety Endpoint: TIMI Major Bleeding
* Age >65 yrs, diabetes, 2
nd
prior MI, multivessel CAD,
or chronic non-end stage renal dysfunction
Min 12 months of Follow Up
Event-driven trial
Ticagrelor
60 mg bid
>_
Study Schema for PEGASUS-TIMI 54. CAD, Coronary artery disease; MI, myocardial infarction.
438 Bonaca et al
American Heart Journal
April 2014
patients with a history of ischemic stroke,
8,18-21
such
patients were also excluded from PEGASUS-TIMI 54.
However, it should be noted that within PLATO, there
was no evidence of heterogeneity of risk based on a history
of ischemic stroke.
9,22
Approximately 21,000 eligible patients were random-
ized in a 1:1:1 ratio to receive either ticagrelor 90 mg
twice daily, ticagrelor 60 mg twice daily, or placebo. The
first patient was randomized October 29, 2010. Random-
ization was performed using a central computerized
telephone or web based system. Treatment allocation
was double-blind. Randomized patients are to be
followed up for all clinical endpoints and serious adverse
events until the end of the study which will occur after
accrual of approximately 1,360 primary endpoint events
(cardiovascular death, MI, or stroke) confirmed by central
adjudication or a follow-up of at least 12 months for the
last patient randomized, whichever is later. The median
follow-up for randomized patients is anticipated to be
greater than 2 years.
The study is being performed in accordance with ethical
principles in a manner consistent with the Declaration of
Helsinki, ICH Good Clinical Practice guidelines, and
applicable regulatory requirements. The final study protocol
and informed consent has been reviewed and approved by
the corresponding health authorities and ethics boards/IRBs
for all participating study sites. Randomized patients gave
informed consent for participation in the trial.
Treatment protocol and
follow-up procedures
Treatment dose selection
Based on the results of the PLATO trial 90 mg twice
daily was a logical dose to be tested in PEGASUS-TIMI 54.
However, recognizing that in the chronic setting the
optimal intensity of platelet inhibition for long-term
therapy is unknown and might be less than what is
needed in the acute setting, a second dose arm using
ticagrelor 60 mg twice daily was added, which, based on
pharmacokinetic and pharmacodynamic modeling, is
expected to provide less platelet inhibition than 90 mg
twice daily, but greater mean platelet inhibition and less
variability than clopidogrel 75 mg daily. Because the
study population is stable, no loading dose is adminis-
tered. All patients take 2 tablets twice daily, one 90 mg or
matching placebo, and one 60 mg or matching placebo.
Only one of the 2 tablets taken at any occasion is active
ticagrelor, or neither if the patient is allocated to the
placebo group. During the study it is anticipated that
some patients will develop an indication for P2Y
12
Table I. Inclusion/Exclusion Criteria
Inclusion Exclusion
At least 50 years old Planned use of ADP receptor blockers, dipyridamole or cilostazol
Spontaneous MI 1-3 years prior Planned revascularization (coronary, peripheral, cerebrovascular)
plus at least one of the following risk factors Potent inducer/inhibitor/substrate of CYP3A use
Age of 65 Chronic anticoagulation
Diabetes mellitus on medication Known bleeding diathesis or coagulation disorder
A second prior MI
Multivessel CAD
(50% in 2+ coronary territories)
Chronic renal dysfunction
(non-end stage, est. creat. cl. b60 mL/min)
Taking ASA 75-150 mg daily
Increased risk of bleeding defined as:
Contraception in women of child-bearing potential
A history of intracranial bleed at any time,
Provides written informed consent
A central nervous system tumor or intracranial vascular
abnormality (eg, aneurysm, arteriovenous malformation) at any time,
Intracranial or spinal cord surgery within 5 years, or
A gastrointestinal (GI) bleed within the past 6 months, or major
surgery within 30 days
History of ischemic stroke
Patients considered to be at risk of bradycardic events (eg, known
sick sinus syndrome or second or third degree atrioventricular [AV] block)
unless already treated with a permanent pacemaker
Coronary-artery bypass grafting in the last 5 years
Known severe liver disease
Renal failure requiring dialysis
Pregnancy or lactation
Life-expectancy b1 year
Any condition judged by the investigator to make participation unsafe
for the patient
Concern for inability to comply with the protocol
Prior participation in a trial with ticagrelor (if treated with active ticagrelor)
Involvement in planning or conduct of the study
Participation in another clinical study with an investigational product
during the prior 30 days
Bonaca et al 439
American Heart Journal
Volume 167, Number 4
receptor blockade. A modified study treatment option is
provided to investigators for use in this situation that
assigns patients originally randomized to either ticagrelor
dose to a 180 mg loading dose followed by 90 mg twice
daily and assigns those originally randomized to placebo
to clopidogrel (see Supplement for details).
Concomitant therapies
All patients in PEGASUS-TIMI 54 are recommended to
be on standard secondary prevention therapy including
aspirin b 150 mg daily, consistent with recommendations
for secondary prevention and with approved dosing
labels for ticagrelor.
23-25
Additional anti-thrombotic ther-
apy is prohibited including other P2Y
12
receptor
antagonists, chronic anticoagulants at therapeutic doses,
and other platelet inhibitors. Additional details are
described in the online supplement Appendix A.
Recommendations for patients undergoing procedures
Patients undergoing elective major non-cardiovascular
procedures are advised to stop study treatment 5 days
prior to the procedure and resume when determined
appropriate by the treating physician. Management of
study treatment in the context of minor surgery or invasive
procedures is at the discretion of the treating physician.
Visit schedule and follow up
Randomized patients return for study visits at 4-month
intervals during the first year of follow up followed by 6-
month visits thereafter until the end of the trial. During
follow-up visits patients are assessed for adverse and
potential endpoint events, and blood and urine are
sampled for central laboratory testing. All patients are to
undergo an End of Treatment visit when permanently
stopping therapy and a follow-up contact approximately
2 weeks after their last dose of study drug. It is
recommended that all randomized patients attend the
final study visit in person regardless of whether or not
they are taking randomized study treatment. Vital status
assessment will be attempted in all patients at the end of
the trial.
Study end points
The primary end point of the trial is a composite of
cardiovascular death, MI, or stroke. Secondary endpoints
include cardiovascular death and all-cause mortality.
Other efficacy endpoints include: the composite of
cardiovascular death or coronary or cerebrovascular
arterial thrombosis hospitalization (defined as myocardial
infarction, stroke, or hospitalization for urgent coronary
revascularization, unstable angina, or transient ischemic
attack); the composite of coronary heart disease death,
MI, or stroke; coronary stent thrombosis; and quality of
life as measured using the Euro Quality of Life-5
Dimensions (EQ-5D) instrument. Definitions of efficacy
endpoints are detailed in online Appendix B.
The primary safety endpoint is bleeding as defined by
the TIMI, PLATO, GUSTO, and International Society of
Thrombosis and Hemostasis (ISTH) classification sys-
tems with specific focus on events qualifying as TIMI
major, TIMI major or minor, and PLATO major.
8,26-30
(online Appendix B) Safety will also be assessed through
standard ascertainment of site-reported adverse events
(AEs) as well as through central measurement of safety
laboratory measurements.
All efficacy and safety endpoints are site reported in an
electronic web based capture system with submission of
supporting source documentation where applicable. Ad-
judication for each event is performed according to defi-
nitions in the PEGASUS-TIMI 54 Clinical Endpoints
Committee Charter (online Appendix B) by an indepen-
dent, blinded, and trained Clinical Endpoints Committee
with board certification in either Cardiology or Neurol-
ogy depending on the event type.
Statistical considerations
The primary efficacy analysis of PEGASUS-TIMI 54 will
be based on the time from randomized treatment
assignment to the first occurrence of any element of the
primary composite endpoint including cardiovascular
death, MI, or stroke. Each treatment dose (ie, 90 mg twice
daily or 60 mg twice daily) will be tested independently
against placebo. To control the overall type I error at 5%,
alpha will be apportioned equally to each ticagrelor dose
versus placebo comparison.
Secondary endpoints (including time to cardiovascular
death and time to all-cause mortality respectively) will be
tested in a hierarchical manner for each dose if the primary
endpoint is confirmed for that dose. An exploratory
analysis of efficacy for both doses combined compared
with placebo will also be performed. All efficacy analyses
will be performed according to an intention-to-treatment
principle among all patients randomized irrespective of
protocol adherence or the duration of exposure to study
treatment. Safety evaluations will include all randomized
patients who receive at least one dose of study treatment
and for whom post-dose data are available.
Trial sample size determination was made with the
assumptions of a 3.5% per year event rate for the primary
endpoint in the placebo group based on prior studies in
similar populations and a target relative risk reduction for
the 90 mg dose of 20% and approximately 19% for the 60
mg dose compared with placebo.
11,12
The estimates for
the relative risk reductions were based on observations in
studies comparing DAPT to monotherapy in similar stable
populations.
12
The risk reduction of the lower dose of
ticagrelor was modeled using inhibition of platelet
aggregation data from the DISPERSE trial
14
and assuming
that the log hazard ratio for clinical outcomes is
440 Bonaca et al
American Heart Journal
April 2014
proportional to the ratio of mean inhibition of platelet
aggregation for the 60 mg dose relative to the 90 mg dose.
Based on these assumptions it was estimated that a total
of 1360 primary endpoint events would provide approx-
imately 90% power for the 90 mg dose and approximately
83% power for the 60 mg dose when compared with
placebo independently. Randomization of 21,000 pa-
tients over 2 to 3 years with slightly over 1 year of follow-
up from the last patient randomized is anticipated to
allow accrual of approximately 1360 adjudicated primary
endpoint events; however, follow-up will continue until
the target number of endpoints is achieved which is
anticipated to occur in the latter half of 2014. The
Executive Committee will monitor the blinded aggregate
event rate data as well as other trial metrics and may
modify the trial in order to preserve adequate power to
test the primary study hypothesis, or duration of follow-
up to achieve the target number of events.
An independent data monitoring committee (IDMC)
has responsibility for monitoring safety during the trial
and in addition will perform at least one interim analysis
of efficacy when approximately half of the anticipated
primary endpoints have been accrued and adjudicated.
The IDMC at its discretion may perform additional
efficacy looks. An alpha spending function will govern
interimand final statistical testing to control the an overall
Type I error of 5%.
Substudies
A series of scientific substudies are planned in patients
randomized in selected countries, including measure-
ment of plasma and serum biomarkers at baseline and 4
months, pharmacogenetics, pharmacodynamics as mea-
sured through platelet function testing, pharmacokinet-
ics, health economics and quality of life.
Study organization
The PEGASUS-TIMI 54 trial is being conducted in 31
countries and more than 1,145 sites. Recruitment began
in the USA in October 2010 and was completed in April
2013. Initial baseline characteristics of the trial cohort are
presented in Table II.
The trial operations group is a partnership composed of
members of the TIMI Study Group and Astra Zeneca, the
trial sponsor (online Appendix C). An Executive Com-
mittee monitors ongoing conduct in the trial. A Steering
committee composed of academic experts and National
Lead Investigators for each country is responsible for the
protocol and its implementation. An IDMC is responsible
for period reviews of patient safety during the trial.
PEGASUS-TIMI 54 was designed by the TIMI Study
Group in cooperation with the trial sponsor and the
Executive and Steering Committee. Data analyses will be
conducted by the TIMI Study Group with validation by
the trial sponsor. The TIMI Study Group will have free
and complete access to all trial data and will submit the
results of the study for publication in a peer-reviewed
medical journal. The PEGASUS-TIMI 54 trial has been
registered under number NCT01225562.
The PEGASUS-TIMI 54 study is supported by a research
grant from AstraZeneca. The authors are solely respon-
sible for the design and conduct of this study all study
analyses, the drafting and editing of the manuscript, and
its final contents.
Discussion
The PEGASUS-TIMI 54 trial will define the role of dual-
antiplatelet therapy with aspirin and ticagrelor in stable
patients with a history of MI between 1 and 3 years
previously and at least one additional atherothrombotic
risk factor. Although background therapies have im-
proved, patients with prior MI remain at heightened risk
of recurrent events.
31
New long-term therapies are
needed for this high-risk population.
31,32
The addition of a P2Y
12
receptor antagonist is
uniformly recommended by professional guidelines
through 12 months of treatment after MI.
24,33
The
extension of this therapeutic strategy beyond that time
frame has not been demonstrated. A series of randomized
trials have not shown a benefit to prolonged DAPT
Table II. Baseline characteristics
Baseline characteristic N = 21,162
Age, y, median (IQR) 65 (59-71)
Female 24%
White 87%
Weight, kg, median (IQR) 81 (70-92)
BMI, median (IQR) 28 (25-31)
Region enrolled
Asia/Australia 11%
Europe/South Africa 59%
North America 18%
South America 12%
Qualifying Event and Cardiovascular History
Time from MI to rando (y), median (IQR) 1.7 (1,2)
Qualifying-NSTEMI 41%
Qualifying-STEMI 54%
Qualifying-MI, type not specified 5%
History of PCI 83%
History of CABG 5%
History of PAD 5%
Qualifying risk factors
Age 65 years 55%
Diabetes mellitus requiring medication 28%
A second prior MI 17%
Multivessel CAD 59%
Chronic renal dysfunction 6%
Data based on interim snapshot taken July 2013 after completion of enrollment but
during ongoing trial and data cleaning. Not based on 100% clean data.
Non-end stage renal dysfunction with stable estimated creatinine clearance
b60 mL/min.
Bonaca et al 441
American Heart Journal
Volume 167, Number 4
following percutaneous coronary intervention (PCI)
(including after ACS), but these studies have been
relatively small and enrolled relatively low risk pa-
tients.
34-36
Ongoing studies will help provide more
definitive evidence regarding the optimal duration of
DAPT in patients undergoing PCI with stenting, but
primarily for elective indications.
37
With regard to stable patients with prior MI, to date, 2
large-scale rigorous evaluations of the benefits and risks of
more intensive long-term antiplatelet therapy have been
performed. In the CHARISMA trial, over 15,000 stable
patients with either established atherosclerotic vascular
disease or risk factors for atherothrombosis but no known
disease were randomized to clopidogrel in addition to
aspirin compared with aspirin monotherapy.
11
Although
the trial overall did not show benefit (RR 0.93, 95% CI
0.83-1.05, P = .22), there was an apparent gradient of
benefit based on a patients risk, with relative risk
reductions of cardiovascular death, MI, or stroke of 7%
in the overall cohort, 12% in patients with clinically
evident atherothrombosis, 17% in those with prior MI,
stroke, or PAD, and 23% in those with prior MI.
11,12
In the
TRA2P-TIMI 50 trial, over 26,000 patients with stable
vascular disease were randomized to vorapaxar or
placebo, a novel antiplatelet drug that blocks the effect
of thrombin on the protease-activated receptor 1.
20
Among
the subset of over 17,000 patients with prior MI, more
intensive antiplatelet therapy reduced the risk of cardio-
vascular death, MI or stroke by 20% (8.1% vs. 9.7%, HR
0.80, 95%CI 0.72-0.89, P b .0001), with consistent findings
both in patients randomized more than 6 months from
their index MI and for events more than 1 year after
randomization.
38
Moreover, the recently reported TRILO-
GY study compared therapy with prasugrel vs. clopidogrel
for a median of 17 months in patients medically managed
after an ACS. Although the trial overall did not show
benefit, it suggested that more intensive antiplatelet
therapy may be beneficial beyond 1 year in those with
angiographically confirmed coronary artery disease.
39,40
Together, these data support the hypothesis that pro-
longed more intensive antiplatelet therapy will reduce
cardiovascular death and ischemic complications in high-
risk patients with prior MI.
Summary
PEGASUS-TIMI 54 is investigating whether addition of
ticagrelor to a background of aspirin reduces major
adverse cardiovascular events in stable patients with a
history of myocardial infarction.
Disclosures
Disclosures of relationships with industry disclosures:
The PEGASUS-TIMI 54 Study was funded through a
grant from AstraZeneca.
The TIMI Study Group has received research grant
support through Brigham and Women's Hospital from
Abbott, Amgen, AstraZeneca, Beckman Coulter, BG
Medicine, BRAHMS, Bristol-Myers Squibb, Buhlmann,
Critical Diagnostics, CV Therapeutics, Daiichi Sankyo
Co Ltd, Eli Lilly and Co, GlaxoSmithKline, Genzyme,
Merck and Co, Intarcia, Merck, Nanosphere, Novartis
Pharmaceuticals, Ortho-Clinical Diagnostics, Pfizer, Ran-
dox, Roche Diagnostics, Sanofi-Aventis, Siemens, Singu-
lex, and Takeda.
Dr Bonaca reports consulting for Roche Diagnostics.
Dr Deepak L. Bhatt discloses the following relation-
ships: Advisory Board: Elsevier Practice Update Cardiol-
ogy, Medscape Cardiology, Regado Biosciences; Board of
Directors: Boston VA Research Institute, Society of
Cardiovascular Patient Care; Chair: American Heart
Association Get With The Guidelines Steering Commit-
tee; Data Monitoring Committees: Duke Clinical Re-
search Institute, Harvard Clinical Research Institute,
Mayo Clinic, Population Health Research Institute;
Honoraria: American College of Cardiology (Editor,
Clinical Trials, Cardiosource), Belvoir Publications (Edi-
tor in Chief, Harvard Heart Letter), Duke Clinical
Research Institute (clinical trial steering committees),
Harvard Clinical Research Institute (clinical trial steering
committee), HMP Communications (Editor in Chief,
Journal of Invasive Cardiology); Population Health
Research Institute (clinical trial steering committee),
Slack Publications (Chief Medical Editor, Cardiology
Today's Intervention), WebMD (CME steering commit-
tees); Other: Clinical Cardiology (Associate Editor);
Journal of the American College of Cardiology (Section
Editor, Pharmacology); Research Grants: Amarin, Astra-
Zeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic,
Roche, Sanofi Aventis, The Medicines Company; Unfund-
ed Research: FlowCo, PLx Pharma, Takeda.
Dr Braunwald reports no additional disclosures.
Dr Cohen reports Speakers Bureau and Advisory Board
consultant for Astra Zenca, Lilly, and Bristol-Myers
Squibb.
Dr Steg reports receiving honorariumfromAstraZeneca
for steering committee membership and support for
travel to study meetings. In addition, he has received
personal fees from Amarin, AstraZeneca, Bayer, Boehrin-
ger-Ingelheim, Bristol-Myers-Squibb, Daiichi-Sankyo,
GlaxoSmithKline, Lilly, Merck-Sharpe-Dohme, Novartis,
Otsuka, Pfizer, Roche, Sanofi, Servier, The Medicines
Company, and Vivus and research grants from Sanofi and
Servier outside the submitted work.
Dr Storey reports receiving honorarium from AstraZe-
neca for steering committee membership and support for
travel to study meetings. In addition, he has received
personal fees from Amarin, AstraZeneca, Bayer, Boehrin-
ger-Ingelheim, Bristol-Myers-Squibb, Daiichi-Sankyo,
GlaxoSmithKline, Lilly, Merck-Sharpe-Dohme, Novartis,
Otsuka, Pfizer, Roche, Sanofi, Servier, The Medicines
442 Bonaca et al
American Heart Journal
April 2014
Company, and Vivus and research grants from Sanofi and
Servier outside the submitted work.
Dr Held reports no additional disclosures.
Dr Jensen reports no additional disclosures.
Dr Sabatine report the following financial disclosures
over past 12 months and research grant support through
Brigham and Women's Hospital from:
Significant
Pharmaceutical and biotechnology companies: Amgen;
AstraZeneca, AstraZeneca/Bristol-Myers Squibb Alliance,
Bristol-Myers Squibb/Sanofi-aventis Joint Venture, Daii-
chi-Sankyo, Eisai, Genzyme, GlaxoSmithKline, Intarcia,
Merck, Sanofi-aventis, and Takeda.
Significant
Medical diagnostic companies: Abbott Laboratories,
Critical Diagnostics, Nanosphere, Roche Diagnostics.
Modest
Consulting for Aegerion, Amgen, AstraZeneca/Bristol-
Myers Squibb Alliance, GlaxoSmithKline, Intarcia, Merck,
Pfizer, Sanofi-aventis, Vertex.
Dr Sabatine was supported in part by grant R01
HL099692, grant R01 HL096738, and contract
HHSN268201000033C from the National Health, Lung,
and Blood Institute.
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18. Diener HC, Bogousslavsky J, Brass LM, et al. Aspirin and clopidogrel
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19. Diener HC, Sacco RL, Yusuf S, et al. Effects of aspirin plus extended-
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444 Bonaca et al
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Appendix A. Online Supplement
Concomitant therapies
Patients requiring treatment with these therapies must
stop study treatment for the duration of such therapy
with the exception of modified study treatment. Patients
requiring treatment with strong CYP3A inhibitors or
CYP3A substrates with a narrow therapeutic index also
must stop study treatment for the duration of therapy.
Treatment with strong CYP3A inducers is discouraged
where alternatives are available.
Modified study treatment
During the study it is anticipated that some patients
will develop an indication for ADP receptor blockade.
Because study treatment allocation includes a placebo arm
this scenario could force premature cessation of study
treatment and utilization of open-label therapy. A
modified study treatment option is provided to
investigators for use in this situation if the investigators
treatment choice would have been clopidogrel. Use of the
modified study treatment assigns patients originally
randomized to either ticagrelor dose to a 180 mg loading
dose followed by 90 mg twice daily, consistent with the
dosing used in the PLATO trial. Patients originally
randomized to placebo are assigned to receive active
clopidogrel with the loading dose at the discretion of the
treating physician (eg, 300-600 mg) and a recommended
maintenance dose of 75 mg daily. Thus, all patients
receive active P2Y
12
receptor antagonist. Modified study
drug is dispensed as ticagrelor 90 mg (or matching
placebo) and clopidogrel 75 mg (or matching placebo).
Allocation of modified study treatment is managed by the
central randomization system ensuring maintenance of
the double-blind. Modified treatment is continued for the
duration determined by the treating physician, after
which time the patient is to return to the original
randomized therapy.
Supplementary Figure
Modified study treatment.
Modified Study Treatment for randomized patients
who develop an indication for ADP receptor blockade/
dual anti-platelet therapy during the trial. Loading doses
are at the discretion of the treating physician. BID,
twice daily.
Appendix B. Endpoint definitions
Efficacy event definitions and classifications
Death. All deaths reported post-enrollment will be
recorded and adjudicated. Deaths will be sub-classified
by cardiovascular and non-cardiovascular primary cause.
Cardiovascular death includes sudden cardiac death,
death due to acute myocardial infarction, death due to
heart failure, death due to a cerebrovascular event,
death due to other cardiovascular causes (eg, pulmo-
nary embolism, aortic disease, cardiovascular interven-
tion), and deaths for which there was no clearly
documented non-cardiovascular cause (presumed car-
diovascular death).
Additionally, deaths will be sub-classified by coronary
heart diseases death (CHD death) and non-CHD death.
CHD death includes sudden cardiac death, death due to
acute MI, and the subset of death due to other
cardiovascular causes that are secondary to a coronary
revascularization procedure.
Definition of myocardial infarction. MI is diagnosed
based on the Universal MI definition published by
Thygesen et al in 2007.
38
:
For a spontaneous MI, detection of rise and/or fall of
cardiac biomarkers, preferably troponin, with at least
one value above the 99th percentile of the upper
reference limit (URL) together with evidence of
myocardial ischemia with at least one of the following:
Symptoms of myocardial ischemia
ECG changes (ST segment, T waves, or new left
bundle branch block) indicative of new ischemia
Development of pathologic Q waves on the ECG
Imaging evidence of new loss of viable myocardium
or new regional wall motion abnormality
Sudden unexpected cardiac death, involving cardiac
arrest, often with symptoms suggestive of myocardial
ischemia, and accompanied by presumably new ST-
elevation or new LBBB, and/or evidence of fresh
thrombus by coronary angiography and/or autopsy,
but death occurring before blood samples could be
obtained, or at a time before the appearance of cardiac
biomarkers in the blood.
PCI-related MI: elevation of cardiac biomarkers N3
99th percentile of the URL within 48 hours after PCI.
CABG-related MI: Elevation of cardiac biomarkers N5
99th percentile of the URL within 72 hours after
CABG, plus either new pathological Q waves or new
LBBB, or angiographically documented new graft or
native coronary occlusion, or imaging evidence of loss
of viable myocardium.
Silent MI based on ECG or imaging findings.
Pathological findings of an acute MI not otherwise
meeting above definitions.
Definition of stroke. Stroke is defined as an acute
episode of neurologic dysfunction attributed to a central
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Volume 167, Number 4
nervous system vascular cause. Stroke should be docu-
mented by imaging (eg, CT scan or magnetic resonance
imaging [MRI] scan). Evidence obtained fromautopsy can
also confirm the diagnosis. Stroke will be sub classified,
when possible, as either:
Primary ischemic stroke: defined as an acute
episode of focal brain, spinal, or retinal dysfunction
caused by an infarction of central nervous system
tissue and documented by imaging. A primary
ischemic stroke may also undergo hemorrhagic
transformation (i.e., no evidence of hemorrhage on
an initial imaging study, but appearance on a
subsequent scan).
Primary hemorrhagic stroke: defined as an acute
episode of focal or global brain, spinal, or retinal
dysfunction caused by non-traumatic intraparenchy-
mal, intraventricular, or subarachnoid hemorrhage as
documented by neuroimaging or autopsy. Microhe-
morrhages (b10 mm) evident only on MRI are not
considered to be a hemorrhagic stroke. Subdural and
epidural bleeding will be considered intracranial
hemorrhage, but not strokes.
UA stroke with unknown etiology will be classified as
an unclassified stroke if the type of stroke could not be
determined by imaging or other means.
Definition of Urgent Coronary Revascularization.
The diagnosis of urgent coronary revascularization re-
quires both of the 2 following criteria are met:
1. Ischemic chest pain (or equivalent) at rest 10
minutes in duration or repeated episodes at rest
lasting 5 minutes considered to be myocardial
ischemia upon final diagnosis, and
2. Prompting hospitalization and percutaneous
coronary revascularization within 7 days of the
symptoms or surgical coronary revascularization
within 14 days of symptoms.
Definition of Unstable Angina. The diagnosis of
unstable angina will require ischemic chest pain (or
equivalent) at rest 10 minutes in duration considered to
be myocardial ischemia upon final diagnosis and
prompting hospitalization within 24 hours of the most
recent symptoms, and without elevation in cardiac
biomarkers of necrosis, and the presence of objective
evidence of ischemia as defined by at least 1 of the
following criteria:
1. New or worsening ST or T wave changes in 2
anatomically contiguous leads on a resting ECG (in
the absence of LVH and LBBB):
a. Transient (b20 minutes) ST elevation at the J
point 0.2 mV in men (N 0.25 mV in men b 40
years old) or 0.15 mV in women in leads V2-V3
and/or 0.1 mV in other leads, or
b. Horizontal or down-sloping ST depression 0.10
mV, or c) T-wave inversion 0.2 mV
2. Definite evidence of myocardial ischemia on
myocardial scintiography (clear reversible perfu-
sion defect), stress echocardiography (reversible
wall motion abnormality), or MRI (myocardial
perfusion deficit under pharmacologic stress) that
is believed to be responsible for the myocardial
ischemic symptoms/signs.
3. Angiographic evidence of 70% lesion and/or
thrombus in an epicardial coronary artery that is
believed to be responsible for the myocardial
ischemic symptoms/signs.
Definition of Transient Ischemic Attack. TIA is
defined as a transient episode of neurological dysfunction
caused by focal brain, spinal cord, or retinal ischemia,
without acute infarction.
42
Patients are required to be
hospitalized within 48 hours of their most recent
neurologic symptoms.
Definition of Coronary Stent Thrombosis. Stent
thrombosis will be classified as per the Academic
Research Consortium Definition.
43
All cases of reported death, myocardial infarction,
urgent coronary revascularization, and unstable
angina requiring hospitalization will be reviewed and
adjudicated as defined by the Academic Research
Consortium (ARC) Definitions of Stent Thrombosis for
Definite/Confirmed, Probable, or Possible stent
thrombosis:
Definite Stent Thrombosis:. Definite stent throm-
bosis is considered to have occurred by either
angiographic or
pathological confirmation:
1. Angiographic confirmation of stent thrombosis
The presence of a thrombus that originates in
the stent or in the segment 5 mm proximal or
distal to the stent and presence of at least 1 of
the following criteria within a 48-hour time
window:
a. Acute onset of ischemic symptoms at rest
b. New ischemic ECG changes that suggest acute
ischemia
c. Typical rise and fall in cardiac biomarkers (refer
to definition of spontaneous MI: Troponin or CK-
MB N 99th percentile of URL)
d. Nonocclusive thrombus
- Intracoronary thrombus is defined as a
(spheric, ovoid, or irregular) noncalcified
filling defect or lucency surrounded by
contrast material (on 3 sides or within a
coronary stenosis) seen in multiple projec-
tions, or persistence of contrast material
within the lumen, or a visible embolization of
intraluminal material downstream
444.e2 Bonaca et al
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April 2014
e. Occlusive thrombus
- TIMI 0 or TIMI 1 intrastent or proximal to a
stent up to the most adjacent proximal side
branch or main branch (if originates from the
side branch)
2. Evidence of recent thrombus within the stent
determined at autopsy or via examination of tissue
retrieved following thrombectomy.
Probable Stent Thrombosis. Clinical definition of
probable stent thrombosis is considered to have occurred
after intracoronary stenting in the following cases:
1. Any unexplained death within the first 30 days from
intracoronary stenting
2. Irrespective of the time after the index procedure,
any MI that is related to documented acute
ischemia in the territory of the implanted stent
without angiographic confirmation of stent
thrombosis and in the absence of any other
obvious cause
Possible Stent Thrombosis. Clinical definition of
possible stent thrombosis is considered to have occurred
with any unexplained death from 30 days after intracor-
onary stenting until end of trial follow-up.
The incidental angiographic documentation of stent
occlusion in the absence of clinical signs or symptoms is
not considered a confirmed stent thrombosis (silent
occlusion).
Intracoronary thrombus.
Bleeding Definitions and classifications
TIMI Bleeding Classification. Major:
1) Any intracranial* bleeding, OR
2) Clinically overt signs of hemorrhage associated
with a drop in hemoglobin (Hgb) of 5 g/dL (or,
when hemoglobin is not available, a fall in
hematocrit of 15%),
OR
3) Fatal bleeding (a bleeding event that directly led to
death within 7 days)
Minor: Any clinically overt sign of hemorrhage
(including imaging) that is associated with a fall in Hgb of
3 to b 5 g/dL (or, when hemoglobin is not available, a fall
in hematocrit of 9 to b 15%).
Note: To account for transfusions, Hgb measure-
ments will be adjusted for any packed red blood
cells (PRBCs) or whole blood given between
baseline and post-transfusion measurements. A trans-
fusion of one unit of blood will be assumed to
result in an increase by 1 gm/dL in Hgb. Thus, to
calculate the true change in hemoglobin, if there
has been an intervening transfusion between 2
blood measurements, the following calculations
should be performed:
4Hgb Baseline HgbPost transfusion Hgb
etransfused units
h i
4Hematocrit Baseline Hctpost transfusion Hct
number of transfused unit 3
Medical Attention: Any overt sign of hemorrhage that
meets one of the following criteria and that does not meet
criteria for a major or minor bleeding event, as defined
above.
Requiring Intervention: defined as medical
practitioner-guided medical or surgical treatment
to stop or treat bleeding including temporarily
or permanently discontinuing or changing the
dose of a medication or study drug
Leading to Hospitalization: defined as leading to or
prolonging hospitalization
Prompting Evaluation: defined as leading to
unscheduled contact with a healthcare professional
and diagnostic testing (laboratory or imaging)
Minimal: Any overt bleeding event that does not meet
the criteria above.
*See further details for ICH definition under Cerebro-
vascular events
PLATO Bleeding Classification. PLATO Major
Bleeding
Fatal/Life-threateningincludes bleeding events
that meet any of the following criteria
Fatal bleeding
Intracranial bleeding (ICH)*
Intrapericardial bleeding with cardiac tamponade
Hypovolemic shock or severe hypotension due to
bleeding and requiring pressors/inotropes or
surgery
Decline in hemoglobin of 5 g/dL or more (or,
when hemoglobin is not available, a fall in
hematocrit of 15%),
Transfusion or 4 or more units (whole blood
or packed red blood cells [PRBCs]) for
bleeding
Major bleedotherincludes bleeding events that
meet any of the following criteria
Significantly disabling (eg, intraocular with per-
manent vision loss)
Clinically overt or apparent bleeding associated
with a decrease in hemoglobin (Hb) of 3-5 g/dL
(or, when hemoglobin is not available, a fall in
hematocrit of 9 to b 15%)
Transfusion of 2-3 U (whole blood or PRBCs) for
bleeding
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PLATO Minor Bleeding
Bleeding that does not meet criteria for PLATO
Major Bleeding
AND
Requires medical intervention to stop or treat
bleeding (eg, epistaxis requiring visit to medical
facility for packing)
PLATO Minimal Bleeding.
Bleeding that does not meet criteria for PLATO
major or minor bleeding
AND
Includes all other bleeding events (eg, bruising,
bleeding gums, oozing from injection sites, etc) not
requiring intervention or treatment
*See further details for ICH definition under Cerebro-
vascular events
GUSTO Bleeding Classification:
Severe: Bleeding* that was fatal, intracranial**, or that
caused hemodynamic compromise requiring interven-
tion (e.g. systolic blood pressure b90 mm Hg that
required blood or fluid replacement, or vasopressor/
inotropic support***, or surgical intervention)
Moderate: Bleeding* requiring transfusion of whole
blood or packed red blood cells**** without hemody-
namic compromise (as defined above)
Mild: Bleeding* without blood transfusion or hemody-
namic compromise
*In all cases, bleeding must be clinically overt.
**See further details for ICH definition under Cere-
brovascular events
***Need for vasopressor/inotropic support for hemo-
dynamic compromise, even if blood pressure is N90 mm
Hg with treatment.
****Does not include cell-saver transfusion during CABG
ISTH Bleeding Classification:
ISTH Major
Clinically overt bleeding (including imaging) that is
associated with at least one of the following:
Fatal bleeding, or
Symptomatic bleeding in a critical area or organ
such as intracranial*, intraspinal, intraocular,
retroperitoneal, intra-articular, pericardial, or in-
tramuscular bleeding with compartment syn-
drome, or
A fall in hemoglobin of 2 g/dL or more, or a
transfusion of 2 or more units of packed red blood
cells or whole blood
ISTH Minor
All non-major bleeds will be considered minor and will
be divided in clinically relevant and not clinically relevant
minor bleeds. Clinically relevant minor bleeds are defined
as a clinically overt bleed that leads to at least one of the
following:
A hospital admission for bleeding
Physician-guided medical or surgical treatment for
bleeding
A change in antithrombotic therapy (including
interruption of discontinuation of antithrombotic
therapy)
*See further details for ICH definition under Cerebro-
vascular events
Bleeding in the setting of CABG. As a drop in
hemoglobin and transfusions are commonplace in
routine CABG cases, one of the following criteria must
be met to qualify for major bleeding in any of the
preceding definitions:
1. Fatal bleeding (ie bleeding that directly results in
death)
2. Perioperative intracranial bleeding
3. Reoperation following closure of the sternotomy
incision for the purpose of controlling bleeding
4. Transfusion of 5 units of packed red blood cells
(PRBCs) or whole blood within a 48 hours period.
Cell saver transfusion will not be counted in
calculations of blood products
5. Chest tube output N2 L within a 24 hour period
Appendix C. Committees and Leadership
TIMI Study Group
Eugene Braunwald, MD, Chairman
Marc S. Sabatine, MD, MPH, Principal Investigator
Marc Bonaca, MD, MPH, Co-Principal Investigator
Suzanne Morin, Director of Operations
M. Polly Fish, Senior Project Director
Emily Dantzer, Project Director
Sponsor Leadership
Peter Held, MD, PhD
Eva C. Jensen, MD, PhD
Olof Bengtsson, Principal Statistician, PhD
Ann Maxe Ahlbom, Clinical Programme Director
Helene Depui Ekdal, Clinical Delivery Director
Barbro Boberg, Study Operation Program Leader
Executive Committee
Eugene Braunwald, MD, Chairman
Marc S. Sabatine, MD, MPH, International Coordinating
Investigator
Deepak L. Bhatt, MD, MPH
Marc Cohen, MD
P. Gabriel Steg, MD
Robert Storey, BSc, MCRP, DM
Peter Held, MD, PhD (non-voting)
444.e4 Bonaca et al
American Heart Journal
April 2014
Steering Committee includes Members of the Executive
Committee and the following National Lead Investigators:
Maria Teresa Abola (Philippines)
Diego Ardissino (Italy)
Philip Aylward (Australia)
Andrzej Budaj (Poland)
Ramon Corbalan (Chile)
Anthony Dalby (South Africa)
Mikael Dellborg (Sweden)
Doina Dimulescu (Romania)
Shinya Goto (Japan)
Assen Goudev (Bulgaria)
Sema Guneri (Turkey)
Christian Hamm (Germany)
Dayi Hu (China)
Daniel Isaza (Colombia)
Gabriel Kamensky (Slovakia)
Robert Kiss (Hungary)
Frederic Kontny (Norway)
Jose Lopez Sendon (Spain)
Felix Medina (Peru)
Gilles Montalescot (France)
Jose Nicolau (Brazil)
Ton Oude Ophuis (Netherlands)
Ernesto Paolasso (Argentina)
Alexander Parkhomenko (Ukraine)
Mikhail Ruda (Russia)
Ki-Bae Seung (Republic of Korea)
Jindrich Spinar (Czech Republic)
Pierre Theroux (Canada)
Frans Van de Werf (Belgium)
Independent Data Monitoring Committee
Jeffrey L. Anderson, MD, Chair
Harvey D. White, DSc
Freek W.A.Verheugt, MD
Terje R. Pedersen, MD, PhD
David L. DeMets, PhD, Statistician
Clinical Endpoints Committee:
Stephen D. Wiviott, MDChairman
Eric Awtry, MD
Clifford Berger, MD
Kevin Croce, MD
Akshay Desai, MD
Eli Gelfand, MD
Carolyn Ho, MD
David Leeman, MD
Mark Link MD
Andrew Norden, MD
Ashvin Pande, MD
Natalia Rost, MD
Frederick Ruberg, MD
Scott Silverman, MD
Aneesh Singhal, MD
Joseph Vita, MD
444.e5 Bonaca et al
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April 2014