The n e w e ng l a n d j o u r na l of m e dic i n e

Original Article

Ticagrelor with or without Aspirin

in High-Risk Patients after PCI
R. Mehran, U. Baber, S.K. Sharma, D.J. Cohen, D.J. Angiolillo, C. Briguori,
J.Y. Cha, T. Collier, G. Dangas, D. Dudek, V. Džavík, J. Escaned, R. Gil, P. Gurbel,
C.W. Hamm, T. Henry, K. Huber, A. Kastrati, U. Kaul, R. Kornowski, M. Krucoff,
V. Kunadian, S.O. Marx, S.R. Mehta, D. Moliterno, E.M. Ohman, K. Oldroyd,
G. Sardella, S. Sartori, R. Shlofmitz, P.G. Steg, G. Weisz, B. Witzenbichler,
Y. Han, S. Pocock, and C.M. Gibson​​

A BS T R AC T

BACKGROUND
The authors’ full names, academic de- Monotherapy with a P2Y12 inhibitor after a minimum period of dual antiplatelet
grees, and affiliations are listed in the therapy is an emerging approach to reduce the risk of bleeding after percutaneous
Appendix. Address reprint requests to Dr.
Mehran at the Icahn School of Medicine coronary intervention (PCI).
at Mount Sinai, 1 Gustav L. Levy Place,
Box 1030, New York, NY 10029, or at METHODS
­roxana​.­mehran@​­mountsinai​.­org. In a double-blind trial, we examined the effect of ticagrelor alone as compared with
Drs. Mehran and Baber contributed ticagrelor plus aspirin with regard to clinically relevant bleeding among patients
equally to this article. who were at high risk for bleeding or an ischemic event and had undergone PCI.
This article was published on September After 3 months of treatment with ticagrelor plus aspirin, patients who had not had
26, 2019, at NEJM.org. a major bleeding event or ischemic event continued to take ticagrelor and were
N Engl J Med 2019;381:2032-42. randomly assigned to receive aspirin or placebo for 1 year. The primary end point
DOI: 10.1056/NEJMoa1908419 was Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding. We
Copyright © 2019 Massachusetts Medical Society.
also evaluated the composite end point of death from any cause, nonfatal myocar-
dial infarction, or nonfatal stroke, using a noninferiority hypothesis with an ab-
solute margin of 1.6 percentage points.
RESULTS
We enrolled 9006 patients, and 7119 underwent randomization after 3 months.
Between randomization and 1 year, the incidence of the primary end point was
4.0% among patients randomly assigned to receive ticagrelor plus placebo and
7.1% among patients assigned to receive ticagrelor plus aspirin (hazard ratio, 0.56;
95% confidence interval [CI], 0.45 to 0.68; P<0.001). The difference in risk between
the groups was similar for BARC type 3 or 5 bleeding (incidence, 1.0% among
patients receiving ticagrelor plus placebo and 2.0% among patients receiving tica­
grelor plus aspirin; hazard ratio, 0.49; 95% CI, 0.33 to 0.74). The incidence of death
from any cause, nonfatal myocardial infarction, or nonfatal stroke was 3.9% in
both groups (difference, −0.06 percentage points; 95% CI, −0.97 to 0.84; hazard
ratio, 0.99; 95% CI, 0.78 to 1.25; P<0.001 for noninferiority).
CONCLUSIONS
Among high-risk patients who underwent PCI and completed 3 months of dual
antiplatelet therapy, ticagrelor monotherapy was associated with a lower incidence
of clinically relevant bleeding than ticagrelor plus aspirin, with no higher risk of
death, myocardial infarction, or stroke. (Funded by AstraZeneca; TWILIGHT
ClinicalTrials.gov number, NCT02270242.)

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 Ticagrelor with or without Aspirin after PCI

A
mong patients who have an acute ously.17 The Icahn School of Medicine at Mount
coronary syndrome or who have under- Sinai designed and sponsored the trial, which
gone percutaneous coronary intervention was supported by an investigator-initiated grant
(PCI), the risk of thrombotic events is lower with from AstraZeneca. The executive and steering
dual antiplatelet therapy with aspirin and a P2Y12 committees were responsible for trial conduct,
receptor inhibitor than with aspirin alone.1 Even the integrity of the data analysis, and the report-
with dual antiplatelet therapy, the risk of adverse ing of results. National regulatory agencies and
events remains unacceptably high among pa- institutional review boards or ethics committees
tients with enhanced thrombotic risk due to of participating centers approved the trial proto-
clinical factors (e.g., diabetes mellitus) or angio- col, which is available with the full text of this
graphic factors (e.g., complex coronary artery article at NEJM.org. An independent data and
disease).2-5 The use of more potent P2Y12 inhibi- safety monitoring board provided external over-
tors or extension of the duration of dual anti- sight to ensure the safety of the trial partici-
platelet therapy lowers residual ischemic risk pants. All the authors vouch for the adherence of
among such patients but increases bleeding.6-9 the trial to the protocol, and the first, second,
Although previously considered relatively benign, and last authors vouch for the accuracy and com-
post-PCI bleeding has been shown to be associ- pleteness of the data. The committee members
ated with a substantial and durable risk of death, and participating investigators are listed in Table
approximating or even exceeding that associated S1 in the Supplementary Appendix, available at
with myocardial infarction.2,10,11 NEJM.org. AstraZeneca provided financial sup-
Addressing the clinical imperatives of lower- port and supplied ticagrelor for the trial but had
ing the risk of bleeding while preserving ische­ no role in the design, collection, analysis, or
mic benefit requires therapeutic strategies that interpretation of the data, in the preparation of
decouple thrombotic risk from hemorrhagic risk. the manuscript, or in the decision to submit the
One approach involves shortening the duration manuscript for publication.
of dual antiplatelet therapy through early with-
drawal of P2Y12 inhibition.12 Although several Trial Population
studies have shown the feasibility of this ap- Patients who underwent successful PCI with at
proach, they generally have enrolled predomi- least one locally approved drug-eluting stent and
nantly low-risk patients and were underpowered whom the treating clinician intended to dis-
for ischemic events.13-15 Reducing the duration ofcharge with a regimen of ticagrelor plus aspirin
aspirin therapy may allow for more prolonged were eligible to participate. Patients also had to
use of potent P2Y12 inhibitors while avoiding have at least one additional clinical feature and
aspirin-related bleeding risk, particularly with one angiographic feature associated with a high
respect to gastrointestinal toxicity.16 We designed
risk of ischemic or bleeding events.2-5,17 The
the Ticagrelor with Aspirin or Alone in High-Risk clinical criteria for high risk were an age of at
Patients after Coronary Intervention (TWILIGHT) least 65 years, female sex, troponin-positive acute
trial to test the hypothesis that in patients un- coronary syndrome, established vascular disease,
dergoing PCI who are at high risk for ischemic diabetes mellitus that was being treated with
or hemorrhagic complications and who have medication, and chronic kidney disease. Angio-
completed a 3-month course of dual antiplatelet graphic criteria included multivessel coronary
therapy with ticagrelor plus aspirin, continued artery disease, a total stent length of more than
treatment with ticagrelor monotherapy would be 30 mm, a thrombotic target lesion, a bifurcation
superior to ticagrelor plus aspirin with respect to
lesion treated with two stents, an obstructive left
clinically relevant bleeding and would not lead main or proximal left anterior descending le-
to ischemic harm. sion, and a calcified target lesion treated with
atherectomy. Key exclusion criteria included pre-
sentation with ST-segment elevation myocardial
Me thods
infarction, cardiogenic shock, ongoing long-term
Trial Design and Oversight treatment with oral anticoagulants, or contrain-
We conducted this randomized, placebo-controlled dication to aspirin or ticagrelor. (Tables S2 and
trial in 187 sites across 11 countries. The trial S3 show all the criteria and their relation to
rationale and design have been described previ- bleeding and ischemic risks.)

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Trial Regimen points included BARC type 3 or 5 bleeding20;

All enrolled patients received open-label ticagrel­ Thrombolysis in Myocardial Infarction (TIMI)
or (90 mg twice daily) and enteric-coated aspirin major or minor bleeding21; Global Utilization of
(81 to 100 mg daily) after the index PCI. At 3 Streptokinase and Tissue Plasminogen Activator
months after hospital discharge, patients who for Occluded Coronary Arteries (GUSTO) moder-
had not had a major bleeding event (see below) ate, severe, or life-threatening bleeding22; or
or an ischemic event (stroke, myocardial infarc- major bleeding as defined by the International
tion, or coronary revascularization) were eligible Society on Thrombosis or Haemostasis (ISTH).23
to be randomly assigned in a 1:1 ratio in a Other secondary end points included death from
double-blind fashion to receive aspirin or match- cardiovascular causes, myocardial infarction,
ing placebo for an additional 12 months along ischemic stroke, and definite or probable stent
with continuation of open-label ticagrelor treat- thrombosis. Myocardial infarction was defined
ment. For the determination of eligibility for according to the third universal definition,24 and
randomization, we defined a major bleeding revascularization and stent thrombosis were clas-
event as Bleeding Academic Research Consor- sified according to the Academic Research Con-
tium (BARC) type 3b or higher. BARC bleeding sortium.25 Table S4 lists the primary and all
types range from 0 (no bleeding) to 5 (fatal secondary end points and their associated defi-
bleeding); type 3b indicates overt bleeding lead- nitions. All clinical events were adjudicated by
ing to a decrease in hemoglobin level of at least an external independent committee, the mem-
5 mg per deciliter, cardiac tamponade, surgical bers of which were unaware of the treatment-
intervention, or intravenous treatment with vaso- group assignments.
active drugs. Nonadherence to treatment with
ticagrelor or aspirin rendered patients ineligible Statistical Analysis
for randomization. A 3-month course of dual The sample-size and power calculation was based
antiplatelet therapy before randomization was on a superiority assumption for the primary end
considered sufficient on the basis of trials that point of BARC type 2, 3, or 5 bleeding. Assum-
have suggested equipoise for such a duration.13,18 ing a bleeding incidence of 4.5% at 1 year with
Randomization was performed with a secure ticagrelor plus aspirin, we chose a sample size of
Web-based system; an independent statistician 8200, which provided 80% power to detect a
who was not involved with the trial generated 28% lower incidence in the ticagrelor-plus-placebo
the randomization sequence, which was strati- group with a type I error rate of 0.05. The key
fied according to site with randomly varying secondary end point (composite of death from
block sizes of 4, 6, and 8. Follow-up was per- any cause, nonfatal myocardial infarction, or non-
formed by telephone at 1 month after random- fatal stroke) was evaluated with the use of a
ization and in person at 6 and 12 months after prespecified noninferiority hypothesis. Under the
randomization. Adherence was assessed with assumption of an incidence of 8.0% at 1 year in
manual pill counts, and nonadherence was clas- the ticagrelor-plus-aspirin group, a sample size
sified according to the underlying reason, as de- of 8200 provided 80% power to rule out an ab-
scribed previously.19 After 12 months of protocol- solute difference in risk of 1.6 percentage points,
mandated therapy, patients were switched to a with a one-sided type I error rate of 0.025. This
standard-of-care antiplatelet regimen at the dis- margin is consistent with those in other trials
cretion of their treating physician, followed by that have evaluated pharmacologic and device-
final telephone follow-up 3 months later. based interventions within a noninferiority
framework.13,26
End Points The cumulative incidence of the primary and
The primary end point was the first occurrence secondary end points was estimated by the
of BARC type 2, 3, or 5 bleeding between ran- Kaplan–Meier method. Data from patients who
domization and 1 year in a time-to-event analy- had not had a primary end-point event between
sis. The key secondary end point was the first randomization and 1 year were censored at the
occurrence of death from any cause, nonfatal time of death, the time of last known contact, or
myocardial infarction, or nonfatal stroke in a 365 days, whichever came first. Hazard ratios
time-to-event analysis. Secondary bleeding end and 95% confidence intervals were generated

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 Ticagrelor with or without Aspirin after PCI

with Cox proportional-hazards models. Absolute7119 were randomly assigned 3 months later to
differences and 95% confidence intervals for receive ticagrelor plus placebo or ticagrelor plus
primary and key secondary end points at 1 yearaspirin (intention-to-treat population). The last
were calculated with Kaplan–Meier estimates patient underwent randomization in April 2018,
and Greenwood standard errors.27 Primary analy-
and the database was locked in July 2019. Details
ses of bleeding and ischemic end points were regarding the reasons for 1887 enrolled patients
performed in the intention-to-treat and per-proto-
not undergoing randomization, the baseline clin-
col populations, respectively. Patients who under-
ical and procedural characteristics among patients
went randomization and did not fulfill enroll-who did and those who did not undergo ran-
ment criteria, were not eligible for randomization,
domization, and adverse events among patients
or never received protocol-mandated therapy were
who did not undergo randomization are provided
excluded from the per-protocol analysis. in Tables S5 through S9.
Ascertainment of the primary end point was
complete in 98.4% of the patients who under-
R e sult s
went randomization, and data on vital status
Patient Characteristics were obtained in 99.7% (Fig. 1). Demographic,
From July 2015 through December 2017, a total clinical, and procedural characteristics were well
of 9006 patients were enrolled after PCI, and balanced between the treatment groups; the mean

9006 Patients were enrolled

1887 Were excluded from randomization

106 Were lost to follow-up
243 Had adverse events
111 Had myocardial infarction, stroke, or death
134 Had any revascularization
52 Had BARC type 3b or higher bleeding event
1148 Were not adherent to DAPT
267 Withdrew consent or declined to participate
123 Had other reasons

7119 Underwent randomization

3555 Received ticagrelor plus placebo 3564 Received ticagrelor plus aspirin

25 Withdrew consent
18 Withdrew consent 27 Were lost to follow-up
41 Were lost to follow-up 1 Was withdrawn by physician

3496 (98.3%) Completed follow-up 3511 (98.5%) Completed follow-up

at mo 15 (including 34 who died) at mo 15 (including 48 who died)

3546 (99.7%) Had vital status 3554 (99.7%) Had vital status
available at mo 15 available at mo 15

Figure 1. Enrollment, Randomization, and Follow-up.

Patients could have been excluded from randomization for more than one type of adverse event. BARC denotes
Bleeding Academic Research Consortium, and DAPT dual antiplatelet therapy.

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 The n e w e ng l a n d j o u r na l of m e dic i n e

age was 65 years, 23.8% of the patients were Bleeding

female, 36.8% had diabetes mellitus, and 64.8% Table 2 shows the incidences of primary (BARC)
underwent PCI for an acute coronary syndrome and secondary (TIMI, GUSTO, and ISTH) bleed-
indication (29.8% with non–ST-segment eleva- ing end points, and Figure 2 shows the Kaplan–
tion myocardial infarction) (Table 1 and Table Meier curves for the primary end point. The
S10). Adherence to ticagrelor treatment 1 year primary end point occurred in 141 patients
after randomization was similar in the ticagrelor- (4.0%) who received ticagrelor plus placebo, as
plus-placebo group and the ticagrelor-plus-­ compared with 250 patients (7.1%) who received
aspirin group (87.1% and 85.9%, respectively) ticagrelor plus aspirin (hazard ratio, 0.56; 95%
(Fig. S1).19 confidence interval [CI], 0.45 to 0.68; P<0.001),

Table 1. Baseline Characteristics of the Patients Who Underwent Randomization.*

Ticagrelor plus Placebo Ticagrelor plus Aspirin

Characteristic (N = 3555) (N = 3564)
Age — yr 65.2±10.3 65.1±10.4
Female sex — no. (%) 846 (23.8) 852 (23.9)
Nonwhite race — no. (%)† 1110 (31.2) 1086 (30.5)
Body-mass index‡ 28.6±5.5 28.5±5.6
Enrolling region — no. (%)
North America 1484 (41.7) 1488 (41.8)
Europe 1251 (35.2) 1258 (35.3)
Asia 820 (23.1) 818 (23.0)
Diabetes mellitus — no. (%) 1319 (37.1) 1301 (36.5)
Diabetes treated with insulin — no. (%) 335 (9.4) 374 (10.5)
Chronic kidney disease — no./total no. (%)§ 572/3410 (16.8) 573/3425 (16.7)
Anemia — no./total no. (%) 675/3405 (19.8) 654/3423 (19.1)
Current smoker — no./total no. (%) 726/3553 (20.4) 822/3562 (23.1)
Hypercholesterolemia — no. (%) 2157 (60.7) 2146 (60.2)
Hypertension — no./total no. (%) 2580/3555 (72.6) 2574/3563 (72.2)
Peripheral arterial disease — no. (%) 245 (6.9) 244 (6.8)
Previous myocardial infarction — no. (%) 1020 (28.7) 1020 (28.6)
Previous PCI — no. (%) 1502 (42.3) 1496 (42.0)
Previous CABG — no./total no. (%) 362/3554 (10.2) 348/3564 (9.8)
Multivessel coronary artery disease — no. (%) 2272 (63.9) 2194 (61.6)
Previous major bleeding event — no. (%) 31 (0.9) 32 (0.9)
Indication for PCI — no./total no. (%)
Asymptomatic 234/3554 (6.6) 223/3563 (6.3)
Stable angina 1047/3554 (29.5) 999/3563 (28.0)
Unstable angina 1249/3554 (35.1) 1245/3563 (34.9)
NSTEMI 1024/3554 (28.8) 1096/3563 (30.8)

* Plus–minus values are means ±SD. Percentages may not total 100 because of rounding. CABG denotes coronary artery
bypass graft, NSTEMI non–ST-segment elevation myocardial infarction, and PCI percutaneous coronary intervention.
† Race was reported by the patient.
‡ The body-mass index is the weight in kilograms divided by the square of the height in meters.
§ Chronic kidney disease was defined as an estimated glomerular filtration rate of less than 60 ml per minute per 1.73 m2
of body-surface area.

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 Ticagrelor with or without Aspirin after PCI

Table 2. Bleeding and Ischemic Events 1 Year after Randomization.*

Ticagrelor plus Ticagrelor plus

Placebo Aspirin Hazard Ratio
Variable (N = 3555) (N = 3564) (95% CI)† P Value

no. of patients (%)‡

Bleeding end points
Primary end point: BARC type 2, 3, or 5§ 141 (4.0) 250 (7.1) 0.56 (0.45–0.68) <0.001¶
BARC type 3 or 5§ 34 (1.0) 69 (2.0) 0.49 (0.33–0.74)
TIMI minor or major 141 (4.0) 250 (7.1) 0.56 (0.45–0.68)
GUSTO moderate or severe 26 (0.7) 49 (1.4) 0.53 (0.33–0.85)
ISTH major 39 (1.1) 72 (2.1) 0.54 (0.37–0.80)
Ischemic end points
Death from any cause, nonfatal myocardial 135 (3.9) 137 (3.9) 0.99 (0.78–1.25) <0.001‖
infarction, or nonfatal stroke
Death from cardiovascular causes, nonfatal 126 (3.6) 130 (3.7) 0.97 (0.76–1.24)
myocardial infarction, or nonfatal
ischemic stroke
Death from any cause 34 (1.0) 45 (1.3) 0.75 (0.48–1.18)
Death from cardiovascular causes 26 (0.8) 37 (1.1) 0.70 (0.43–1.16)
Myocardial infarction 95 (2.7) 95 (2.7) 1.00 (0.75–1.33)
Ischemic stroke 16 (0.5) 8 (0.2) 2.00 (0.86–4.67)
Stent thrombosis, definite or probable 14 (0.4) 19 (0.6) 0.74 (0.37–1.47)

* Bleeding end points were evaluated in the intention-to-treat population (the 7119 patients who underwent randomization),
and ischemic end points were evaluated in the per-protocol population (the 7039 patients who underwent randomiza-
tion and had no major deviations from the protocol [3524 who received ticagrelor plus placebo and 3515 who received
ticagrelor plus aspirin]). All primary and secondary end points and their associated definitions are listed in Table S4.
GUSTO denotes Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries,
ISTH International Society on Thrombosis and Hemostasis, and TIMI Thrombolysis in Myocardial Infarction.
† The 95% confidence intervals for secondary end points have not been adjusted for multiplicity, and therefore inferences
drawn from these intervals may not be reproducible.
‡ Event percentages are Kaplan–Meier estimates of the incidence of the end point at 12 months after randomization.
§ Bleeding Academic Research Consortium (BARC) types range from 0 (no bleeding) to 5 (fatal bleeding).
¶ The difference in the risk of the primary end point of BARC 2, 3, or 5 bleeding was −3.08 percentage points (95% CI,
−4.15 to −2.01).
‖ The difference in the risk of the key secondary end point of death from any cause, nonfatal myocardial infarction, or
nonfatal stroke was −0.06 percentage points (95% CI, −0.97 to 0.84). For the key secondary end point, the upper limit
of the 95% confidence interval for the difference indicated noninferiority (P<0.001).

for a difference in risk of −3.08 percentage who underwent randomization and had no major
points (95% CI, −4.15 to −2.01). The incidence ofdeviations from the protocol (3524 who received
BARC type 3 or 5 bleeding was 1.0% in the ticagrelor plus placebo and 3515 who received
group that received ticagrelor plus placebo and ticagrelor plus aspirin). The key secondary com-
2.0% in the group that received ticagrelor plus posite end point of death from any cause, non-
aspirin (hazard ratio, 0.49; 95% CI, 0.33 to 0.74).
fatal myocardial infarction, or nonfatal stroke
The treatment effect for the primary end point occurred in 135 patients (3.9%) who received tica­
was consistent across predefined subgroups grelor plus placebo and in 137 patients (3.9%)
(Fig. S2). who received ticagrelor plus aspirin (hazard ratio,
0.99; 95% CI, 0.78 to 1.25), for a difference in
Ischemic Events risk of −0.06 percentage points (95% CI, −0.97
Ischemic events were analyzed in the per-proto- to 0.84) (Fig. 3). The incidence of death from any
col population, which included the 7039 patients cause was similar in group that received ticagrel­

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 The n e w e ng l a n d j o u r na l of m e dic i n e

stent thrombosis (0.4% and 0.6%) (Table 2).

100 10
Hazard ratio, 0.56 (95% CI, 0.45–0.68) There were 16 instances of ischemic stroke in
P<0.001 the group that received ticagrelor plus placebo
8
Cumulative Incidence (%)
80 Ticagrelor plus aspirin
and 8 instances of ischemic stroke in the group
6
60 that received ticagrelor plus aspirin (0.5% and
4 0.2% of patients, respectively). The effect of tica­
40 2
grelor monotherapy on the key secondary end
Ticagrelor plus placebo point was consistent across predefined subgroups
20 0 (Fig. S3).
0 3 6 9 12

0 Additional Analyses
0 3 6 9 12
Months since Randomization
Landmark analyses of the period from 15 to 18
months after PCI showed similar incidences of
No. at Risk
Ticagrelor plus aspirin 3564 3454 3357 3277 3213 BARC type 2, 3, or 5 bleeding in the group that
Ticagrelor plus placebo 3555 3474 3424 3366 3321 received ticagrelor plus placebo and the group
that received ticagrelor plus aspirin (0.7% and
Figure 2. Kaplan–Meier Estimates of the Incidence of BARC Type 2, 3,
0.5%, respectively; hazard ratio, 1.24; 95% CI,
or 5 Bleeding 1 Year after Randomization (Intention-to-Treat Population).
0.64 to 2.40); the incidence of death, myocardial
The hazard ratio shown is for ticagrelor plus placebo versus ticagrelor plus
aspirin. Bleeding Academic Research Consortium (BARC) types range from infarction, or stroke was also similar in the two
0 (no bleeding) to 5 (fatal bleeding). The inset shows the same data on an groups (0.9% and 1.1%; hazard ratio, 0.84; 95%
expanded y axis. CI denotes confidence interval. CI, 0.51 to 1.40). Sensitivity analyses conducted
with an imputation-based approach to account
for the 112 patients who were lost to clinical
follow-up yielded similar effects for the primary
100 10
Hazard ratio, 0.99 (95% CI, 0.78–1.25)
and key secondary end points.28 (Details of these
8 analyses are provided in Tables S11 and S12 and
Cumulative Incidence (%)

80
6
Fig. S4.)
60
4 Ticagrelor plus placebo
Discussion
40 2
Ticagrelor plus aspirin Our trial was designed to examine the effect of
20 0
0 3 6 9 12 withdrawing treatment with aspirin while con-
tinuing treatment with ticagrelor alone after
0
0 3 6 9 12 3 months of dual antiplatelet therapy in patients
Months since Randomization who received drug-eluting stents and were at high
No. at Risk
risk for bleeding or ischemic events. Ticagrelor
Ticagrelor plus aspirin 3515 3466 3415 3361 3320 monotherapy was associated with a 44% lower
Ticagrelor plus placebo 3524 3457 3412 3365 3330 risk of BARC type 2, 3, or 5 bleeding over 1 year
than ticagrelor plus aspirin (absolute difference
Figure 3. Kaplan–Meier Estimates of the Incidence of Death from Any Cause,
Nonfatal Myocardial Infarction, or Nonfatal Stroke 1 Year after Randomization in risk, 3.1 percentage points). The bleeding-
(Per-Protocol Population). related benefits of ticagrelor monotherapy ex-
The per-protocol population included patients who underwent randomiza- tended to more severe BARC type 3 or 5 bleeds
tion and had no major deviations from the protocol. The hazard ratio shown and persisted when alternative bleeding scales
is for ticagrelor plus placebo versus ticagrelor plus aspirin. The inset shows were considered. In this trial, there was no evi-
the same data on an expanded y axis.
dence of a higher risk of death, myocardial in-
farction, or stroke among patients who received
ticagrelor monotherapy than among those who
or plus placebo and the group that received tica­ received ticagrelor plus aspirin. The treatment
grelor plus aspirin (1.0% and 1.3%, respectively), effect with respect to both bleeding and ische­
as were the incidences of myocardial infarction mic end points was consistent across subgroups.
(2.7% in both groups) and definite or probable In aggregate, these results show that a transition

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 Ticagrelor with or without Aspirin after PCI

to an antiplatelet strategy of treatment with tica­ to ischemic events, we enrolled patients with a
grelor alone after a 3-month course of dual anti­ high risk of such events to identify signals of harm
platelet therapy in high-risk patients who had after withdrawal of aspirin therapy. Although
undergone PCI provided a clinical benefit of less most of the prespecified criteria are associated
bleeding without ischemic harm. with excess thrombosis (e.g., diabetes mellitus),
Two previous studies showed that among pa- others are linked to both types of events (e.g.,
tients who had undergone PCI and were at rela- renal impairment). Moreover, only patients whom
tively low risk for ischemic events, clopidogrel a clinician had already decided to treat with as-
monotherapy after 1 to 3 months of dual anti- pirin and ticagrelor were eligible for enrollment,
platelet therapy was associated with a significant­ which resulted in a trial population with a level
ly lower incidence of bleeding than clopidogrel of ischemic and bleeding risk that reflects the
plus aspirin, without an apparent difference in overall trial design and clinical preferences for
ischemic risk.29,30 The modest size of those ticagrelor use.
studies, as well as the low-risk nature of the Major adverse events occurring early after PCI
patient population, precluded conclusive inference and nonadherence to dual antiplatelet therapy
regarding the effect of clopidogrel monotherapy precluded randomization at 90 days, criteria that
on ischemic end points. Distinct from these trials, led to the population of patients who underwent
we enrolled a larger population of patients who randomization having a clinical and angiographic
more commonly had both clinical and angio- profile distinct from that of the initially enrolled
graphic high-risk criteria and were treated with participants. Nonetheless, several high-risk char-
a more potent P2Y12 inhibitor, tica­grelor. acteristics (e.g., diabetes mellitus and long stent
In contrast to our findings, the findings of the length) remained prevalent among the patients
GLOBAL LEADERS trial showed that 1 month of who underwent randomization. Moreover, the in-
dual antiplatelet therapy followed by ticagrelor cidences of bleeding and ischemic events at 1 year
monotherapy for an additional 23 months was in these patients were similar to or higher than
not associated with a lower incidence of bleeding those reported in trials in which all events from
than a conventional antiplatelet strategy.31 These PCI onward were considered, thereby substantiat-
results may be attributable to differences in trial ing the high-risk nature of our trial population.29-31
design (double-blind vs. open-label), patient case Although guidelines recommend ticagrelor in
mix (high-risk patients vs. all comers), duration the context of acute coronary syndrome alone,
of therapy after randomization (12 months vs. 33% of the trial participants were in stable con-
23 months), comparator regimens (ticagrelor plus dition at the time of enrollment.1 Potential rea-
aspirin vs. dual antiplatelet therapy followed by sons for the inclusion of such patients by trial
aspirin), bleeding ascertainment (adjudicated vs. investigators may have included a perceived lack
site-reported), or protocol adherence. Conse- of benefit with clopidogrel or clinical equipoise
quently, any putative bleeding-related advantage with regard to P2Y12 inhibitor choice in high-risk
associated with the withdrawal of aspirin therapy patients who are stable after PCI. Corroborating
may have been attenuated in GLOBAL LEADERS. such tendencies, findings from usual-care regis-
For instance, ticagrelor monotherapy was associ- tries show that in current practice, more than
ated with a nonsignificant 14% lower incidence of 10% of patients who have undergone PCI and are
BARC type 3 or 5 bleeding at 1 year in GLOBAL treated with ticagrelor initially present with a
LEADERS, whereas a 51% lower incidence was non–acute coronary syndrome indication.32,33 From
observed in our trial. a clinical standpoint, our results suggest that
To be included in our trial, patients had to ticagrelor monotherapy may be a suitable anti-
have clinical and angiographic factors associated platelet strategy to lower the risk of bleeding
with a high risk of either bleeding or ischemic while simultaneously preserving ischemic bene-
events after PCI, design features that reflect the fit in patients who have undergone PCI and are
primary and key secondary end points of the characterized by a minimum threshold of risk.
trial. With respect to bleeding, patients at high These effects appear consistent in patients whose
risk are most likely to have a benefit from re- condition is either stable or acute. Whether the
duced exposure to antiplatelet therapy. With regard findings would be similar in a lower-risk popu-

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 The n e w e ng l a n d j o u r na l of m e dic i n e

lation or if a different antithrombotic regimen and honoraria from Haemonetics, PhaseBio, PLx Pharma, Pfizer,
and the Medicines Company, grant support and fees for review
were used remains unknown. activities from CeloNova, fees for review activities from St. Jude
The limitations of our trial include the lack of Medical, and grant support from CSL Behring, Eisai, Gilead,
power to detect differences in the risk of impor- Idorsia Pharmaceuticals, Matsutani Chemical Industry, Novartis,
Osprey Medical, and RenalGuard Solutions; Dr. Dangas, receiv-
tant yet rare clinical events, such as stent throm- ing consulting fees and advisory board fees from AstraZeneca,
bosis and stroke. Although ischemic strokes consulting fees from Biosensors, and previously holding stock
were more common among patients who re- in Medtronic; Dr. Escaned, receiving consulting fees and lecture
fees from Abbott, Philips, Boston Scientific, and Medtronic, and
ceived placebo than among those who continued lecture fees from Abiomed, Terumo, and Biosensors; Dr. Gurbel,
to receive aspirin, only 24 such events occurred receiving grant support and consulting fees from Bayer, Medi-
during the trial, thereby precluding conclusive cure, US WorldMeds, and Merck, grant support from Instru-
mentation Laboratory, Haemonetics, Amgen, Idorsia, Janssen,
inference for this end point. Other studies have and Ionis, and holding patent 9188597 on detection of resteno-
shown that P2Y12 inhibitor monotherapy is not sis risk in patients receiving a stent by measuring the character-
associated with a higher risk of cerebrovascular istics of blood clotting, including measurement of maximum
thrombin-induced clot strength; Dr. Hamm, receiving lecture fees
events than dual antiplatelet therapy.29,30,34 Re- and advisory board fees from AstraZeneca; Dr. Huber, receiving
sults from this trial may not be generalizable to lecture fees from AstraZeneca and Bayer; Dr. Mehta, receiving
all patients who have undergone PCI, given the grant support from and serving on an executive committee and
as site investigator for AstraZeneca; Dr. Ohman, receiving con-
requirement in our trial for both high-risk (clini- sulting fees from 3D Communications, ACI Clinical, Biotie, Cara
cal and angiographic) features and a willingness Therapeutics, Cardinal Health, Faculty Connection, Imbria,
to be treated with ticagrelor. In addition, the Impulse Medical, Janssen Pharmaceuticals, Medscape, Milestone
Pharmaceuticals, and XyloCor, grant support and consulting
observed treatment effects do not apply to all fees from Abiomed, and grant support from Chiesi and Portola;
enrolled participants but rather to those patients Dr. Oldroyd, receiving grant support and lecture fees from Astra­
who were able to take 3 months of dual anti- Zeneca; Dr. Steg, receiving grant support and fees for serving on
a steering committee from Bayer/Janssen, grant support and
platelet therapy without any major adverse events. lecture fees from Merck, grant support, fees for serving as co-
Our primary end point included bleeding events chair of trials, consulting fees, and lecture fees from Sanofi,
of varying severity, which may have altered the grant support, fees for serving on an executive steering commit-
tee, and consulting fees from Amarin, consulting fees and lec-
risk–benefit calculation for considering ticagrel­ ture fees from Amgen, consulting fees, lecture fees, and fees for
or monotherapy. A lower-than-expected incidence serving on a critical event committee from Bristol-Myers Squibb,
of the composite end point of death, myocardial fees for serving on an executive steering committee from Boeh-
ringer Ingelheim, fees for serving on a critical event committee
infarction, or stroke may have biased our results from Pfizer, fees for serving on a steering committee and con-
for this key secondary end point toward the null. sulting fees from Novartis, consulting fees from Regeneron, Eli
Our trial showed that in high-risk patients Lilly, and Novo Nordisk, consulting fees and lecture fees from
AstraZeneca, grant support, fees for serving as chair of a data
who had undergone PCI and were treated with
monitoring committee, and fees for serving as chair of a registry
ticagrelor and aspirin for 3 months, an anti- from Servier, and fees for serving on a steering committee from
platelet strategy of continuing ticagrelor alone Idorsia; Dr. Weisz, receiving grant support and advisory board
fees from and holding equity in Corindus, advisory board fees
resulted in substantially less bleeding than tica­
from and holding equity in Filterlex, serving on an advisory
grelor plus aspirin, without leading to ischemic board for and holding options in Trisol, and receiving grant sup-
harm over a period of 1 year. port from Abbott, CSI, and RenalGuard; Dr. Gibson, receiving
grant support and consulting fees from Angel Medical, Bayer,
Supported by AstraZeneca. CSL Behring, Janssen Pharmaceuticals, Johnson & Johnson, and
Dr. Mehran reports receiving consulting fees from Abbott Portola Pharmaceuticals, consulting fees from the Medicines
Vascular Laboratories, Boston Scientific, Medscape/WebMD, Company, Eli Lilly, Gilead Sciences, Novo Nordisk, WebMD,
Siemens Medical Solutions, Phillips/Volcano/Spectranetics, Roviant UpToDate Cardiovascular Medicine, Amarin Pharma, Amgen,
Sciences, Sanofi Italy, Bracco Group, Janssen, and AstraZeneca, Boehringer Ingelheim, Chiesi, Merck, PharmaMar, Sanofi, Somah-
grant support, paid to her institution, from Bayer, CSL Behring, lution, Verreseon Corporation, Boston Scientific, Impact Bio,
DSI, Medtronic, Novartis Pharmaceuticals, OrbusNeich, Osprey MedImmume, Medtelligence, MicroPort, PERT Consortium, and
Medical, PLC/RenalGuard, and Abbott Vascular, grant support GE Healthcare, holding equity in nference, serving as chief ex-
and advisory board fees, paid to her institution, from BMS, fees ecutive officer of Baim Institute, and receiving grant support,
for serving on a data and safety monitoring board from Water- paid to Baim Institute, from Bristol-Myers Squibb. No other po-
mark Research Funding, advisory fees and lecture fees from tential conflict of interest relevant to this article was reported.
Medintelligence (Janssen), and lecture fees from Bayer; Dr. Baber, Disclosure forms provided by the authors are available with
receiving honoraria from AstraZeneca and Boston Scientific; Dr. the full text of this article at NEJM.org.
Cohen, receiving grant support, paid to his institution, and A data sharing statement provided by the authors is available
consulting fees from AstraZeneca, Medtronic, and Abbott Vas- with the full text of this article at NEJM.org.
cular, and grant support, paid to his institution, from Boston We thank Rishi Chandiramani, M.D., of the Icahn School of
Scientific; Dr. Angiolillo, receiving grant support, consulting Medicine at Mount Sinai, and Alexandra Howson, Ph.D., of This-
fees, and honoraria from Amgen, Aralez, Bayer, Biosensors, tle Editorial, for assistance with preparation of an earlier version
Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, Daiichi of the manuscript (funded by the Icahn School of Medicine at
Sankyo, Eli Lilly, Janssen, Merck, and Sanofi, consulting fees Mount Sinai).

2040 n engl j med 381;21 nejm.org  November 21, 2019

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Copyright © 2019 Massachusetts Medical Society. All rights reserved.
 Ticagrelor with or without Aspirin after PCI

Appendix
The authors’ full names and academic degrees are as follows: Roxana Mehran, M.D., Usman Baber, M.D., Samin K. Sharma, M.D.,
David J. Cohen, M.D., Dominick J. Angiolillo, M.D., Ph.D., Carlo Briguori, M.D., Ph.D., Jin Y. Cha, B.S., Timothy Collier, M.Sc., George
Dangas, M.D., Ph.D., Dariusz Dudek, M.D., Ph.D., Vladimír Džavík, M.D., Javier Escaned, M.D., Ph.D., Robert Gil, M.D., Ph.D., Paul
Gurbel, M.D., Christian W. Hamm, M.D., Timothy Henry, M.D., Kurt Huber, M.D., Adnan Kastrati, M.D., Upendra Kaul, M.D., Ran
Kornowski, M.D., Mitchell Krucoff, M.D., Vijay Kunadian, M.B., B.S., M.D., Steven O. Marx, M.D., Shamir R. Mehta, M.D., David
Moliterno, M.D., E. Magnus Ohman, M.D., Keith Oldroyd, M.B., Ch.B., M.D., Gennaro Sardella, M.D., Samantha Sartori, Ph.D., Richard
Shlofmitz, M.D., P. Gabriel Steg, M.D., Giora Weisz, M.D., Bernhard Witzenbichler, M.D., Ya‑ling Han, M.D., Ph.D., Stuart Pocock,
Ph.D., and C. Michael Gibson, M.D.
The authors’ affiliations are as follows: the Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai Hospital (R.M., U.B.,
J.Y.C., G.D., S.S.), Mount Sinai Health System (S.K.S.), Columbia University Medical Center (S.O.M.), Icahn School of Medicine at
Mount Sinai (S.S.), and Montefiore Medical Center (G.W.), New York, and St. Francis Hospital, Roslyn (R.S.) — all in New York; Kan-
sas City, Missouri (D.J.C.); the University of Florida–Shands, Jacksonville (D.J.A.); Clinica Mediterranea, Naples (C.B.), and Policlinico
Umberto I University, Rome (G.S.) — both in Italy; the London School of Hygiene and Tropical Medicine, London (T.C., S.P.), Institute
of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, and Cardiothoracic Centre, Freeman Hospital, Newcastle upon
Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne (V.K.), and the West of Scotland Heart and Lung Centre, Golden Jubilee
National Hospital, Glasgow (K.O.) — all in the United Kingdom; the 2nd Department of Cardiology Jagiellonian University Medical
College, Krakow (D.D.), and the Department of Invasive Cardiology, Center of Postgraduate Medical Education, Central Clinical Hospi-
tal of the Ministry of Interior and Administration, Warsaw (R.G.) — both in Poland; Research and Innovation in Interventional Cardiol-
ogy and Cardiac Intensive Care, Peter Munk Cardiac Centre, University Health Network, Toronto (V.D.), and Hamilton Health Sciences,
Hamilton, ON (S.R.M.) — both in Canada; Instituto de Investigación Sanitaria del Hospital Clínico San Carlos and Complutense Univer-
sity, Madrid (J.E.); Sinai Hospital of Baltimore System, Baltimore (P.G.); Kerckhoff Clinic, Bad Nauheim (C.W.H.), Deutsches Herzzentrum
München, Munich (A.K.), and Helios Amper-Klinikum, Dachau (B.W.) — all in Germany; the Carl and Edyth Lindner Center for Re-
search and Education at the Christ Hospital, Cincinnati (T.H.); Wilhelminenhospital, Vienna (K.H.); Batra Hospital and Medical Re-
search Centre, New Delhi, India (U.K.); Rabin Medical Center, Petach Tikva, Israel (R.K.); Duke University Medical Center–Duke Clini-
cal Research Institute, Durham, NC (M.K., E.M.O.); the University of Kentucky, Lexington (D.M.); Groupe Hospitalier Bichat–Claude-
Bernard, Paris (P.G.S.); Shenyang North Hospital, Shenyang, China (Y.H.); and Beth Israel Deaconess Medical Center, Boston (C.M.G.).

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