Reduction in Subtypes and Sizes of Myocardial Infarction With [629731]

Reduction in Subtypes and Sizes of Myocardial Infarction With
Ticagrelor in PEGASUS –TIMI 54
Marc P. Bonaca, MD, MPH; Stephen D. Wiviott, MD; David A. Morrow, MD, MPH; P. Gabriel Steg, MD; Christian Hamm, MD;
Deepak L. Bhatt, MD, MPH; Robert F. Storey, MD; Marc Cohen, MD; Julia Kuder, BS; KyungAh Im, PhD; Giulia Magnani, MD;
Andrzej Budaj, MD; Jos /C19e C. Nicolau, MD; Alexander Parkhomenko, MD; Jos /C19eL/C19opez-Send /C19on, MD; Mikael Dellborg, MD; Rafael Diaz, MD;
Frans Van de Werf; Ram /C19on Corbal /C19an, MD; Assen Goudev, MD; Eva C. Jensen, MD; Per Johanson, MD; Eugene Braunwald, MD;
Marc S. Sabatine, MD, MPH
Background- —Ticagrelor reduced cardiovascular death, myocardial infarction (MI), or stroke in patients with prior MI in PEGASUS-
TIMI 54 (Prevention of Cardiovascular Events [eg, Death From Heart or Vascular Disease, Heart Attack, or Stroke] in Patients With
Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin). MI can occur in diverse settings and withvarying severity; therefore, understanding the types and sizes of MI events prevented is of clinical importance.
Methods and Results- —MIs were adjudicated by a blinded clinical events committee and categorized by subtype and fold
elevation of peak cardiac troponin over the upper limit of normal. A total of 1042 MIs occurred in 898 of the 21 162 randomized
patients over a median follow-up of 33 months. The majority of the MIs (76%) were spontaneous (Type 1), with demand MI (Type2) and stent thrombosis (Type 4b) accounting for 13% and 9%, respectively; sudden death (Type 3), percutaneous coronaryintervention –related (Type 4a) and coronary artery bypass graft –related (Type 5) each accounted for <1%. Half of MIs (520, 50%)
had a peak troponin ≥10x upper limit of normal and 21% of MIs (220) had a peak troponin ≥1009upper limit of normal. A total
of 21% (224) were ST-segment –elevation MI STEMI. Overall ticagrelor reduced MI (4.47% versus 5.25%, hazard ratio 0.83, 95%
confidence interval 0.72 –0.95, P=0.0055). The bene fit was consistent among the subtypes, including a 31% reduction in MIs
with a peak troponin ≥1009upper limit of normal (hazard ratio 0.69, 95% con fidence interval 0.53 –0.92, P=0.0096) and a 40%
reduction in ST-segment elevation MI (hazard ratio 0.60, 95% con fidence interval 0.46 –0.78, P=0.0002).
Conclusions- —In stable outpatients with prior MI, the majority of recurrent MIs are spontaneous and associated with a high bio-
marker elevation. Ticagrelor reduces the MI consistently among subtypes and sizes including large MIs and ST-segment elevation MI.
Clinical Trial Registration- —URL: https://www.clinicaltrials.gov. Unique identi fier: NCT01225562. (J Am Heart Assoc . 2018;7:
e009260. DOI: 10.1161/JAHA.118.009260)
Key Words: antiplatelet therapy myocardial infarction ST-segment elevation myocardial infarction ticagrelor troponin
Patients with prior myocardial infarction (MI) are at long-
term heightened risk of recurrent ischemic events.1
PEGASUS-TIMI 54 (Prevention of Cardiovascular Events [eg,Death From Heart or Vascular Disease, Heart Attack, orStroke] in Patients With Prior Heart Attack Using Ticagrelor
Compared to Placebo on a Background of Aspirin) demon-
strated that long-term secondary prevention with ticagrelor,
added to aspirin, reduced the primary composite end point of
From the TIMI Study Group, Brigham and Women ’s Hospital, Boston, MA (M.P.B., S.D.W., D.A.M., D.L.B., J.K., K.I., E.B., M.S.S.); FACT, DHU FIRE, H ^opital Bichat,
Assistance Publique-H ^opitaux de Paris, Paris, France (P.G.S.); Department of Medicine, Kerckhoff Heart Center, BadNauheim, Germany (C.H.); Department of
Medicine, University of Shef field, United Kingdom (R.F.S.); Newark Beth Israel Medical Center, Rutgers-New Jersey Medical School, Newark, NJ (M.C.);
Universit €atsSpital Z €urich (USZ) & Z €urich Heart House, University Hospital of Zurich, Switzerland (G.M.); Postgraduate Medical School, Grochowski Hospital,
Warsaw, Poland (A.B.); Heart Institute (InCor), University of S ~ao Paulo Medical School, S ~ao Paulo, Brazil (J.C.N.); Department of Medicine, Institute of Cardiology,
Kiev, Ukraine (A.P.); Department of Medicine, Hosp Univrio La Paz, Madrid, Spain (J.L.S.); Sahlgrenska Acad, University of Gothenburg, Sweden (M.D .);
Department of Medicine, ECLA (Estudios Cl /C19ınicos Latino Am /C19erica), Rosario, Argentina (R.D.); Department of Medicine, University of Leuven, Belgium (F.V.d.W.);
Department of Medicine, Ponti ficia Univ Catolica de Chile, Santiago, Chile (R.C.); Medical University of So fia, Queen Ioanna University Hospital, So fia, Bulgaria
(A.G.); AstraZeneca, M €olndal, Sweden (E.C.J., P.J.).
Accompanying Tables S1, Figures S1 and S2 are available at https://www.ahajournals.org/doi/suppl/10.1161/JAHA.118.009260Correspondence to: Marc P. Bonaca, MD, MPH, TIMI Study Group, Cardiovascular Division, Brigham and Women ’s Hospital, 75 Francis St, Boston, MA 02115.
E-mail: mbonaca@partners.org
Received March 23, 2018; accepted September 14, 2018.ă2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. This is an open access article under the terms of the Creative C ommons
Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the u se is non-
commercial and no modi fications or adaptations are made.
DOI: 10.1161/JAHA.118.009260 Journal of the American Heart Association 1ORIGINAL RESEARCH
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MI, stroke, or cardiovascular death by /C2515%.2Overall, the
magnitude of relative risk reduction was similar for all of the
components of the composite end point, including cardiovas-
cular death and ischemic stroke; however, the most frequent
outcome was recurrent MI.
The de finition and natural history of MI has evolved over the
past decade.3The measurement of circulating cardiac troponin,
measured with increasingly sensitive assays that are able to
detect very small levels of myocardial injury, has become central
to the diagnosis of MI. Because of the increasing sensitivity oftroponin assays, events categorized as MI re flect a broadening
spectrum of events in terms of cause, size, and severity.
4In
addition, events reported in clinical trials may differ from those
commonly coded in public data sets.5In acute populations
undergoing intervention, for example, serial biomarkers may
detect largely procedural MI, although differentiating procedural
injury from index events may be challenging.6–8Understanding
and further characterizing MI events is therefore important in
understanding their clinical signi ficance, particularly in the
context of therapies with safety concerns such as bleeding.9
We hypothesized that in the stable high-risk PEGASUS-TIMI
54 population, recurrent MI would be largely spontaneous and
associated with signi ficant elevation in circulating cardiac
biomarkers. In addition, we hypothesized that the bene fits of
ticagrelor for reducing MI would be present across cause and
size of MI but would be particularly notable for MI clearly
mediated by coronary thrombosis such as ST-segment –
elevation MI (STEMI).Methods
Study Population
PEGASUS-TIMI 54 randomized patients with prior MI toticagrelor 60 mg twice daily, ticagrelor 90 mg twice daily,
or placebo, all on a background of low-dose aspirin. The
protocol was approved by the relevant ethics committee at
each participating site. Written informed consent was
obtained from all the patients. The design
10and primary
results of the trial have been published.2Patients aged at
least 50 years were enrolled with a spontaneous MI
occurring 1 to 3 years before enrollment and at least 1
of the following additional high-risk features: age ≥65 years,
diabetes mellitus requiring medication, a second prior
spontaneous MI, multivessel coronary artery disease, orchronic renal dysfunction, de fined as a creatinine clearance
<60 mL/min as estimated by the Cockroft-Gault equation.
Patients were ineligible if there was planned use of a P2Y
12
receptor antagonist or anticoagulant therapy during thestudy period; if they had a bleeding disorder, a history of
intracranial bleeding, a central nervous system tumor, or an
intracranial vascular abnormality; or if they had had
gastrointestinal bleeding within the previous 6 months or
major surgery within the previous month.
End Points
The primary ef ficacy end point was MI, and subtypes of MI in
this article. All potential events were adjudicated by a clinical
events committee, which was blinded to treatment allocation.All con firmed MI events were further categorized by the clinical
events committee into clinical subtype as de fined in the
Universal De finition of MI as well as the associated peak
troponin elevation (available in 88%). Stent thrombosis (Type
4b MI) was adjudicated through collection and formal review of
coronary angiograms. Type 2 MI events had to meet criteria for
a spontaneous MI as de fined in the charter, not meet criteria
for another MI subtype, and had to occur in the setting of a
clinical picture consistent with ischemia caused by eitherincreased oxygen demand or decreased supply, (eg, coronary
artery spasm, coronary embolism, anemia, arrhythmias, hyper-
tension, or hypotension). Although even low-level elevations in
cardiac troponin have been associated with adverse prognosis
in patients with acute coronary syndrome,
11elevations of at
least 10-fold have generally been regarded as indicating larger
events and enable detection of important events in the setting
of procedures such as bypass surgery.3In order to evaluate the
consistency of bene fit for ticagrelor across MI size, serial
thresholds were examined also including 25 9,5 09,1 0 09,
and 200 9the upper limit of normal. In addition, events were
categorized into the core clinical categories of STEMI and non –
ST segment –elevation MI with ECGs collected by the clinicalClinical Perspective
What Is New?
Debates regarding the duration of dual antiplatelet therapy
often center around the concept of stent protection.
This article demonstrates that in high-risk patients with prior
myocardial infarction (MI), recurrent events are primarilylarge, spontaneous, de novo events rather than stentthrombosis and that long-term ticagrelor consistentlyreduces recurrent MI regardless of size or cause.
What Are the Clinical Implications?
When evaluating patients for long-term secondary pre-
vention with ticagrelor, patient risk pro file should be
considered.
High-risk patients with prior MI have long-term risk of
recurrent spontaneous events including large MIs and ST-segment –elevation MI.
Long-term ticagrelor signi ficantly reduces MI regardless
of cause including large MIs, ST-segment –elevation
MI, and the composite of fatal MI or sudden cardiac death.
These findings should be considered when weighing the
risks and bene fits of long-term therapy with ticagrelor.
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events committee (in 1021 of 1042 or 98.6% of events).
Additional ef ficacy end points included fatal MI, sudden cardiac
death (presumed largely coronary in origin in a post-MI
population) and the combination of these 2.
Statistical Considerations
Cumulative event rates at 3 years following randomization
were calculated by the complement of Kaplan –Meier survival
estimates. The treatment comparisons were based on the Cox
proportional-hazards model including treatment assignment
as an indicator variable. Since this was a large randomized
trial, no additional adjustment was made in this model. We
have also examined the risks of MI and subtypes of MI in thecontext of competing risks for consistency. The proportional
hazards assumption was assessed by creating an interaction
of the treatment assignment indicator and a function of
survival time and included in the model. All models met this
assumption. Ef ficacy analyses were performed on an inten-
tion-to-treat basis. Patients could have more than 1 MI during
follow-up, so analyses evaluating subtypes of MI included the
first MI of that subtype. The data for this analysis will not be
made available to other researchers for purposes of repro-ducing the results or replicating the procedure. The analytic
methods are described and the study materials (trial protocol)
have been published with primary results. Results are
summarized by hazard ratios and 95% con fidence intervals
and all reported Pvalues are 2-sided. No adjustment was
made for the signi ficance level for multiple testing. Analyses
were performed using SAS v9.4 (SAS Institute Inc, Cary, NC)
and R software version 3.2.2 (www.r-project.org).
Results
A total of 21 162 patients were randomized with 7067 to
placebo, 7045 to ticagrelor 60 mg twice daily, and 7050 to
ticagrelor 90 mg twice daily. A total of 1042 MI events
occurred in a total of 898 patients at a median of 460 days(interquartile range 222 –721) following randomization.
Patients who had MI during the trial were older, had a greater
prevalence of risk factors, had more severe vascular disease,
and were more likely to have had an index non –ST segment –
elevation MI relative to STEMI (Table S1). For patients
randomized to placebo, the rate of recurrent MI at 3 years
was 5.2% or 1.7% annualized.
Types and Sizes of MI
The majority of MI events that occurred during follow-up were
spontaneous atherothrombotic (76%, Type 1, Figure 1A). A
minority were secondary to demand (13%, Type 2) or stentthrombosis (9%, Type 4b). Only 6 MI events were associated
with troponin elevation in the setting of percutaneous
intervention (Type 4a) and there was 1 MI event occurring
in the setting of coronary artery bypass surgery (Type 5).
When evaluating by subtype in the placebo arm, the highest
rate was for spontaneous MI (4.1%, Figure S1). Rates of all
other subtypes were <1% over 3 years (Figure S1).
There was a broad distribution of peak troponin elevation
associated with MI events (Figure 1B). The majority of MI
events were associated with a peak troponin elevation of 10times the upper limit of normal or more.
Efficacy of Ticagrelor
Both doses of ticagrelor signi ficantly reduced the risk of MI
(ticagrelor 60 mg, hazard ratio (HR) 0.84, 95% con fidence
interval (CI) 0.72 –0.98, P=0.031; ticagrelor 90 mg, HR 0.81,
95% CI 0.69 –0.95, P=0.010). The effect of ticagrelor at reducing
MI was evident early and continued through the 3 years of
follow-up (Figure 2). When stratifying by the Universal De fini-
tion of Myocardial Infarction subtypes (Figure 3), the bene fito f
ticagrelor appeared consistent for spontaneous (Type 1),
demand (Type 2), and angiographically veri fied stent-thrombo-
sis-related (Type 4b) with insuf ficient numbers of Type 3 (n =7),
Type 4a (n =6), and Type 5 (n =1) MI to evaluate ef ficacy.
When evaluating by peak troponin as a measure of MI size,
there was a consistent bene fit with ticagrelor with increasing
elevation of peak troponin (Figure 4). This included a 31% risk
reduction in MIs with at least a 100-fold elevation of peak
troponin (ticagrelor doses pooled, HR 0.69, 95% CI 0.53 –0.92;
ticagrelor 60 mg, HR 0.63, 95% CI 0.45 –0.89; ticagrelor
90 mg, HR 0.76, 95% CI 0.55 –1.04, Figure 4). The proportion
offirst MI events with a troponin elevation ≥50 times the upper
limit of normal was signi ficantly lower with ticagrelor versus
placebo (30% versus 37%, P=0.049), with the difference even
greater for spontaneous (Type 1) MIs with a troponin elevation
≥50 times the upper limit of normal (27% versus 36%, P=0.019).
MI was also strati fied by the core clinical subtypes of
STEMI and non –ST-segment –elevation MI. Patients random-
ized to placebo experienced STEMI at a roughly linear rate
during follow-up with no apparent plateau over time (Fig-ure 5). Ticagrelor signi ficantly reduced STEMI by 40% (tica-
grelor doses pooled: HR 0.60, 95% CI 0.46 –0.78, P=0.0002),
with consistent ef ficacy with both the 60 mg and 90 mg
ticagrelor doses (Figure 5). The incidence of non –ST seg-
ment –elevation MI also tended to be lower (ticagrelor doses
pooled: HR 0.91, 95% CI 0.77 –1.06).
Fatal MI or Sudden Cardiac Death
A total of 330 patients had a fatal MI (n =61, 5.85% of all MIs)
or sudden cardiac death (n =269). Ticagrelor reduced the risk
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of these events by 23% (HR 0.77, 95% CI 0.62 –0.96,
P=0.020), with similar effects on fatal MI (HR 0.72, 95% CI
0.43–1.20) and on sudden cardiac death (HR 0.78, 95% CI
0.61–0.997, Figure S2).Discussion
This analysis demonstrates 3 major findings: first, that the
risk of recurrent MI over 3 years in well-treated patients with
history of MI >1 year prior exceeds 5% ( /C251.7% per year);
Figure 1. A, Distribution of myocardial infarction events occurring during follow-up by Universal De finition
of MI subtype. B, Distribution of myocardial infarction events occurring during follow-up by fold elevation in
peak biomarker (includes 913 events with troponin available). CABG indicates coronary artery bypass
grafting surgery; MI, myocardial infarction; PCI, percutaneous coronary intervention; Tn, troponin; ULN,upper limit of normal.
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secondly, that even in the era of sensitive troponin assays,
these recurrent events in stable secondary prevention pop-
ulations are largely new spontaneous events and thatdemand-related myocardial injury and stent complications
accounted for only a minority of MIs; and finally, that long-
term treatment with ticagrelor on a background of aspirin
Figure 2. Myocardial infarction occurring over 3 years by randomized treatment. CI indicates con fidence
interval; HR, hazard ratio; MI, myocardial infarction.
Figure 3. Reduction in MI by treatment (red —ticagrelor 90 mg twice daily, blue —ticagrelor 60 mg twice
daily, purple —ticagrelor doses pooled) for MI overall and by MI subtype. CI indicates con fidence interval;
HR, hazard ratio; KM, Kaplan –Meier; MI, myocardial infarction; PCI, percutaneous coronary intervention.
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significantly reduces the incidence of recurrent MI by 15% to
20%, reduces STEMI by 40%, and reduces the risk of fatal MI
or sudden cardiac death by 23%.In PEGASUS-TIMI 54, patients were purposely selected in
the stable phase at least 1 year from MI.2Patients who were
unstable, critically ill, or planned for procedures were
Figure 4. Reduction in MI by treatment (red —ticagrelor 90 mg twice daily, blue ticagrelor 60 mg twice daily,
purple —ticagrelor doses pooled) for MI overall and by fold elevation of peak biomarker. CI indicates con fidence
interval; HR, hazard ratio; KM, Kaplan –Meier; MI, myocardial infarction; Tn, troponin; ULN, upper limit of normal.
Figure 5. STEMI occurring over 3 years by randomized treatment. CI indicates con fidence interval; HR,
hazard ratio; STEMI, ST-segment –elevation myocardial infarction.
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excluded. In addition, utilization of indicated background
therapy was high, with >99% using aspirin, >90% receiving
statins, and >80% on b-blockers. Nevertheless, recurrent MI
continued to occur at a roughly linear rate even 3 years after
randomization. This observation underscores the ongoing risk
of spontaneous plaque rupture in the post-MI population in
spite of intensive medical therapy.
When evaluating the rate of recurrent MI, it is important to
understand the subtype of event. As troponin has evolved to
become the key component of the de finition of MI and as
troponin assays have continued to improve in sensitivity and
speci ficity, there is debate about the clinical relevance of MI,
particularly when occurring in the context of critical illness
(demand or Type 2 MI) or elective percutaneous coronary
intervention (procedural or Type 4 MI).4,12Although degree of
biomarker elevation may represent several factors beyond the
event itself (eg, time to diagnosis, door-to-balloon time), more
than half of the MI events that occurred were associated with
cardiac biomarker levels more than 10 9the upper limit of
normal. The current analysis demonstrates that the majority
of MI events ascertained and adjudicated in a modern clinicaltrial are spontaneous and associated with signi ficant elevation
in circulating biomarkers.
Long-term secondary prevention with ticagrelor 60 mg
twice daily or 90 mg twice daily signi ficantly reduced the risk
of recurrent MI by 15% to 20%. This bene fit was consistent
when restricting to only spontaneous (Type 1) MIs as well as
when restricting to large MIs with a 100-fold or greater
elevation of cardiac troponin. Although there is debate as to
the meaning of biomarker cut points in determining theseverity of MI, STEMI is broadly recognized as a severe, life-
threatening event. We observed that the bene fit of ticagrelor
appeared of even greater magnitude for STEMI with a 40%
reduction, an observation that is intuitive given the high levels
of platelet P2Y
12receptor inhibition achieved by both doses of
ticagrelor and the important role of the platelet P2Y 12
receptor in amplifying and sustaining arterial thrombussufficiently to achieve complete arterial occlusion.
13–15
The bene fit of ticagrelor in reducing STEMI and large MI
translated into a reduction in MI-related mortality either as
fatal MI or sudden death. These data support the position thatpotent antithrombotic strategies in high-risk populations have
the potential to reduce the mortality related to MI even
beyond the bene fits of currently utilized preventive strategies.
There are several limitations to this analysis. Systemic
serial sampling of biomarkers was not performed after
coronary interventions, which may have led to underascer-
tainment of periprocedural (percutaneous coronary interven-
tion or coronary artery bypass grafting surgery) MI. This,
however, would lead to an underestimate of overall risk andmight underestimate the absolute bene fit of ticagrelor in this
population. During the course of the trial, the Third UniversalDefinition of MI was published and modi fied the de finition of
Type 4a MI and added Type 4c MI (because of restenosis).
Type 4a was made more stringent, increasing the threshold of
troponin to 5 9upper limit of normal and requiring additional
evidence of ischemia (eg, syndrome, angiographic evidence,
ECG changes); however, because there were only 6 Type 4a
MIs, this change would not impact the findings of this analysis
and therefore events were not re-adjudicated with the
updated de finition. In addition, Type 4c MI was not captured.
Similarly, there are limitations with the de finition and the
ability to discriminate Type 2 MI from other subtypes. As
outlined in the Methods section, events classi fied as Type 2
MI had to meet criteria as an MI and had to occur in a setting
consistent with supply –demand mismatch. Nonetheless, it is
possible that some of these events were primarily thrombotic
in cause or had a thrombotic component, an observation that
would be supported by the trend towards bene fit with
ticagrelor in this analysis. Overall, only 13% of MI events
were classi fied as Type 2 and inclusion of some Type 1 events
would only reduce frequency in this population, underscoring
the observation that Type 1 events are the predominant causeof MI in this population. An additional limitation is the use of
different troponin assays of differing sensitivity across sites.
Utilization of high thresholds (eg, 100-fold elevations) in peak
troponin was intended to select for large events regardless of
assay, and differing assays would not impact the consistent
findings shown with STEMI.
Conclusions
In stable outpatients with a history of MI, the majority of
recurrent MI events are spontaneous and associated with ahigh biomarker elevation. Ticagrelor signi ficantly reduces the
incidence of MI consistently among different subtypes and
biomarker sizes, with the greatest absolute reduction in
spontaneous MIs, large MIs, and STEMI.
Sources of Funding
This study was supported by a grant to Brigham and Women ’s
Hospital from AstraZeneca.
Disclosures
The TIMI Study Group has received signi ficant research grant
support from Accumetrics, Amgen, AstraZeneca, Beckman
Coulter, Bristol-Myers Squibb, CV Therapeutics, Daiichi
Sankyo Co Ltd, Eli Lilly and Co, GlaxoSmithKline, Integrated
Therapeutics, MedImmune, Merck and Co, Nanosphere,
Novartis Pharmaceuticals, Nuvelo, Ortho-Clinical Diagnostics,
Pfizer, Roche Diagnostics, Sano fi-Aventis, Sano fi-Synthelabo,
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Siemens Medical Solutions, and Singulex. Bonaca reports
consulting for AstraZeneca, Merck, Aralez, Bayer. Wiviott
reports grants and consulting fees from AstraZeneca, Bristol
Myers Squibb, Eisai, Arena, Merck, Eli Lilly, and Daiichi
Sankyo, consulting fees from Aegerion, Angelmed, Janssen,
Xoma, ICON Clinical, Boston Clinical, Boehringer Ingelheim,
grants from Sano fi-Aventis, and from Amgen. Dr Wiviott ’s wife
is an employee of Merck. Morrow reports Research Grants:
Abbott Laboratories, Amgen, AstraZeneca, Daiichi Sankyo,
Eisai, GlaxoSmithKline, Merck, Novartis, Roche Diagnostics,Takeda. Consultant/Advisory Board; Abbott Laboratories,
Aralez, Bayer, Merck, Peloton, Roche Diagnostics, and
Verseon. Steg reports signi ficant research grants from Merck,
Sano fi, and Servier; other personal fees and non financial
support from AstraZeneca, Sano fi, Servier; personal fees from
Amarin, Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers
Squibb, Lilly, Merck, Janssen, Novartis, P fizer, GSK, and
Regeneron. Hamm reports consulting and speaker fees for
AstraZeneca, Daiichi-Sankyo, The Medicines Company, Boeh-
ringer Ingelheim, Bayer, Novartis, and Sano fiAventis. Bhatt
reports the following relationships —Advisory Board: Cardax,
Elsevier Practice Update Cardiology, Medscape Cardiology,
Regado Biosciences; Board of Directors: Boston VA Research
Institute, Society of Cardiovascular Patient Care; Chair:
American Heart Association Quality Oversight Committee;
Data Monitoring Committees: Cleveland Clinic, Duke Clinical
Research Institute, Harvard Clinical Research Institute, Mayo
Clinic, Mount Sinai School of Medicine, Population Health
Research Institute; Honoraria: American College of Cardiology
(Senior Associate Editor, Clinical Trials and News , ACC.org),
Belvoir Publications (Editor in Chief, Harvard Heart Letter ),
Duke Clinical Research Institute (clinical trial steering com-
mittees), Harvard Clinical Research Institute (clinical trial
steering committee), HMP Communications (Editor in Chief,
Journal of Invasive Cardiology ),Journal of the American College
of Cardiology (Guest Editor; Associate Editor), Population
Health Research Institute (clinical trial steering committee),
Slack Publications (Chief Medical Editor, Cardiology Today ’s
Intervention ), Society of Cardiovascular Patient Care (Secre-
tary/Treasurer), WebMD (CME steering committees); Other:
Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry
Steering Committee (Chair), VA CART Research and Publica-
tions Committee (Chair); Research Funding: Amarin, Amgen,
AstraZeneca, Bristol-Myers Squibb, Chiesi, Eisai, Ethicon,
Forest Laboratories, Ironwood, Ischemix, Lilly, Medtronic,
Pfizer, Roche, Sano fiAventis, The Medicines Company;
Royalties: Elsevier (Editor, Cardiovascular Intervention: A
Companion to Braunwald ’s Heart Disease ); Site Co-Investiga-
tor: Biotronik, Boston Scienti fic, St. Jude Medical (now
Abbott); Trustee: American College of Cardiology; UnfundedResearch: FlowCo, Merck, PLx Pharma, Takeda. Storey
reports research grants, consultancy fees and honoraria fromAstraZeneca; research grants and consultancy fees from
PlaqueTec; consultancy fees from Actelion, Avacta, Bayer,
Bristol Myers Squibb/P fizer alliance, Novartis, The Medicines
Company, and ThermoFisher Scienti fic. Cohen reports grants
and personal fees from AstraZeneca, during the conduct of
the study; personal fees from Merck, personal fees from
Janssen, personal fees from Maquet, personal fees from
malpractice attorneys, grants from Janssen, grants fromEdwards, personal fees from Merck, personal fees from BMS/
Pfizer, personal fees from Janssen, personal fees from BI,
personal fees from Lilly, outside the submitted work. Budaj
reports grants and personal fees from AstraZeneca, during the
conduct of the study; grants and personal fees from
GlaxoSmithKline, Bristol Myers Squibb/P fizer; grants from
Sano fi-Aventis, Boehringer Ingelheim, Novartis, Eisai, outside
the submitted work. Nicolau reports grants and personal fees
from AstraZeneca, during the conduct of the study;
grants from Jansen, grants, personal fees, and non financial
support from Sano fi, non financial support from Bayer, grants
and personal fees from Boeheringer Ingelheim, and grants
from BMS, outside the submitted work. Parkhomenko reportsgrants and personal fees from AstraZeneca, during the
conduct of the study; grants and personal fees from Bristol
Myers Squibb/P fizer, Sano fi-Aventis, Bayer, Janssen; and
research grants from Servier, Daiichi-Sankyo, outside the
submitted work. Dellborg reports personal fees from Astra-
Zeneca, during the conduct of the study; and personal fees
from Boehringer Ingelheim, Novartis, and Amgen, outside the
submitted work. Werf reports personal fees from AstraZeneca
for lectures and advisory board meetings. Jensen is anemployee of AstraZeneca. Johanson is an employee of
AstraZeneca. Braunwald reports grant support to institution
from AstraZeneca. Sabatine reports research grant support
through Brigham and Women ’s Hospital from: Abbott Labo-
ratories; Amgen; AstraZeneca; Critical Diagnostics; Daiichi-
Sankyo; Eisai; Genzyme; Gilead; GlaxoSmithKline; Intarcia;
Janssen Research Development; MedImmune; Merck; Novar-
tis; Poxel; P fizer; Roche Diagnostics; Takeda (All >$10 000
per year). Consulting for: Alnylam; Amgen; AstraZeneca;
Cubist; CVS Caremark; Esperion; Intarcia; Ionis; Medicines
Company; MedImmune; Merck; MyoKardia; Zeus Scienti fic (all
≤$10 000 per year except Amgen, Esperion, and Ionis). The
remaining authors have no disclosures to report.
References
1. Bhatt DL, Eagle KA, Ohman EM, Hirsch AT, Goto S, Mahoney EM, Wilson PW,
Alberts MJ, D ’Agostino R, Liau CS, Mas JL, Rother J, Smith SC Jr, Salette G,
Contant CF, Massaro JM, Steg PG; REACH Registry Investigators. Comparativedeterminants of 4-year cardiovascular event rates in stable outpatients at risk
of or with atherothrombosis. JAMA . 2010;304:1350 –1357.
2. Bonaca MP, Bhatt DL, Steg PG, Storey RF, Cohen M, Im K, Oude Ophuis T,
Budaj A, Goto S, Lopez-Sendon J, Diaz R, Dalby A, Van de Werf F, Ardissino D,
Montalescot G, Aylward P, Magnani G, Jensen EC, Held P, Braunwald E,
Sabatine MS. Ischaemic risk and ef ficacy of ticagrelor in relation to time from
DOI: 10.1161/JAHA.118.009260 Journal of the American Heart Association 8Reduction in Myocardial Infarction With Ticagrelor Bonaca et alORIGINAL RESEARCH
Downloaded from http://ahajournals.org by on December 23, 2018

P2Y12 inhibitor withdrawal in patients with prior myocardial infarction:
insights from PEGASUS-TIMI 54. Eur Heart J . 2016;37:1133 –1142.
3. Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD; the
Writing Group on behalf of the Joint ESC/ACCF/AHA/WHF Task Force for the
Universal De finition of Myocardial Infarction. Third universal de finition of
myocardial infarction. Circulation . 2012;126:2020 –2035.
4. Tricoci P. Consensus or controversy?: evolution of criteria for myocardial
infarction after percutaneous coronary intervention. Clin Chem . 2017;63:82 –
90.
5. Diaz-Garzon J, Sandoval Y, Smith SW, Love S, Schulz K, Thordsen SE, Johnson
BK, Driver B, Jacoby K, Carlson MD, Dodd KW, Moore J, Scott NL, Bruen CA,
Hatch R, Apple FS. Discordance between ICD-coded myocardial infarction anddiagnosis according to the universal de finition of myocardial infarction. Clin
Chem . 2017;63:415 –419.
6. Morrow DA, Wiviott SD, White HD, Nicolau JC, Bramucci E, Murphy SA, Bonaca
MP, Ruff CT, Scirica BM, McCabe CH, Antman EM, Braunwald E. Effect of thenovel thienopyridine prasugrel compared with clopidogrel on spontaneous and
procedural myocardial infarction in the Trial to Assess Improvement in
Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-
Thrombolysis in Myocardial Infarction 38: an application of the classi fication
system from the universal de finition of myocardial infarction. Circulation .
2009;119:2758 –2764.
7. Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S,
Neumann FJ, Ardissino D, De Servi S, Murphy SA, Riesmeyer J, Weerakkody G,
Gibson CM, Antman EM; TRITON-TIMI 38 Investigators. Prasugrel versus
clopidogrel in patients with acute coronary syndromes. N Engl J Med .
2007;357:2001 –2015.
8. Cavender MA, Bhatt DL, Stone GW, White HD, Steg PG, Gibson CM, Hamm CW,
Price MJ, Leonardi S, Prats J, Deliargyris EN, Mahaffey KW, Harrington RA;
CHAMPION PHOENIX Investigators. Consistent reduction in periprocedural
myocardial infarction with cangrelor as assessed by multiple de finitions:
findings from CHAMPION PHOENIX (Cangrelor Versus Standard Therapy to
Achieve Optimal Management of Platelet Inhibition). Circulation . 2016;134:
723–733.9. Kidd SK, Bonaca MP, Braunwald E, De Ferrari GM, Lewis BS, Merlini PA,
Murphy SA, Scirica BM, White HD, Morrow DA. Universal classi fication system
type of incident myocardial infarction in patients with stable atherosclerosis:
observations from thrombin receptor antagonist in secondary prevention of
atherothrombotic ischemic events (TRA 2 degrees P)-TIMI 50. J Am Heart
Assoc . 2016;5:e003237. DOI: 10.1161/JAHA.116.003237.
10. Bonaca MP, Bhatt DL, Braunwald E, Cohen M, Steg PG, Storey RF, Held P,
Jensen EC, Sabatine MS. Design and rationale for the prevention of
cardiovascular events in patients with prior heart attack using ticagrelor
compared to placebo on a background of aspirin-thrombolysis in myocardial
infarction 54 (PEGASUS-TIMI 54) trial. Am Heart J . 2014;167:437 –444.e5.
11. Bonaca M, Scirica B, Sabatine M, Dalby A, Spinar J, Murphy SA, Jarolim P,
Braunwald E, Morrow DA. Prospective evaluation of the prognostic implica-
tions of improved assay performance with a sensitive assay for cardiac
troponin I. J Am Coll Cardiol . 2010;55:2118 –2124.
12. Gaggin HK, Liu Y, Lyass A, van Kimmenade RR, Motiwala SR, Kelly NP, Mallick
A, Gandhi PU, Ibrahim NE, Simon ML, Bhardwaj A, Belcher AM, Harisiades JE,
Massaro JM, D ’Agostino RBS, Januzzi JL Jr. Incident type 2 myocardial
infarction in a cohort of patients undergoing coronary or peripheral arterial
angiography. Circulation . 2017;135:116 –127.
13. Andre P, Delaney SM, LaRocca T, Vincent D, DeGuzman F, Jurek M, Koller B,
Phillips DR, Conley PB. P2Y12 regulates platelet adhesion/activation,
thrombus growth, and thrombus stability in injured arteries. J Clin Invest .
2003;112:398 –406.
14. Storey RF, Angiolillo DJ, Bonaca MP, Thomas MR, Judge HM, Rollini F,
Franchi F, Ahsan AJ, Bhatt DL, Kuder JF, Steg PG, Cohen M, Muthusamy R,
Braunwald E, Sabatine MS. Platelet inhibition with ticagrelor 60 mg versus
90 mg twice daily in the PEGASUS-TIMI 54 Trial. J Am Coll Cardiol .
2016;67:1145 –1154.
15. Wang K, Zhou X, Zhou Z, Tarakji K, Carneiro M, Penn MS, Murray D, Klein A,
Humphries RG, Turner J, Thomas JD, Topol EJ, Lincoff AM. Blockade of the
platelet P2Y12 receptor by AR-C69931MX sustains coronary artery recanal-
ization and improves the myocardial tissue perfusion in a canine thrombosis
model. Arterioscler Thromb Vasc Biol . 2003;23:357 –362.
DOI: 10.1161/JAHA.118.009260 Journal of the American Heart Association 9Reduction in Myocardial Infarction With Ticagrelor Bonaca et alORIGINAL RESEARCH
Downloaded from http://ahajournals.org by on December 23, 2018

Supplement al Material

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Table S1. Baseline Characteristics by Recurrent Myocardial Infarction .

SD-standard deviation, mmHG -millimeters of mercury, eGFR -estimated glomerular filtration rate, MDRD –
Modification of Diet in Renal Disease, PAD -peripheral artery disease, CHF -congestive heart failure, MI –
myocardial infarction, CABG -coronary artery bypass grafting surgery, PCI -percutaneous intervention, DES -drug
eluting st ent, NSTEMI -non-ST elevation myocardial infarction Characteristic No MI MI p-value
N=20,264 N=898

Age, mean (SD) 65.3 (8.32) 66.2 (9.02) 0.0027
Female, n(%) 4842 (23.89%) 218 (24.28%) 0.7931
Body Mass Index, median (range) 27.8
(25.14, 31.14) 28.4
(25.31, 31.59) 0.0248
SBP (mmHg), mean (SD) 132.5 (16.89) 135.1 (18.72) 0.0002

History Hypertension, n (%) 15660 (77.29%) 747 (83.18%) <.0001
History of Hypercholesterolaemia, n (%) 15540 (76.7%) 701 (78.06%) 0.3452
Current Smoker, n (%) 3347 (16.52%) 189 (21.05%) 0.0004
History of Diabetes, n (%) 6439 (31.78%) 367 (40.87%) <.0001
eGFR < 60 (MDRD), n (%) 4570 (22.84%) 279 (31.38%) <.0001

History of PAD, n (%) 1057 (5.22%) 86 (9.58%) <.0001
History of Atrial Fibrillation, n (%) 809 (3.99%) 58 (6.46%) 0.0003
History of CHF, n (%) 4005 (19.77%) 221 (24.61%) 0.0004
Prior Angina, n (%) 6196 (30.58%) 359 (39.98%) <.0001
Multivessel Coronary Artery Disease, n (%) 11959 (59.03%) 599 (66.7%) <.0001
History of Second Prior MI, n (%) 3201 (15.8%) 298 (33.18%) <.0001
Prior CABG, n (%) 842 (4.16%) 133 (14.81%) <.0001
History of PCI with stenting, n (%) 16184 (80.15%) 707 (78.82%) 0.3296
Prior PCI with DES (1=Yes, 0=No), n (%) 7880 (48.69%) 409 (57.85%) <.0001
Qualifying MI: NSTEMI, n (%) 8124 (40.14%) 459 (51.11%) <.0001

Region <.0001
North America, n (%) 3680 (18.16%) 227 (25.28%)
South America, n (%) 2372 (11.71%) 86 (9.58%)
Western Europe (incl. S Af), n (%) 5847 (28.85%) 291 (32.41%)
Eastern Europe, n (%) 6066 (29.93%) 224 (24.94%)
Asia/Australia/New Zealand, n (%) 2299 (11.35%) 70 (7.8%)
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Figure S1. Cumulative incidence of myocardial infarction subtypes occurring in patients
randomized to placebo (on aspirin monotherapy) during follow up .

0%1%2%3%4%5%6%
0 90 180 270 360 450 540 630 720 810 900 990 1080Effect of Ticagrelor on MI
Days from RandomizationKaplan -Meier Event Rate (%)All MI Events
5.2%
Spontaneous
(Type 1)
4.1%
Demand
(Type 2)
0.75%
Type 3 -5
0.60%
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Figure S2. Ticagrelor and fatal myocardial infarction, sudden cardiac death and the
composite of both .

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