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Listen to this manuscript’s
audio summary by
JACC Editor-in-Chief
Dr. Valentin Fuster.
J O U R N A L O F T H E AM E R I C A N C O L L E G E O F C A R D I O L O G Y V O L . 6 7 , N O . 2 3 , 2 0 1 6
ª 2 0 1 6 B Y T H E AM E R I C A N C O L L E G E O F C A R D I O L O G Y F O UN DA T I O N I S S N 0 7 3 5 - 1 0 9 7 / $ 3 6 . 0 0
P U B L I S H E D B Y E L S E V I E R h t t p : / / d x . d o i . o r g / 1 0 . 1 0 1 6 / j . j a c c . 2 0 1 6 . 0 3 . 5 2 4
Ticagrelor for Prevention of IschemicEvents After Myocardial Infarction inPatients With Peripheral Artery Disease
Marc P. Bonaca, MD, MPH,a Deepak L. Bhatt, MD, MPH,a Robert F. Storey, MD,b Ph. Gabriel Steg, MD,cMarc Cohen, MD,d Julia Kuder, MS,a Erica Goodrich, MS,a José C. Nicolau, MD, PHD,e Alexander Parkhomenko, MD,f
José López-Sendón, MD,g Mikael Dellborg, MD,h Anthony Dalby, MD,i Jind�rich �Spinar, MD,j Philip Aylward, MD,k
Ramón Corbalán, MD,l Maria Teresa B. Abola, MD,m Eva C. Jensen, MD, PHD,n Peter Held, MD, PHD,n
Eugene Braunwald, MD,a Marc S. Sabatine, MD, MPHa
ABSTRACT
Fro
Inf
dio
Sch
Pa
tig
GokD
vis
Me
BACKGROUND Peripheral artery disease (PAD) is associated with heightened ischemic and bleeding risk in patients
with prior myocardial infarction (MI).
OBJECTIVES This study evaluated the efficacy and safety of ticagrelor on major cardiovascular (CV) events and major
adverse limb events in patients with PAD and a prior MI.
METHODS PEGASUS-TIMI 54 (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) randomized 21,162 patients
with prior MI (1 to 3 years) to ticagrelor 90 mg twice daily, ticagrelor 60 mg twice daily, or placebo, all on a background of
low-dose aspirin. History of PAD was obtained at baseline. Occurrences of major adverse cardiovascular events (MACE)
(defined as CV death, MI, or stroke) and major adverse limb events (MALE) (defined as acute limb ischemia or peripheral
revascularization for ischemia) were recorded in follow-up.
RESULTS A total of 1,143 patients (5%) had known PAD. In the placebo arm, those with PAD (n ¼ 404) had higher rates
of MACE at 3 years than those without (n ¼ 6,663; 19.3% vs. 8.4%; p < 0.001), which persisted after adjusting for
baseline differences (adjusted hazard ratio: 1.60; 95% confidence interval: 1.20 to 2.13; p ¼ 0.0013), and higher rates of
acute limb ischemia (1.0% vs. 0.1%) and peripheral revascularization procedures (9.15% vs. 0.46%). Whereas the
relative risk reduction in MACE with ticagrelor was consistent, regardless of PAD, patients with PAD had a greater ab-
solute risk reduction of 4.1% (number needed to treat: 25) due to their higher absolute risk. The absolute excess of TIMI
major bleeding was 0.12% (number needed to harm: 834). The 60-mg dose had particularly favorable outcomes for CV
and all-cause mortality. Ticagrelor (pooled doses) reduced the risk of MALE (hazard ratio: 0.65; 95% confidence interval:
0.44 to 0.95; p ¼ 0.026).
CONCLUSIONS Among stable patients with prior MI, those with concomitant PAD have heightened ischemic risk. In
these patients, ticagrelor reduced MACE, with a large absolute risk reduction, and MALE. (Prevention of Cardiovascular
Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin [PEGASUS-
TIMI 54]; NCT01225562) (J Am Coll Cardiol 2016;67:2719–28) © 2016 by the American College of Cardiology Foundation.
m the aTIMI Study Group, Brigham and Women’s Hospital Heart & Vascular Center, Boston, Massachusetts; bDepartment of
ection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom; cFrench Alliance for Car-
vascular Trials, Université Paris-Diderot, Paris, France; dCardiovascular Division, Newark Beth Israel Medical Center, Icahn
ool of Medicine at Mount Sinai, New York, New York; eHeart Institute (InCor)–University of São Paulo Medical School, São
ulo, Brazil; fUkranian Strazhesko Institute of Cardiology, Kiev, Ukraine; gHospital Universitario La Paz, Instituto de Inves-
ación La Paz, Madrid, Spain; hDepartment of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg,
thenburg, Sweden; iLife Fourways Hospital, Randburg, South Africa; jUniversity Hospital, Jihlavska, Brno, Czech Republic;
ivision of Medicine, Cardiac & Critical Care Services, Flinders Medical Centre, South Australia, Australia; lCardiovascular Di-
ion, Pontificia Universidad Católica de Chile, Santiago, Chile; mPhilippine Heart Center, University of the Philippines College of
dicine, Manila, Philippines; and nAstraZeneca R&D, Mölndal, Sweden. The TIMI Study Group has received significant research
grant supp
Dr. Bhatt h
Bioscience
is chair of
Clinical Re
received h
Publication
Clinical Re
ology), Jou
trial steeri
Patient Car
served as v
Publication
Laboratorie
(Editor, Ca
Scientific,
FlowCo, PL
received p
Scientific.
Amarin, A
Janssen, M
personal fe
Janssen, M
grants from
support fro
and Sanofi
Novartis, a
received p
Boehringer
received a
received gr
of the stud
and as a sp
and has re
Institute. D
received in
and Wom
GlaxoSmith
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ABBR EV I A T I ON S
AND ACRONYMS
ALI = acute limb ischemia
CABG = coronary artery
bypass graft
CI = confidence interval
HR = hazard ratio
MACE = major adverse
cardiovascular event(s)
MALE = major adverse limb
event(s)
MI = myocardial infarction
PAD = peripheral artery
disease
TIA = transient ischemic attack
TIMI = Thrombolysis In
Myocardial Infarction
Bonaca et al. J A C C V O L . 6 7 , N O . 2 3 , 2 0 1 6
Ticagrelor in Patients With PAD and Prior MI J U N E 1 4 , 2 0 1 6 : 2 7 1 9 – 2 8
2720
P atients with peripheral artery dis-ease (PAD) are at heightened risk ofmajor adverse cardiovascular events
(MACE), including myocardial infarction(MI) and stroke. The presence of concomitantsymptomatic PAD in patients with coronarydisease (i.e., polyvascular disease), has beenassociated with a further heightened risk ofischemic events and mortality beyond thatassociated with symptomatic disease ineither vascular territory (coronary or periph-eral artery) alone (1–4).
SEE PAGE 2729
Intensive antithrombotic strategies aimedat reducing risk of MACE in patients withPAD have shown mixed results. Whereasantiplatelet monotherapy has been shown to
ort from AstraZeneca. Dr. Bonaca has received consulting fees from
as served on the advisory board of Cardax, Elsevier Practice Up
s; has served on the Board of Directors of Boston VA Research Inst
the American Heart Association Quality Oversight Committee; has
search Institute, Harvard Clinical Research Institute, Mayo Clinic
onoraria from the American College of Cardiology (Senior Associa
s (Editor-in-Chief, Harvard Heart Letter), Duke Clinical Research
search Institute (clinical trial steering committee), HMP Commun
rnal of the American College of Cardiology (Guest Editor; Associate E
ng committee), Slack Publications (Chief Medical Editor, Cardiol
e (Secretary/Treasurer), and WebMD (CME steering committees); h
ice-chair of the NCDR-ACTION Registry Steering Committee; ha
s Committee; has received research funding from Amarin, Astra
s, Ischemix, Medtronic, Pfizer, Roche, Sanofi, and The Medicin
rdiovascular Intervention: A Companion to Braunwald’s Heart Di
and St. Jude Medical; is a trustee of the American College of Ca
x Pharma, and Takeda. Dr. Storey has received grants, personal
ersonal/consultancy fees from Aspen, PlaqueTec, Correvio, The M
Dr. Steg has received research grants from Merck, Sanofi, and Se
straZeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, C
erck, Novartis, Pfizer, Regeneron, Sanofi, Servier, and The Medi
es from AstraZeneca during the conduct of the study; outside of t
aquet, malpractice attorneys, Merck, Bristol-Myers Squibb/Pfizer
Janssen and Edwards Lifesciences. Dr. Nicolau has received
m Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer
. Dr. López-Sendón has received research grants from AstraZen
nd Servier; and has received honoraria from AstraZeneca, Lilly
ersonal fees from AstraZeneca during the conduct of the study;
Ingelheim, DiscoveryHealth, Lilly, Novartis, Pfizer, Sanofi, and Se
research grant, has received honoraria for speaking, and served
ants andmodest personal/speaker fees from and served on the loc
y; as an investigator in other ticagrelor trials has received modest
eaker for Pfizer; has received modest personal fees as speaker fo
ceived modest investigator fees from Bayer, Boehringer Ingelhei
r. Jensen is an employee of AstraZeneca. Dr. Held is an employee
stitutional grant support from AstraZeneca. Dr. Sabatine has
en’s Hospital from Abbott Laboratories, Amgen, AstraZeneca,
Kline, Intarcia, Merck, Novartis, Poxel, Roche Diagnostics, Sano
mgen, AstraZeneca, Cubist, CVS Caremark, Intarcia, and Merck (
ave no relationships relevant to the contents of this paper to dis
t received February 23, 2016; revised manuscript received March
reduce ischemic risk in patientswith symptomatic PAD(4–6), the combination of aspirin and a P2Y12 inhibitorin patients with PAD undergoing lower extremitybypass surgery did not reduce a broad composite ofcardiovascular and limb endpoints (7). However, largerstudies evaluating the combination of aspirin andclopidogrel have shown trends of benefit for reducingMACE in patients with symptomatic vascular disease,including those with PAD (8,9). More recently, theaddition of a PAR-1 antagonist, vorapaxar, was shownto reduce the risk of MACE in patients with prior MI orPAD but increase GUSTO (Global Use of Strategies toOpen Occluded Arteries) moderate or severe bleeding(10). In addition to reducing MACE, vorapaxar wasshown to reduce limb morbidity, including acute limbischemia (ALI) and peripheral revascularization pro-cedures, when added to aspirin and/or clopidogrel(11,12). These findings highlight the potential of
AstraZeneca, Merck, Bayer, and Roche Diagnostics.
date Cardiology, Medscape Cardiology, and Regado
itute, and the Society of Cardiovascular Patient Care;
served on the data monitoring committees of Duke
, and the Population Health Research Institute; has
te Editor, Clinical Trials and News, ACC.org), Belvoir
Institute (clinical trial steering committees), Harvard
ications (Editor-in-Chief, Journal of Invasive Cardi-
ditor), Population Health Research Institute (clinical
ogy Today’s Intervention), Society of Cardiovascular
as served as deputy editor of Clinical Cardiology; has
s served as the chair of the VA CART Research and
Zeneca, Bristol-Myers Squibb, Eisai, Ethicon, Forest
es Company; has received royalties from Elsevier
sease); is a site coinvestigator for Biotronik, Boston
rdiology; and has performed unfunded research for
fees, and travel support from AstraZeneca; and has
edicines Company, Medscape, and Thermo Fisher
rvier; and has served as a consultant or speaker for
SL Behring, Daiichi-Sankyo-Lilly, GlaxoSmithKline,
cines Company. Dr. Cohen has received grants and
his study he has received personal fees from Merck,
, Boehringer Ingelheim, and Lilly; and has received
speaker/consulting honoraria and/or research grant
Ingelheim, GlaxoSmithKline, Merck, Novartis, Pfizer,
eca, Lilly/Daiichi-Sankyo, GlaxoSmithKline, Pfizer,
/Daiichi-Sankyo, Merck, and Sanofi. Dr. Dalby has
and has received personal fees from Aspen, Bayer,
rvier outside of the submitted work. Dr. Aylward has
on the advisory board of AstraZeneca. Dr. Abola has
al advisory board for AstraZeneca during the conduct
personal fees as a member of the advisory board of
r Bayer, Boehringer Ingelheim, and Daiichi-Sankyo;
m, Daiichi-Sankyo, and Population Health Research
and stockholder of AstraZeneca. Dr. Braunwald has
received research grant support through Brigham
Critical Diagnostics, Daiichi-Sankyo, Eisai, Gilead,
fi, and Takeda; and has served as a consultant for
all #$10,000/year). All other authors have reported
close.
23, 2016, accepted March 25, 2016.
TABLE 1 Baseline Characteristics
No PAD(n ¼ 20,017)
PAD(n ¼ 1,143) p Value
Age, yrs 65 (59–71) 66 (60–73) 0.0003
Age $75 yrs 2,892 (14.45) 191 (16.71) 0.035
Female 4,806 (24.01) 254 (22.22) 0.1682
Body mass index, kg/m2 27.8 (25.16–31.16) 27.8 (24.84–31.14) 0.0845
Caucasian 17,260 (86.23) 1,066 (93.26) <0.0001
History of hypertension 15,441 (77.14) 966 (84.51) <0.0001
History of hypercholesterolemia 15,317 (76.53) 924 (80.84) 0.0008
Current smoker 3,191 (15.95) 345 (30.18) <0.0001
History of COPD 444 (6.66) 68 (16.83) <0.0001
eGFR <60 ml/min/1.73 m2 (MDRD) 4,494 (22.73) 355 (31.47) <0.0001
History of diabetes 6,324 (31.59) 482 (42.17) <0.0001
History of CHF 3,888 (19.42) 338 (29.57) <0.0001
History of stroke or TIA 312 (1.56) 35 (3.06) 0.0001
History of second prior MI 3,207 (16.02) 292 (25.55) <0.0001
Multivessel coronary artery disease 11,821 (59.07) 736 (64.39) 0.0004
Prior angina 6,097 (30.46) 458 (40.07) <0.0001
Prior CABG 827 (4.13) 148 (12.95) <0.0001
History of PCI with stenting 16,028 (80.07) 863 (75.5) <0.0001
ABI #0.90 0 217 (18.99) —
Peripheral revascularization 0 389 (34.03) —
History of claudication 0 747 (65.35) —
Region <0.0001
North America 3,669 (18.33) 238 (20.82)
South America 2,342 (11.7) 116 (10.15)
Western Europe (including South Africa) 5,819 (29.07) 317 (27.73)
Eastern Europe 5,867 (29.31) 423 (37.01)
Asia/Australia/New Zealand 2,320 (11.59) 49 (4.29)
Time from qualifying MI, yrs 1.7 (1.24–2.33) 1.7 (1.23–2.35) 0.762
Qualifying MI type <0.0001
Unknown 1,142 (5.71) 81 (7.11)
STEMI 10,814 (54.09) 515 (45.18)
NSTEMI 8,037 (40.2) 544 (47.72)
Qualifying MI $2 yrs prior 7,707 (38.55) 447 (39.21) 0.6551
Time from last dose of P2Y12 inhibitor, days 152 (16–418) 86 (6.5–361.5) <0.0001
Aspirin use at baseline 19,989 (99.86) 1,142 (99.91) 0.6414
Statin use at baseline 18,537 (92.61) 1,067 (93.35) 0.3483
Beta-blocker use at baseline 16,541 (82.63) 944 (82.59) 0.9688
ACE-I or ARB use at baseline 16,093 (80.4) 936 (81.89) 0.2155
Values are median (IQR) or n (%).
ABI ¼ ankle-brachial index; ACE ¼ angiotensin-converting enzyme; ARB ¼ angiotensin receptor blocker;CABG ¼ coronary artery bypass graft; CHF ¼ congestive heart failure; COPD ¼ chronic obstructive pulmonarydisease; eGFR ¼ estimated glomerular filtration rate; IQR ¼ interquartile range; MDRD ¼ Modification of Diet inRenal Disease; MI ¼ myocardial infarction; NSTEMI ¼ non–ST-segment elevation myocardial infarction; PAD ¼peripheral artery disease; PCI ¼ percutaneous coronary intervention; STEMI ¼ ST-segment elevation myocardialinfarction; TIA ¼ transient ischemic attack.
J A C C V O L . 6 7 , N O . 2 3 , 2 0 1 6 Bonaca et al.J U N E 1 4 , 2 0 1 6 : 2 7 1 9 – 2 8 Ticagrelor in Patients With PAD and Prior MI
2721
antithrombotic therapies to reduce limb morbidity inpatients with PAD.
The association of concomitant PAD with anincreased risk of ischemic events is complicated by thefact that PAD is also associated with an increased riskof bleeding (13). There are many shared comorbiditiesthat increase the risk of both PAD and bleeding,including age and renal dysfunction. In addition, it ispossible that the diseased vasculature in PAD patientsmay be more prone to injury or procedural complica-tions leading to bleeding. In trials of potent antith-rombotic strategies for prevention in PAD, there havebeen significant increases in bleeding risk, particu-larly with full-dose anticoagulants (7,8,10,14).
The PEGASUS-TIMI 54 (Prevention of Cardiovas-cular Events in Patients With Prior Heart Attack Us-ing Ticagrelor Compared to Placebo on a Backgroundof Aspirin–Thrombolysis In Myocardial Infarction 54)trial demonstrated that the addition of ticagrelor, apotent, reversible P2Y12 inhibitor, reduces long-termischemic risk in patients with a history of MI. Thisreduction in ischemic risk was accompanied by anincrease in TIMI (Thrombolysis In Myocardial Infarc-tion) major bleeding. We therefore investigated theischemic and bleeding risks associated with concomi-tant symptomatic PAD and whether the effects ofticagrelor on MACE and major adverse limb events(MALE) were modified by the presence of PAD.
METHODS
STUDY POPULATION. The PEGASUS-TIMI 54 trialrandomized patients with prior MI to ticagrelor 90 mgtwice daily, ticagrelor 60 mg twice daily, or placebo,all on a background of low-dose aspirin. The design(15) and primary results of the trial have been pub-lished (16). In brief, the trial enrolled 21,162 patientswith a spontaneous MI occurring 1 to 3 years prior toenrollment and at least 1 of the following additionalhigh-risk features: age $65 years; diabetes mellitusrequiring medication; a second prior spontaneous MI;multivessel coronary artery disease; or chronic renaldysfunction, defined as a creatinine clearance <60ml/min, as estimated by the Cockcroft-Gault equa-tion. Patients were ineligible if there was planned useof a P2Y12 receptor antagonist or anticoagulant ther-apy during the study period; if they had a bleedingdisorder, or a history of an ischemic stroke or intra-cranial bleeding, a central nervous system tumor, oran intracranial vascular abnormality; or if they hadhad gastrointestinal bleeding within the previous 6months or major surgery within the previous month.The presence of PAD was determined at baseline in21,160 patients. In addition, among patients with
PAD sites were to report whether there was anankle-brachial index (ABI) #0.90, a history of periph-eral revascularization, or a history of claudication.ENDPOINTS. The primary efficacy endpoint was thecomposite of CV death, MI, or stroke (MACE). ALIwas prospectively collected and adjudicated usinga previously published definition that requiredboth a clinical presentation consistent with acuteischemia and findings either on physical examinationor by imaging (12). Peripheral revascularization
Bonaca et al. J A C C V O L . 6 7 , N O . 2 3 , 2 0 1 6
Ticagrelor in Patients With PAD and Prior MI J U N E 1 4 , 2 0 1 6 : 2 7 1 9 – 2 8
2722
procedures were site reported and were collectedprospectively on a dedicated electronic case reportform. A trained reviewer (M.P.B.), blinded to treat-ment assignment, identified peripheral revasculari-zation for ischemia (e.g., chronic critical limb
FIGURE 1 Outcomes in Placebo Patients by PAD at Baseline
Risk of MACE with P25%
20%
15%
10%
5%
0%0 180 360 54
Unadjusted HR 2.46 (95% CAdjusted HR 1.60 (95% CI 1
Days from Ra
CV D
eath
, MI,
or S
trok
e (%
)
Number at RiskPAD 404 384 367 34
No PAD 6663 6508 6394 615
no PAD
HR(95%CI)p–value
3.32(2.30–4.79)
P<0.001
1.93(1.35-2.75)P<0.001
16%
3.0%
5.0%
9.6% 9.5%
1.8%
4.0%
0.1%
1.0%
7.0%
12.
14%
12%
10%
8%
6%
4%
2%
0%CVD Myocardial
InfarctionStroke Acute limb
ischemiaCoronaRevasc
2.80(1.68–4.67)
P<0.001
13.70(3.67–50.90)
P<0.001
1.7(1.31–2P<0.0
N=6663
A
B
KM R
ate
at 3
Yea
rs (%
)
(A) CV death, MI, or stroke at 3 years in the placebo arm by known PAD
endpoints at 3 years in the placebo arm by known PAD at baseline. Unad
patients with PAD versus no PAD. ARR ¼ absolute risk reduction; CI ¼ c
intracranial hemorrhage; KM ¼ Kaplan-Meier; MACE ¼ major adverse ca
artery disease; TIMI ¼ Thrombosis In Myocardial Infarction.
ischemia, ALI, or claudication). The endpoint ofMALE was defined as the composite of ALI and pe-ripheral revascularization for ischemia. Amputationwas collected as a safety event and included ampu-tations for any cause (e.g., trauma, infection, or
AD vs no PAD
0 720 900 1080
I 1.92 – 3.15), p<0.001.20 – 2.13), p=0.0013
ndomization
PAD PatientsN=40419.3%
Patients without PADN=6663
8.4%
4 309 223 1049 5567 4120 1924
5%
9.2%
4.6%
1.0%1.6% 1.4%
2.2%
0.6%1.3%
0.5%
14.0%
ry.
PeripheralRevasc.
All CauseMortality
TIMI MajorBleeding
TIMIMajor/Minor
Bleeding
ICH or FatalBleeding
8.43)01
19.04(11.47–31.59)
P<0.001
3.16(2.35–4.27)
P<0.001
1.47(0.53–4.07)
P=0.46
1.67(0.72–3.85)
P=0.23
2.05(0.62–6.76)
P=0.24
PADN=404
at baseline with unadjusted and adjusted HRs. (B) Efficacy and safety
justed HRs, 95% CIs, and p values are shown for outcomes in placebo
onfidence interval; CV ¼ cardiovascular; HR ¼ hazard ratio; ICH ¼rdiovascular events; MI ¼ myocardial infarction; PAD ¼ peripheral
FIGURE 2 Risk of MACE by Type of PAD
0.1 0.75 2.5 5 101.0
2.8720.9
18.6
17.7 8.4
8.4
8.4 (1.94 – 4.26) <0.001
No PAD Group = 6,663
(1.69 – 3.27) <0.001
(0.91 – 4.06) 0.085Ankle Brachial Index ≤ 0.90N=48
ClaudicationN=222
Hazard Ratio forCVD/MI/Stroke
3 Year KMRate (%)
PAD No PAD (95% CI) P–Value
Prior PeripheralRevascularizationN=133
2.35
1.93
Risk of major adverse cardiovascular events by type of PAD versus no PAD (n ¼ 6,663) at
baseline in placebo arm. Categories were hierarchical including any history of peripheral
revascularization, claudication with no history of peripheral revascularization, and
abnormal ankle brachial index (#0.90) only with no claudication or history of peripheral
revascularization. CVD ¼ cardiovascular death; other abbreviations as in Figure 1.
FIGURE 3 Adjusted Risk of Efficacy and Safety Events by PAD Status
Adjusted* HazardRatio
3 Year KMRate (%)
PAD No PAD (95% CI) P-Value
CVD /MI / Stroke
CV Death
Myocardial Infarction
Stroke
Mortality
TIMI Major Bleeding
1.84
1.60
1.33
2.31
2.05
1.57
19.3
9.6
9.5
4.0
14.0
1.6
4.6
1.0
3.0
8.4
5.0
1.8
(1.20 – 2.13)
(1.16 – 2.94)
(0.91 – 1.94)
(1.26 – 4.25)
(1.43 – 2.94)
(0.47 – 5.22)
0.0013
0.0102
0.14
0.46
0.0071
<0.001
1.00.1 10PAD PADBetter Worse
Adjusted risk of efficacy and safety endpoints in the placebo arm by known PAD versus no
PAD at baseline. HRs, 95% CIs, and p values shown are all from the adjusted model.
*Adjusted for age, race, MI type, second prior MI, diabetes, multivessel disease, hyper-
tension, hypercholesterolemia, smoking, CHF, COPD, prior stroke/TIA, angina, CABG, PCI
with stenting, time from P2Y12 withdrawal, eGFR, and region. Abbreviations as in Figures 1
and 2.
J A C C V O L . 6 7 , N O . 2 3 , 2 0 1 6 Bonaca et al.J U N E 1 4 , 2 0 1 6 : 2 7 1 9 – 2 8 Ticagrelor in Patients With PAD and Prior MI
2723
ischemia). Due to the lack of specificity, this outcomewas not included in the MALE endpoint for thisanalysis, but was included in a sensitivity analysis ofMALE by treatment arm. The primary safety endpointwas TIMI major bleeding. Additional safety endpointswere TIMI minor bleeding, intracranial hemorrhage(ICH), and fatal bleeding. A clinical events committeeblinded to treatment allocation adjudicated all pri-mary efficacy outcomes, ALI, and bleeding events.STATISTICAL ANALYSIS. Baseline characteristicswere summarized using medians and quartiles forcontinuous variables and frequencies and percent-ages for categorical variables. Differences were testedwith the Wilcoxon rank sum test for continuous var-iables and with the Pearson chi-square test for cate-gorical data. Cox proportional hazard models wereused to assess the risk of MACE. Associations betweenPAD and the risk of MACE were adjusted for baselineclinical characteristics that differed significantly be-tween patients with and without PAD (age, race,MI type, second prior MI, diabetes, multivessel dis-ease, hypertension, hypercholesterolemia, smoking,congestive heart failure, chronic obstructive pulmo-nary disease, prior stroke/transient ischemic attack,angina, coronary artery bypass graft [CABG], timefrom P2Y12 withdrawal, history of percutaneous cor-onary intervention with stenting, estimated glomer-ular filtration rate, and region). Clinical predictors ofMALE were evaluated in patients overall and then inthose with known PAD at baseline. Clinical baselinecharacteristics that differed (p < 0.1) were enteredinto a backward model selection to identify inde-pendent predictors with variables with p values>0.05, which were removed 1 at a time until all var-iables remaining had a p value <0.05. Analyses of theefficacy and safety of ticagrelor were not adjustedbecause treatment was randomized; therefore, base-line characteristics and potential confounders wereapproximately balanced (Online Table 1). The pro-portional hazards assumption was visually examinedby scaled Schoenfeld residual plot, and the validity ofthis assumption was not violated. Efficacy analyseswere performed on an intention-to-treat basis. Safetyanalyses included all patients who received at least 1dose of study drug and included all events occurringafter receipt of the first dose and within 7 days of thelast dose of study drug. The prognostic accuracy ofthe models was compared using the area under thecurve derived from receiver-operating characteristiccurves (C-statistic) (17). The ability of the model toenhance discrimination and correctly reclassify sub-jects was additionally tested with the integrateddiscrimination improvement and the category-freenet reclassification improvement (18,19).
RESULTS
A total of 21,162 patients were enrolled into thePEGASUS-TIMI 54 trial with prior MI and 1,143 (5%)had known PAD at randomization. Patients with
CENTRAL IL
Bonaca, M.P. et al
Efficacy of ticagrelo
reduction; CI ¼ confi
Bonaca et al. J A C C V O L . 6 7 , N O . 2 3 , 2 0 1 6
Ticagrelor in Patients With PAD and Prior MI J U N E 1 4 , 2 0 1 6 : 2 7 1 9 – 2 8
2724
known PAD primarily had a history of claudication(65%), with approximately one-third (34%) having ahistory of a peripheral revascularization procedureand only 48 (w4%) with an abnormal ABI onlywithout prior revascularization or symptoms(Table 1). Baseline characteristics in those with andwithout PAD at baseline are shown in Table 1, and bytreatment arm within the PAD group in OnlineTable 1. The presence of PAD at baseline was associ-ated with older age, qualifying non–ST-segmentelevation MI relative to ST-segment elevation MI,diabetes, renal dysfunction, smoking status, heartfailure, history of stroke or transient ischemic attack,and time from last dose of P2Y12 inhibitor prior torandomization (Table 1). Patients with PAD at baseline
LUSTRATION Ticagrelor in Patients With PAD and Pr
. J Am Coll Cardiol. 2016;67(23):2719–28.
r in patients with PAD: CV death, MI, or stroke at 3 years with ticagrelor (po
dence interval; CV ¼ cardiovascular; HR ¼ hazard ratio; MI ¼myocardial infarc
were more likely to have multivessel coronary diseaseand a history of CABG, and less likely to have a historyof percutaneous coronary intervention (Table 1). Useof background medical therapy, including aspirin(99.9%), statins (93%), beta-blockers (83%), andangiotensin-converting enzyme inhibitors or angio-tensin receptor blockers (80.5%) was high andsimilar, regardless of known PAD.
PAD AND RISK IN PATIENTS RANDOMIZED TO
PLACEBO. At 3 years, patients with concomitant PADat baseline randomized to placebo had more than a2-fold increase in the rate of MACE events relative topatients without concomitant PAD (19.3% vs. 8.4%;unadjusted hazard ratio [HR]: 2.46; 95% confidence
ior MI: 3-Year Results
oled doses, purple) versus placebo (green). ARR ¼ absolute risk
tion; NNT ¼ number needed to treat; PAD ¼ peripheral artery disease.
J A C C V O L . 6 7 , N O . 2 3 , 2 0 1 6 Bonaca et al.J U N E 1 4 , 2 0 1 6 : 2 7 1 9 – 2 8 Ticagrelor in Patients With PAD and Prior MI
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interval [CI]: 1.92 to 3.15) (Figure 1A). Rates of theindividual components of CV death, MI, or stroke, aswell as all-cause mortality were also higher in pa-tients with PAD (Figure 1B). The risk of MACE associ-ated with PAD at baseline was highest in patients witha history of prior peripheral revascularization, fol-lowed by those with claudication but no history ofrevascularization, and patients with an abnormal ABI(#0.90) alone (Figure 2). Among patients with PAD,components of MALE, including peripheral revascu-larization, occurred in 9.2% of patients and ALI in1.0%, whereas (as expected) these events occurredin <1% of patients without known PAD at randomi-zation (Figure 1B). Overall, beyond PAD history, in-dependent predictors of MALE at baseline were priorCABG, current smoking, hypertension, chronicobstructive pulmonary disease, and diabetes (OnlineTable 2). For the patients with known PAD, a priorhistory of peripheral revascularization (HR: 3.76; 95%CI: 2.26 to 6.25; p < 0.001) was the only independentpredictor of future MALE.
Patients in the placebo arm with PAD tended tohave higher rates of bleeding at 3 years comparedwith patients without known PAD, including TIMImajor bleeding (1.56% vs. 1.03%; HR: 1.47; 95% CI:0.53 to 4.07; p ¼ 0.46) (Figure 1B), TIMI major or mi-nor bleeding (2.21% vs. 1.37%; HR: 1.67; 95% CI: 0.72to 3.85; p ¼ 0.23), and the composite of ICH or fatalbleeding (1.25% vs. 0.57%; HR: 2.05; 95% CI: 0.62 to6.76, p ¼ 0.24) (Figure 1B).
After adjusting for differences in baseline charac-teristics, patients with concomitant PAD at baseline
TABLE 2 Efficacy and Safety of Ticagrelor in Patients With PAD
Placebon, %
Ticagrelor 60 mgn, %
Efficacy outcomes, N 404 368
CV death, MI, stroke 71, 19.3 47, 14.1
CV death 34, 9.6 15, 4.2
All-cause mortality 51, 14.0 25, 8.2
Stroke 17, 4.0 8, 2.9
Ischemic stroke 16, 3.7 8, 2.9
Safety outcomes, N 399 363
TIMI major 4, 1.6 4, 1.6
TIMI major or minor 6, 2.2 7, 3.2
ICH or fatal bleeding 3, 1.3 0, —
Values are n, 3-year Kaplan-Meier (%), unless otherwise indicated.
CI ¼ confidence interval; CV ¼ cardiovascular; HR ¼ hazard ratio; ICH ¼ intracranial h
had a significantly higher risk of MACE relative topatients without concomitant PAD (adjusted HR:1.60; 95% CI: 1.20 to 2.13; p ¼ 0.0013) (Figure 1A). El-ements of the model before and after the addition ofPAD, as well as the C-statistic change and measures ofreclassification, are shown in Online Tables 3 to 5.Directionally similar results existed for the compo-nents of MACE, particularly CV death (adjusted HR:1.84; 95% CI: 1.16 to 2.94; p ¼ 0.0102) and stroke(adjusted HR: 2.31; 95% CI: 1.26 to 4.25; p ¼ 0.0071).All-cause mortality was also significantly higher(adjusted HR: 2.05; 95% CI: 1.43 to 2.94; p < 0.001)(Figure 3). The adjusted risk of TIMI major bleeding(adjusted HR: 1.57; 95% CI: 0.47 to 5.22; p ¼ 0.46)(Figure 3), TIMI major or minor bleeding (adjustedHR: 1.51; 95% CI: 0.53 to 4.30; p ¼ 0.44), and thecomposite of ICH or fatal bleeding (adjusted HR: 1.97;95% CI: 0.44 to 8.80; p ¼ 0.37) tended to remainhigher in patients with PAD.
EFFICACY AND SAFETY OF TICAGRELOR FOR MACE
IN PATIENTS WITH PRIOR MI AND PAD. There was noheterogeneity in the relative risk reduction withticagrelor for MACE in patients on the basis of thepresence of PAD at baseline (p interaction ¼ 0.41)(Central Illustration). However, by nature of theirgreater absolute risk, patients with PAD had anumerically greater absolute risk reduction at 3 years(4.1%; 95% CI: �1.07% to 9.29%) relative to thosewithout PAD (1.0%; 95% CI: 0.14% to 1.9%) (CentralIllustration). The efficacy versus placebo was gener-ally similar for the 2 doses of ticagrelor, but, of note,
Ticagrelor 90 mgn, %
Ticagrelor 60 mgHR (95% CI)
p Value
Ticagrelor 90 mgHR (95% CI)
p Value
371
54, 16.3 0.69 (0.47–0.99)p ¼ 0.045
0.81 (0.57–1.15)p ¼ 0.24
26, 7.9 0.47 (0.25–0.86)p ¼ 0.014
0.83 (0.50–1.38)p ¼ 0.46
41, 11.7 0.52 (0.32–0.84)p ¼ 0.0074
0.88 (0.58–1.32)p ¼ 0.53
10, 3.1 0.49 (0.21–1.14)p ¼ 0.097
0.63 (0.29–1.38)p ¼ 0.25
7, 2.0 0.52 (0.22–1.22)p ¼ 0.13
0.47 (0.19–1.14)p ¼ 0.095
368
5, 1.8 1.18 (0.29–4.70)p ¼ 0.82
1.46 (0.39–5.43)p ¼ 0.57
8, 3.1 1.36 (0.46–4.05)p ¼ 0.58
1.57 (0.54–4.53)p ¼ 0.40
1, 0.4 — 0.39 (0.04–3.75)p ¼ 0.42
emorrhage; MI ¼ myocardial infarction; TIMI ¼ Thrombosis In Myocardial infarction.
FIGURE 4 Efficacy and Safety of Ticagrelor in Patients With PAD
CVD / MI / Stroke
CV Death
Stroke
Mortality
TIMI Major Bleeding
Myocardial Infarction
0.11.0
10Ticagrelor Better Placebo Better
Absolute RiskDifference at
3 Years HR (95% CI) P-Value
Ticagrelor 90 mgTicagrelor 60 mg
– 3.0– 5.2
– 1.7– 5.4
– 2.0– 1.0
– 0.9– 1.1
– 2.3– 5.7
0.220.02
0.81 (0.57 – 1.15)0.69 (0.47 – 0.99)
0.83 (0.50 – 1.38)0.47 (0.25 – 0.86)
0.76 (0.45 – 1.28)0.87 (0.53 – 1.44)
0.63 (0.29 – 1.38)0.49 (0.21 – 1.14)
0.88 (0.58 – 1.32)0.52 (0.32 – 0.84)
1.46 (0.39 – 5.43)1.18 (0.29 – 4.70)
0.0450.24
0.0140.46
0.590.30
0.0970.25
0.820.57
0.00740.53
Efficacy and safety of ticagrelor 60 mg twice daily (purple) and ticagrelor 90 mg twice
daily (green) versus placebo in patients with PAD. Abbreviations as in Figures 1 and 2.
FIGURE 5 Ticagrel
Acut
e Li
mb
Isch
emia
or
Perip
hera
l Rev
ascu
lariz
atio
n fo
r Isc
hem
ia (%
)
1.0%
0.8%
0.6%
0.4%
0.2%
0.0%
Number at RiskPlacebo
Ticagrelor
0
706714095
MALE at 3 years wit
major adverse limb e
Bonaca et al. J A C C V O L . 6 7 , N O . 2 3 , 2 0 1 6
Ticagrelor in Patients With PAD and Prior MI J U N E 1 4 , 2 0 1 6 : 2 7 1 9 – 2 8
2726
the 60-mg dose resulted in a significant reduction inCV mortality (HR: 0.47; 95% CI: 0.25 to 0.86;p ¼ 0.014) (Table 2, Figure 4), which drove a reductionin all-cause mortality (HR: 0.52; 95% CI: 0.32 to 0.84;p ¼ 0.0074).
Ticagrelor increased TIMI major bleeding consis-tently for patients with PAD (pooled doses HR: 1.32;95% CI: 0.41 to 4.29) and without PAD (HR: 2.59; 95%CI: 1.91 to 3.52; p interaction ¼ 0.28). Although pa-tients with PAD randomized to placebo were atgreater absolute risk of bleeding, the absolute risk
or and MALE in Patients With PAD
Placebo Ticagrelor Pooled
0.71%
0.46%
HR 0.6595% CI (0.44 – 0.95)
P=0.026
180 360 540 720 900 1080
698813929
691213789
670113425
607712186
45189154
21234296
Days from Randomization
h ticagrelor (pooled doses, purple) versus placebo (green). MALE ¼vents; other abbreviations as in Figure 1.
increase with ticagrelor at 3 years was numericallylower for those with PAD (0.12%; 95% CI: �1.79% to2.04%) relative to those without PAD (1.46%; 95%CI: 1.01% to 1.91%) at baseline, although events wereinfrequent. Secondary bleeding outcomes by baselinePAD for both ticagrelor doses are shown in Table 2.Rates of intracranial hemorrhage and fatal bleeding inpatients with PAD were low.
MALE WITH TICAGRELOR. Overall, ticagrelorreduced MALE (HR: 0.65; 95% CI: 0.44 to 0.95;p ¼ 0.026) (Figure 5), with a numerically greaterrelative risk reduction with the 90-mg dose (HR: 0.49;95% CI: 0.30 to 0.81; p ¼ 0.005) relative to the 60-mgdose (HR: 0.81; 95% CI: 0.53 to 1.24; p ¼ 0.33)(Table 3). The effects were consistent for both areduction in ALI (pooled doses HR: 0.56; 95% CI: 0.23to 1.37) and peripheral revascularization for limbischemia (pooled doses HR: 0.63; 95% CI: 0.43 to 0.93)(Online Figure 1). Results were similar in thesubgroup of patients with a known history of PAD(Online Table 6) as well as when including amputa-tion for any reason (Online Table 7).
DISCUSSION
This study demonstrates that in outpatients in stablecondition with a history of MI, concomitant PADis associated with significantly heightened risk ofsystemic ischemic events, limb ischemic events,bleeding, and all-cause mortality. In addition, thebenefit of ticagrelor for the relative risk reduction ofMACE was consistent, regardless of the presence orabsence of known PAD; however, by nature of theirheightened risk, patients with PAD had a particularlyrobust absolute risk reduction (Central Illustration).Finally, the combination of aspirin and ticagrelorreduced MALE relative to aspirin monotherapy.
The association of PAD with increased MACE risk inpatients who are already at heightened risk by natureof a prior MI is complex. Possible explanationsinclude that the presence of disease in more than 1bed indicates a more severe form of atheroscleroticvascular disease. In addition, PAD is associated withother markers of atherothrombotic risk, includingage, renal dysfunction, diabetes, and smoking. Afteradjustment for these baseline differences, however,PAD remained a potent marker of systemic ischemicrisk. Regardless of whether PAD is a marker of a moresevere vascular phenotype, an integrator of multipleadverse risk factors, or both, in practice it is an easilyidentifiable and potent indicator of future risk. In thecurrent study, the magnitude of risk for MACE asso-ciated with claudication was similar to that of ahistory of peripheral revascularization, providing
TABLE 3 Limb Vascular Efficacy With Ticagrelor
Placebo(n ¼ 7,067)
n, %
Ticagrelor 60 mg(n ¼ 7,045)
n, %
Ticagrelor 90 mg(n ¼ 7,050)
n, %
Ticagrelor 60 mgHR (95% CI)
p Value
Ticagrelor 90 mgHR (95% CI)
p Value
Acute limb ischemia or peripheral revascularizationfor ischemia
47, 0.71 38, 0.60 23, 0.32 0.81 (0.53–1.24)p ¼ 0.33
0.49 (0.30–0.81)p ¼ 0.005
Acute limb ischemia 9, 0.13 6, 0.11 4, 0.06 0.67 (0.24–1.87) 0.45 (0.14–1.45)
Peripheral revascularization for ischemia 46, 0.70 37, 0.59 21, 0.29 0.80 (0.52–1.24) 0.46 (0.27–0.76)
Peripheral revascularization 60, 0.94 46, 0.74 38, 0.55 0.77 (0.52–1.13) 0.63 (0.42–0.95)
Values are n, 3-year Kaplan-Meier (%), unless otherwise indicated.
Abbreviations as in Table 2.
J A C C V O L . 6 7 , N O . 2 3 , 2 0 1 6 Bonaca et al.J U N E 1 4 , 2 0 1 6 : 2 7 1 9 – 2 8 Ticagrelor in Patients With PAD and Prior MI
2727
validity to this clinical indicator of PAD. These find-ings underscore the importance of identifyingcomorbid PAD in the clinic to inform future risks ofboth MACE and MALE.
Identification of heightened MACE risk is particu-larly useful if it informs clinical decision-making. ThePEGASUS-TIMI 54 trial demonstrated that ticagreloris efficacious for the reduction of MACE in patientswith prior MI. Still, the need to balance ischemic ef-ficacy and bleeding risk has created a desire toexplore subgroups where ticagrelor has particularlyrobust efficacy. In the current analysis, we demon-strate that the presence of PAD does not modifythe relative efficacy of ticagrelor. However, due totheir more than 2-fold higher MACE risk, patientswith PAD enjoyed a robust absolute risk reduction of4.1% at 3 years, translating into a number needed totreat (NNT) of 25 (annualized NNT ¼ 74). Althougheach dose was tested independently against placebo,and there was no formal interaction between the ef-ficacy of either dose and the baseline presence ofknown PAD, the clearest benefit occurred with the60-mg dose, with a 5.2% absolute risk reduction inMACE and NNT of 20 (annualized NNT ¼ 58), as wellas significant reductions in both CV death and all-cause mortality. At the same time, bleeding withticagrelor appeared to be similar in patients with andwithout PAD. Therefore, the presence of PAD may behelpful to clinicians in identifying patients with priorMI who are likely to have a robust benefit withticagrelor.
In addition to MACE risk, patients with PAD in thePEGASUS-TIMI 54 trial were at heightened risk ofMALE. Limb revascularization for ischemia was asfrequent as MI and occurred at more than twice therate of stroke in patients with PAD. A history ofperipheral revascularization was a predictor of MALEin patients with PAD in this analysis, corroboratingobservations from other studies (11).
To date, dual antiplatelet therapy with aspirin andclopidogrel has not been prospectively shown to be
efficacious for reducing limb vascular events in pa-tients with PAD (7). Although not powered to addressthis question, the current study suggests that dualantiplatelet therapy with aspirin and ticagrelor maybe efficacious for reducing ALI if studied in larger,higher-risk cohorts. In addition, the reduction in theexploratory endpoint of peripheral revascularizationfor ischemia also supports potential antithromboticbenefits of ticagrelor on the limb circulation. Whetherpotent antiplatelet therapy can reduce elective revas-cularization for claudication, as has been observedwith other mechanisms, remains unknown (11). Thesequestions will be evaluated as secondary outcomes inthe ongoing EUCLID (A Study Comparing Cardiovas-cular Effects of Ticagrelor and Clopidogrel in PatientsWith Peripheral Artery Disease [NCT01732822]) trial,which is comparing ticagrelor and clopidogrel asmonotherapy for a primary endpoint of MACE.STUDY LIMITATIONS. The PAD cohort, althoughcomprising more than 1,000 patients, was a subgroupof the PEGASUS-TIMI 54 trial and thus had morelimited power for exploration of the more rareendpoints, such as ALI. In addition, patients wereidentified as having PAD at baseline by study in-vestigators, but no formal screening was required,and some patients may therefore have entered thetrial with undiagnosed PAD. Questionnaires toimprove the ascertainment and enable adjudicationof claudication as a marker of PAD were not used,thereby potentially decreasing the specificity of thisbaseline characteristic. Amputations were collectedas safety data and were not adjudicated, therebylimiting ascertainment and specificity of thisoutcome. In addition, details regarding procedurestypically considered in the endpoint of MALE (e.g.,thrombolysis/thrombectomy) were not available,underscoring the importance of examining theseoutcomes in dedicated studies in patients withPAD. Finally, peripheral revascularizations weresite-reported; however, they were collected on aspecific case report form page with instructions.
PERSPECTIVES
COMPETENCY IN PATIENT CARE: Prolonged
therapy with ticagrelor reduced ischemic risk and
increased bleeding in patients with prior MI, and in a
subgroup analysis, those with concomitant PAD
appeared to derive greater absolute benefit than
those without PAD.
TRANSLATIONAL OUTLOOK: An ongoing pro-
spective trial of ticagrelor as antiplatelet monotherapy
should providemore insight into the efficacy and safety
of ticagrelor monotherapy versus clopidogrel mono-
therapy in a broad population of patients with PAD,
including those without concomitant coronary disease.
Bonaca et al. J A C C V O L . 6 7 , N O . 2 3 , 2 0 1 6
Ticagrelor in Patients With PAD and Prior MI J U N E 1 4 , 2 0 1 6 : 2 7 1 9 – 2 8
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CONCLUSIONS
In patients with prior MI, concomitant PAD is asso-ciated with heightened risk of ischemic vascularcomplications and mortality, even after adjusting fortheir extensive comorbidities. In these patients, thecombination of ticagrelor and aspirin for long-termsecondary prevention appeared to reduce ischemicrisk with a particularly robust absolute risk reduction,including reductions in MACE and limb vascularevents.
REPRINT REQUESTS AND CORRESPONDENCE: Dr.Marc P. Bonaca, TIMI Study Group, CardiovascularDivision, Brigham and Women’s Hospital, 75 FrancisStreet, Boston, Massachusetts 02115. E-mail:[email protected].
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KEY WORDS acute limb ischemia, majoradverse cardiovascular events, major adverselimb events, peripheral arterial disease,ticagrelor
APPENDIX For supplemental tables and afigure, please see the online version of thisarticle.