European Heart Journal (2022) 43, 5037–5044 CLINICAL RESEARCH

https://doi.org/10.1093/eurheartj/ehac402 Clinical trials

Patient selection for long-term secondary

prevention with ticagrelor: insights from

Downloaded from https://academic.oup.com/eurheartj/article/43/48/5037/6823782 by European Society of Cardiology user on 28 May 2023

PEGASUS-TIMI 54
Marc P. Bonaca 1*, KyungAh Im 2, Giulia Magnani 3, Sameer Bansilal4,
Mikael Dellborg 5, Robert F. Storey 6, Deepak L. Bhatt 2, P. Gabriel Steg7,
Marc Cohen8, Per Johanson 9, Eugene Braunwald 2, and Marc S. Sabatine2*
1
Department of Cardiology and Vascular Medicine, University of Colorado School of Medicine, 2115 N Scranton St Suite 2040, Aurora, CO 80045, USA; 2TIMI Study Group, Division of
Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA; 3Parma University Hospital, Parma, Italy; 4Bayer, Whippany, New Jersey, USA;
5
Department of Medicine/Östra, Sahlgrenska University Hospital, Göteborg, Sweden; 6Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Beech Hill
Road, Sheffield S10 2RX, UK; 7Université Paris-Cité, INSERM U-1148 and AP-HP, Hôpital Bichat, FACT (French Alliance for Cardiovascular Trials) Paris, France; 8Newark Beth Israel
Medical Center, Rutgers Medical School, Newark, New Jersey, USA; and 9AstraZeneca, Gothenburg, Sweden

Received 21 September 2021; revised 20 April 2022; accepted 12 July 2022; online publish-ahead-of-print 11 November 2022

See the editorial comment for this article ‘Platelet antiaggregation after an acute coronary syndrome: what about the elderly?’, by
K. Huber, https://doi.org/10.1093/eurheartj/ehac405.

Abstract

Aim In patients with prior myocardial infarction (MI) on aspirin, the addition of ticagrelor reduces ischaemic risk but increases
bleeding risk. The simultaneous assessment of baseline ischaemic and bleeding risk may assist clinicians in selecting pa­
tients who are most likely to have a favourable risk/benefit profile with long-term ticagrelor.
.........................................................................................................................................................................................
Methods PEGASUS-TIMI 54 randomized 21 162 prior MI patients, 13 956 of which to the approved 60 mg dose or placebo and
and results who had all necessary data. The primary efficacy endpoint was cardiovascular death, MI, or stroke, and the primary safety
outcome was TIMI major bleeding; differences in Kaplan–Meier event rates at 3 years are presented. Post-hoc subgroups
based on predictors of bleeding and ischaemic risk were merged into a selection algorithm. Patients were divided into
four groups: those with a bleeding predictor (n = 2721, 19%) and then those without a bleeding predictor and either 0–1
ischaemic risk factor (IRF; n = 3004, 22%), 2 IRF (n = 4903, 35%), or ≥3 IRF (n = 3328, 24%). In patients at high bleeding
risk, ticagrelor increased bleeding [absolute risk difference (ARD) +2.3%, 95% confidence interval (CI) 0.6, 3.9] and did
not reduce the primary efficacy endpoint (ARD +0.08%, 95% CI −2.4 to 2.5). In patients at low bleeding risk, the ARDs in
the primary efficacy endpoint with ticagrelor were −0.5% (−2.2, 1.3), −1.5% (−3.1, 0.02), and −2.6% (−5.0, −0.24, P =
0.03) in those with ≤1, 2, and 3 risk factors, respectively (P = 0.076 for trend across groups). There were significant
trends for greater absolute risk reductions for cardiovascular death (P-trend 0.018), all-cause mortality (P-trend
0.027), and net outcomes (P-trend 0.037) with ticagrelor across these risk groups.
.........................................................................................................................................................................................
Conclusion In a post-hoc exploratory analysis of patients with prior MI, long-term ticagrelor therapy appears to be best suited for
those with prior MI with multiple IRFs at low bleeding risk.
.........................................................................................................................................................................................
Clinical Trial NCT01225562 ClinicalTrials.gov
Registration

* Corresponding authors. Tel: +1 303 860 9900, Email: marc.bonaca@cpcmed.org (M.P.B.); Tel: +1 617 278 0091, Fax: +1 617 734 7329, Email: msabatine@bwh.harvard.edu (M.S.S.)
© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail:
journals.permissions@oup.com
5038 M.P. Bonaca et al.

Structured Graphical Abstract

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identified a gradient of absolute risk reductions in the primary and other efficacy
endpoints.

Characteristics (left) and distribution of patients (middle) in PEGASUS-TIMI 54 by categories of high bleeding risk, low bleeding risk with 0–1
ischaemic risk factors, low bleeding risk with 2 ischaemic risk factors, and low bleeding risk with ≥ 3 ischaemic risk factors and the absolute
risk difference for the composite of cardiovascular death, myocardial infarction or stroke with ticagrelor vs. placebo over 3 years for each group
(right). CAD, coronary artery disease; CV, cardiovascular; MI, myocardial infarction.
.........................................................................................................................................................................................
Keywords Long-term ticagrelor • Myocardial infarction • Net benefit
Patient selection for long-term secondary prevention with ticagrelor
Introduction
Patients with myocardial infarction (MI) are at heightened risk of is­
chaemic events even years after the event occurred. Intensive anti­
platelet therapy with the combination of aspirin and a P2Y12
inhibitor (dual antiplatelet therapy or DAPT) is initiated at the time
of MI to reduce this risk and is indicated for at least a year in patients
who are not at elevated bleeding risk.1–3 Long-term use of DAPT has
been shown to reduce ischaemic risk in patients with prior MI and
PEGASUS-TIMI 54 prospectively demonstrated that long-term ticagre­
lor at a dose of 60 mg twice daily reduces major adverse cardiovascular
events (MACEs) in this population.4 The benefit of this therapeutic
approach has also extended to patients with diabetes and coronary
disease who have never had MI, especially in those with prior percutan­
eous coronary revascularization.5,6
Strategies using long-term DAPT to reduce ischaemic risk after MI,
however, also increase the risk of bleeding.4,7 Although this bleeding
risk did not extend to irreversible harm events such as intracranial
haemorrhage (ICH) or fatal bleeding in the trials, major bleeding is
an undesirable event and can lead to hospitalization and cessation
of beneficial therapies and is associated with worse outcomes includ­
ing mortality.1,3,8–10 Such observations necessitate personalized appli­
cation of these strategies rather than generalized use in all patients
with prior MI.1–3,11 Although algorithms have been developed to en­
able selection of patients at lower bleeding risk, this approach is com­
plicated by the observation that many predictors of bleeding are also
predictors of ischaemic risk.8,11 In addition, other scoring systems de­
veloped in broader populations immediately after percutaneous cor­
onary intervention (PCI) may not apply in long-term patients with
prior MI some of whom were treated medically and where patient
characteristics and comorbidities are likely more important drivers
of risk relative to stent or procedural characteristics.11–13
Therefore, we developed a stepwise patient selection algorithm
for long-term treatment with ticagrelor 60 mg twice daily utilizing
subgroups previously observed to be at higher bleeding risk8 and is­
chaemic risk.14–19 We then evaluated bleeding, ischaemic risk, mor­
tality, and net outcomes with ticagrelor 60 mg twice daily vs. placebo
by risk group in PEGASUS-TIMI 54.
Methods
Study population
The PEGASUS-TIMI 54 trial described previously, randomized 21 162
patients with a prior history of spontaneous MI occurring 1–3 years prior
to enrolment, who had at least one additional atherothrombotic risk fac­
tor (age ≥65 years, diabetes mellitus requiring medication, a second prior
spontaneous MI, chronic renal dysfunction, or multivessel coronary ar­
tery disease) to ticagrelor 60 mg b.i.d., ticagrelor 90 mg b.i.d., or placebo,
all on a background of low-dose (75–150 mg) aspirin.4 Patients were fol­
lowed for a median of 33 months. Exclusion criteria included planned use
of a P2Y12 receptor antagonist or anticoagulant therapy, a known bleed­
ing disorder, history of stroke, a central nervous system tumour, gastro­
intestinal bleeding within the previous 6 months, or major surgery within
the previous 30 days. Enrolling sites were requested to indicate if there
was any history of bleeding leading to hospitalization. All patients had
central laboratory testing for haemoglobin at baseline. Anaemia was de­
fined as a haemoglobin ≤13.5 g/dL for men and ≤12.0 g/dL for women.8
Because this analysis is focused on an algorithm to select patients for
5039
long-term ticagrelor use in patients with an MI at least 1 year prior,
the population was restricted to the 14 112 randomized to the approved
dose of 60 mg twice daily or placebo. A total of 156 patients were ex­
cluded from the analyses due to missing ischaemic and/or bleeding risk
factors with 13 956 included in the analysis cohort.
Endpoints
The primary efficacy endpoint was MACE, consisting of the composite of
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cardiovascular (CV) death, MI, or stroke.4 The primary safety endpoint
was TIMI major bleeding defined as any ICH, or clinically overt signs of
haemorrhage associated with a reduction in haemoglobin ≥5 g/dL (or,
when haemoglobin was not available, a fall in haematocrit ≥15%), or fatal
bleeding (a bleeding event that directly led to death within 7 days). TIMI
minor bleeding was defined as any clinically overt haemorrhage (including
that detected by imaging) that was associated with a fall in haemoglobin
of 3 to <5 g/dL (or, when haemoglobin was not available, a fall in haem­
atocrit of 9 to <15%). Haemoglobin measurements were adjusted for
any packed red blood cells or whole blood given between baseline and
post-transfusion measurement; transfusion of one unit of blood was as­
sumed to result in an increase of 1 g/dL of haemoglobin. Bleeding events
leading directly to mortality were classified as fatal bleeding events. All
bleeding events, as well as their relationship to mortality, were adjudi­
cated by a Clinical Events Committee blinded to treatment allocation.
A net clinical benefit analysis was defined as a composite outcome con­
sisting of CV death, MI, stroke, ICH, or fatal bleeding.
Patient selection algorithm
A post-hoc algorithm conceptually aligned with the risk stratification ap­
proach described by the European Society of Cardiology (ESC) guidelines
for a second antithrombotic therapy was developed, including first identi­
fying high-bleeding risk patients and then stratifying low-bleeding risk pa­
tients into thrombotic risk categories (one risk criteria and two or more
risk criteria).2 Previously identified independent predictors of bleeding,
but not ischaemic risk, were anaemia at baseline and prior history of spon­
taneous bleeding requiring hospitalization.8 Factors that were not inde­
pendent predictors of bleeding or were predictors of both ischaemic
risk and bleeding (e.g. age, kidney dysfunction) were excluded as published
previously.8 Patients with at least one of these criteria had three-fold high­
er rates of TIMI major or minor bleeding with ticagrelor 60 mg vs. placebo
compared with those with neither feature.8
The initial step in the stratification approach, therefore, was to exclude
patients at high bleeding risk, defined by the presence of either or both of
the bleeding risk predictors. Patients identified as low bleeding risk were
stratified according to ischaemic risk factors. Because PEGASUS-TIMI 54
included medically managed patients (for whom complexity of coronary
disease was unknown), an approach based solely on the number of clinical
risk factors was utilized. Factors included the pre-specified enrichment
criteria for the trial that have also been observed to be associated with
greater ischaemic risk (see Supplementary material online, Figure S2) in­
cluding type 2 diabetes mellitus,14 non-end-stage chronic kidney disease,17
multivessel coronary disease,18 and multiple prior MIs. In addition, more
recent MI or P2Y12 inhibition which showed formal heterogeneity for
benefit of ticagrelor and was the basis for the EU label19 and polyvascular
disease (comorbid peripheral artery disease) which was associated with
greater risk and more favourable risk benefit were included.16,20 A sum­
mary of risk factors chosen, criteria and rationale for exclusion are shown
in Supplementary material online, Table S1. Low-bleeding risk patients
were then grouped according to 0–1 ischaemic risk factor, 2 risk ischae­
mic factors, and ≥3 ischaemic risk factors in general alignment with lower
and higher ischaemic risk, respectively.1
5040
Statistics
As per the pre-specified statistical analysis plan, the primary efficacy ana­
lysis and net clinical outcome were conducted on an intention-to-treat
basis, whereas safety analyses included all patients who underwent ran­
domization and received at least one dose of study drug. Event rates for
ticagrelor and placebo were estimated by Kaplan–Meier methods from
baseline to 3 years and compared with the log-rank test. This was exam­
ined separately by treatment arm over time. Categorical variables were
compared using χ2 tests and continuous variable with either a t test or
Wilcoxon rank-sum test, as appropriate. The hazard ratio (HR) for given
outcome of interest between ticagrelor and placebo was examined using
a Cox regression model with treatment as a model term in each risk
stratification group defined by bleeding and ischaemic risk profiles de­
scribed in previous section. The proportional hazards assumption was
examined and tested by scaled Schoenfeld residuals. In addition, the ab­
solute risk differences (ARDs) between ticagrelor and placebo groups
were calculated by subtracting the cumulative incidence in the placebo
group from that of the treatment group. The cumulative incidence was
defined by the complement of the Kaplan–Meier survival estimates.
The null hypothesis that the gradient of risk differences across the level
of subgroup is zero was tested by weighted least square regression, with
weights being the inverse of variance.21 A sensitivity analysis was also per­
formed estimating the hypothetical ARDs for the primary endpoint by
applying the overall HR to the risk group specific baseline risk. All statis­
tical computations were performed with the use of SAS software, ver­
sion 9.4 (SAS Institute, Cary, NC, USA).
Results
Overall, of 14 112 patients randomized to ticagrelor 60 mg twice dai­
ly or placebo, a total of 2721 (19%) had at least one bleeding risk fac­
tor and were categorized as high bleeding risk. Among those without
a bleeding predictor, 3004 (22% of the total) had only 0–1 ischaemic
risk factor, 4903 (35%) had 2 ischaemic risk factors, and 3328 (24%)
had 3 or more ischaemic risk factors. The baseline characteristics of
these patients are shown in Table 1. When excluding the 156 patients
with missing ischaemic and/or bleeding risk factors there were no
consistent statistically significant imbalances in baseline characteris­
tics between the placebo and ticagrelor arms across the three risk
groups (see Supplementary material online, Tables S2A–C).
In the placebo arm, patients at high risk of bleeding had rates of
major bleeding at 3 years that were almost double those in the pa­
tients categorized as low bleeding risk (1.7 vs. 0.9%, P = 0.040,
Supplementary material online, Figure S1). With regard to ischaemic
risk, in the placebo arm, the ischaemic risk characteristics were asso­
ciated with higher rates of the primary endpoint at 3 years (see
Supplementary material online, Figure S2). Overall application of
the algorithm categorized 19% of the population as high bleeding
risk and 81% as low bleeding risk, with those categorized as 22%
with 0–1 ischaemic risk factors, 35% with 2 ischaemic risk factors,
and 24% with ≥ 3 ischaemic risk factors (Graphical abstract).
Safety with ticagrelor 60 mg vs. placebo
by risk group
Whereas the relative increase in bleeding risk with ticagrelor 60 mg
twice daily vs. placebo was consistent across the risk groups, due to their
higher baseline bleeding risk, there was an approximately two-fold high­
er ARD in TIMI major bleeding in high-bleeding risk patients vs. those at
M.P. Bonaca et al.
low bleeding risk (regardless of ischaemic risk factors): +2.3% [95% con­
fidence interval (CI) 0.60–3.9] vs. +1.0% (95% CI 0.5, 1.5) (P = 0.25). The
ARDs in bleeding across ischaemic risk groups among patients with low
bleeding risk was similar (P-trend for ARD 0.96).
Drug discontinuation rates at 3 years were higher in those at high
bleeding risk vs. those at low bleeding risk both in the placebo arm
(26.5% in high bleeding risk, 22.7% in low bleeding risk and 0–1 ischae­
mic risk factors, 20.8% in low bleeding risk and 2 ischaemic risk factors,
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and 25.9% in low bleeding risk and ≥ 3 ischaemic risk factors) and the
ticagrelor arm (33.8, 30.3, 28.9, and 33.7%, respectively).
Efficacy with ticagrelor 60 mg vs. placebo
by risk group
The relative reduction in the risk of MACE with ticagrelor was 2%
(HR 0.98, 95% CI 0.77–1.26, P = 0.88), 13% (HR 0.87, 95% CI
0.63–1.22, P = 0.42), 19% (HR 0.81, 95% CI 0.64–1.01, P = 0.062),
and 23% (HR 0.77, 95% CI 0.62–0.95, P = 0.013; Figure 1A) in patients
at high bleeding risk and at low bleeding risk with 0–1, 2, and ≥3 risk
factors, respectively. Furthermore, the ARDs in the primary end­
point of MACE at 3 years in those groups were +0.08% (95% CI
−2.39, 2.54), −0.47% (95% CI −2.21, 1.26), −1.53% (95% CI −3.1,
0.024), and −2.61% (95% CI −4.99, −0.24) with a P-value for the trend
in ARD of 0.076 across the three groups. An alternative approach es­
timating the hypothetical ARDs for the primary endpoint in the groups
by applying the overall HR to the placebo event rate in each group is
shown in Supplementary material online, Table S3. In patients at high
bleeding risk, 2154 had 2 or more ischaemic risk factors and 549 had
0–1 ischaemic risk factors with a non-significant trend towards an
∼10% reduction in risk in those with multiple risk factors (HR 0.90,
95% CI 0.69–1.18) and no apparent benefit in those with 0–1 risk fac­
tors (HR 1.81, 95% CI 0.91–3.61; P-interaction 0.0714).
Likewise, the effect of ticagrelor on CV death varied across these
four patient subgroups, with no benefit (HR 1.24, 95% CI 0.87–1.76,
ARD +1.0%, 95% CI −0.8, 2.8) in patients at high bleeding risk, a 19%
relative risk reduction (RRR; HR 0.81, 95% CI 0.46–1.42) and −0.2
ARD (95% CI −1.3, +0.9, P = 0.46) in patients at low bleeding risk
and 0–1 ischaemic risk factor, a 32% RRR (HR 0.68, 95% CI 0.45–
1.03, P = 0.070) and −0.86% ARD (95% CI −1.86, 0.13) in patients at
low bleeding risk and 2 ischaemic risk factors, and a 36% RRR (HR
0.64, 95% CI 0.44–0.93, P = 0.0020) and −1.62% ARD (95% CI
−3.12, −0.14, P-trend for HR 0.0083, P-trend for ARR 0.018,
Figure 1B) in those with ≥ 3 ischaemic risk factors. Similar patterns
were seen for the effect of ticagrelor on all-cause mortality (high bleed­
ing risk HR 1.14; 95% CI 0.86 to 1.50, ARD 1.46; 95% CI −0.85 to 3.78;
low bleeding risk with 0–1 risk factor HR 0.90; 95% CI 0.59 to 1.38;
ARD −0.25; 95% CI −1.62 to 1.13; low bleeding risk with 2 risk factors
HR 0.83; 95% CI 0.60 to 1.15; ARD −0.53; 95% CI −1.69 to 0.63; low
bleeding risk with 3 risk factors HR 0.71; 95% CI 0.52 to 0.96; ARD
−2.01; 95% CI −3.82 to −0.20; P-trend for HR 0.021, P-trend for
ARD 0.027, Figure 1C) as well as on coronary heart disease death, MI,
and stroke (see Supplementary material online, Figure S3).
Net outcomes with ticagrelor 60 mg
vs. placebo by risk group
In terms of the net clinical outcome of CV death, MI, stroke, intracra­
nial bleeding, or fatal bleeding, there was no benefit in patients at high
Patient selection for long-term secondary prevention with ticagrelor 5041

Table 1 Baseline characteristics by bleeding and ischemic risk categories

High Low bleeding risk and Low bleeding risk and Low bleeding risk and P-value
bleeding risk ≤ 1 risk factor 2 risk factors ≥3 risk factors
N = 2721 N = 3004 N = 4903 N = 3328
.................................................................................................................................................................................
Age, years, median (IQR) 68.0 (62.0, 74.0) 67.0 (63.0, 72.0) 62.0 (57.0, 69.0) 64.0 (58.0, 71.0) <0.0001
Female sex, n (%) 571 (21.0) 760 (25.3) 1107 (22.6) 906 (27.2) <0.0001

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2
Body mass index, kg/m , median (IQR) 27.1 (24.2, 30.4) 27.6 (25.1, 30.2) 28.0 (25.3, 31.2) 28.7 (25.7, 32.2) <0.0001
Caucasian, n (%) 2153 (79.1) 2750 (91.5) 4280 (87.3) 2879 (86.5) <0.0001
Hypertension, n (%) 2168 (79.7) 2148 (71.5) 3696 (75.4) 2804 (84.3) <0.0001
Hypercholesterolemia, n (%) 2031 (74.6) 2225 (74.1) 3777 (77.0) 2681 (80.6) <0.0001
Current smoker, n (%) 312 (11.5) 454 (15.1) 941 (19.2) 614 (18.5) <0.0001
History of CHF, n (%) 616 (22.6) 560 (18.6) 863 (17.6) 759 (22.8) <0.0001
History of stroke or TIA, n (%) 57 (2.1) 46 (1.5) 55 (1.1) 64 (1.9) 0.0033
Prior angina, n (%) 889 (32.7) 862 (28.7) 1435 (29.3) 1158 (34.8) <0.0001
Prior CABG, n (%) 165 (6.1) 32 (1.1) 104 (2.1) 349 (10.5) <0.0001
History of PCI with stenting, n (%) 2207 (81.1) 2271 (75.6) 4178 (85.2) 2932 (88.1) <0.0001
Qualifying MI type, n (%) 2114 (78.1) 2182 (72.9) 4043 (82.7) 2818 (85.0) <0.0001
NSTEMI, n (%) 1393 (51.3) 1636 (54.5) 2793 (57.0) 1662 (50.0) <0.0001
STEMI, n (%) 1155 (42.6) 1158 (38.6) 1825 (37.3) 1482 (44.6)
Unknown, n (%) 166 (6.1) 209 (7.0) 279 (5.7) 180 (5.4)
Aspirin 75–100 mg at baseline, n (%) 2640 (97.2) 2918 (97.3) 4774 (97.5) 3238 (97.4) 0.8603
Statin use at baseline, n (%) 2497 (91.8) 2760 (91.9) 4578 (93.4) 3101 (93.2) 0.0124
Beta blocker use at baseline, n (%) 2185 (80.3) 2380 (79.2) 4144 (84.5) 2830 (85.0) <0.0001
ACE-I or ARB use at baseline, n (%) 2204 (81.0) 2315 (77.1) 3921 (80.0) 2757 (82.8) <0.0001
Risk Factors for Algorithm
Qualifying MI ≥2 years, n (%) 1038 (38.2) 1978 (65.9) 1446 (29.5) 901 (27.1) <0.0001
Time from last dose of P2Y12 inhibitor, 63.0 (1.0, 348.0) 425.0 (102.0, 618.5) 64.0 (1.0, 290.0) 39.0 (1.0, 223.0) <0.0001
days, median (IQR)
Multivessel disease, n (%) 1582 (58.2) 736 (24.5) 3191 (65.1) 2802 (84.2) <0.0001
History of diabetes, n (%) 1118 (41.1) 309 (10.3) 1183 (24.1) 1904 (57.2) <0.0001
Peripheral artery disease, n (%) 209 (7.7) 19 (0.6) 76 (1.6) 461 (13.9) <0.0001
eGFR <60 mL/min (MDRD), n (%) 946 (35.0) 152 (5.1) 662 (13.5) 1435 (43.1) <0.0001
Multiple prior MIs, n (%) 469 (17.2) 105 (3.5) 479 (9.8) 1280 (38.5) <0.0001

ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; CABG, coronary artery bypass graft; CHF, congestive heart failure; eGFR, estimated glomerular
filtration rate; IQR, interquartile range; MDRD, Modification of Diet in Renal Disease; MI, myocardial infarction; NSTEMI, non-ST-elevation myocardial infarction; PCI, percutaneous
coronary intervention; STEMI, ST-elevation myocardial infarction; TIA, transient ischaemic attack.

bleeding risk (HR 1.03, 95% CI 0.81–1.31; ARD 0.56, 95% CI −1.95,
3.06) and a gradient of benefit in those at low bleeding risk by
whether they had 0–1 (HR 0.93, 95% CI 0.67–1.28; ARD −0.21,
95% CI −1.97, 1.56); 2 (HR 0.82, 95% CI 0.66–1.03; ARD −1.45,
95% CI −3.02, 0.12); or ≥3 ischaemic risk factors (HR 0.77, 95%
CI 0.62–0.94; ARD −2.64, 95% CI −5.03, −0.25). There was a con­
sistent pattern for the primary outcome and net outcomes with tica­
grelor 90 mg vs. placebo in the three risk groups (see Supplementary
material online, Table S4).
Discussion
The current analysis provides novel observations regarding the appli­
cation of long-term DAPT in patients with prior MI. First, a stepwise
approach based on the paradigm espoused by the most recent ESC
guidelines for selection of patients at lower bleeding risk and higher
thrombotic risk for additional antithrombotic therapy applied in a
trial of long-term ticagrelor in patients with prior MI identifies a sig­
nificant proportion of the population (∼60% of the PEGASUS-TIMI
5042 M.P. Bonaca et al.

A Relative Risk with Absolute Risk Difference B Relative Risk with Absolute Risk Difference
Ticagrelor vs. Placebo with Ticagrelor vs. Ticagrelor vs. Placebo with Ticagrelor vs.
by Risk Group Placebo by Risk Group by Risk Group Placebo by Risk Group
P-trend forhazard 3 Year KM Rate P-trend for absolute risk P-trend for hazard 3 Year KM Rate P-trend for absolute risk
Ticagrelor Placebo
0.1

-6

-5

-4

-3

-2

-1
Ticagrelor Placebo

0.1
ratio= 0.13 ratio =0.0083

10

-4

-3

-2

-1
10
difference 0.076 difference 0.018

3
1

1
0.98 0.08% 1.24 1.02%
High Bleeding Risk 10.42% 10.35% High Bleeding Risk 5.57% 4.55%
2721 (19%) 2721 (19%)

Low Bleeding Risk 0.87 -0.47% Low Bleeding Risk 0.81 -0.19%
≤ 1 Ischemic Risk Factor 4.98% 5.46% ≤ 1 Ischemic Risk Factor 1.79% 1.98%
3004 (22%) 3004 (22%)
Low Bleeding Risk 0.81 -1.53% Low Bleeding Risk 0.68 -0.86%
2 Ischemic Risk Factors 6.22
% 7.75% 2 Ischemic Risk Factors 1.91% 2.77%

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4903 (35%) 4903 (35%)

Low Bleeding Risk 0.77 -2.61% Low Bleeding Risk 0.64 -1.62%
3+ Ischemic Risk Factors 10.57% 13.18% 3+ Ischemic Risk Factors 3.05% 4.68%
3328 (24%) 3328 (24%)

0.5 0.8 1 1.5 -2.5 0 2.5 0.5 0.8 1 1.5 -3.0 -1.5 0 2.5

Ticagrelor 60 mg Placebo Ticagrelor 60 mg Placebo Ticagrelor 60 mg Placebo Ticagrelor 60 mg Placebo

twice daily Better Better twice daily Better Better twice daily Better Better twice daily Better Better

C Relative Risk with Absolute Risk Difference D Relative Risk with Absolute Risk Difference
Ticagrelor vs. Placebo with Ticagrelor vs. Ticagrelor vs. Placebo with Ticagrelor vs.
by Risk Group Placebo by Risk Group by Risk Group Placebo by Risk Group
P-trend for hazard 3 Year KM Rate P-trend for absolute risk P-trend for hazard 3 Year KM Rate P-trend for absolute risk
Ticagrelor Placebo Ticagrelor Placebo

-6

-5

-4

-3

-2

-1
ratio= 0.021 ratio= 0.057

0.1

4
10
0.1

difference 0.027 difference 0.037

10
-5

-4

-3

-2

-1

1
0

5
1

1.14 1.46 1.03 0.56%

High Bleeding Risk 9.11% 7.64% High Bleeding Risk 11.13% 10.57%
2721 (19%) 2721 (19%)

Low Bleeding Risk 0.90 -0.25 Low Bleeding Risk 0.93 -0.21%
≤ 1 Ischemic Risk Factor 2.96% 3.21% ≤ 1 Ischemic Risk Factor 5.32% 5.53%
3004 (22%) 3004 (22%)
Low Bleeding Risk 0.83 -0.53% Low Bleeding Risk 0.82 -1.45%
2 Ischemic Risk Factors 3.14% 3.67% 2 Ischemic Risk Factors 6.48% 7.93%
4903 (35%) 4903 (35%)

Low Bleeding Risk 0.71 -2.01% Low Bleeding Risk 0.77 -2.64%
3+ Ischemic Risk Factors 4.89% 6.90% 3+ Ischemic Risk Factors 10.79% 13.43%
3328 (24%) 3328 (24%)

0.5 0.8 1 1.5 -3.0 -1.0 0 1.00 0.5 0.8 1 1.5 -3.0 -1.5 0 3.0

Ticagrelor 60 mg Placebo Ticagrelor 60 mg Placebo Ticagrelor 60 mg Placebo Ticagrelor 60 mg Placebo

twice daily Better Better twice daily Better Better twice daily Better Better twice daily Better Better

Figure 1 Outcomes at 3 years with ticagrelor 60 mg twice daily vs. placebo by difference in hazard (left) and absolute risk difference (right) for
(A) primary outcome composite of cardiovascular death, myocardial infarction, or stroke, (B) cardiovascular death, (C) all-cause mortality, and
(D) net composite outcome of cardiovascular death, myocardial infarction, stroke, intracranial haemorrhage, or fatal bleeding.

54 population) that is at low bleeding risk and has two or more into two groups, higher thrombotic risk and lower thrombotic risk
thrombotic risk factors. Second, use of such an algorithm identifies (called moderate risk in the guideline).1 The current analysis evalu­
a population that derives greater absolute benefit, with less bleeding ates an approach conceptually aligned with this paradigm and incor­
and resulting favourable findings for CV death and net outcomes. porates the pre-specified risk criteria for the trial along with
Patients with prior MI have been described through a number of subgroup findings and the guideline characteristics to approximate
trials to be at long-term heightened risk of recurrent atherothrombo­ this approach. Use of this approach not only identified a lower risk
sis. More potent antiplatelet therapy reduces this risk but increases group for bleeding on ticagrelor but also identified a gradient of is­
bleeding requiring clinicians to personalize the approach, which ac­ chaemic risk within the low-bleeding risk group enabling further per­
knowledges heterogeneity in the population both for ischaemic and sonalization. This approach translated to greater absolute benefits
bleeding risk. Established risk scores have shown the ability to discrim­ for MACE, heterogeneity with lower rates of CV death and greater
inate ischaemic risk in broad atherosclerosis populations but have not net benefit in those at the highest ischaemic risk (at least 2 risk fac­
evaluated bleeding risk with P2Y12 inhibition, limiting utilization for tors). In fact, the 59% of the population at low bleeding risk and with
long-term ticagrelor. Scores developed to evaluate net outcomes either 2 or ≥3 ischaemic risk factors may be the optimal population
such as the DAPT score13 have utility at the time of stenting in broad for the use of long-term ticagrelor 60 mg. Although those at high
populations but do not necessarily translate to stable post-MI patients bleeding risk had ischaemic events, premature discontinuation of
where procedural aspects are less relevant to risk relative to clinical study treatment and potentially other background therapies may
characteristics and a significant proportion of patients have not had partially explain the attenuation of benefit. Future studies may help
PCI. More recently, scores like PRECISE-DAPT11 have shown the abil­ to further elucidate the exact reasons why those at high bleeding
ity to risk stratify in acute coronary syndrome (ACS) but are focused risk do not benefit from prolonged DAPT and explore how much
predominantly on bleeding rather than both bleeding and ischaemic any benefit is offset by ischaemic complications occurring in the con­
risk and have been derived in ACS or PCI populations. Therefore, text of bleeding events. Regardless, these observations support the
there is an unmet need for a patient selection algorithm for long-term guideline recommendation that long-term therapy should be consid­
ticagrelor in stable patients with a history of MI more than a year ago ered (Class IIa recommendation) in such patients and provide exten­
even if they have not been treated with PCI. sive data for outcomes and net benefit that may be useful to clinicians
The most recent ESC guidelines for non-ST-elevation ACS de­ in communicating risk/benefit to patients.
scribe an algorithm where patients at lower bleeding risk are first There are several limitations to this analysis. First, the data are de­
identified and then those at lower bleeding risk are categorized rived from a single data set and have not been validated externally;
Patient selection for long-term secondary prevention with ticagrelor
however, there are few large data sets examining long-term ticagre­
lor in a randomized trial. Second, although not all factors outlined in
the ESC guidelines were available for inclusion, the characteristics
identified for both bleeding risk and ischaemic risk have been identi­
fied as independent predictors in other data sets and scores.1 Third,
there was no effect modification for relative benefit for the primary
endpoint by risk category; however, the goal of the analysis was to
characterize ARDs that were strongly statistically significant.
Fourth, the results are a post-hoc exploratory analysis and therefore
should be considered hypothesis generating. Fifth, the ARDs were
calculated by using the subgroup specific rates which was felt to be
more conservative in highlighting that the high bleeding risk group
may derive lesser benefit. An alternative approach to using the ob­
served ARDs and instead applying the overall trial HR to the placebo
event rate in each subgroup showed a more consistent absolute dif­
ference between groups. Sixth, this study assigned equal weights to
ischaemic risk factors included in this study and readers cannot infer a
definitive threshold for number of ischaemic risk factors for net
benefit; future studies should derive a scoring system using predictive
modelling methods. Finally, PEGASUS specifically excluded patients
at highest risk of bleeding (history of previous intracranial bleed at
any time, gastrointestinal (GI) bleed within the past 6 months, or ma­
jor surgery within 30 days), and, like most randomized trials, enrolled
a selected population that may not be entirely representative of
post-ACS patients encountered in routine clinical care.22 Further val­
idation in ‘real-world’ cohorts, including those with history of gastro­
intestinal bleeding, will lead to understanding of performance in a
broader population of patients.
Conclusions
In conclusion, in stable patients with prior MI, a stepwise patient se­
lection approach evaluating bleeding and ischaemic risk based on
post-hoc subgroups may be useful in identifying patients who may
derive greater net benefit with long-term ticagrelor. Specifically,
those at lower bleeding risk with at least two ischaemic risk factors
appeared to have the most favourable risk–benefit profile. This sim­
ple patient selection approach may be useful for clinicians identifying
patients who may benefit from a strategy of long-term ticagrelor
after MI.
Supplementary material
Supplementary material is available at European Heart Journal online.
Funding
This study was supported by a grant to Brigham and Women’s Hospital
from AstraZeneca.
Conflict of interest: The TIMI Study Group has received significant
research grant support from Abbott, Amgen, Aralez, AstraZeneca,
Bayer HealthCare Pharmaceuticals, Inc., BRAHMS, Daiichi Sankyo,
Eisai, GlaxoSmithKline, Intarcia, Janssen, MedImmune, Merck, Novartis,
Pfizer, Poxel, Quark Pharmaceuticals, Roche, Takeda, The Medicines
Company, Zora Biosciences. M.P.B. reports grant support to CPC clinical
research from Amgen, AstraZeneca, Bayer, Janssen, Merck, Novo
Nordisk, Pfizer, Sanofi, Wraser. M.D. reports personal fees for lectures
and trial steering committee participation from AstraZeneca and
5043
Novartis, personal fees for lectures from Boehringer Ingelheim, Sanofi
and Bayer. Advisory Board: Amgen, Novo Nordisk, AstraZeneca,
Novartis. Personal fees for serving on the Data Monitoring
Committee: for the DAPA-MI trial, funded by AstraZeneca. R.F.S. re­
ports institutional research grants/support from AstraZeneca,
Cytosorbents, GlyCardial Diagnostics, and Thromboserin; and personal
fees from Alnylam, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb/
Pfizer, Chiesi, CSL Behring, Cytosorbents, GlyCardial Diagnostics,
Hengrui, Idorsia, Intas Pharmaceuticals, Medscape, Novartis, PhaseBio,
Downloaded from https://academic.oup.com/eurheartj/article/43/48/5037/6823782 by European Society of Cardiology user on 28 May 2023
Sanofi Aventis, and Thromboserin. D.L.B discloses the following relation­
ships—Advisory Board: Bayer, Boehringer Ingelheim, Cardax,
CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology,
Janssen, Level Ex, Medscape Cardiology, Merck, MyoKardia, NirvaMed,
Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, and Stasys;
Board of Directors: Bristol Myers Squibb (stock), Boston VA Research
Institute, DRS.LINQ (stock options), Society of Cardiovascular Patient
Care, TobeSoft; Chair: Inaugural Chair, American Heart Association
Quality Oversight Committee; Data Monitoring Committees: Acesion
Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for
Clinical Research (formerly Harvard Clinical Research Institute, for the
PORTICO trial, funded by St Jude Medical, now Abbott), Boston
Scientific (Chair, PEITHO trial), Cleveland Clinic (including for the
ExCEED trial, funded by Edwards), Contego Medical (Chair,
PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic,
Mount Sinai School of Medicine (for the ENVISAGE trial, funded by
Daiichi Sankyo; for the ABILITY-DM trial, funded by Concept Medical),
Novartis, Population Health Research Institute; Rutgers University (for
the NIH-funded MINT Trial); Honoraria: American College of
Cardiology (Senior Associate Editor, Clinical Trials and News,
ACC.org; Chair, ACC Accreditation Oversight Committee), Arnold
and Porter law firm (work related to Sanofi/Bristol Myers Squibb clopi­
dogrel litigation), Baim Institute for Clinical Research (formerly Harvard
Clinical Research Institute; RE-DUAL PCI clinical trial steering committee
funded by Boehringer Ingelheim; AEGIS-II executive committee funded
by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart
Letter), Canadian Medical and Surgical Knowledge Translation
Research Group (clinical trial steering committees), Cowen and
Company, Duke Clinical Research Institute (clinical trial steering commit­
tees, including for the PRONOUNCE trial, funded by Ferring
Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive
Cardiology), Journal of the American College of Cardiology (Guest
Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum),
Level Ex, Medtelligence/ReachMD (CME steering committees), MJH
Life Sciences, Piper Sandler, Population Health Research Institute (for
the COMPASS operations committee, publications committee, steering
committee, and USA national co-leader, funded by Bayer), Slack
Publications (Chief Medical Editor, Cardiology Today’s Intervention),
Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD
(CME steering committees), Wiley (steering committee); Other:
Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry
Steering Committee (Chair), VA CART Research and Publications
Committee (Chair); Research Funding: Abbott, Afimmune, Aker
Biomarine, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer
Ingelheim, Bristol Myers Squibb, Cardax, CellProthera, Cereno
Scientific, Chiesi, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals,
Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS
Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon,
Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis,
Novo Nordisk, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio,
Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic,
The Medicines Company, 89Bio; Royalties: Elsevier (Editor,
Braunwald’s Heart Disease); Site Co-Investigator: Abbott, Biotronik,
5044
Boston Scientific, CSI, St Jude Medical (now Abbott), Philips, Svelte;
Trustee: American College of Cardiology; Unfunded Research:
FlowCo, Takeda. P.G.S. reports research grants from Amarin, Bayer,
Merck, Sanofi, and Servier, speaking or consulting fees from Amarin,
Amgen, AstraZeneca, Bayer/Janssen, Boehringer Ingelheim, Bristol
Myers Squibb, Idorsia, Lilly, Merck, Novartis, Novo Nordisk, Pfizer,
Regeneron, Sanofi, and Servier. M.C. reports grants and personal fees
from AstraZeneca, during the conduct of the study; personal fees
from Merck, personal fees from Janssen, personal fees from Maquet, per­
sonal fees from malpractice attorneys, grants from Janssen, grants from
Edwards, personal fees from Merck, personal fees from BMS/Pfizer, per­
sonal fees from Janssen, personal fees from BI, personal fees from Lilly,
outside the submitted work. K.I. is the member of the TIMI Study
Group which has received institutional research grant support through
Brigham and Women’s Hospital from Abbott, Amgen, Aralez,
AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc., BRAHMS,
Daiichi Sankyo, Eisai, GlaxoSmithKline, Intarcia, Janssen, MedImmune,
Merck, Novartis, Pfizer, Poxel, Quark Pharmaceuticals, Roche, Takeda,
The Medicines Company, and Zora Biosciences. P.J. is an employee of
AstraZeneca. E.B. reports grant support through Brigham and
Women’s Hospital from AstraZeneca, Daiichi Sankyo, Merck, and
Novartis, Consultancies with Amgen, Cardurion, MyoKardia, Novo
Nordisk, and Verve. M.S.S. received research grant support through
Brigham and Women’s Hospital from Abbott, Amgen, Anthos
Therapeutics, AstraZeneca, Bayer, Daiichi Sankyo, Eisai, Intarcia, Ionis,
Medicines Company, MedImmune, Merck, Novartis, Pfizer, and Quark
Pharmaceuticals. Consulting for Althera, Amgen, Anthos Therapeutics,
AstraZeneca, Beren Therapeutics, Bristol Myers Squibb, DalCor, Dr
Reddy’s Laboratories, Fibrogen, Intarcia, Merck, Moderna, Novo
Nordisk, and Silence Therapeutics. Additionally, Dr Sabatine is a member
of the TIMI Study Group, which has also received institutional research
grant support through Brigham and Women’s Hospital from: ARCA
Biopharma, Inc., Janssen Research and Development, LLC, Siemens
Healthcare Diagnostics, Inc., Softcell Medical Limited, Regeneron,
Roche, and Zora Biosciences.
Data availability
Data for the analyses cannot be shared by those interested in collabor­
ation are encouraged to contact the corresponding author.
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