European Heart Journal (2020) 41, 3533–3545 CLINICAL RESEARCH

doi:10.1093/eurheartj/ehaa670 Acute Coronary Syndromes

Ticagrelor alone vs. ticagrelor plus aspirin

following percutaneous coronary intervention
in patients with non-ST-segment elevation acute
coronary syndromes: TWILIGHT-ACS

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Usman Baber1,2, George Dangas2, Dominick Joseph Angiolillo 3,
David Joel Cohen 4, Samin Kumar Sharma2, Johny Nicolas 2, Carlo Briguori 5,
Jin Yu Cha2, Timothy Collier 6, Dariusz Dudek7, Vladimir D zavik8,
Javier Escaned 9, Robert Gil 10, Paul Gurbel11, Christian W. Hamm12,
Timothy Henry13, Kurt Huber 14, Adnan Kastrati 15, Upendra Kaul16,
Ran Kornowski17, Mitchell Krucoff18, Vijay Kunadian 19,20, Steven Owen Marx 21,
Shamir Mehta22, David Moliterno 23, Erik Magnus Ohman18, Keith Oldroyd 24,
Gennaro Sardella25, Samantha Sartori 2, Richard Shlofmitz 26,
Philippe Gabriel Steg27, Giora Weisz28, Bernhard Witzenbichler 29, Ya-Ling Han30,
Stuart Pocock 6, Charles Michael Gibson31, and Roxana Mehran 2*
1
Department of Cardiology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; 2Department of Cardiology, The Zena and Michael A.
Wiener Cardiovascular Institute, Mount Sinai Hospital, One Gustave L. Levy Place, Box 1030, New York, NY 10029-6574, USA; 3Department of Cardiology, University of
Florida–Shands, Jacksonville, FL 32218, USA; 4Department of Cardiology, University of Missouri-Kansas CIty, Kansas City, MO 64110, USA; 5Department of Cardiology, Clinica
Mediterranea, 80122 Napoli NA, Italy; 6Department of Cardiology, London School of Hygiene and Tropical Medicine, Keppel St, Bloomsbury, London WC1E 7HT, UK; 7The 2nd
Department of Cardiology Jagiellonian University Medical College, Swietej Anny 12, 31-008 Krakow, Poland; 8Department of Interventional Cardiology, Research and Innovation
in Interventional Cardiology and Cardiac Intensive Care, Peter Munk Cardiac Centre, University Health Network, 200 Elizabeth St, Toronto, ON M5G 2CA, Canada;
9
Department of Cardiology, Instituto de Investigacion Sanitaria del Hospital Clinico San Carlos and Complutense University, Calle del Prof Martin Lagos, s/n, 28040 Madrid,
Spain; 10Department of Invasive Cardiology, Center of Postgraduate Medical Education, Central Clinical Hospital of the Ministry of Interior and Administration, 137 Woloska Str,
02-507 Warsaw, Poland; 11Department of Cardiology, Sinai Hospital of Baltimore System, Baltimore, MD 21215, USA; 12Department of Cardiology, Kerckhoff Clinic,
Benekestrabe 2-8, 61231 Bad Nauheim, Germany; 13Department of Cardiology, The Carl and Edyth Lindner Center for Research and Education at the Christ Hospital,
Cincinnati, OH 45219, USA; 14Department of Cardiology, Wilhelminenhospital, Montleartstrabe 37, 1160 Wien, Austria; 15Department of Cardiology, Deutsches Herzzentrum
Munchen, Lazarettstrabe 36, 80636 Munchen, Germany; 16Department of Cardiology, Batra Hospital and Medical Research Centre, New Delhi 110062, India; 17Department of
Cardiology, Rabin Medical Center, Zeev Jabutinsky Rd 39, Petach Tikva 49100, Israel; 18Department of Cardiology, Duke University Medical Center–Duke Clinical Research
Institute, Durham, NC 27710, USA; 19Department of Cardiology, Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Freeman Road, High Heaton,
NE7 7DN Newcastle upon Tyne, UK; 20Department of Cardiology, Cardiothoracic Centre, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Freeman
Road, High Heaton, NE7 7DN Newcastle upon Tyne, UK; 21Department of Cardiology, Columbia University Medical Center, New York, NY 10027, USA; 22Department of
Cardiology, Hamilton Health Sciences, Hamilton, ON L8N 3Z5, Canada; 23Department of Cardiology, University of Kentucky, Lexington, KY 40506, USA; 24Department of
Cardiology, The West of Scotland Heart and Lung Centre, Golden Jubilee National Hospital, Agamemnon St, Clydebank G81 4DY, UK; 25Department of Cardiology, Policlinico
Umberto I University, 00161 Roma, Italy; 26Department of Cardiology, St. Francis Hospital, Roslyn, 100 Port Washington Blvd, Roslyn, NY 11576, USA; 27Department of
Cardiology, Groupe Hospitalier Bichat–Claude-Bernard, 46 Rue Henri Huchard, 75018 Paris, France; 28Department of Cardiology, Montefiore Medical Center, The Bronx, NY
10467, USA; 29Department of Cardiology, Helios Amper-Klinikum, Krankenhausstrabe 15, 85221 Dachau, Germany; 30Department of Cardiology, Shenyang North Hospital,
Huanggu Qu, Shenyang Shi, Liaoning Sheng, China; and 31Department of Cardiology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA

Received 8 January 2020; revised 8 April 2020; editorial decision 29 July 2020; accepted 29 July 2020

Listen to the audio abstract of this contribution

See page 3546 for the editorial comment on this article (doi: 10.1093/eurheartj/ehaa644)

* Corresponding author. Center for Interventional Cardiovascular Research and Clinical Trials, The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of
Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1030, New York, NY 10029-6574, USA. Tel: þ1 212 659 9641, Email: roxana.mehran@mountsinai.org
C The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.
Published on behalf of the European Society of Cardiology. All rights reserved. V
3534 U. Baber et al.

Aims The aim of this study was to determine the effect of ticagrelor monotherapy on clinically relevant bleeding and
major ischaemic events in relation to clinical presentation with and without non-ST elevation acute coronary syn-
dromes (NSTE-ACS) among patients undergoing percutaneous coronary intervention (PCI) with drug-eluting stents
(DES).
...................................................................................................................................................................................................
Methods We conducted a pre-specified subgroup analysis of The Ticagrelor With Aspirin or Alone in High Risk Patients
and results After Coronary Intervention (TWILIGHT) trial, which enrolled 9006 patients with high-risk features undergoing
PCI with DES. After 3 months of dual antiplatelet therapy (DAPT) with ticagrelor plus aspirin, 7119 adherent and
event-free patients were randomized in a double-blind manner to ticagrelor plus placebo versus ticagrelor plus as-
pirin for 12 months. The primary outcome was Bleeding Academic Research Consortium (BARC) type 2, 3, or 5
bleeding while the composite of all-cause death, myocardial infarction (MI), or stroke was the key secondary out-
come. Among patients with NSTE-ACS (n = 4614), ticagrelor monotherapy reduced BARC 2, 3, or 5 bleeding by
53% [3.6% vs. 7.6%; hazard ratio (HR) 0.47; 95% confidence interval (CI) 0.36–0.61; P < 0.001) and in stable

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patients (n = 2503) by 24% (4.8% vs. 6.2%; HR 0.76; 95% CI 0.54–1.06; P = 0.11; nominal Pint = 0.03). Rates of all-
cause death, MI, or stroke among those with (4.3% vs. 4.4%; HR 0.97; 95% CI 0.74–1.28; P = 0.84) and without
(3.1% vs. 3.2%; HR 0.96; 95% CI 0.61–1.49; P = 0.85) NSTE-ACS were similar between treatment arms irrespective
of clinical presentation (Pint = 0.96).
...................................................................................................................................................................................................
Conclusion Among patients with or without NSTE-ACS who have completed an initial 3-month course of DAPT following PCI
with DES, ticagrelor monotherapy reduced clinically meaningful bleeding events without increasing ischaemic risk as
compared with ticagrelor plus aspirin. The benefits of ticagrelor monotherapy with respect to bleeding events
were more pronounced in patients with NSTE-ACS.
...................................................................................................................................................................................................
Trial registration Clinicaltrials.gov identifier: NCT02270242.
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Graphical Abstract

...................................................................................................................................................................................................

Keywords Acute coronary syndrome • Ticagrelor • Bleeding

Ticagrelor alone vs. ticagrelor plus aspirin in NSTE-ACS 3535

.. bifurcation lesion requiring two stents, obstructive left main or proximal

Introduction ..
.. left anterior descending lesion, or calcified target lesion requiring atherec-
The prevailing construct of dual antiplatelet therapy (DAPT) as the
.. tomy. Key exclusion criteria included presentation with STEMI, cardio-
..
preferred treatment for patients with acute coronary syndromes .. genic shock, need for oral anticoagulation, or contraindication to aspirin
(ACS) originated from clinical trials showing that the addition of an
.. or ticagrelor. For purposes of the present analysis, patients with NSTE-
..
oral P2Y12 inhibitor to aspirin significantly lowers recurrent ischaemic .. ACS included those presenting with either unstable angina or non-ST ele-
.. vation MI (NSTEMI).
events as compared with aspirin alone.1 These benefits extend to ..
patients with ACS undergoing percutaneous coronary intervention ..
.. Trial regimen
(PCI) and persist beyond 1 year.1–4 However, as these trials were .. All enrolled patients received open-label ticagrelor (90 mg twice daily)
designed with aspirin as a background antiplatelet agent, the observed ..
.. and enteric-coated aspirin (81–100 mg daily) after the index PCI. After
reductions in ischaemic events attributed to DAPT reflect the incre- .. 3 months, patients without major adverse events were randomized 1:1 in
mental effects of P2Y12 inhibition, not aspirin. As a corollary, the ben- ..
.. a double-blind fashion to aspirin or matching placebo for an additional
efits, or harms, of continuing aspirin as a long-term component of .. 12 months with the continuation of open-label ticagrelor. Patients who

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DAPT in the setting of ACS remain unknown. .. sustained Bleeding Academic Research Consortium (BARC) type 3b or
..
This distinction is clinically relevant as prolonged exposure to .. higher bleeds or ischaemic events (stroke, MI, or coronary revasculariza-
DAPT increases haemorrhagic risk and bleeding following PCI or .. tion) between enrolment and 3 months were not eligible for randomiza-
..
ACS associates with a large and significant risk for mortality.4,5 While .. tion. Non-adherence to ticagrelor or aspirin also rendered patients
reducing the duration of P2Y12 inhibition lowers bleeding and
.. ineligible for randomization. Randomization was performed using a se-
..
appears safe in low-risk patients , 6 this strategy increased coronary .. cure web-based system; an independent statistician not involved with the
thrombosis in the setting of ST-segment elevation myocardial infarc-
.. trial generated the allocation sequence, which was stratified by site with
.. randomly varying block sizes of 4, 6, or 8. Follow-up occurred 1 month
tion (MI).7 An alternative approach for patients with ACS involves ..
withdrawal of aspirin with continuation of a potent P2Y12 inhibitor,
.. after randomization via phone and in-person at 6 and 12 months after
.. randomization. After 12 months of protocol-mandated therapy, patients
thus preventing aspirin-related bleeding while maintaining the bene- ..
.. were switched to a standard-of-care antiplatelet regimen at the discretion
fits of P2Y12 platelet inhibition.8 Accordingly, we conducted a pre- .. of their treating physician followed by final telephone follow-up 3 months
specified subgroup analysis in the Ticagrelor With Aspirin or Alone in .. later.
..
High-Risk Patients after Coronary Intervention (TWILIGHT) trial to ..
examine the effect of ticagrelor monotherapy vs. ticagrelor plus as- .. Outcomes
..
pirin among patients with or without non-ST-segment elevation .. The primary endpoint was the time to first occurrence of BARC type 2,
acute coronary syndrome (NSTE-ACS) who were treated with PCI.9 .. 3, or 5 bleeding between randomization and 1 year. The key secondary
..
.. endpoint was the time to first occurrence of all-cause death, MI, or
.. stroke. Secondary bleeding endpoints included BARC type 3 or 5 bleed-
..
Methods .. ing (Take home figure),14 15Thrombolysis in Myocardial Infarction (TIMI)
.. major or minor bleeding, Global Use of Strategies to Open Occluded
Trial design and oversight .. Arteries moderate, severe, or life-threatening bleeding,16 or major bleed-
..
TWILIGHT was a randomized, placebo-controlled trial conducted in 187 .. ing as defined by the International Society of Thrombosis or
sites across 11 countries. The trial rationale, design, and principal results
.. Hemostasis.17 Other secondary endpoints included cardiovascular death,
..
have been reported previously.10 The Icahn School of Medicine at Mount .. non-fatal MI, ischaemic stroke, and definite or probable stent thrombosis.
Sinai designed and sponsored the trial, which was supported by an .. Myocardial infarction was defined according to the third universal defin-
.. ition, and revascularization and stent thrombosis were classified accord-
investigator-initiated grant from AstraZeneca. The executive and steering ..
committees were responsible for trial conduct, integrity of data analysis, .. ing to the Academic Research Consortium.18,19 All clinical events were
and reporting of results. National regulatory agencies and institutional re-
.. adjudicated by an external blinded independent committee.
..
view boards or ethics committees of participating centres approved the ..
trial protocol. An independent data safety monitoring board provided ex- .. Statistical analyses
..
ternal oversight to ensure the safety of all trial participants. AstraZeneca .. Clinical and procedural characteristics are summarized by randomized
provided financial support and supplied ticagrelor for the trial but had no .. group according to clinical presentation (NSTE-ACS vs. non-ACS) using
role in the design, collection, analysis, or interpretation of the data.
..
.. means (standard deviation) and frequencies for continuous and categoric-
.. al variables, respectively. The cumulative incidence rates for both primary
Trial population .. and secondary endpoints were estimated using the Kaplan–Meier
..
Patients undergoing successful PCI with at least one drug-eluting stent .. method. Patients without a primary endpoint between randomization
whom the treating clinician intended to discharge on ticagrelor plus as- .. and 1 year were censored at the time of death, last known contact, or
..
pirin were eligible to participate. Trial inclusion required the presence of .. 365 days, whichever came first. Hazard ratios and 95% confidence inter-
at least one clinical and one angiographic feature associated with a high .. vals (CIs) were generated using Cox proportional hazards models.
risk of ischaemic or bleeding events.5,11–13 Clinical criteria included age
.. Formal interaction tests between the main exposure of treatment alloca-
..
>_65 years, female sex, troponin positive ACS, atherosclerotic vascular .. tion (placebo vs. aspirin) and clinical presentation (NSTE-ACS vs. non-
disease (prior MI, coronary revascularization or peripheral arterial dis- .. ACS) on the primary and secondary endpoints were performed using
..
ease), diabetes mellitus requiring medication, or chronic kidney disease .. Cox regression. All analyses were performed using the intention to treat
(estimated glomerular filtration rate <60 mL/min/1.73 m2 or creatinine .. approach. As a sensitivity analysis, treatment effects were estimated
clearance <60 cc/min). Angiographic criteria included multivessel coron-
.. according to presentation with unstable angina and NSTEMI with formal
..
ary artery disease, total stent length > 30 mm, thrombotic target lesion, . interaction testing to assess for effect modification. Treatment effects
3536 U. Baber et al.

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Figure 1 Disposition of study participants. ACS, acute coronary syndrome; ASA, aspirin; BARC, Bleeding Academic Research Consortium; DAPT,
dual antiplatelet therapy; MI, myocardial infarction; NSTE-ACS, non-ST-segment elevation acute coronary syndrome; TICA, ticagrelor.

Table 1 Baseline clinical characteristics in randomized patients according to clinical presentation

NSTE-ACS Non-ACS
........................................................................... ...........................................................................
Tica 1 placebo Tica 1 aspirin P-value Tica 1 placebo Tica 1 aspirin P-value
(n 5 2273) (n 5 2341) (n 5 1281) (n 5 1222)
....................................................................................................................................................................................................................
Age (years) 64.2 ± 10.5 64.2 ± 10.6 0.99 67.0 ± 9.5 66.9 ± 9.7 0.98
Female sex, n (%) 580 (25.5) 581 (24.8) 0.45 266 (20.8) 271 (22.2) 0.39
Nonwhite race, n (%)a 872 (38.4) 854 (36.5) 0.62 238 (18.6) 231 (18.9) 0.43
Enrolling region 0.82 0.99
North America 882 (38.8) 917 (39.2) 601 (46.9) 571 (46.7)
Europe 698 (30.7) 730 (31.2) 553 (43.2) 528 (43.2)
Asia 693 (30.5) 694 (29.7) 127 (9.9) 123 (10.1)
Body mass index (kg/m2)b 28.4 ± 5.5 28.4 ± 5.7 0.85 28.9 ± 5.6 28.9 ± 5.4 0.99
Diabetes mellitus, n (%) 810 (35.6) 804 (34.3) 0.36 395 (30.8) 360 (29.5) 0.15
Insulin requiring, n (%) 221 (9.7) 237 (10.1) 0.47 114 (8.9) 137 (11.2) 0.15
Current smoking, n (%) 528 (23.3) 622 (26.6) 0.02 198 (15.5) 200 (16.4) 0.53
Hypertension, n (%) 1534 (67.5) 1577 (67.4) 0.95 1045 (81.6) 997 (81.6) 0.99
Peripheral artery disease, n (%) 130 (5.7) 132 (5.6) 0.91 114 (8.9) 112 (9.2) 0.82
Prior MI, n (%) 578 (25.4) 589 (25.2) 0.83 442 (34.5) 431 (35.3) 0.69
Prior PCI, n (%) 778 (34.2) 805 (34.4) 0.91 724 (56.5) 691 (56.6) 0.99
Prior CABG, n (%) 201 (8.8) 199 (8.5) 0.68 161 (12.6) 149 (12.2) 0.78
Prior major bleeding, n (%) 21 (0.9) 17 (0.7) 0.46 10 (0.8) 15 (1.2) 0.26
CKD, n (%)c 321 (14.6) 341 (15.1) 0.68 251 (20.6) 232 (19.9) 0.67
Anemia, n (%) 435 (19.9) 441 (19.5) 0.76 240 (19.8) 213 (18.4) 0.38

Values are expressed as n (%) or mean ± standard deviation; percentages may not total 100 because of rounding.
ACS, acute coronary syndrome; CABG, coronary artery bypass graft; CKD, chronic kidney disease; MI, myocardial infarction; NSTE-ACS, non-ST elevation acute coronary syn-
drome; PCI, percutaneous coronary intervention; Tica, ticagrelor.
a
Race was reported by the patient.
b
The body mass index is the weight in kilograms divided by the square of the height in metres.
c
Chronic kidney disease was defined as an estimated glomerular filtration rate of <60 mL/min/1.73 m2 of body surface area.
Ticagrelor alone vs. ticagrelor plus aspirin in NSTE-ACS 3537

Table 2 Baseline procedural variables in randomized patients according to clinical presentation

NSTE-ACS Non-ACS
........................................................................... ...........................................................................
Tica 1 placebo Tica 1 aspirin P-value Tica 1 placebo Tica 1 aspirin P-value
(n 5 2273) (n 5 2341) (n 5 1281) (n 5 1222)
....................................................................................................................................................................................................................
Multivessel CAD, n (%) 1409 (61.9) 1392 (59.5) 0.08 863 (67.4) 802 (65.6) 0.36
Target vessel, n (%)
Left main 117 (5.2) 120 (5.1) 0.97 49 (3.8) 67 (5.5) 0.05
LAD 1311 (57.7) 1368 (58.4) 0.60 682 (53.2) 641 (52.5) 0.69
LCX 742 (32.6) 771 (32.9) 0.83 408 (31.9) 375 (30.7) 0.53
RCA 795 (34.9) 795 (33.9) 0.47 448 (35.0) 462 (37.8) 0.14

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Radial artery access, n (%) 1743 (76.7) 1786 (76.3) 0.78 856 (66.8) 799 (65.4) 0.20
Stent length (mm) 40.5 ± 24.5 39.8 ± 24.6 0.35 39.4 ± 23.7 39.3 ± 23.6 0.95
Minimal stent diameter (mm) 2.9 ± 0.5 2.9 ± 0.5 0.16 2.8 ± 0.5 2.8 ± 0.5 0.96
Number of lesions treated, n 1.5 ± 0.7 1.5 ± 0.7 0.52 1.5 ± 0.7 1.5 ± 0.7 0.72
Lesion morphology,a n (%)
Moderate-to-severe calcification 272 (12.0) 278 (11.9) 0.92 226 (17.6) 210 (17.2) 0.76
Bifurcation 285 (12.5) 294 (12.6) 0.98 149 (11.6) 137 (11.2) 0.74
Total occlusion 128 (5.6) 143 (6.1) 0.49 94 (7.3) 81 (6.6) 0.49
Thrombotic 338 (14.9) 361 (15.4) 0.60 31 (2.4) 19 (1.6) 0.12

Values are expressed as n (%) or mean ± standard deviation.

ACS, acute coronary syndrome; CAD, coronary artery disease; LAD, left anterior descending; LCX, left circumflex; NSTE-ACS, non-ST elevation acute coronary syndrome;
RCA, right coronary artery; Tica, ticagrelor.
a
Lesion features were site-reported.

..
were also examined in the per protocol cohort after excluding patients .. mellitus and current smoking as compared with their counterparts pre-
with major deviations (n = 80). Additional exploratory analyses were per- .. senting without ACS. Other comorbid risk factors, including prior MI,
formed in the NSTE-ACS cohort to evaluate treatment effects in relation
..
.. prior coronary revascularization, and chronic kidney disease, were more
to risk factor burden, quantified at a patient level as the sum of pre- .. frequently observed in the non-ACS cohort. Target lesions were more
specified clinical and angiographic features (1–3; 4–5; 6–9). One-year ..
.. frequently characterized as thrombotic among those with NSTE-ACS
event rates were estimated using the Kaplan–Meier method within each .. while moderate-to-severe coronary calcification was more prevalent in
stratum of risk according to treatment allocation. Formal interaction test- ..
ing between risk stratum and treatment was performed using Cox
.. stable patients (Table 2). While most clinical and procedural parameters
.. were well-balanced across treatment arms, in the setting of NSTE-ACS
regression. ..
.. current smoking was significantly less frequent among those randomized
.. to ticagrelor plus placebo vs. ticagrelor plus aspirin (23.3% vs. 26.6%;
..
Results .. P = 0.02). In the NSTE-ACS cohort, rates of permanent ticagrelor dis-
..
.. continuation at 1 year were 12.2% and 13.6% among those randomized
Patient characteristics .. to ticagrelor plus placebo vs. ticagrelor plus aspirin ASA, respectively
..
As shown in Figure 1, among the 9006 patients enrolled in .. (P = 0.15), while results for blinded study drug discontinuation were
TWILIGHT, we excluded five with missing data as to type of presen- .. 16.3% and 17.1%, respectively (P = 0.46). In non-ACS patients, the rates
..
tation. Among the 5739 enrolled participants with NSTE-ACS, 19.6% .. of permanent ticagrelor discontinuation at 1 year were 14.2% and 14.9%
(n = 1125) were excluded from randomization over the ensuing
.. among those randomized to ticagrelor plus placebo vs. ticagrelor plus
..
3 months. The most common reasons for exclusion included non- .. ASA, respectively (P = 0.57). Analogous results for blinded study drug
adherence to DAPT (n = 637), major adverse events (n = 173), and
.. discontinuation were 18.4% and 18.9%, respectively (P = 0.69).
..
consent withdrawal or refusal (n = 158). Similar patterns were ..
.. Bleeding
observed for the 3262 enrolled patients without ACS. Hence, the ..
final cohort for the present analysis comprised 4614 randomized sub- .. In the NSTE-ACS cohort, BARC 2, 3, or 5 bleeding occurred in 81
..
jects with NSTE-ACS and 2503 randomized patients with stable pre- .. patients (3.6%) randomized to ticagrelor plus placebo vs. 175
sentations. The proportion of patients presenting with unstable .. patients (7.6%) randomized to ticagrelor plus aspirin (HR 0.47; 95%
..
angina and NSTEMI was 35.0% (n = 2494) and 29.8% (n = 2120), re- .. CI 0.36–0.61; P < 0.001), as shown in Table 3 and Figure 2A.
spectively. Clinical follow-up was available in 98.4% of randomized .. Analogous rates of BARC 2, 3, or 5 bleeding among those without
..
participants. .. ACS were 4.8% and 6.2% (HR 0.76; 95% CI 0.54–1.06; P = 0.11),
As shown in Table 1, patients with NSTE-ACS were generally
.. yielding a nominal interaction P-value of 0.03. Similar patterns were
..
younger, more often female and Asian with a higher burden of diabetes . observed for more severe bleeding and across different scales with
 3538

Table 3 Clinical outcomes over 1 year by randomized groups, stratified by clinical presentation

NSTE-ACS Non-ACS Interaction

..................................................................................................... .................................................................................................. P-value
Tica 1 placebo Tica 1 aspirin HR (95% CI) P-value Tica 1 placebo Tica 1 aspirin HR (95% CI) P-value
(n 5 2273), (n 5 2341), (n 5 1281), (n 5 1222),
n (%)a n (%)a n (%)a n (%)a
..........................
..................................................................................................................................................................................................................................................................................................
Bleeding outcomes
BARC 2, 3, or 5 81 (3.6) 175 (7.6) 0.47 (0.36–0.61) <0.001 60 (4.8) 75 (6.2) 0.76 (0.54–1.06) 0.11 0.03
BARC 3 or 5 17 (0.8) 49 (2.1) 0.36 (0.20–0.62) <0.001 17 (1.4) 20 (1.7) 0.81 (0.43–1.55) 0.53 0.06
GUSTO moderate or severe 13 (0.6) 36 (1.6) 0.37 (0.20–0.70) 0.002 13 (1.0) 13 (1.1) 0.96 (0.44–2.07) 0.91 0.06
TIMI major 12 (0.5) 23 (1.0) 0.54 (0.27–1.08) 0.08 5 (0.4) 11 (0.9) 0.43 (0.15–1.25) 0.12 0.74
ISTH major 20 (0.9) 51 (2.2) 0.40 (0.24–0.67) 0.001 19 (1.5) 21 (1.7) 0.87 (0.47–1.61) 0.65 0.06
Ischaemic outcomes
All-cause death, MI or stroke 96 (4.3) 102 (4.4) 0.97 (0.74–1.28) 0.84 39 (3.1) 39 (3.2) 0.96 (0.61–1.49) 0.85 0.96
CV death, MI or ischaemic stroke 90 (4.0) 97 (4.2) 0.96 (0.72–1.28) 0.77 36 (2.9) 35 (2.9) 0.98 (0.62–1.57) 0.95 0.92
All-cause death 22 (1.0) 34 (1.5) 0.67 (0.39–1.14) 0.14 12 (0.9) 14 (1.2) 0.82 (0.38–1.77) 0.61 0.67
MI 70 (3.1) 72 (3.1) 1.00 (0.72–1.39) 0.99 25 (2.0) 25 (2.1) 0.96 (0.55–1.66) 0.87 0.88
Ischaemic stroke 11 (0.5) 6 (0.3) 1.89 (0.70–5.10) 0.21 5 (0.4) 2 (0.2) 2.40 (0.47–12.38) 0.30 0.81
Definite/probable stent thrombosis 8 (0.4) 14 (0.6) 0.59 (0.25–1.40) 0.23 6 (0.5) 6 (0.5) 0.96 (0.31–2.97) 0.94 0.50

ACS, acute coronary syndrome; BARC, Bleeding Academic Research Consortium types range from 0 (no bleeding) to 5 (fatal bleeding); CI, confidence interval; CV, cardiovascular; GUSTO, Global Utilization of Streptokinase and Tissue
Plasminogen Activator for Occluded Coronary Arteries; HR, hazard ratio; ISTH, International Society on Thrombosis and Hemostasis; MI, myocardial infarction; NSTE-ACS, non-ST elevation acute coronary syndrome; Tica, ticagrelor; TIMI,
Thrombolysis in Myocardial Infarction.
a
Event percentages are Kaplan–Meier estimates of the incidence of the endpoint at 12 months after randomization.
U. Baber et al.

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Ticagrelor alone vs. ticagrelor plus aspirin in NSTE-ACS 3539

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Figure 2 (A) Kaplan–Meier estimates of Bleeding Academic Research Consortium 2, 3, or 5 bleeding with ticagrelor plus placebo and ticagrelor
plus aspirin in relation to clinical presentation. (B) Kaplan–Meier estimates of all-cause death, myocardial infarction or stroke with ticagrelor plus pla-
cebo and ticagrelor plus aspirin in relation to clinical presentation. ACS, acute coronary syndrome; BARC, Bleeding Academic Research Consortium
types range from 0 (no bleeding) to 5 (fatal bleeding); CI, confidence interval; HR, hazard ratio; MI, myocardial infarction; NSTE-ACS, non-ST elevation
myocardial infarction acute coronary syndrome; Tica, ticagrelor.

..
larger effect sizes detected among those with NSTE-ACS with the .. to ticagrelor plus placebo vs. 102 patients (4.4%) randomized to tica-
exception of TIMI major bleeding, which yielded comparable esti- .. grelor plus aspirin (HR 0.97; 95% CI 0.74–1.28; P = 0.84), as shown in
..
mates in acute and stable patients (Table 3). .. Table 3 and Figure 2B. Rates of all-cause death (1.0% vs. 1.5%), MI
.. (3.1% vs. 3.1%), ischaemic stroke (0.5% vs. 0.3%), and definite or
..
Ischaemic events .. probable stent thrombosis (0.4% vs. 0.6%) were similar (all P-value
Among patients with NSTE-ACS, the composite outcome of all- .. >0.1) (Table 3). Analogous rates of all-cause death, MI, or stroke in
..
cause death, MI, or stroke occurred in 96 patients (4.3%) randomized . non-ACS patients were 3.1% and 3.2% (HR 0.96; 95% CI 0.61–1.49;
3540 U. Baber et al.

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Take-home figure Among high-risk patients who have completed an initial 3-month course of dual antiplatelet therapy following percutan-
eous coronary intervention for non-ST-segment elevation acute coronary syndrome, ticagrelor monotherapy significantly reduced bleeding without
increasing ischaemic events compared with ticagrelor plus aspirin. BARC, Bleeding Academic Research Consortium types range from 0 (no bleeding)
to 5 (fatal bleeding); DAPT, dual antiplatelet therapy; MI, myocardial infarction; NSTE-ACS, non-ST-segment elevation acute coronary syndrome;
PCI, percutaneous coronary intervention.

..
P = 0.85). Patterns of risk were similar across treatment arms for .. Discussion
other endpoints in the non-ACS cohort, with no evidence of inter-
..
..
action between clinical presentation and treatment for any ischaemic .. Principal findings from the pre-specified TWILIGHT-ACS subgroup
.. analysis reported herein include: (i) ticagrelor monotherapy, as com-
outcome (all Pint > 0.1). ..
.. pared with ticagrelor plus ASA, reduced the incidence of clinically
.. relevant BARC 2, 3, or 5 bleeding over 1 year by 53% among those
..
Exploratory analyses .. with NSTE-ACS whereas in stable patients a more modest 24% rela-
Additional analyses in the NSTE-ACS cohort are presented in the
..
.. tive reduction was observed; (ii) the benefit of ticagrelor monother-
Supplementary material online, Tables and Figures. As shown in .. apy with respect to more severe BARC 3 or 5 bleeding was also
..
Supplementary material online, Table 1, the effect of ticagrelor mono- .. more pronounced among those with acute vs. stable syndromes
therapy on the primary and key secondary outcomes was consistent .. (64% vs. 19%); (iii) 1-year rates of ischaemic events, including all-
..
among patients with unstable angina or NSTEMI with no evidence of .. cause death, MI, and definite/probable stent thrombosis, appeared
effect modification. Results in Supplementary material online, Table 2
.. similar between treatment arms irrespective of clinical presentation;
..
show that findings in the per protocol cohort were consistent with .. and (iv) treatment effects with respect to ischaemic and bleeding out-
..
the intention to treat analysis. Supplementary material online, Figure 1 .. comes were consistent among patients presenting with unstable an-
displays the overall distribution of clinical and angiographic risk fac- .. gina or NSTEMI. In aggregate, these results suggest that the clinical
..
tors in the NSTE-ACS cohort. The proportion of patients with 1–3, .. benefits of ticagrelor monotherapy observed in the main TWILIGHT
4–5, or 6–9 risk factors was 34.2%, 49.1%, and 16.7%, respectively. As .. trial cohort are well preserved among patients presenting with
..
shown in Supplementary material online, Figure 2A, ticagrelor mono- .. NSTE-ACS.9
therapy significantly reduced BARC 2, 3, or 5 bleeding across these
.. Reductions in clinically relevant and major bleeding associated
..
risk strata in a consistent manner (Pint = 0.77). Analogous results for .. with ASA withdrawal were larger in magnitude among those with vs.
..
the outcome of all-cause death, MI, or stroke are displayed in .. without NSTE-ACS in the present analysis. Similar findings were
Supplementary material online, Figure 2B, which demonstrates no in- .. reported in a separate ACS cohort treated with ticagrelor as a back-
..
crease in ischaemic risk with ticagrelor monotherapy across risk .. ground antiplatelet agent.20 These results may reflect differences in
groups (Pint = 0.77).
.. the underlying clinical and demographic case-mix between patients
Ticagrelor alone vs. ticagrelor plus aspirin in NSTE-ACS 3541

..
with acute and stable syndromes randomized in TWILIGHT. For ex- .. Despite guideline recommendations to the contrary, clopidogrel
ample, the prevalence of study participants enrolled in Asia was ap- .. remains a commonly prescribed P2Y12 inhibitor among patients with
..
proximately three-fold higher among those with NSTE-ACS and the .. NSTE-ACS, and switching from a potent agent to clopidogrel (i.e. de-
bleeding-related effects of ASA may be accentuated in Asian as com- .. escalation) is relatively common after an acute thrombotic event.36–
.. 40
pared with non-Asian subjects.21 Moreover, patients with NSTE- .. These practice patterns may be driven by bleeding-related safety
ACS were younger and more often female and the relative hazards .. concerns as patients receiving potent P2Y12 inhibitors are usually
..
associated with ASA use appear larger in such individuals.22,23 .. characterized by a lower-risk clinical profile compared with their
Notwithstanding such considerations, these conclusions should be
.. counterparts treated with clopidogrel.41,42 Considered in this con-
..
considered exploratory and whether an aspirin-free strategy yields a .. text, our findings are particularly relevant since ticagrelor monother-
.. apy may enable patients with NSTE-ACS to realize the long-term
preferential benefit to patients with ACS requires further study. ..
Consistent with previously reported findings from the overall .. benefits of potent P2Y12 inhibition (as endorsed by practice guide-
.. lines), while avoiding aspirin-related bleeding complications. An alter-
study cohort, ticagrelor monotherapy was not associated with an ..
.. native bleeding reduction strategy recommended for patients unable

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increased risk of all-cause death, MI, or stroke in patients with NSTE-
.. to tolerate 12 months of DAPT with a potent PY12 inhibitor involves
ACS enrolled in TWILIGHT.9 We now extend these earlier findings ..
by demonstrating a similar pattern for the individual endpoint com- .. de-escalation from prasugrel or ticagrelor to clopidogrel, ideally
.. guided by the results of platelet function and genetic testing.36
ponents, as well as for other ischaemic events such as cardiovascular ..
death, MI, and definite/probable stent thrombosis. Similarly, no differ-
.. Although pre-specified, our findings should be considered
.. hypothesis-generating and warrant dedicated prospective confirm-
ences in the composite outcome of death or Q-wave MI were ..
observed between ticagrelor monotherapy and a conventional anti-
.. ation. Our results do not apply to all enrolled participants but only
.. those who were able to tolerate 3 months of DAPT without sustain-
platelet strategy of DAPT followed by aspirin alone among patients ..
.. ing a major adverse event; a relevant distinction as the risk-benefit cal-
with ACS enrolled in the GLOBAL LEADERS trial.24 Our results, ..
coupled with earlier observations, suggest that, following a short .. culus for ticagrelor monotherapy may vary between enrolled and
.. randomized patients. In addition, our findings may not generalize to
period of DAPT, the antithrombotic effect of ticagrelor monotherapy ..
may be sufficient that the need for concomitant long-term ASA is .. patients treated with clopidogrel or prasugrel after NSTE-ACS, an
.. important consideration as variability in pharmacodynamic response
obviated, even in the patients with NSTE-ACS we studied. ..
Nonetheless, ischaemic events occurred less frequently than original-
.. to either agent—particularly clopidogrel—may render patients sus-
.. ceptible to thrombosis upon aspirin withdrawal.43,44 The null effects
ly anticipated, reducing power to detect modest differences between ..
treatment strategies.
.. with respect to ischaemic events warrant cautious interpretation as a
.. type II error is possible in the context of an underpowered subgroup
Experimental studies provide a physiological basis and biological ..
.. analysis. Moreover, the observed point estimates and 95% CI for is-
rationale for the lack of incremental thrombosis upon aspirin with- ..
.. chaemic events include the potential for incremental harm upon ASA
drawal while maintaining ticagrelor alone. For example, pharmacody-
.. withdrawal, thus indicating the need for larger and adequately pow-
namic investigations have shown that aspirin provides limited .. ered studies to confirm our null results. The safety and efficacy of
additional platelet inhibition in platelets isolated from healthy volun- ..
.. P2Y12 inhibitor monotherapy in patients with STEMI was not
teers treated with potent P2Y12 inhibitors.25–27 These results are ..
.. addressed by the present study, since these patients were excluded
concordant with those of a nested substudy within the TWILIGHT .. from participation. Inference surrounding the effects of aspirin with-
trial wherein ASA withdrawal at the time of randomization did not .. drawal in very high-risk patients, such as those with NSTEMI and con-
modulate ex vivo thrombus formation generated under conditions of
..
.. comitant CKD or PAD, is not possible as these patients were
shear stress and dynamic flow.28 Analogously, Franchi et al.29 found .. relatively underrepresented in TWILIGHT. However, results from
that validated indices of blood thrombogenicity did not significantly
..
.. other high-risk cohorts within TWILIGHT, such as those with DM or
vary following ASA withdrawal among patients receiving different .. complex PCI, have shown consistent results to those presented
..
antithrombotic agents. .. herein.45,46 We included patients with a clinical diagnosis of unstable
Our findings may appear somewhat discordant to those of trials ..
.. angina in our NSTE-ACS cohort, although greater utilization of high-
showing the benefits of DAPT among patients undergoing PCI, pre- .. sensitive troponin assay has rendered this diagnosis less prevalent.47
senting with ACS or with a prior history of MI.1,30–32 However, the ..
.. Power was limited to detect rare, yet clinically important event differ-
incremental gains in antithrombotic efficacy associated with DAPT in .. ences, including stent thrombosis or stroke. Although differences
these studies reflect the addition of a P2Y12 inhibitor on a background
..
.. were not statistically significant, the incidence of stroke was numeric-
of aspirin. In contrast, the addition of aspirin to background therapy .. ally higher among patients receiving placebo vs. aspirin, irrespective
with a P2Y12 inhibitor did not reduce ischaemic risk but increased
..
.. of clinical presentation. However, other studies have shown that
bleeding in prior studies examining relatively low-risk patients under- .. P2Y12 inhibitor monotherapy does not increase cerebrovascular risk
..
going PCI or those with a recent cerebrovascular event.33–35 Our .. as compared to DAPT.33
results extend these earlier observations to an NSTE-ACS cohort .. In conclusion, among patients with or without NSTE-ACS who
..
and demonstrate that the benefits of DAPT with respect to ischaemic .. remained event-free after 3 months of DAPT following PCI, ticagre-
events are preserved via potent P2Y12 inhibition in the absence of .. lor monotherapy reduced clinically relevant bleeding without increas-
..
concomitant aspirin. Hence, the present results challenge the con- .. ing ischaemic risk as compared with ticagrelor plus aspirin. The effect
ventional paradigm of maintaining aspirin as a long-term component
.. of ticagrelor monotherapy with respect to bleeding events was more
..
of DAPT among patients with NSTE-ACS undergoing PCI.36–38 . pronounced in patients with NSTE-ACS.
3542 U. Baber et al.

.. fees and lecture fees from AstraZeneca, grant support, fees for serving as
Data availability ..
.. chair of a data monitoring committee, and fees for serving as chair of a
The data underlying this article will be shared on reasonable request
.. registry from Servier, and fees for serving on a steering committee from
..
to the corresponding author. .. Idorsia. G.W. has received grant support and advisory board fees from
.. and hold equity in Corindus, advisory board fees from and hold equity in
.. Filterlex, served on an advisory board for and hold options in Trisol, and
..
Supplementary material .. received grant support from Abbott, CSI, and RenalGuard. S.P. has
.. received personal fees from AstraZeneca. C.M.G. has received grant sup-
..
Supplementary material is available at European Heart Journal online. .. port and consulting fees from Angel Medical, Bayer, CSL Behring, Janssen
.. Pharmaceuticals, Johnson & Johnson, and Portola Pharmaceuticals, con-
.. sulting fees from the Medicines Company, Eli Lilly, Gilead Sciences, Novo
Acknowledgements ..
The authors thank all patients and staff who participated in this trial. .. Nordisk, WebMD, UpToDate Cardiovascular Medicine, Amarin Pharma,
.. Amgen, Boehringer Ingelheim, Chiesi, Merck, PharmaMar, Sanofi,
..
Funding .. Somahlution, Verreseon Corporation, Boston Scientific, Impact Bio,

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This work was supported by an investigator-initiated grant from
.. MedImmume, Medtelligence, MicroPort, PERT Consortium, and GE
.. Healthcare, hold equity in nference, served as chief executive officer of
AstraZeneca. ..
.. Baim Institute, and received grant support, paid to Baim Institute, from
.. Bristol-Myers Squibb. R.M. has received institutional research grants from
Conflict of interest: U.B. has received honoraria from AstraZeneca
..
.. Abbott Laboratories, Abiomed, Applied Therapeutics, AstraZeneca,
and Boston Scientific. G.D. has received consulting fees and advisory .. Bayer, Beth Israel Deaconess, Bristol-Myers Squibb, CERC, Chiesi,
board fees from AstraZeneca, consulting fees from Biosensors, and previ- .. Concept Medical, CSL Behring, DSI, Medtronic, Novartis Pharmaceuticals,
..
ously holding stock in Medtronic. D.J.A. has received payment as an indi- .. and OrbusNeich, consultant fees from Abbott Laboratories, Boston
vidual for: reports receiving payments as an individual for: a) Consulting .. Scientific, Janssen Scientific Affairs, Medscape/WebMD, Medtelligence
fee or honorarium from Abbott, Amgen, Aralez, AstraZeneca, Bayer,
..
.. (Janssen Scientific Affairs), Roivant Sciences, Sanofi, Siemens and Medical
Biosensors, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, Daiichi- .. Solutions, consultant fees, paid to the institution, from Abbott
Sankyo, Eli Lilly, Haemonetics, Janssen, Merck, PhaseBio, PLx Pharma, .. Laboratories and Bristol-Myers Squibb, advisory board, funding paid to
..
Pfizer, Sanofi, and The Medicines Company; b) Participation in review .. the institution, from Spectranetics/Philips/Volcano Corp, consultant
activities from CeloNova and St. Jude Medical. Institutional payments for .. (spouse) from Abiomed, The Medicines Company, and Merck, equity
grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL
..
.. <1% from Claret Medical and Elixir Medical, DSMB membership fees,
Behring, Daiichi-Sankyo, Eisai, Eli-Lilly, Gilead, Idorsia, Janssen, Matsutani .. paid to the institution, from Watermark Research Partners, and consult-
Chemical Industry Co., Merck, Novartis, Osprey Medical, Renal Guard .. ing (no fee) from Idorsia Pharmaceuticals Ltd, Regeneron Pharmaceuticals
..
Solutions and the Scott R. MacKenzie Foundation. S.K.S. has received .. and is an associate editor for ACC and AMA. No other potential conflict
from Abbott Vascular, Boston Scientific, and Cardiovascular Systems, Inc. .. of interest relevant to this article was reported.
..
J.E. has received consulting fees and lecture fees from Abbott, Philips, ..
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