De Escalation From Ticagrelor To Clopidogrel in Patients With Acute Myocardial I

CORONARY INTERVENTIONS
CLINICAL RESEARCH
EuroIntervention 2023;19-online publish-ahead-of-print September 2023

De-escalation from ticagrelor to clopidogrel in patients with
acute myocardial infarction: the TALOS-AMI HBR substudy
Min Chul Kim1, MD, PhD; Sung Gyun Ahn2, MD, PhD; Kyung Hoon Cho1, MD, PhD;
Doo Sun Sim1, MD, PhD; Young Joon Hong1, MD, PhD; Ju Han Kim1, MD, PhD; Myung Ho Jeong1, MD, PhD;
Jun-Won Lee2, MD, PhD; Young-Jin Youn2, MD, PhD; Hee-Yeol Kim3, MD, PhD; Ki-Dong Yoo4, MD, PhD;
Doo-Soo Jeon5, MD, PhD; Eun-Seok Shin6, MD, PhD; Young-Hoon Jeong7, MD, PhD; Kiyuk Chang8, MD, PhD;
Youngkeun Ahn1*, MD, PhD
1. Division of Cardiology, Department of Internal Medicine, Chonnam National University Hospital, Chonnam National
University Medical School, Gwangju, South Korea; 2. Division of Cardiology, Department of Internal Medicine, Wonju
Severance Christian Hospital, Wonju, South Korea; 3. Division of Cardiology, Department of Internal Medicine, Bucheon St
Mary’s Hospital, Bucheon, South Korea; 4. Division of Cardiology, Department of Internal Medicine, The Catholic University of
Korea, St Vincent’s Hospital, Suwon, South Korea; 5. Division of Cardiology, Department of Internal Medicine, Incheon St Mary’s
Hospital, Incheon, South Korea; 6. Division of Cardiology, Department of Internal Medicine, Ulsan University Hospital, Ulsan,
South Korea; 7. Division of Cardiology, Department of Internal Medicine, Chung-Ang University Gwangmyeong Hospital,
Gwangmyeong, South Korea; 8. Division of Cardiology, Department of Internal Medicine, The Catholic University of Korea,
Seoul St Mary’s Hospital, Seoul, South Korea
M.C. Kim and S.G. Ahn contributed equally to this work.
This paper also includes supplementary data published online at: https://eurointervention.pcronline.com/doi/10.4244/EIJ-D-23-00427
KEYWORDS
Abstract
Background: The benefits of de-escalation of P2Y12 inhibition after percutaneous coronary intervention
(PCI) may differ by high bleeding risk (HBR) status.
• adjunctive
Aims: We investigated the efficacy and safety of de-escalation from ticagrelor to clopidogrel after PCI by
pharmacotherapy
HBR status.
• clinical trials
Methods: This is a non-prespecified post hoc analysis of the TicAgrelor Versus CLOpidogrel in Stabilized
• NSTEMI
Patients with Acute Myocardial Infarction (TALOS-AMI) trial. Net adverse clinical events (a composite of
• STEMI
cardiovascular death, myocardial infarction, stroke, or Bleeding Academic Research Consortium [BARC]
bleeding type 2, 3, or 5) at 1 year post-PCI were compared between the de-escalation (clopidogrel plus aspi-
rin) and the active control (ticagrelor plus aspirin) groups by HBR status, as defined by the modification of
the Academic Research Consortium (ARC) criteria.
Results: A total of 2,625 patients in the TALOS-AMI trial were analysed. Of these, 589 (22.4%) met the
modified ARC-HBR criteria. The de-escalation group had lower primary endpoint rates than the control
group in both HBR (hazard ratio [HR] 0.47, 95% confidence interval [CI]: 0.26-0.84) and non-HBR (HR
0.59, 95% CI: 0.41-0.84) patients. There were no differences in treatment effect for the primary endpoint
regardless of HBR status (p for interaction=0.904). BARC bleeding type 3 or 5 was less common in the de-
DOI: 10.4244/EIJ-D-23-00427
escalation than the control group among HBR patients only (HR 0.24, 95% CI: 0.07-0.84).
Conclusions: In stabilised acute myocardial infarction patients, unguided de-escalation from ticagrelor to
clopidogrel was associated with a lower rate of net adverse clinical outcomes irrespective of HBR status.
The effect of de-escalation of P2Y12 inhibition on reducing haemorrhagic events was greater in patients
with HBR.
*Corresponding author: Division of Cardiology, Department of Internal Medicine, Cardiovascular Center, Chonnam National University
Hospital, Chonnam National University School of Medicine, 42 Jebong-ro, Dong-gu, Gwangju 61469, South Korea. E-mail: [email protected].
© Europa Digital & Publishing 2023. All rights reserved. SUBMITTED ON 29/05/2023 - REVISION RECEIVED ON 15/07/2023 - ACCEPTED ON 15/08/2023
1
Abbreviations outcomes from 1 to 12 months compared to the active control strat-

AMI acute myocardial infarction egy (maintenance of ticagrelor for 12 months). All patients received
ARC Academic Research Consortium aspirin and ticagrelor during the screening period (1 month after
CKD chronic kidney disease PCI), and those without any adverse clinical events were randomised
DAPT dual antiplatelet therapy in the outpatient department. The protocol was approved by the insti-
DES drug-eluting stent tutional review board or ethics committee of each participating cen-
HBR high bleeding risk tre, and all procedures adhered to the principles of the Declaration
MACCE major adverse cardiac and cerebrovascular of Helsinki. All patients provided written informed consent.
events
PCI percutaneous coronary intervention STUDY DEFINITIONS AND ENDPOINTS
PRECISE-DAPT PREdicting bleeding Complications In patients The current study investigates whether the benefits of the TALOS-AMI
undergoing Stent Implantation and subsEquent trial were maintained by patients both at HBR and non-HBR. HBR
Dual Anti Platelet Therapy was defined as a modification of the Academic Research Consortium
TALOS-AMI TicAgrelor Versus CLOpidogrel in Stabilized for High Bleeding Risk (ABC-HBR) criteria5, because in the TALOS-
Patients with Acute Myocardial Infarction AMI trial, i) many HBR patients were excluded at baseline and during
the first month after index PCI9,16 and ii) of 204 patients who were not
Introduction screened in the first month, bleeding events occurred in 10 patients
Ticagrelor and prasugrel are potent P2Y12 inhibitors and are prefer- (Supplementary Table 1). This was not unexpected given the original
able to clopidogrel in patients with acute myocardial infarction data (on 43 patients) in terms of the incidence of BARC bleeding type
(AMI) undergoing percutaneous coronary intervention (PCI), as 3 or 59. Also, hidden bleeding events could have occurred in patients
revealed by pivotal randomised trials1,2 and subsequent guideline who were not followed up during screening, given the high risk of
updates3,4. However, clopidogrel is still recommended when the major bleeding events associated with ticagrelor compared to clopi-
bleeding risk outweighs the thrombotic risk associated with potent dogrel in Korean patients17. Therefore, we modified the ARC-HBR
P2Y12 inhibitors3,5. As both thrombotic and haemorrhagic events criteria to include as many HBR patients as possible. Supplementary
are linked to poor clinical outcomes6,7, various strategies − such Table 2 lists our major and minor HBR criteria and the differences
as shortening the mandatory duration of dual antiplatelet therapy from the ARC-HBR criteria. Nine major and two minor ARC-HBR
(DAPT)8, switching from potent P2Y12 inhibitors to clopidogrel9, criteria that served as exclusion criteria for the TALOS-AMI trial were,
decreasing the doses of potent P2Y12 inhibitors10, and P2Y12 inhib- thus, not used to define HBR in the present work. Rather, two minor
itor monotherapy (thus dropping aspirin)11-14 − have sought to cre- ARC-HBR criteria − age ≥75 years and moderate chronic kidney dis-
ate trade-offs between thrombosis and haemorrhage. ease (CKD) − were transferred to the major HBR criteria in the cur-
As time elapses after PCI, both the thrombotic and bleeding risks rent study, because these were associated with significant bleeding
diminish, and the bleeding risk becomes higher than the ischaemic (BARC bleeding type 3 or 5 rates >4%) in several validation stud-
risk after 1 month15. Thus, the recent TicAgrelor Versus CLOpidogrel ies employing the ARC-HBR criteria18,19. Moreover, a combination of
in Stabilized Patients with Acute Myocardial Infarction (TALOS- age ≥75 years and moderate CKD was associated with a higher inci-
AMI) trial evaluated uniform unguided de-escalation of P2Y12 inhi- dence of BARC bleeding type 3 or 5 than all other ARC-HBR compo-
bition (from ticagrelor to clopidogrel) at 1 month in AMI patients nents combined18. Consequently, we defined HBR when 1 major or 2
with no thrombotic or haemorrhagic events9. This reduced the net minor modified HBR criteria were fulfilled (Supplementary Table 2).
adverse clinical outcomes (principally bleeding events) compared A detailed study protocol (including definitions and endpoints)
to those patients on standard ticagrelor-based 12-month DAPT. We has been previously published9,16. Briefly, the primary endpoint was
hypothesised that the benefit of de-escalation might be more pro- a net adverse clinical event − a composite of cardiovascular death,
found in patients with HBR than those with non-HBR. Therefore, myocardial infarction, stroke, or BARC bleeding type 2, 3, or 5 −
using TALOS-AMI trial data, we explored the efficacy and safety of from 1 to 12 months after the index PCI. The key secondary endpoint
de-escalation in patients with HBR and those with non-HBR. was BARC bleeding type 3 or 5. Other secondary endpoints included
a major adverse cardiac and cerebrovascular event (MACCE;
Methods a composite of cardiovascular death, myocardial infarction, or
STUDY DESIGN AND POPULATION stroke), BARC bleeding type 2, 3, or 5, a composite of MACCE
This study is a non-prespecified post hoc analysis of the TALOS- and BARC bleeding type 3 or 5, all-cause death, cardiovascular
AMI trial, which was an open-label, assessor-masked, multicen- death, myocardial infarction, stroke, ischaemia-driven revascularisa-
tre, non-inferiority, randomised trial conducted at 32 centres in tion, and stent thrombosis from 1 to 12 months after the index PCI.
South Korea between February 2014 and December 20189,16. The
trial explored whether de-escalation from ticagrelor to clopidogrel STATISTICAL ANALYSIS
1 month after PCI using drug-eluting stents (DES) in stabilised AMI Continuous variables are presented as means±standard deviations
patients was non-inferior in terms of net ischaemic and bleeding and were compared using the unpaired t-test. Categorical variables
2
De-escalation from ticagrelor to clopidogrel in HBR patients

are expressed as counts with percentages and were compared using modified HBR criteria) after excluding 72 patients for whom data
Pearson’s chi-square test or Fisher’s exact test. We constructed on at least one of the modified criteria were missing (Supplementary
Kaplan-Meier curves and used the log-rank test to compare the Table 2). Using the modified criteria, 589 patients (22.4%) were at
groups in terms of the primary and secondary endpoints (MACCE, HBR and the other 2,036 (77.6%) were at non-HBR. The preva-
BARC bleeding type 3 or 5, and a composite of MACCE and BARC lence of the modified HBR criteria in the HBR group are shown
bleeding type 3 or 5). Cox’s proportional hazards models were used in Supplementary Figure 1. Age ≥75 years (53.0%) and moderate
to calculate hazard ratios (HR) with 95% confidence intervals (CI). CKD (48.9%) were the most common major criteria. Of the minor
The proportional hazards assumption was evaluated using the log- criteria, the prevalence of mild anaemia was 39.6%, but the rate of
minus-log plot and the Schoenfeld residual test; all Cox’s propor- ischaemic stroke was only 7.0%. The incidence of BARC bleeding
tional hazards models of clinical endpoints satisfied the proportional type 3 or 5 between 1 and 12 months was ≥4% (major and minor
hazards assumption. A formal interaction test was performed to criteria). However, the incidence of major bleeding was <4% in iso-
assess the consistency of the de-escalation effects (compared to lation (without other concomitant criteria). Supplementary Figure 2
those of active control) in patients at HBR and non-HBR. shows the clinical impacts of multiple HBR criteria. The proportions
The primary and secondary endpoints of the 2 groups were com- of multiple HBR criteria were 70.5% (1 criterion), 22.8% (2 crite-
pared by HBR and non-HBR status. Sensitivity analysis employed ria), 6.3% (3 criteria), and 0.5% (4 criteria; which included only
the PREdicting bleeding Complications In patients undergoing 3 patients). Increased numbers of HBR criteria modestly predicted
Stent Implantation and subsEquent Dual Anti Platelet Therapy the clinical outcome (a composite of MACCE and BARC bleeding
(PRECISE-DAPT) scores and the original ARC-HBR criteria5,20. type 3 or 5) with incremental prognostic value, but the risk of BARC
Of the variables contributing to the PRECISE-DAPT score, previ- bleeding type 3 or 5 increased with the number of HBR criteria.
ous bleeding, which was excluded in the TALOS-AMI trial, was
ignored. Therefore, only 4 variables were used when calculating this BASELINE CHARACTERISTICS AND CLINICAL OUTCOMES
score (www.precisedaptscore.com). All analyses were performed on BETWEEN HBR AND NON-HBR BY MODIFIED ARC-HBR
an intention-to-treat principle, all were 2-tailed, and p<0.05 indi- CRITERIA
cated statistical significance. All analyses were performed with the Baseline characteristics and the procedural profiles are shown in
aid of Stata/MP version 16.0 software (StataCorp). Supplementary Table 3. The HBR group contained higher propor-
tions of elderly and female patients. In terms of medical history, the
Results HBR group featured more hypertensive and diabetic patients than
ASSESSMENT OF MODIFIED HBR CRITERIA the non-HBR group and also those with higher incidences of pre-
Figure 1 shows the study flow. Between February 2014 and vious PCI and cerebrovascular accidents. However, the incidences
December 2018, 2,697 patients were enrolled in the TALOS-AMI of dyslipidaemia and current smokers were higher in the non-HBR
trial, of whom 2,625 were analysed in the present study (using the group. In terms of laboratory findings, the creatinine clearance
The TALOS-AMI high bleeding risk substudy
2,697 patients enrolled in the TALOS-AMI trial
72 patients with at least 1 missing value of HBR criteria
2,625 patients with HBR criteria
According to HBR
HBR (n=589) Non-HBR (n=2,036)
De-escalation Active control De-escalation Active control

(n=300) (n=289) (n=1,011) (n=1,025)
Figure 1. Study flowchart. HBR: high bleeding risk; TALOS-AMI: TicAgrelor Versus CLOpidogrel in Stabilized Patients with Acute
Myocardial Infarction
3
rate, the haemoglobin and platelet levels, and the white blood cell and BARC bleeding type 3 or 5, all-cause mortality, cardiovas-
count were lower in the HBR group. The rates of left ventricular cular mortality, and spontaneous myocardial infarction) were all
ejection fraction <40% were 13.5% in the HBR group and 5.9% higher in the HBR group. There were no between-group differ-
in the non-HBR group (p<0.001). There were no between-group ences in the incidences of stroke, ischaemia-driven revascularisa-
differences in terms of clinical presentation or the access site. In tion, or stent thrombosis.
both groups, the most frequently infarct-related artery was the left
anterior descending artery. Multivessel treatment was performed BASELINE CHARACTERISTICS AND CLINICAL OUTCOMES
more in the HBR group than the non-HBR group (33.3 vs 28.7%; ACCORDING TO HBR BY MODIFIED ARC-HBR CRITERIA AND
p=0.034). The clinical outcomes are shown in Supplementary TREATMENT ARM
Table 4 and Figure 2. The primary endpoint incidence was signifi- For both the HBR and non-HBR groups, the characteristics and
cantly higher in the HBR group (8.7 vs 5.2%, HR 1.75, 95%: CI: outcomes were investigated by the treatment arm (Figure 1). Of the
1.26-2.45; p=0.001). The key secondary endpoint, BARC bleed- HBR group, 300 were allocated to the de-escalation group and 289
ing type 3 or 5, was also more common in the HBR group (2.5 to the active control group. In the non-HBR group, 1,011 patients
vs 1.3%, HR: 2.01, 95% CI: 1.07-3.78; p=0.030). The incidences were in the de-escalation group and 1,025 in the active control
of other secondary endpoints (MACCE, a composite of MACCE group. The baseline and procedural characteristics were balanced
A Cardiovascular death, MI, stroke, and BARC bleeding type 2, 3 or 5 B Cardiovascular death, MI or stroke
(%) 15 (%) 15
Non-HBR Non-HBR
HBR HBR
Cumulative incidence
Log-rank p=0.0009 Cumulative incidence Log-rank p<0.0001

10 8.7% 10
5.2% 4.6%
5 5
1.7%
0 0
100 200 300 100 200 300
Days Days
Number at risk Number at risk
HBR 589 528 494 464 HBR 589 537 514 481
Non-HBR 2,036 1,908 1,827 1,753 Non-HBR 2,036 1,940 1,877 1,812
C BARC bleeding type 3 or 5 D Cardiovascular death, MI, stroke, and BARC bleeding type 3 or 5
(%) 15 (%) 15
Non-HBR Non-HBR
HBR HBR
Log-rank p=0.0267 Log-rank p<0.0001

10 10
6.5%
5 5
2.5% 2.7%
1.3%
0 0
100 200 300 100 200 300
Days Days
HBR 589 539 517 489 HBR 589 533 508 476
Non-HBR 2,036 1,938 1,885 1,813 Non-HBR 2,036 1,934 1,867 1,798
Figure 2. Cumulative incidence of the primary and secondary outcomes by HBR. A) Primary endpoint: a composite of cardiovascular death, myocardial infarction, stroke, or
BARC bleeding type 2, 3, or 5. B) Secondary endpoint: a major adverse cardiac and cerebrovascular event (MACCE; a composite of cardiovascular death, myocardial infarction,
or stroke). C) Key secondary endpoint: BARC type 3 or 5 bleeding. D) Secondary endpoint: a composite of MACCE and BARC bleeding type 3 or 5. BARC: Bleeding Academic
Research Consortium; HBR: high bleeding risk; MI: myocardial infarction
4

between the de-escalation and active control groups for both HBR 0.47, 95%: CI: 0.26-0.84; p=0.011) (Table 2, Figure 3). The inci-
and non-HBR patients (Table 1). Among the HBR patients, the dence of BARC bleeding type 3 or 5 (1.0 vs 4.2%, HR 0.24, 95%
primary endpoint occurred less frequently in the de-escalation CI: 0.07-0.84; p=0.026) and a composite of MACCE and BARC
group compared to the active control group (5.7 vs 11.8%, HR bleeding type 3 or 5 (4.0. vs 9.0%, HR 0.43, 95% CI: 0.22-0.86;
Table 1. Baseline and procedural characteristics by HBR and treatment arm.

HBR (n=589) Non-HBR (n=2,036)
p-value p-value
(n=300) (n=289) (n=1,011) (n=1,025)
Demographics Age, years 70.7±10.8 71.2±10.2 0.522 57.0±9.3 56.6±9.5 0.421
Male 198 (66.0) 191 (66.1) 0.982 898 (88.8) 892 (87.0) 0.213
Body mass index, kg/m2 24.0±3.3 23.5±4.0 0.103 24.9±3.2 24.8±3.4 0.832
Medical Hypertension 191 (63.7) 190 (65.7) 0.598 443 (43.8) 453 (44.2) 0.864
history
Diabetes 104 (34.7) 94 (32.5) 0.582 245 (24.2) 265 (25.9) 0.399
Diabetes treated with insulin 10 (3.3) 10 (3.5) 0.932 16 (1.6) 18 (1.8) 0.760
Dyslipidaemia 115 (38.3) 102 (35.3) 0.445 427 (42.2) 443 (43.2) 0.654
Current smoker 92 (30.7) 79 (27.3) 0.373 557 (55.1) 576 (56.2) 0.617
Impaired renal function* 160 (53.3) 144 (49.8) 0.395 – – –
Past medical Previous PCI 17 (5.7) 25 (8.7) 0.159 42 (4.2) 32 (3.1) 0.213
history
Previous CABG 2 (0.7) 1 (0.3) 1.000 1 (0.1) – –
Previous CVA 23 (7.7) 18 (6.2) 0.493 27 (2.7) 30 (2.9) 0.726
Clinical presentation
STEMI 150 (50.0) 152 (52.6) 0.529 560 (55.4) 550 (53.7) 0.433
NSTEMI 150 (50.0) 137 (47.4) 451 (44.6) 475 (46.3)
Laboratory Creatinine clearance†, mL/
68.2±25.1 68.6±26.6 0.859 91.8±20.7 94.1±22.9 0.016
findings min/1.73 m2
Haemoglobin, g/dL 13.3±1.9 13.1±1.9 0.248 15.0±1.3 14.9±1.4 0.301
Platelet, 109/L 233.8±61.5 234.0±64.6 0.959 242.7±61.0 239.7±55.9 0.256
White blood cell count, 10 /L 9
9.8±3.4 9.6±3.4 0.348 10.4±3.4 10.6±3.5 0.162
LVEF <40% 40/289 (13.8) 36/273 (13.2) 0.821 59/979 (6.0) 56/980 (5.7) 0.769
Access site
Radial 136 (45.3) 123 (42.6) 0.427 482 (47.7) 514 (50.1) 0.528
Femoral 152 (50.7) 148 (51.2) 479 (47.4) 461 (45.0)
Glycoprotein IIb/IIIa inhibitor 74 (24.7) 67 (23.2) 0.673 234 (23.1) 241 (23.5) 0.845
Infarct-related artery
Left main coronary artery 7 (2.3) 10 (3.5) 14 (1.4) 14 (1.4)
Left anterior descending artery 134 (44.8) 120 (41.8) 0.766 524 (52.3) 495 (48.7) 0.044
Left circumflex artery 38 (12.7) 40 (13.9) 160 (16.0) 212 (20.9)
Right coronary artery 120 (40.1) 117 (40.8) 303 (30.3) 295 (29.0)
Number of treated vessels 1.4±0.6 1.4±0.7 0.394 1.4±0.6 1.4±0.6 0.830
Multivessel treatment 98 (32.7) 98 (33.9) 0.749 287 (28.4) 298 (29.1) 0.733
Numbers of stents for infarct-related artery 1.2±0.4 1.2±0.4 0.765 1.2±0.5 1.2±0.4 0.584
Total stent length of infarct-related artery, mm 30.9±13.7 30.7±15.3 0.915 29.7±18.9 29.1±13.4 0.406
Stent diameter of infarct-related artery, mm
3.2±0.4 3.2±0.5 0.696 3.2±0.5 3.2±1.0 0.613
Intravascular Optical coherence tomography 9 (3.0) 10 (3.5) 0.752 38 (3.8) 25 (2.4) 0.086
imaging
Intravascular ultrasonography 69 (23.0) 65 (22.5) 0.883 252 (24.9) 238 (23.2) 0.368
Values are expressed as mean±SD, n (%) or n/N (%). *Impaired renal function was defined as an estimated glomerular filtration rate of less than 60 mL/
min/1.73 m2 of body surface area at presentation. †Creatinine clearance was calculated by the MDRD (Modification of Diet in Renal Disease)
formula: 186 *(serum creatinine)−1.154 *(age)−0.203 *0.742 (for women). CABG: coronary artery bypass graft; CVA: cerebrovascular accident;
HBR: high bleeding risk; LVEF: left ventricular ejection fraction; NSTEMI: non-ST-segment elevation myocardial infarction; PCI: percutaneous coronary
intervention; SD: standard deviation; STEMI: ST-segment elevation myocardial infarction
5
Table 2. Primary and secondary outcomes by HBR and treatment arm.

HBR (n=589) Non-HBR (n=2,036)
Active Hazard Active Hazard p-value for
De-escalation De-escalation interaction
control ratio (95% p-value control ratio p-value
(n=300) (n=1,011)
(n=289) CI) (n=1,025) (95% CI)
Primary endpoint* 0.47 0.59
17 (5.7) 34 (11.8) 0.011 40 (4.0) 66 (6.4) 0.009 0.904
(0.26-0.84) (0.40-0.88)
Secondary BARC bleeding type 3 0.24 0.79
3 (1.0) 12 (4.2) 0.026 12 (1.2) 15 (1.5) 0.542 0.413
endpoints or 5 (0.07-0.84) (0.37-1.69)
MACCE† 0.65 0.69
11 (3.7) 16 (5.5) 0.269 14 (1.4) 20 (2.0) 0.285 0.088
(0.30-1.40) (0.35-1.36)
BARC bleeding type 0.38 0.60
8 (2.7) 20 (6.9) 0.019 30 (3.0) 49 (4.8) 0.029 0.226
2, 3 or 5 (0.17-0.85) (0.38-0.95)
BARC bleeding type 2 0.67 0.51
7 (2.3) 10 (3.5) 0.417 20 (2.0) 39 (3.8) 0.013 0.593
(0.26-1.76) (0.30-0.87)
BARC bleeding type 3 0.24 0.79
3 (1.0) 12 (4.2) 0.026 12 (1.2) 15 (1.5) 0.542 0.413
(0.07-0.84) (0.37-1.69)
BARC bleeding type 5 1 (0.3) – – – – – – – –
MACCE and BARC 0.43 0.68
12 (4.0) 26 (9.0) 0.017 22 (2.2) 32 (3.1) 0.157 0.553
bleeding type 3 or 5 (0.22-0.86) (0.39-1.16)
All-cause death 0.53 4.95
5 (1.7) 9 (3.1) 0.252 5 (0.5) 1 (0.1) 0.144 0.058
(0.18-1.58) (0.58-42.37)
Cardiovascular death 0.38 2.98
2 (0.7) 5 (1.7) 0.249 3 (0.3) 1 (0.1) 0.345 0.464
(0.07-1.96) (0.31-28.61)
Myocardial Any myocardial 0.59 0.63
5 (1.7) 8 (2.8) 0.354 7 (0.7) 11 (1.1) 0.332 0.376
infarction infarction (0.19-1.80) (0.24-1.61)
Spontaneous 0.79 0.56
5 (1.7) 6 (2.1) 0.692 4 (0.4) 7 (0.7) 0.358 0.092
(0.24-2.58) (0.16-1.92)
Periprocedural 0.74
– 2 (0.7) – – 3 (0.3) 4 (0.4) 0.692 –
(0.17-3.30)
Target vessel 0.47 0.98
1 (0.3) 2 (0.7) 0.538 6 (0.6) 6 (0.6) 0.975 0.588
myocardial infarction (0.04-5.19) (0.32-3.05)
Stroke 0.95 0.50
4 (1.3) 4 (1.4) 0.938 4 (0.4) 8 (0.8) 0.251 0.217
(0.24-3.79) (0.15-1.65)
Ischaemia-driven Target lesion 0.94 1.69
2 (0.7) 2 (0.7) 0.949 12 (1.2) 7 (0.7) 0.270 0.711
revascularisation revascularisation (0.13-6.66) (0.67-4.29)
Target vessel 0.70 1.06
3 (1.0) 4 (1.4) 0.643 14 (1.4) 13 (1.3) 0.881 0.670
revascularisation (0.16-3.14) (0.50-2.25)
Any revascularisation 0.63 0.91
8 (2.7) 12 (4.2) 0.305 24 (2.4) 26 (2.5) 0.728 0.927
(0.26-1.53) (0.52-1.58)
Stent thrombosis 0.93 0.98
1 (0.3) 1 (0.3) 0.959 2 (0.2) 2 (0.2) 0.987 0.668
(0.06-14.86) (0.14-6.99)
Values are expressed as n (%). *Composite of cardiovascular death, myocardial infarction, stroke, or BARC bleeding type 2, 3, or 5. †Composite of
cardiovascular death, myocardial infarction, or stroke. BARC: Bleeding Academic Research Consortium; CI: confidence interval; HBR: high bleeding
risk; MACCE: major adverse cardiac and cerebrovascular event
p=0.017) were also lower in the de-escalation group. The inci- rates, assessed by pill count adherence in the HBR subgroup of
dence rates of other secondary endpoints were similar between the the intention-to-treat population at 6 months and 12 months after
groups. In the non-HBR group, the risks of the primary endpoint index PCI (5 and 11 months after randomisation), were 97.6% in
(4.0 vs 6.4%, HR 0.59, 95% CI: 0.40-0.88; p=0.009) and BARC the de-escalation group and 98.1% in the active control group at
bleeding type 2, 3, or 5 (HR 0.60, 95% CI: 0.38-0.95; p=0.029) 6 months and 97.6% in the de-escalation group and 97.5% in the
were lower in the de-escalation group (Table 2, Figure 4). active control group at 12 months, respectively. The adherence
However, the incidence of BARC bleeding type 3 or 5 did not dif- rates in the non-HBR subgroup at 6 months and 12 months after
fer between the groups (1.2 vs 1.5%, HR 0.79, 95% CI: 0.37-1.69; index PCI were 98.7% in the de-escalation group and 97.6% in the
p=0.542). No interaction was evident between the de-escalation active control group at 6 months and 98.7% in the de-escalation
and active control groups for the primary endpoint or other sec- group and 97.2% in the active control group at 12 months, respec-
ondary endpoints (Table 2, Central illustration). The adherence tively. There were no significant differences in adherence.
6

(%) 15 (%) 15
Active control 11.8% Active control
De-escalation De-escalation
Log-rank p=0.0053 Log-rank p<0.2658
10 10
5.7% 5.5%
5 5
3.7%
0 0
100 200 300 100 200 300
Days Days
De-escalation 300 272 259 248 De-escalation 300 274 265 253
Active control 289 258 236 216 Active control 289 264 250 229
(%) 15 (%) 15
Active control Active control
Log-rank p=0.0151 Log-rank p=0.0137 9.0%
10 10
5 4.2% 5 4.0%
1.0%
0 0
100 200 300 100 200 300
Days Days
De-escalation 300 277 269 258 De-escalation 300 273 264 253
Active control 289 263 248 231 Active control 289 261 245 223
Figure 3. Cumulative incidence of the primary and secondary outcomes by HBR and treatment arm. A) Primary endpoint: a composite of
cardiovascular death, myocardial infarction, stroke, or BARC bleeding type 2, 3, or 5. B) Secondary endpoint: a major adverse cardiac and
cerebrovascular event (MACCE; a composite of cardiovascular death, myocardial infarction, or stroke). C) Key secondary endpoint: BARC
type 3 or 5 bleeding. D) Secondary endpoint: a composite of MACCE and BARC bleeding type 3 or 5. BARC: Bleeding Academic Research
Consortium; HBR: high bleeding risk; MI: myocardial infarction
VALIDATION BY PRECISE-DAPT SCORE AND ARC-HBR PRECISE-DAPT score and ARC-HBR criteria (Supplementary
CRITERIA Table 7, Supplementary Table 8). The PRECISE-DAPT anal-
The prevalence of HBR was 13.5% (355 patients) by the ysis revealed that the incidence of the primary endpoint (HR
PRECISE-DAPT score and 11.5% (303 patients) by the ARC- 0.54, 95% CI: 0.38-0.78; p=0.001) and a composite of MACCE
HBR criteria (Supplementary Figure 3, Supplementary Figure 4). and BARC bleeding type 3 or 5 (HR 0.57, 95% CI: 0.35-0.95;
The baseline characteristics and clinical outcomes of HBR and p=0.035) were significantly lower in de-escalation only in the
non-HBR patients identified via the PRECISE-DAPT score and non-HBR group. In the HBR group, although de-escalation some-
ARC-HBR criteria were comparable to those of patients grouped what reduced the incidence rate of the primary endpoint (7.2 vs
using the modified HBR criteria (Supplementary Table 5, 12.1%, HR 0.59, 95% CI: 0.29-1.17) and BARC bleeding type 3
Supplementary Table 6, Supplementary Figure 5, Supplementary or 5 (2.2 vs 5.2%, HR 0.42, 95% CI: 0.13-1.38), statistical sig-
Figure 6). The treatment arms according to the PRECISE-DAPT nificance was lacking (Supplementary Table 9, Supplementary
scores and ARC-HBR criteria are shown in Supplementary Figure 7, Supplementary Figure 8). In the ARC-HBR analy-
Figure 3. The baseline and procedural characteristics were well sis, the primary endpoint occurred less on de-escalation (com-
balanced between the de-escalation and active control groups pared to control) in both the HBR (6.2 vs 13.4%, HR 0.43, 95%
for both HBR and non-HBR patients, as revealed by both the CI: 0.20-0.95; p=0.036) and non-HBR (4.1 vs 6.8%, HR 0.59,
7
(%) 10 (%) 10
Log-rank p=0.0079 6.4% Log-rank p<0.3587
5 5
4.0%
2.0%
1.4%
0 0
100 200 300 100 200 300
Days Days
De-escalation 1,011 964 933 893 De-escalation 1,011 974 950 917
Active control 1,025 945 895 860 Active control 1,025 967 927 895
(%) 10 (%) 10
Log-rank p=0.5414 Log-rank p=0.1934
5 5
3.1%
1.5%
2.2%
1.2%
0 0
100 200 300 100 200 300
Days Days
De-escalation 1,011 972 956 914 De-escalation 1,011 971 947 911
Active control 1,025 967 930 899 Active control 1,025 964 920 887
Figure 4. Cumulative incidence of the primary and secondary outcomes by non-HBR and treatment arm. A) Primary endpoint: a composite of
cardiovascular death, myocardial infarction, stroke, or BARC bleeding type 2, 3, or 5. B) Secondary endpoint: a major adverse cardiac and
cerebrovascular event (MACCE; a composite of cardiovascular death, myocardial infarction, or stroke). C) Key secondary endpoint: BARC
type 3 or 5 bleeding. D) Secondary endpoint: a composite of MACCE and BARC bleeding type 3 or 5. BARC: Bleeding Academic Research
Consortium; HBR: high bleeding risk; MI: myocardial infarction
95% CI: 0.41-0.84; p=0.004) groups. There was no signifi- events but with maintenance of anti-ischaemic efficacy, and 3)
cant difference in the incidence of BARC bleeding type 3 or 5 BARC bleeding type 3 or 5 was less common in the de-escalation
between the treatment arms of either the HBR group or non- group than the ticagrelor-based standard 12-month DAPT group
HBR group (Supplementary Table 10, Supplementary Figure 9, among patients with HBR alone; this was not the case for those
Supplementary Figure 10). with non-HBR.
Discussion UNFAVOURABLE PCI OUTCOMES IN AN HBR POPULATION

We explored whether the benefit of uniform, unguided de-escala- DAPT duration, the choice of P2Y12 inhibitor (with aspirin as
tion of the P2Y12 inhibitor from ticagrelor to clopidogrel 1 month the bedrock), and a decision on aspirin or P2Y12 monotherapy
after index PCI for AMI patients would be more noticeable in after DAPT are determined via the thorough assessment of indi-
subjects at HBR, using the modified ARC-HBR criteria. The key vidual thrombotic and bleeding risks, because post-PCI clinical
findings are as follows: 1) de-escalation of DAPT from ticagre- outcomes are influenced by a complex interplay between the
lor to clopidogrel reduced the net ischaemic and bleeding events risks4,21,22. Bleeding per se is closely linked to increased throm-
both in patients at HBR and non-HBR, 2) the improved clinical bosis via multiple mechanisms such as discontinuation of anti-
outcomes were principally attributable to reduced haemorrhagic platelet agents, nitric oxide-depleted blood transfusions, and
8

EuroIntervention
CENTRAL ILLUSTRATION Effects of ticagrelor-based de-escalation in patients with AMI who undergoing PCI using DES
according to high bleeding risk.
A C
Cardiovascular death, MI, stroke, High bleeding risk Non-high bleeding risk
and BARC bleeding type 2, 3, or 5 Cardiovascular death, MI, stroke and BARC bleeding type 2, 3 or 5
(%) 15
HBR: A+T (11.8%)
Non-HBR: A+T (6.4%) Hazard ratio 0.59 Interaction p-value Hazard ratio 0.47
HBR: A+C (5.7%) 95% CI: 0.40-0.88 0.904 95% CI: 0.26-0.84
10 Non-HBR: A+C (4.0%)

Log-rank p<0.0001
5
BARC bleeding type 3 or 5
Hazard ratio 0.79 Interaction p-value Hazard ratio 0.24

0 95% CI: 0.37-1.69 0.413 95% CI: 0.07-0.84
100 200 300
Number at risk Days
Non-HBR: A+C 1,011 964 933 893
Non-HBR: A+T 1,025 945 895 860
HBR: A+C 300 272 259 248
Cardiovascular death, MI and stroke
HBR: A+T 289 259 236 216
B Hazard ratio 0.69 Interaction p-value Hazard ratio 0.65
BARC bleeding type 3 or 5 95% CI: 0.35-1.36 0.088 95% CI: 0.30-1.40
(%) 5
HBR: A+T (4.2%)
4 Non-HBR: A+T (1.5%) BARC bleeding type 2, 3 or 5
HBR: A+C (1.2%)
Non-HBR: A+C (1.0%)

3
Log-rank p=0.0017 Hazard ratio 0.60 Interaction p-value Hazard ratio 0.38
95% CI: 0.38-0.95 0.226 95% CI: 0.17-0.85
2
Cardiovascular death, MI, stroke and BARC bleeding type 2, 3 or 5

0
100 200 300
Days
Hazard ratio 0.88 Interaction p-value Hazard ratio 0.43
Number at risk
Non-HBR: A+C 1,011 972 956 914 95% CI: 0.39-1.16 0.553 95% CI: 0.22-0.86
Non-HBR: A+T 1,025 967 930 899
HBR: A+C 300 277 269 258
HBR: A+T 289 263 248 231 De-escalation Active control
A) Cumulative incidence of the primary endpoint (net clinical outcome) according to HBR and treatment arm. B) Cumulative incidence of
BARC bleeding type 3 or 5 according to the HBR and treatment arm. C) Cumulative event rates between 1 and 12 months in patients with
HBR and non-HBR. A: active control; AMI: acute myocardial infarction; BARC: Bleeding Academic Research Consortium;
C: clopidogrel; CI: confidence interval; DES: drug-eluting stent; HBR: high bleeding risk; MI: myocardial infarction; PCI: percutaneous
coronary intervention; T: ticagrelor; TALOS-AMI: TicAgrelor Versus CLOpidogrel in Stabilized Patients with Acute Myocardial Infarction
bleeding-induced enhancement of inflammation and thrombo- DE-ESCALATION OF DAPT STRATEGIES IN AMI PATIENTS AT
sis22. Patients aged 75 years (a minor ARC-HBR criterion) are HBR
associated with many cardiometabolic comorbidities such as dia- The current standard DAPT regimen for AMI patients undergoing
betes, CKD, and extensive polyvascular disease, all of which PCI consists of aspirin and a P2Y12 inhibitor, such as ticagrelor or
increase thrombotic risk. Moreover, reduced creatinine clear- prasugrel in preference to clopidogrel3,4. Recently, various modi-
ance is both a high thrombotic and bleeding risk3,5. For these fied strategies have emerged to create a trade-off between throm-
reasons, patients at HBR exhibited a poorer prognosis than those bosis and haemorrhage. Such strategies include a shortened DAPT
with non-HBR7,23. In the present study, we found that HBR sta- period8, a reduced dose (5 mg) of prasugrel10, de-escalation of the
tus by the modified ARC-HBR criteria was linked to increased P2Y12 inhibitor from ticagrelor to clopidogrel9, and P2Y12 inhibitor
BARC bleeding type 3 or 5 and more ischaemic events. monotherapy11-14. The benefits of these strategies were particularly
9
marked in patients at HBR8,23. Our results show that net adverse were only introduced after this. Therefore, the next guidelines
clinical outcomes occurred less frequently in the de-escalation (2023 ESC Guidelines for ACS) may reflect the evidence from
group than in the active control group, regardless of the HBR sta- these more recent trials, and de-escalation of DAPT strategy may
tus. However, the incidence of BARC bleeding type 3 or 5 events be recommended more, especially in patients with HBR.
was lower in the de-escalation group among only HBR, not non-
HBR, patients. Limitations
Notably, unguided DAPT de-escalation from ticagrelor to clopi- Several limitations exist in the present study. First, this is a post
dogrel did not increase the incidence of thrombotic events even hoc analysis using data from the TALOS-AMI trial. Our findings
in AMI patients at high thrombotic risk, in line with the results only generate hypotheses, and research validation is essential.
of previous trials that alternated the standard DAPT8-12,14,24,25. Second, patients at HBR in our study do not reflect our daily PCI
Any benefit of prolonged DAPT in terms of decreasing ischae- practice, as subjects with HBR and those having actual bleeding
mic events is offset by more haemorrhagic events when a high episodes or coagulopathy were excluded from the study at enrol-
thrombotic risk and an HBR coexist26. In such a situation, the ment. Third, we arbitrarily modified the definition of ARC-HBR,
HBR may dominate. Over time (approximately 1 month after an because we lacked data on some ARC-HBR criteria. We consid-
acute coronary syndrome), the bleeding risk surpasses the ischae- ered that age 75 years and moderate CKD (an ARC-HBR minor
mic risk15. Therefore, in AMI patients who are stabilised 1 month criterion) were important in terms of the HBR. Both factors were
after PCI, de-escalation of the DAPT strategy from ticagrelor to individually associated with more bleeding episodes in the pre-
clopidogrel, reducing the dose of prasugrel from 10 to 5 mg, or sent study and in previous trials18,19. However, major bleeding
ticagrelor monotherapy (thus dropping aspirin) are viable alterna- only occurred in less than 4% of patients in isolation of major
tives to ticagrelor- or prasugrel-based 12-month DAPT, especially criteria and without any other coexisting criteria, and 70.5% of
for those at HBR. the distribution of HBR subgroups corresponds to only one HBR
definition. Nevertheless, a sensitivity analysis using the original
GUIDED AND UNGUIDED DE-ESCALATION DAPT ARC-HBR definition and the PRECISE-DAPT scores yielded
STRATEGIES IN HBR PATIENTS findings consistent with our principal results. Compared to the
The current study is a post hoc analysis of the TALOS-AMI trial ticagrelor-based 12-month DAPT, the de-escalation strategy
which evaluated an unguided ticagrelor-based de-escalation strat- tended to lower the incidence of bleeding events in patients with
egy in HBR patients; the POPular Genetics and TROPICAL- HBR using the ARC-HBR definition and the PRECISE-DAPT
ACS trials evaluated guided de-escalation of DAPT strategy in score. Fourth, there were no data for CYP2C19 genotyping.
this population27,28. In the individual patient-level meta-analysis, However, the TALOS-AMI study aimed to evaluate the benefits
which included the 3 randomised trials mentioned above and the of an unguided de-escalation of DAPT strategy. Fifth, we could
HOST REDUCE POLYTECH ACS trial, ischaemic and bleeding not check the prescription rate of proton pump inhibitors (PPI),
endpoints were significantly lower in the de-escalation strategy which have been associated with reduced gastrointestinal bleed-
compared to the standard antiplatelet strategy10,29. Notably, bleeding. In other trials regarding antiplatelet strategies performed in
ing endpoints were more reduced with unguided de-escalation South Korea, the prescription rate for PPI was about 18%, and we
than with the guided de-escalation strategy, and this was proved think the rate of PPI prescription in this subgroup analysis may
in another meta-analysis30. This prominent reduction of bleed- have been similar to that of the abovementioned trials10. Finally,
ing endpoints with the unguided de-escalation strategy might be the interaction p-values for all outcomes are >0.05, which indi-
associated with several factors, such as study population (the tri- cates that there were no statistically significant differences in
als regarding unguided de-escalation strategy only enrolled Asian de-escalation treatment effects between the HBR and non-HBR
patients) or the timing of de-escalation. The current post hoc anal- groups despite large differences in the hazard ratios in some out-
ysis of the TALOS-AMI trial shows the benefits of a ticagrelor- comes, such as major bleeding. This finding suggests that the
based de-escalation strategy in HBR patients. As far as we know, current study had inadequate power; thus, the results should be
there are only a few studies which have investigated the efficacy interpreted cautiously.
and safety of guided de-escalation strategy in HBR patients.
In the ESC Guidelines for the management of acute coronary Conclusions
syndromes, DAPT de-escalation may be considered as an alterna- Uniform unguided de-escalation of the P2Y12 inhibitor from tica-
tive treatment regimen based on whether it is guided or unguided grelor to clopidogrel 1 month after AMI was safe and efficacious
by platelet function test or CYP2C19 genotyping (Class IIb, Level in terms of decreasing the rate of net adverse clinical outcomes,
of Evidence A)3. However, this recommendation was based on the regardless of HBR status by the modified ARC-HBR criteria.
results of the POPular Genetics and TROPICAL-ACS trials, both The effect of de-escalation of DAPT strategy on reductions in
of which evaluated guided de-escalation strategies27,28; the results BARC bleeding type 3 or 5 was profound for patients at HBR.
of large trials which evaluated unguided de-escalation strategies De-escalating DAPT from ticagrelor to clopidogrel might be
(the TALOS-AMI and HOST REDUCE POLYTECH ACS trials) a reasonable option in stabilised AMI patients with HBR.
10

investigators. Prasugrel-based de-escalation of dual antiplatelet therapy after percutaneous
Impact on daily practice coronary intervention in patients with acute coronary syndrome (HOST-REDUCE-
Compared to ongoing ticagrelor-based DAPT, for AMI patients POLYTECH-ACS): an open-label, multicentre, non-inferiority randomised trial. Lancet.
2020;396:1079-89.
undergoing PCI with DES, switching from ticagrelor to clopi-
11. Mehran R, Baber U, Sharma SK, Cohen DJ, Angiolillo DJ, Briguori C, Cha JY,
dogrel after 1 month reduced haemorrhage while maintaining Collier T, Dangas G, Dudek D, Džavík V, Escaned J, Gil R, Gurbel P, Hamm CW,
protection against thrombotic events in both HBR and non-HBR Henry T, Huber K, Kastrati A, Kaul U, Kornowski R, Krucoff M, Kunadian V,
Marx SO, Mehta SR, Moliterno D, Ohman EM, Oldroyd K, Sardella G, Sartori S,
patients. Future studies should investigate the impact of the de- Shlofmitz R, Steg PG, Weisz G, Witzenbichler B, Han YL, Pocock S, Gibson CM.
escalation of DAPT strategy from ticagrelor to clopidogrel in Ticagrelor with or without Aspirin in High-Risk Patients after PCI. N Engl J Med.
2019;381:2032-42.
AMI patients with HBR at earlier timepoints after PCI.
12. Kim BK, Hong SJ, Cho YH, Yun KH, Kim YH, Suh Y, Cho JY, Her AY, Cho S,
Jeon DW, Yoo SY, Cho DK, Hong BK, Kwon H, Ahn CM, Shin DH, Nam CM, Kim JS,
Ko YG, Choi D, Hong MK, Jang Y; TICO Investigators. Effect of Ticagrelor
Conflict of interest statement Monotherapy vs Ticagrelor With Aspirin on Major Bleeding and Cardiovascular
Events in Patients With Acute Coronary Syndrome: The TICO Randomized Clinical
The authors have no conflicts of interest to declare. Trial. JAMA. 2020;323:2407-16.
13. Hahn JY, Song YB, Oh JH, Chun WJ, Park YH, Jang WJ, Im ES, Jeong JO,
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coronary intervention (TALOS-AMI): an investigator-initiated, open-label, multicen- Oldroyd KG, Sardella G, Sharma SK, Shlofmitz R, Weisz G, Witzenbichler B,
tre, non-inferiority, randomised trial. Lancet. 2021;398:1305-16. Pocock S, Mehran R. Ticagrelor monotherapy in patients at high bleeding risk under-
10. Kim HS, Kang J, Hwang D, Han JK, Yang HM, Kang HJ, Koo BK, Rhew JY, Chun KJ, going percutaneous coronary intervention: TWILIGHT-HBR. Eur Heart J. 2021;42:
Lim YH, Bong JM, Bae JW, Lee BK, Park KW; HOST-REDUCE-POLYTECH-ACS 4624-34.
11
24. Dangas G, Baber U, Sharma S, Giustino G, Mehta S, Cohen DJ, Angiolillo DJ, Supplementary Table 5. Baseline and procedural characteristics
Sartori S, Chandiramani R, Briguori C, Dudek D, Escaned J, Huber K, Collier T,
by PRECISE-DAPT score-based HBR and ARC-HBR criteria.
Kornowski R, Kunadian V, Kaul U, Oldroyd K, Sardella G, Shlofmitz R,
Witzenbichler B, Ya-Ling H, Pocock S, Gibson CM, Mehran R. Ticagrelor With or Supplementary Table 6. Primary and secondary outcomes by
Without Aspirin After Complex PCI. J Am Coll Cardiol. 2020;75:2414-24. PRECISE-DAPT score-based HBR and ARC-HBR criteria.
25. Valgimigli M, Smits PC, Frigoli E, Bongiovanni D, Tijssen J, Hovasse T, Mafragi A,
Ruifrok WT, Karageorgiev D, Aminian A, Garducci S, Merkely B, Routledge H,
Supplementary Table 7. Baseline and procedural characteristics
Ando K, Diaz Fernandez JF, Cuisset T, Nesa Malik FT, Halabi M, Belle L, Din J, by PRECISE-DAPT score-based HBR and treatment arm.
Beygui F, Abhyankar A, Reczuch K, Pedrazzini G, Heg D, Vranckx P; MASTER
DAPT Investigators. Duration of antiplatelet therapy after complex percutaneous coro-
nary intervention in patients at high bleeding risk: a MASTER DAPT trial sub-analy- by ARC-HBR criteria and treatment arm.
sis. Eur Heart J. 2022;43:3100-14. Supplementary Table 9. Primary and secondary outcomes by
26. Costa F, Van Klaveren D, Feres F, James S, Räber L, Pilgrim T, Hong MK, Kim HS,
PRECISE-DAPT score-based HBR and treatment arm.
Colombo A, Steg PG, Bhatt DL, Stone GW, Windecker S, Steyerberg EW, Valgimigli M;
PRECISE-DAPT Study Investigators. Dual Antiplatelet Therapy Duration Based on Supplementary Table 10. Primary and secondary outcomes by
Ischemic and Bleeding Risks After Coronary Stenting. J Am Coll Cardiol. 2019;73: ARC-HBR criteria and treatment arm.
741-54.
Supplementary Figure 1. Prevalence of HBR criteria within the
27. Claassens DMF, Vos GJA, Bergmeijer TO, Hermanides RS, van ‘t Hof AWJ, van
der Harst P, Barbato E, Morisco C, Tjon Joe Gin RM, Asselbergs FW, Mosterd A, HBR group and impact on major bleeding outcome.
Herrman JR, Dewilde WJM, Janssen PWA, Kelder JC, Postma MJ, de Boer A, Supplementary Figure 2. Clinical impact of multiple HBR criteria.
Boersma C, Deneer VHM, Ten Berg JM. A Genotype-Guided Strategy for Oral P2Y12
Inhibitors in Primary PCI. N Engl J Med. 2019;381:1621-31. Supplementary Figure 3. Study flow according to PRECISE-
28. Sibbing D, Aradi D, Jacobshagen C, Gross L, Trenk D, Geisler T, Orban M, DAPT score and ARC-HBR criteria.
Hadamitzky M, Merkely B, Kiss RG, Komócsi A, Dézsi CA, Holdt L, Felix SB, Supplementary Figure 4. Distribution of study patients by
Parma R, Klopotowski M, Schwinger RHG, Rieber J, Huber K, Neumann FJ,
Koltowski L, Mehilli J, Huczek Z, Massberg S; TROPICAL-ACS Investigators. PRECISE-DAPT score and ARC-HBR criteria.
Guided de-escalation of antiplatelet treatment in patients with acute coronary syn- Supplementary Figure 5. Cumulative incidences of primary and
drome undergoing percutaneous coronary intervention (TROPICAL-ACS): a ran-
domised, open-label, multicentre trial. Lancet. 2017;390:1747-57. secondary outcomes by PRECISE-DAPT score-based HBR.
29. Kang J, Rizas KD, Park KW, Chung J, van den Broek W, Claassens DMF, Supplementary Figure 6. Cumulative incidences of primary and
Choo EH, Aradi D, Massberg S, Hwang D, Han JK, Yang HM, Kang HJ, Chang K, Ten secondary outcomes by ARC-HBR criteria.
Berg JM, Sibbing D, Koo BK, Kim HS. Dual antiplatelet therapy de-escalation in acute
coronary syndrome: an individual patient meta-analysis. Eur Heart J. 2023;44: Supplementary Figure 7. Cumulative incidences of primary and
1360-70. secondary outcomes by PRECISE-DAPT score-based HBR and
30. Kuno T, Fujisaki T, Shoji S, Sahashi Y, Tsugawa Y, Iwagami M, Takagi H, treatment arm.
Briasoulis A, Deharo P, Cuisset T, Latib A, Kohsaka S, Bhatt DL. Comparison of
Unguided De-Escalation Versus Guided Selection of Dual Antiplatelet Therapy After Supplementary Figure 8. Cumulative incidences of primary and
Acute Coronary Syndrome: A Systematic Review and Network Meta-Analysis. Circ secondary outcomes by PRECISE-DAPT score-based non-HBR
Cardiovasc Interv. 2022;15:e011990.
and treatment arm.
Supplementary Figure 9. Cumulative incidences of primary and
Supplementary data secondary outcomes by ARC-HBR criteria-based HBR and treat-
Supplementary Table 1. Reasons for screening failure. ment arm.
Supplementary Table 2. Study definitions for major and minor Supplementary Figure 10. Cumulative incidences of primary and
HBR criteria compared with the definitions from ARC-HBR secondary outcomes by ARC-HBR criteria-based non-HBR and
criteria. treatment arm.
by HBR. The supplementary data are published online at:
Supplementary Table 4. Primary and secondary outcomes by https://eurointervention.pcronline.com/
HBR. doi/10.4244/EIJ-D-23-00427
12
Supplementary data
Supplementary Table 1. Reasons for screening failure.

Screening failure
(n = 204)
Follow up loss 92 (45.1)
Fail to visit at randomization 85 (41.7)
Transfer to another institute (follow up loss) 7 (3.4)
Adverse events 14 (6.9)
Death before randomization 4 (2.0)
Stroke (intracranial aneurysm and intracranial bleeding) 4 (2.0)
GI or GU bleeding, or hemoptysis 5 (2.5)
Unspecified bleeding 1 (0.5)
Medication non-adherence 21 (10.3)
Non-compliance 2 (1.0)
Intolerance of study medications 9 (4.4)
Investigator directed 10 (4.9)
Inclusion and exclusion criteria violation 77 (37.7)
Incorrect diagnosis 3 (1.5)
DES not used for PCI 1 (0.5)
Cardiogenic shock 2 (1.0)
Anemia 4 (2.0)
History of intracranial bleeding 1 (0.5)
Concomitant anticoagulation, or NSAIDs 5 (2.5)
COPD 5 (2.5)
Renal replacement therapy, or ESRD 2 (1.0)
Enrolled in another clinical trial 1 (0.5)
Withdrawal of consent 34 (16.7)
Unsuitable for study by investigator 15 (7.4)
Nor certain 4 (2.0)
Values are expressed as n (%).
Abbreviations: COPD, chronic obstructive pulmonary disease; DES, drug-eluting stent; ESRD, end
stage renal disease; GI, gastrointestinal; GU, genitourinary; NSAID, non-steroid anti-inflammatory
drug; PCI, percutaneous coronary intervention.
Supplementary Table 2. Study definitions for major and minor HBR criteria compared with the definitions from ARC-HBR criteria.
Study definition ARC-HBR criteria
Major criteria
Severe CKD Severe CKD (eGFR < 30 mL/min) Severe or end-stage CKD (eGFR < 30 mL/min)
Moderate anemia 10 g/dL ≤ Hemoglobin < 11 g/dL Hemoglobin < 11 g/dL
Age ≥ 75 Transferred from minor criteria Age ≥ 75 years
Moderate CKD Transferred from minor criteria Moderate CKD (eGFR 30-59 mL/min)
Moderate or severe baseline thrombocytopenia (platelet
NA
count < 100 x 109/L)
NA Anticipated use of long-term oral anticoagulation
Spontaneous bleeding requiring hospitalization or
NA
transfusion in the past 6 months or any time, if recurrent
NA Chronic bleeding diathesis
NA Liver cirrhosis with portal hypertension
Active malignancy (excluding nonmelanoma skin cancer)
NA
within the past 12 months
Previous spontaneous ICH (at any time)
Previous traumatic ICH within the past 12 months
NA Presence of a brain arteriovenous malformation
Moderate to severe ischemic stroke within the past 6
months
NA Nondeferrable major surgery on DAPT
Recent major surgery or major trauma within 30 days
NA
before PCI
Minor criteria
Hemoglobin 11-12.9 g/dL for men and 11-11.9 g/dL for
Mild anemia No difference compared to ARC-HBR
women
Any ischemic stroke at any time not meeting the major
Any ischemic stroke No difference compared to ARC-HBR
criterion
Transfer to major criteria Age ≥ 75 years
Transfer to major criteria Moderate CKD (eGFR 30-59 mL/min)
Spontaneous bleeding within the past 12 months not
NA
meeting the major criterion
NA Long-term use of oral NSAIDs or steroids
Abbreviations: ARC-HBR, Academic Research Consortium for High Bleeding Risk; CKD, chronic kidney disease; DAPT, dual antiplatelet therapy; GFR,
glomerular filtration rate; HBR, high bleeding risk; ICH, intracranial hemorrhage; NSAID, non-steroid anti-inflammatory drug.
Supplementary Table 3. Baseline and procedural characteristics by HBR.
HBR Non-HBR
p Value
(n = 589) (n = 2,036)
Demographics
Age, years 71.0 ± 10.5 56.8 ± 9.4 <0.001
Male 389 (66.0) 1,790 (87.9) <0.001
Body mass index, kg/m 2
23.7 ± 3.6 24.9 ± 3.3 <0.001
Medical history
Hypertension 381 (64.7) 896 (44.0) <0.001
Diabetes 198 (33.6) 510 (25.0) <0.001
Diabetes treated with insulin 20 (3.4) 34 (1.7) 0.009
Dyslipidemia 217 (36.8) 870 (42.7) 0.011
Current smoker 171 (29.0) 1,133 (55.6) <0.001
Impaired renal function* 304 (51.6) – –
Past medical history
Previous PCI 42 (7.1) 74 (3.6) <0.001
Previous CABG 3 (0.5) 1 (0.0) 0.037
Previous CVA 41 (7.0) 57 (2.8) <0.001
Clinical presentation 0.164
STEMI 302 (51.3) 1,110 (54.5)
NSTEMI 287 (48.7) 926 (45.5)
Laboratory findings
Creatinine clearance†, mL/min/1.73 m2 68.4 ± 25.8 92.9 ± 21.9 <0.001
Hemoglobin, g/dL 13.2 ± 1.9 15.0 ± 1.4 <0.001
Platelet, 10 /L
9
233.9 ± 63.0 241.2 ± 58.5 0.012
White blood cell count, 109/L 9.7 ± 3.4 10.5 ± 3.5 <0.001
LVEF < 40% 76/562 (13.5) 115/1,959 (5.9) <0.001
Access site 0.102
Radial 259 (44.0) 996 (48.9)
Femoral 300 (50.9) 940 (46.2)
Glycoprotein IIb/IIIa inhibitor 141 (23.9) 475 (23.3) 0.759
Infarct-related artery <0.001
Left main coronary artery 17 (2.9) 28 (1.4)
Left anterior descending artery 254 (43.3) 1,019 (50.5)
Left circumflex artery 78 (13.3) 372 (18.4)
Right coronary artery 237 (40.4) 598 (29.6)
Number of treated vessels 1.4 ± 0.7 1.4 ± 0.6 0.042
Multivessel treatment 196 (33.3) 585 (28.7) 0.034
Numbers of stents for infarct-related artery 1.2 ± 0.4 1.2 ± 0.5 0.155
Total stent length of infarct-related artery, mm 30.8 ± 14.5 29.4 ± 16.4 0.067
Stent diameter of infarct-related artery, mm 3.2 ± 0.5 3.2 ± 0.8 0.218
Intravascular imaging
Optical coherence tomography 19 (3.2) 63 (3.1) 0.872
Intravascular ultrasonography 134 (22.8) 490 (24.1) 0.509
Values are expressed as mean (SD) or n (%). *Impaired renal function was defined as an estimated
glomerular filtration rate of less than 60 mL/ min/1.73 m2 of body surface area at presentation.
†Creatinine clearance was calculated by MDRD (Modification of Diet in Renal Disease) formula:
186 * (serum creatinine)-1.154 * (age)-0.203 * 0.742 (for women).
Abbreviations: CABG, coronary artery bypass graft; CVA, cerebrovascular accident; HBR, high
bleeding risk; LVEF, left ventricular ejection fraction; NSTEMI, non-ST-segment elevation
myocardial infarction; PCI, percutaneous coronary intervention; STEMI, ST-segment elevation
myocardial infarction.
Supplementary Table 4. Primary and secondary outcomes by HBR.
HBR Non-HBR HR
p Value
(n = 589) (n = 2,036) (95% CI)
Primary endpoint* 51 (8.7) 106 (5.2) 1.75 (1.26-2.45) 0.001
Secondary endpoints
BARC bleeding type 3 or 5 15 (2.5) 27 (1.3) 2.01 (1.07-3.78) 0.030
MACCE† 27 (4.6) 34 (1.7) 2.89 (1.75-4.80) <0.001
BARC bleeding type 2, 3 or 5 28 (4.8) 79 (3.9) 1.28 (0.83-1.97) 0.262
BARC bleeding type 2 17 (2.9) 59 (2.9) 1.03 (0.60-1.77) 0.903
BARC bleeding type 3 15 (2.5) 27 (1.3) 2.01 (1.07-3.78) 0.030
BARC bleeding type 5 1 (0.2) 0 – –
MACCE, and BARC bleeding type 3 or 5 28 (6.5) 54 (2.7) 2.57 (1.70-3.90) <0.001
All-cause death 14 (2.4) 6 (0.3) 8.42 (3.24-21.91) <0.001
Cardiovascular death 7 (1.2) 4 (0.2) 6.32 (1.85-21.58) 0.003
Myocardial infarction
Any myocardial infarction 13 (2.2) 18 (0.9) 2.63 (1.29-5.37) 0.008
Spontaneous 11 (1.9) 11 (0.5) 3.64 (1.58-8.39) 0.002
Periprocedural 2 (0.3) 7 (0.3) 1.04 (0.22-5.00) 0.962
Target vessel myocardial infarction 3 (0.5) 12 (0.6) 0.91 (0.26-3.22) 0.882
Stroke 8 (1.4) 12 (0.6) 2.41 (0.98-5.88) 0.055
Ischemia-driven revascularization
Target lesion revascularization 4 (0.7) 19 (0.9) 0.77 (0.26-2.25) 0.628
Target vessel revascularization 7 (1.2) 27 (1.3) 0.94 (0.41-2.16) 0.888
Any revascularization 20 (3.4) 50 (2.5) 1.46 (0.87-2.45) 0.153
Stent thrombosis 2 (0.3) 4 (0.2) 1.83 (0.34-9.99) 0.486
Values are expressed as n (%). *Composite of cardiovascular death, myocardial infarction, stroke,
and BARC bleeding type 2, 3, or 5. †Composite of cardiovascular death, myocardial infarction, or
stroke.
Abbreviations: BARC, Bleeding Academic Research Consortium; CI, confidence interval; HBR,
high bleeding risk; HR, hazard ratio; MACCE, major adverse cardiac and cerebrovascular event.
Supplementary Table 5. Baseline and procedural characteristics by PRECISE-DAPT score-based HBR and ARC-HBR criteria.
PRECISE-DAPT ARC-HBR
HBR Non-HBR HBR Non-HBR
p Value p Value
(n = 355) (n = 2,270) (n = 303) (n = 2,322)
Demographics
Age, years 72.8 ± 9.3 58.0 ± 10.3 <0.001 72.8 ± 9.4 58.3 ± 10.5 <0.001
Male 227 (63.9) 1,952 (86.0) <0.001 180 (59.4) 1,999 (86.1) <0.001
Body mass index, kg/m2 23.5 ± 3.3 24.8 ± 3.4 <0.001 23.2 ± 3.1 24.8 ± 3.4 <0.001
Medical history
Hypertension 243 (68.5) 1,034 (45.6) <0.001 206 (68.0) 1,071 (46.1) <0.001
Diabetes 140 (39.4) 568 (25.0) <0.001 122 (40.3) 586 (25.2) <0.001
Dyslipidemia 127 (35.8) 960 (42.3) 0.020 121 (39.9) 966 (41.6) 0.579
Current smoker 99 (27.9) 1,205 (53.1) <0.001 76 (25.1) 1,228 (52.9) <0.001
Impaired renal function *
208 (58.6) 97 (4.3) <0.001 152 (50.2) 153 (6.6) <0.001
Previous PCI 21 (5.9) 95 (4.2) 0.140 25 (8.3) 91 (3.9) 0.001
Previous CABG 0 4 (0.2) 1.000 1 (0.3) 3 (0.1) 0.388
Previous CVA 24 (6.8) 74 (3.3) 0.001 41 (13.5) 57 (2.5) <0.001
Clinical presentation 0.357 0.010
STEMI 199 (56.1) 1,213 (53.4) 142 (46.9) 1,270 (54.7)
NSTEMI 156 (43.9) 1,057 (46.6) 161 (53.1) 1,052 (45.3)
Laboratory findings
Creatinine clearance†, mL/min/1.73 m2 58.5 ± 17.6 91.9 ± 22.9 <0.001 67.7 ± 27.1 90.0 ± 23.5 <0.001
Hemoglobin, g/dL 13.1 ± 2.0 14.8 ± 1.5 <0.001 12.0 ± 1.5 14.9 ± 1.4 <0.001
Platelet, 10 /L
9
239.8 ± 64.3 239.5 ± 58.9 0.947 232.4 ± 66.3 240.5 ± 58.6 0.027
White blood cell count, 109/L 11.8 ± 4.6 10.1 ± 3.2 <0.001 9.2 ± 3.2 10.4 ± 3.5 <0.001
LVEF < 40% 53/340 (15.6) 138/2,181 (6.3) <0.001 47/292 (16.1) 144/2,229 (6.5) <0.001
Access site 0.006 0.691
Radial 142 (40.0) 1,113 (49.0) 138 (45.5) 1,117 (48.1)
Femoral 192 (54.1) 1,048 (46.2) 150 (49.5) 1,090 (46.9)
Infarct-related artery <0.001 <0.001
Left anterior descending artery 148 (41.7) 1,125 (50.0) 131 (43.7) 1,142 (49.6)
Number of treated vessels 1.4 ± 0.6 1.4 ± 0.6 0.269 1.4 ± 0.6 1.4 ± 0.6 0.057
Numbers of stents for infarct-related artery 1.2 ± 0.4 1.2 ± 0.5 0.432 1.2 ± 0.5 1.2 ± 0.5 0.115
Total stent length of infarct-related artery, mm 31.3 ± 14.6 29.5 ± 16.2 0.036 31.9 ± 15.1 29.5 ± 16.1 0.010
Stent diameter of infarct-related artery, mm 3.2 ± 0.5 3.2 ± 0.8 0.535 3.1 ± 0.4 3.2 ± 0.8 0.014
Optical coherence tomography 8 (2.3) 74 (3.3) 0.311 7 (2.3) 75 (3.2) 0.387
Values are expressed as mean (SD) or n (%). *Impaired renal function was defined as an estimated glomerular filtration rate of less than 60 mL/ min/1.73
m2 of body surface area at presentation. †Creatinine clearance was calculated by MDRD (Modification of Diet in Renal Disease) formula: 186 * (serum
creatinine)-1.154 * (age)-0.203 * 0.742 (for women).
Abbreviations: ARC-HBR, Academic Research Consortium for High Bleeding Risk; CABG, coronary artery bypass graft; CVA, cerebrovascular accident;
HBR, high bleeding risk; LVEF, left ventricular ejection fraction; NSTEMI, non-ST-segment elevation myocardial infarction; PCI, percutaneous coronary
intervention; PRECISE-DAPT, Predicting Bleeding Complications in Patients Undergoing Stent Implantation and Subsequent Dual Antiplatelet Therapy;
STEMI, ST-segment elevation myocardial infarction.
Supplementary Table 6. Primary and secondary outcomes by PRECISE-DAPT score-based HBR and ARC-HBR criteria.
PRECISE-DAPT ARC-HBR
HBR Non-HBR Hazard ratio HBR Non-HBR Hazard ratio
p Value p Value
(n = 355) (n = 2,270) (95% CI) (n = 303) (n = 2,322) (95% CI)
Primary endpoint* 34 (9.6) 123 (5.4) 1.83 (1.26-2.68) 0.002 30 (9.9) 127 (80.9) 1.91 (1.29-2.85) 0.002
Secondary endpoints
BARC bleeding type 3 or 5 13 (3.7) 29 (1.3) 2.96 (1.54-5.69) 0.001 10 (3.3) 32 (1.4) 2.54 (1.25-5.16) 0.012
MACCE† 17 (4.8) 44 (1.9) 2.58 (1.47-4.51) 0.001 18 (5.9) 43 (1.9) 3.41 (1.97-5.91) <0.001
BARC bleeding type 2, 3 or 5 20 (5.6) 87 (3.8) 1.51 (0.93-2.45) 0.110 15 (5.0) 92 (4.0) 1.31 (0.76-2.26) 0.413
BARC bleeding type 2 10 (2.8) 66 (2.9) 0.99 (0.51-1.92) 0.925 9 (3.0) 67 (2.9) 1.07 (0.54-2.15) 0.934
BARC bleeding type 5 1 (0.3) – – – 1 (0.3) – – –
MACCE, and BARC bleeding type 3 or 5 27 (7.6) 65 (2.9) 2.78 (1.77-4.35) <0.001 25 (8.3) 67 (2.9) 3.06 (1.93-4.84) <0.001
All-cause death 11 (3.1) 9 (0.4) 8.03 (3.33-19.37) <0.001 10 (3.3) 10 (0.4) 8.07 (3.36-19.39) <0.001
Cardiovascular death 5 (1.4) 6 (0.3) 5.48 (1.67-17.96) 0.010 5 (1.7) 6 (0.3) 6.73 (2.05-22.04) 0.005
Any myocardial infarction 9 (2.5) 22 (1.0) 2.73 (1.26-5.93) 0.011 9 (3.0) 22 (0.9) 3.34 (1.54-7.26) 0.002
Spontaneous 8 (2.3) 14 (0.6) 3.80 (1.60-9.07) 0.002 7 (2.3) 15 (0.6) 3.80 (1.55-9.33) 0.003
Periprocedural 1 (0.3) 8 (0.4) 0.83 (0.10-6.63) 1.000 2 (0.7) 7 (0.3) 2.33 (0.48-11.20) 0.279
Target vessel myocardial infarction 1 (0.3) 14 (0.6) 0.47 (0.06-3.60) 0.436 2 (0.7) 13 (0.6) 1.25 (0.28-5.56) 0.689
Stroke 4 (1.1) 16 (0.7) 1.65 (0.55-4.92) 0.395 5 (1.7) 15 (0.6) 2.69 (0.98-7.39) 0.072
Target lesion revascularization 2 (0.6) 21 (0.9) 0.63 (0.15-2.69) 0.759 3 (1.0) 20 (0.9) 1.23 (0.36-4.13) 0.821
Target vessel revascularization 4 (1.1) 30 (1.3) 0.88 (0.31-2.50) 1.000 4 (1.3) 30 (1.3) 1.09 (0.38-3.08) 1.000
Any revascularization 12 (3.4) 58 (2.6) 1.38 (0.74-2.57) 0.369 13 (4.3) 57 (2.5) 1.87 (1.02-3.41) 0.062
Stent thrombosis 1 (0.3) 5 (0.2) 1.33 (0.16-11.40) 0.582 1 (0.3) 5 (0.2) 1.64 (0.19-14.05) 0.521
Values are expressed as n (%). *Composite of cardiovascular death, myocardial infarction, stroke, and BARC bleeding type 2, 3, or 5. †Composite of
cardiovascular death, myocardial infarction, or stroke.
Abbreviations: ARC-HBR, Academic Research Consortium for High Bleeding Risk; BARC, Bleeding Academic Research Consortium; CI, confidence
interval; HBR, high bleeding risk; MACCE, major adverse cardiac and cerebrovascular event; PRECISE-DAPT, Predicting Bleeding Complications in
Patients Undergoing Stent Implantation and Subsequent Dual Antiplatelet Therapy.
Supplementary Table 7. Baseline and procedural characteristics by PRECISE-DAPT score-based HBR and treatment arm.
HBR (n = 355) Non-HBR (n = 2,270)
p Value p Value
(n = 181) (n = 174) (n = 1,130) (n = 1,140)
Demographics
Age, years 73.2 ± 9.2 72.4 ± 9.3 0.428 58.0 ± 10.1 57.9 ± 10.5 0.845
Male 117 (64.6) 110 (63.2) 0.780 979 (86.6) 973 (85.4) 0.377
Body mass index, kg/m2 23.8 ± 3.1 23.2 ± 3.4 0.127 24.8 ± 3.3 24.7 ± 3.5 0.620
Medical history
Hypertension 118 (65.2) 125 (71.8) 0.178 516 (45.7) 518 (45.4) 0.914
Diabetes 73 (40.3) 67 (38.5) 0.725 276 (24.4) 292 (25.6) 0.513
Dyslipidemia 65 (35.9) 62 (35.6) 0.956 477 (42.2) 483 (42.4) 0.940
Current smoker 55 (30.4) 44 (25.3) 0.284 594 (52.6) 611 (53.6) 0.623
103 (56.9) 105 (60.3) 0.511 57 (5.0) 40 (3.5) 0.071
Previous PCI 9 (5.0) 12 (6.9) 0.442 50 (4.4) 45 (3.9) 0.570
Previous CABG 0 0 – 3 (0.3) 1 (0.1) 0.372
Previous CVA 11 (6.1) 13 (7.5) 0.601 39 (3.5) 35 (3.1) 0.609
STEMI 99 (54.7) 100 (57.5) 611 (54.1) 602 (52.8)
NSTEMI 82 (45.3) 74 (42.5) 519 (45.9) 538 (47.2)
Laboratory findings
Creatinine clearance†, mL/min/1.73 m2 59.4 ± 18.3 57.5 ± 16.9 0.294 90.7 ± 21.8 93.2 ± 23.8 0.008
Hemoglobin, g/dL 13.2 ± 2.0 13.0 ± 2.0 0.234 14.8 ± 1.5 14.8 ± 1.5 0.370
Platelet, 10 /L
9
242.5 ± 62.5 236.9 ± 66.2 0.415 240.4 ± 61.0 238.7 ± 56.6 0.507
White blood cell count, 109/L 12.0 ± 4.8 11.6 ± 4.4 0.438 10.0 ± 3.1 10.2 ± 3.4 0.132
LVEF < 40% 32/173 (18.5) 21/167 (12.6) 0.132 67/1,095 (6.1) 71/1,086 (6.5) 0.688
Radial 71 (39.2) 71 (40.8) 547 (48.4) 566 (49.6)
Femoral 99 (54.7) 93 (53.4) 532 (47.1) 516 (45.3)
Infarct-related artery 0.875 0.038
Left anterior descending artery 76 (42.0) 72 (41.4) 582 (52.0) 543 (48.1)
Abbreviations: CABG, coronary artery bypass graft; CVA, cerebrovascular accident; HBR, high bleeding risk; LVEF, left ventricular ejection fraction;
NSTEMI, non-ST-segment elevation myocardial infarction; PCI, percutaneous coronary intervention; PRECISE-DAPT, Predicting Bleeding Complications
in Patients Undergoing Stent Implantation and Subsequent Dual Antiplatelet Therapy; STEMI, ST-segment elevation myocardial infarction.
Supplementary Table 8. Baseline and procedural characteristics by ARC-HBR criteria and treatment arm.
HBR (n = 303) Non-HBR (n = 2,322)
p Value p Value
(n = 146) (n = 157) (n = 1,165) (n = 1,157)
Demographics
Age, years 73.0 ± 9.4 72.6 ± 9.5 0.734 58.5 ± 10.4 58.1 ± 10.5 0.380
Male 83 (56.8) 97 (61.8) 0.382 1,013 (87.0) 986 (85.2) 0.228
Body mass index, kg/m2 23.4 ± 3.2 23.0 ± 3.0 0.215 24.8 ± 3.2 24.8 ± 3.6 0.622
Medical history
Hypertension 101 (69.2) 105 (66.9) 0.668 533 (45.8) 538 (46.5) 0.718
Diabetes 62 (42.5) 60 (38.2) 0.451 287 (24.6) 299 (25.8) 0.503
Dyslipidemia 64 (43.8) 57 (36.3) 0.181 478 (41.0) 488 (42.2) 0.575
Current smoker 36 (24.7) 40 (25.5) 0.869 613 (52.6) 615 (53.2) 0.796
75 (51.4) 77 (49.0) 0.686 85 (7.3) 68 (5.9) 0.168
Previous PCI 7 (4.8) 18 (11.5) 0.035 52 (4.5) 39 (3.4) 0.175
Previous CABG 0 1 (0.6) 1.000 3 (0.3) 0 0.250
Previous CVA 23 (15.8) 18 (11.5) 0.276 27 (2.3) 30 (2.6) 0.668
STEMI 62 (42.5) 80 (51.0) 648 (55.6) 622 (53.8)
NSTEMI 84 (57.5) 77 (49.0) 517 (44.4) 535 (46.2)
Laboratory findings
Creatinine clearance†, mL/min/1.73 m2 67.3 ± 27.0 68.0 ± 27.2 0.832 88.7 ± 22.4 91.3 ± 24.6 0.010
Hemoglobin, g/dL 12.0 ± 1.6 12.0 ± 1.5 0.816 14.9 ± 1.3 14.9 ± 1.4 0.375
Platelet, 10 /L
9
236.2 ± 66.0 229.0 ± 66.7 0.345 241.2 ± 60.6 239.8 ± 56.6 0.555
White blood cell count, 109/L 9.4 ± 3.1 9.0 ± 3.4 0.310 10.4 ± 3.5 10.5 ± 3.5 0.189
LVEF < 40% 24/141 (17.0) 23/151 (15.2) 0.678 75/1,127 (6.7) 69/1,102 (6.3) 0.706
Radial 63 (43.2) 75 (47.8) 555 (47.6) 562 (48.6)
Femoral 77 (52.7) 73 (46.5) 554 (47.6) 536 (46.3)
Infarct-related artery 0.382 0.078
Left anterior descending artery 66 (45.5) 65 (41.9) 592 (51.3) 550 (47.9)
Abbreviations: ARC-HBR, Academic Research Consortium for High Bleeding Risk; CABG, coronary artery bypass graft; CVA, cerebrovascular accident;
HBR, high bleeding risk; LVEF, left ventricular ejection fraction; NSTEMI, non-ST-segment elevation myocardial infarction; PCI, percutaneous coronary
intervention; STEMI, ST-segment elevation myocardial infarction.
Supplementary Table 9. Primary and secondary outcomes by PRECISE-DAPT score-based HBR and treatment arm.
HBR (n = 355) Non-HBR (n = 2,270)
De- Active De- Active
Hazard ratio Hazard ratio
escalation control p Value escalation control p Value
(95% CI) (95% CI)
(n = 181) (n = 174) (n = 1,130) (n = 1,140)
Secondary endpoints
MACCE† 8 (4.4) 9 (5.2) 0.85 (0.33-2.20) 0.740 17 (1.5) 27 (2.4) 0.62 (0.34-1.13) 0.135
BARC bleeding type 5 1 (0.6) – – – – – – –
MACCE, and BARC bleeding type 3 or 5 10 (5.5) 17 (9.8) 0.56 (0.26-1.22) 0.131 24 (2.1) 41 (3.6) 0.57 (0.35-0.95) 0.035
All-cause death 4 (2.2) 7 (4.0) 0.55 (0.16-1.87) 0.372 6 (0.5) 3 (0.3) 1.98 (0.49-7.90) 0.310
Spontaneous 4 (2.2) 4 (2.3) 0.96 (0.24-3.82) 1.000 5 (0.4) 9 (0.8) 0.54 (0.18-1.62) 0.291
Periprocedural – 1 (0.6) – – 3 (0.3) 5 (0.4) 0.59 (0.14-2.46) 0.487
Target vessel myocardial infarction 1 (0.6) – – – 6 (0.5) 8 (0.7) 0.73 (0.25-2.11) 0.603
Stroke 2 (1.1) 2 (1.1) 0.96 (1.14-6.85) 1.000 6 (0.5) 10 (0.9) 0.59 (0.21-1.62) 0.324
Target lesion revascularization 2 (1.1) – – – 12 (1.1) 9 (0.8) 1.31 (0.55-3.10) 0.498
Stent thrombosis 1 (0.6) – – – 2 (0.2) 3 (0.3) 0.65 (0.11-3.89) 1.000
Abbreviations: BARC, Bleeding Academic Research Consortium; CI, confidence interval; HBR, high bleeding risk; MACCE, major adverse cardiac and
cerebrovascular event; PRECISE-DAPT, Predicting Bleeding Complications in Patients Undergoing Stent Implantation and Subsequent Dual Antiplatelet
Therapy.
Supplementary Table 10. Primary and secondary outcomes by ARC-HBR criteria and treatment arm.
HBR (n = 303) Non-HBR (n = 2,322)
De- Active De- Active
Hazard ratio Hazard ratio
escalation control p Value escalation control p Value
(95% CI) (95% CI)
(n = 146) (n = 157) (n = 1,165) (n = 1,157)
Secondary endpoints
MACCE† 6 (4.1) 12 (7.6) 0.51 (0.19-1.35) 0.194 19 (1.6) 24 (2.1) 0.77 (0.42-1.40) 0.428
BARC bleeding type 5 1 (0.7) – – – – – – –
MACCE, and BARC bleeding type 3 or 5 7 (4.8) 18 (11.5) 0.39 (0.17-0.94) 0.035 27 (2.3) 40 (3.5) 0.65 (0.40-1.07) 0.101
All-cause death 3 (2.1) 7 (4.5) 0.44 (0.11-1.71) 0.339 7 (0.6) 3 (0.3) 2.28 (0.59-8.82) 0.343
Spontaneous 3 (2.1) 3 (2.5) 0.77 (0.17-3.42) 1.000 6 (0.5) 9 (0.8) 0.65 (0.23-1.82) 0.429
Periprocedural – 2 (1.3) – – 3 (0.3) 4 (0.3) 0.73 (0.16-3.26) 0.725
Target vessel myocardial infarction 1 (0.7) 1 (0.6) 1.01 (0.06-16.20) 1.000 6 (0.5) 7 (0.6) 0.83 (0.28-2.47) 0.771
Stroke 2 (1.4) 3 (1.9) 0.68 (0.11-4.07) 1.000 6 (0.5) 9 (0.8) 0.65 (0.23-1.83) 0.429
Target lesion revascularization 2 (1.4) 1 (0.6) 2.02 (0.18-22.26) 0.611 12 (1.0) 8 (0.7) 1.46 (0.60-3.56) 0.377
Stent thrombosis 1 (0.7) – – – 2 (0.2) 3 (0.3) 0.65 (0.11-3.87) 0.686
Abbreviations: ARC-HBR, Academic Research Consortium for High Bleeding Risk; BARC, Bleeding Academic Research Consortium; CI, confidence
interval; HBR, high bleeding risk; MACCE, major adverse cardiac and cerebrovascular event.
Supplementary Figure 1. Prevalence of HBR criteria within the HBR group and impact on major bleeding outcome.
(Left) Prevalence of HBR criteria within the HBR group. (Right) Cumulative incidence of BARC bleeding type 3 or 5 between 1 and 12 months
in overall patients with a specific HBR criterion. CKD: chronic kidney disease; HBR: High Bleeding Risk
Supplementary Figure 2. Clinical impact of multiple HBR criteria.
(Top Left) Risk of composite MACCE and BARC bleeding type 3 or 5 according to the number of HBR criteria. (Bottom Left) Risk of BARC
bleeding type 3 or 5 according to the number of HBR criteria. (Right) Distribution of HBR patients into subgroups. BARC: Bleeding Academic
Research Consortium; CI: confidence interval; HBR: High Bleeding Risk; HR: hazard ratio; MACCE: major adverse cardiac and cerebrovascular event; MI:
myocardial infarction
Supplementary Figure 3. Study flow according to PRECISE-DAPT score and ARC-HBR criteria.
ARC-HBR: Academic Research Consortium for High Bleeding Risk; HBR: High Bleeding Risk; PRECISE-DAPT: Predicting Bleeding Complications in
Patients Undergoing Stent Implantation and Subsequent Dual Antiplatelet Therapy; TALOS-AMI: Ticagrelor versus Clopidogrel in Stabilized Patients with
Acute Myocardial Infarction
Supplementary Figure 4. Distribution of study patients by PRECISE-DAPT score and ARC-HBR criteria.
ARC-HBR: Academic Research Consortium for High Bleeding Risk; PRECISE-DAPT: Predicting Bleeding Complications in Patients Undergoing Stent
Implantation and Subsequent Dual Antiplatelet Therapy
Supplementary Figure 5. Cumulative incidences of primary and secondary outcomes by PRECISE-DAPT score-based HBR.
BARC: Bleeding Academic Research Consortium; HBR: high bleeding risk; MI: myocardial infarction; PRECISE-DAPT: Predicting Bleeding Complications
in Patients Undergoing Stent Implantation and Subsequent Dual Antiplatelet Therapy
26
Supplementary Figure 6. Cumulative incidences of primary and secondary outcomes by ARC-HBR criteria.
ARC-HBR: Academic Research Consortium for High Bleeding Risk; BARC: Bleeding Academic Research Consortium; HBR: high bleeding risk; MI:
27
Supplementary Figure 7. Cumulative incidences of primary and secondary outcomes by PRECISE-DAPT score-based HBR and treatment arm.
28
Supplementary Figure 8. Cumulative incidences of primary and secondary outcomes by PRECISE-DAPT score-based non-HBR and treatment
arm.
29
Supplementary Figure 9. Cumulative incidences of primary and secondary outcomes by ARC-HBR criteria-based HBR and treatment arm.
Supplementary Figure 10. Cumulative incidences of primary and secondary outcomes by ARC-HBR criteria-based non-HBR and treatment
arm.

De Escalation From Ticagrelor To Clopidogrel in Patients With Acute Myocardial I

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CORONARY INTERVENTIONS

EuroIntervention 2023;19-online publish-ahead-of-print September 2023

Abbreviations outcomes from 1 to 12 months compared to the active control strat-

EuroIntervention 2023;19-online publish-ahead-of-print September 2023

The TALOS-AMI high bleeding risk substudy

2,697 patients enrolled in the TALOS-AMI trial

72 patients with at least 1 missing value of HBR criteria

2,625 patients with HBR criteria

HBR (n=589) Non-HBR (n=2,036)

De-escalation Active control De-escalation Active control

Log-rank p=0.0009 Cumulative incidence Log-rank p<0.0001

Log-rank p=0.0267 Log-rank p<0.0001

EuroIntervention 2023;19-online publish-ahead-of-print September 2023

Table 1. Baseline and procedural characteristics by HBR and treatment arm.

Table 2. Primary and secondary outcomes by HBR and treatment arm.

EuroIntervention 2023;19-online publish-ahead-of-print September 2023

Discussion UNFAVOURABLE PCI OUTCOMES IN AN HBR POPULATION

EuroIntervention 2023;19-online publish-ahead-of-print September 2023

10 Non-HBR: A+C (4.0%)

Hazard ratio 0.79 Interaction p-value Hazard ratio 0.24

Non-HBR: A+C (1.0%)

Cardiovascular death, MI, stroke and BARC bleeding type 2, 3 or 5

EuroIntervention 2023;19-online publish-ahead-of-print September 2023

Supplementary Table 1. Reasons for screening failure.

Study definition ARC-HBR criteria

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