Received: 10 April 2019 Accepted: 21 April 2019

DOI: 10.1002/ccd.28325

ORIGINAL STUDIES

A risk score to predict postdischarge bleeding among acute

coronary syndrome patients undergoing percutaneous
coronary intervention: BRIC-ACS study

Yundai Chen1 | Tong Yin1 | Shaozhi Xi1 | Shuyang Zhang2 | Hongbing Yan3 |
Yida Tang4 | Juying Qian5 | Jiyan Chen6 | Xi Su7 | Zhimin Du8 | Lefeng Wang9 |
Qin Qin10 | Chuanyu Gao11 | Yang Zheng12 | Xianxian Zhao13 | Xiaoshu Cheng14 |
Zhanquan Li15 | Wenqi Zhang16 | Hui Chen17 | Jingping Wang18 |
Zhiming Yang19 | Hui Li20 | Heping Liu21 | Xuchen Zhou22 | Baiming Qu23 |
Dingcheng Xiang24 | Ying Guo25 | Lin Wang26 | Shaoping Nie27 |
Guosheng Fu28 | Ming Yang29 | Shanglang Cai30

1
Department of Cardiology, General Hospital of Chinese People's Liberation Army, Beijing, China
2
Department of Cardiology, Peking Union Medical College Hospital, Beijing, China
3
Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Beijing, China
4
Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College,
Beijing, China
5
Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
6
Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong General
Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
7
Department of Cardiology, Wuhan Asia Heart Hospital, Wuhan, China
8
Cardiology Department, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
9
Heart Canter, Beijing Chao Yang Hospital, Capital Medical University, Beijing, China
10
Department of Cardiology, Tianjin Chest Hospital, Tianjin, China
11
Department of Cardiology, Zhengzhou University People's Hospital (Henan Provincial People's Hospital), Zhengzhou, China
12
Department of Cardiology, The First Hospital of Jilin University, Changchun, China
13
Department of Cardiovasology, Changhai Hospital, Second Military Medical University, Shanghai, China
14
Department of Cardiology, Second Affiliated Hospital, Nanchang University, Nanchang, China
15
Department of Cardiology, The People's Hospital of Liaoning Province, Shenyang, China
16
Department of Cardiology, China-Japan Union Hospital of Jilin University, Changchun, China
17
Cardiovascular Center, Capital Medical University, Beijing Friendship Hospital, Beijing, China
18
Department of Cardiology, Shanxi Cardiovascular Hospital, Taiyuan, China
19
Department of Cardiology, The Second Hospital of Shanxi Medical University, Taiyuan, China
20
Department of Cardiology, Daqing Oilfield General Hospital, Daqing, China
21
Department of Cardiology, Jilin Province People's Hospital, Changchun, China
22
Department of Cardiology, First Affiliated Hospital of Dalian Medical University, Dalian, China
23
Department of Cardiology, Zhejiang Provincial People's Hospital, Hangzhou, China
24
Department of Cardiology, General Hospital of Guang Zhou Military Command, Guangzhou, China
25
Department of Cardiology, Hunan Provincial People's Hospital, Changsha, China
26
Department of Cardiology, Tongji Hospital , Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
27
Emergency & Critical Care Center, Beijing Anzhen Hospital, Capital Medical University, Beijing, China

Catheter Cardiovasc Interv. 2019;1–11. wileyonlinelibrary.com/journal/ccd © 2019 Wiley Periodicals, Inc. 1

2 CHEN ET AL.

28
Department of Cardiology, Biomedical Research (Therapy) Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
29
Department of Cardiology, Fuxing Hospital Affiliated to Capital Medical University, Beijing, China
30
Department of Cardiology, Affiliated Hospital of Qingdao University, Qingdao, China

Correspondence Abstract
Yundai Chen, Department of Cardiology, Background: Dual antiplatelet therapy (DAPT) after percutaneous coronary interven-
General Hospital of Chinese People's
Liberation Army, No. 28 Fu Xing Road, Beijing tion (PCI) prevents ischemic events while increasing bleeding risk. Real-world-based
100853, China. metrics to accurately predict postdischarge bleeding (PDB) occurrence and its poten-
Email: cyundai@vip.163.com
tial impact on postdischarge major cardiovascular event (MACE) remain undefined.
Funding information This study sought to evaluate the impact of PDB on MACE occurrence, and to
Sanofi
develop a score to predict PDB risk among Chinese acute coronary syndrome (ACS)
patients after PCI.
Methods and Results: From May 2014 to January 2016, 2496 ACS patients who under-
went PCI were recruited consecutively from 29 nationally representative Chinese tertiary
hospitals. Among 2,381 patients (95.4%, 2,381/2,496) who completed 1-year follow-up,
the cumulative incidence of PDB (bleeding academic research consortium type [BARC] ≥2)
and postdischarge MACE (a composite of all-cause death, nonfatal myocardial infarction,
ischemic stroke, or urgent revascularization) was 4.9% (n = 117) and 3.3% (n = 79), respec-
tively. The association between PDB and MACE during 1-year follow-up, as well as the
impact of DAPT with ticagrelor or clopidogrel on PDB were evaluated. PDB was associ-
ated with higher risk of postdischarge MACE (7.7 vs. 3.1%; adjusted hazard ratio: 2.59
[95% confidence interval: 1.17–5.74]; p = .02). For ticagrelor versus clopidogrel, PDB risk
was higher (8.0 vs. 4.4%; 2.05 [1.17–3.60]; p = .01), while MACE risk was similar (2.0
vs. 3.4%; 0.70 [0.25–1.93]; p = .49). Based on identified PDB predictors, the constructed
bleeding risk in real world Chinese acute coronary syndrome patients (BRIC-ACS) score for
PDB was established. C-statistic for the score for PDB was 0.67 (95% CI: 0.62–0.73) in the
overall cohort, and >0.70 in subgroups with non-ST- and ST-segment elevation myocardial
infarction, diabetes and receiving more than two drug eluting stents.
Conclusions: In Chinese ACS patients, PDB with BARC ≥2 was associated with higher
risk for MACE after PCI. The constructed BRIC-ACS risk score provides a useful tool
for PDB discrimination, particularly among high ischemic and bleeding risk patients.

KEYWORDS
antiplatelet therapy, bleeding, coronary artery disease, percutaneous coronary intervention

1 | I N T RO D UC T I O N been documented,5,6 the relationship between PDB and postdischarge

ischemic events remains undefined.
Dual antiplatelet therapy (DAPT), that is, aspirin and a P2Y12 inhibitor, To date, most bleeding risk scores (e.g., CRUSADE or ACUITY) for
prevents thrombotic complications following percutaneous coronary ACS or PCI patients have focused on in-hospital events or short-term
intervention (PCI) with drug-eluting stents (DES) of acute coronary syn- risk.7–10 Although these scales are useful to inform clinical decisions
1
drome (ACS). Current guidelines recommend use of newer potent regarding periprocedural antithrombotic therapies or other bleeding
P2Y12 inhibitors such as prasugrel or ticagrelor for 12 months after an avoidance strategies, their utility with respect to long-term use of
ACS managed with PCI.2 However, the greatest anti-ischemic benefit of DAPT is less certain.11 Moreover, the underlying risk factors or their
potent antiplatelet drugs over clopidogrel occurs early, while most respective weights may vary for early as opposed to later bleeding
excess bleeding events, as the most common complication, arise pre- events.8,12 To this end, PRECISE-DAPT was developed and rec-
3,4
dominantly during the maintenance phase. While the impact and con- ommended to evaluate the benefits and risks of different DAPT dura-
tribution of postdischarge bleeding (PDB) events on late mortality has tions based on randomized clinical trials.2,13,14 However, randomized
CHEN ET AL. 3

trials may underestimate the “real-world” incidence of clinically impor- categories were used: gastrointestinal, intracranial, subcutaneous, geni-
tant bleeding events in ACS,15 underscoring the need for stratification tourinary, hemoptysis, and others.
tools focusing on PDB events during the chronic phase of DAPT use, Other outcomes also evaluated in the present study included BARC
that is, within 12 months in a real-world clinical setting. We therefore type ≥3 bleeding events (excluding BARC type 4), BARC type 1 bleeding
evaluated the incidence, predictors, and impact of PDB on post- events, MACE (a composite of all-cause mortality, non-fatal myocardial
discharge major adverse cardiovascular events (MACE) in ACS infarction [MI], urgent coronary revascularization [CRV] and ischemic
patients who underwent successful DES implantation in the large- stroke). All-cause mortality was defined as death due to definite cardio-
scale registry of bleeding risk in real world Chinese acute coronary vascular factors, or due to any other noncardiovascular events. Nonfatal
syndrome patients (BRIC-ACS) study. We also sought to develop a MI was diagnosed according to the diagnostic criteria laid down in the
dedicated risk score specifically designed to predict risks for PDB updated ESC guidelines2,19 including non-ST-segment elevation myocar-

events within 12 months of follow-up to improve risk assessment and dial infarction (Non-STEMI) and ST-segment elevation myocardial infarc-

support clinicians' decisions with respect to personalized DAPT. tion (STEMI). Urgent CRV was defined as re-hospitalization due to ACS
that causes PCI or CABG to be performed within 24 hr.2 Ischemic stroke
was defined as neurologic focal impairment due to an ischemic event,
2 | METHODS with symptoms persisting for at least 24 hr, resulting in death.

2.1 | Study population

2.3 | Statistical analysis
The BRIC-ACS study was a nationwide, multicenter, prospective regis-
try specifically designed to evaluate the bleeding risk in Chinese ACS We calculated that assuming 10 parameters in the final model, 10–15
positive bleeding events could be detected for each parameter, an
patients who underwent PCI. In brief, 2,520 ACS patients who under-
event rate of PDB of 6.8%20 and a dropout rate of 10%, at least 2,451
went PCI during admission were prospectively and consecutively
patients would be required to develop a novel bleeding risk model.
enrolled at 29 tertiary centers between May 2014 and January 2016
16,17 Descriptive statistics are presented as median (IQR) and were
(see Supporting Information). All patients were treated according
compared using the Kruskal–Wallis test; while categorical variables
to usual clinical practice at each site, while one or more DES were suc-
are reported as n (%) and were compared using the Chi-square test or
cessfully implanted using standard techniques followed by clopidogrel
Fisher's exact test. Outcomes based on time to first event were
or ticagrelor alongside aspirin therapy. Patients were excluded if any
assessed by comparison of Kaplan–Meier-based cumulative incidence
of the following criteria was met: ACS as a secondary diagnosis; inabil-
rates with the log-rank test. COX regression analysis (with time-
ity to give informed consent or to undergo 1-year of follow-up; preg-
dependent covariates) was used for univariable and multivariable
nancy or breastfeeding; and lost to follow-up after discharge. Clinical
analyses, with time of first occurrence of PDB, MACE, or all-cause
follow-up was scheduled at 1, 3, 6, and 12 months by phone interview
mortality as the dependent outcome in each model. Forest plots were
or personal contact. Standardized questions were used to assess
also generated for visual inspection.
bleeding episodes, thrombotic events, and use of medications. Data
We also studied the associations between possible predictors and
on bleeding events and MACE, as well as medication and pharmacy
PDB using Cox regression analysis stratified by trial. Potential predic-
dispensation data, were collected. A blinded and independent clinical
tors of PDB were selected using univariable analysis (p < .15). Both
events committee of 5–10 cardiologists held a meeting for adjudicat- the identified potential predictors and other candidate variables
ing all clinical outcome events (PDB and MACE), using the original potentially associated with bleedings based on a comprehensive liter-
records and phone-call recording, according to the BARC standardized ature review and clinical plausibility were included in the multivariable
bleeding criteria18 and the definitions of MACE. Institutional review analysis, then independent PDB predictors were selected using multi-
board approval was obtained at each participating center, and all variable backward selection (p < .05). Curvilinear predictor values
patients signed written informed consent prior to enrollment. were scaled and rounded to a score with integer values between
0 and 60. Patients were then grouped into levels of low, intermediate,
and high risk, with thresholds reflecting clinically meaningful (at least
2.2 | Study objectives and definitions
3.5-fold) gradients in risk from one group to the next. Discrimination
The objectives of the present study were to evaluate the effect of of the bleeding risk score was assessed by the receiver operating
PDB on the postdischarge MACE within 1 year, and finally to develop characteristic curve.21 The primary model was internally validated
a bleeding risk score for predicting PDB risk within 1 year. using the method of Markov Chain Monte Carlo with bootstrap
According to the BARC standardized bleeding Criteria18 developed resampling for 200,000 iterations. For each 10 resampling, one ran-
by a consensus effort of academics, research organizations, industry, dom resampling result was extracted. Then the mean value of each
and regulator representatives for cardiovascular clinical trials, PDB was regression coefficient was compared with that from the direct fitting
defined as clinical-related bleeding occurring after hospital discharge fol- model. Moreover, the model also was validated in analyses of sub-
lowing successful DES implantation with a BARC type ≥2 bleeding groups stratified by ACS type, sex, age, diabetes as comorbidity, and
event (excluding BARC type 4). The following prespecified bleeding site number of implanted DES.
4 CHEN ET AL.

bleeding. The most common site of PDB was gastrointestinal

(Figure 2). Risk of bleeding accrued over time, and PDB primarily
occurred in the early period (<90 days), with a rate of first bleeding of
2.0% (47/2,381) and a proportion of 40.2% (47/117).

3.2 | Impact of PDB on postdischarge MACE

During 1-year follow-up, 79 patients (3.3%) experienced MACE,
including 56 patients (2.4%) with all-cause mortality (24 cardiac mor-
tality), 17 patients with ischemic stroke, and 11 patients with nonfatal
MI or urgent CRV. Risk of MACE accrued over time, with MACE
occurring primarily in the early period (<90 days); rate of first MACE
was 1.6% (37/2,381) with proportion of 46.8% (37/79).
Relative to patients without PDB, patients experiencing PDB had
higher unadjusted rate of the 1-year clinical outcome of MACE after
discharge (7.7 vs. 3.1%, p = .01). Figure 3 shows unadjusted rates for
the composite outcome according to PDB occurrence. After adjust-
ment for demographic characteristics, comorbid conditions, triple-
vessel lesion, and DAPT strategies (including clopidogrel alongside
aspirin, ticagrelor alongside aspirin, and DAPT discontinuation for
>1 month), PDB was significantly associated with higher risk of post-
discharge MACE (adjusted hazard ratio [HR], 2.59; 95% confidence
FIGURE 1 Study flow chart interval [CI]: 1.17–5.74; p = .02; Figure 3). No significant association
was found between PDB and all-cause mortality during 1-year follow-
Statistical significance was defined as p < .05. SAS software 9.4 up (Table 1).
and SPSS software 22.0 were used for statistical analyses.

3.3 | Establishment and validation of the BRIC-ACS

3 | RESULTS score for PDB prediction
In terms of baseline clinical characteristics (Table 2), patients with
3.1 | Incidence and sites of PDB
PDB within 1 year were older, more commonly female, more likely
Among 2,520 patients enrolled in BRIC-ACS study with definitive with lower body mass index (BMI) or hemoglobin and with higher
diagnosis of ACS and who underwent PCI with DES, 2,381 eligible prevalence of hypertension or prior peptic ulcer. Patients experiencing
patients were included in the current analysis: 1,012 patients (42.5%) PDB also were more likely to have had received low-molecular-weight
with unstable angina (UA), 435 patients (18.3%) with NSTEMI and heparin within 48 hr pre-PCI or treated with ticagrelor alongside aspi-
934 patients (39.2%) with STEMI (Figure 1). During 1-year follow-up, rin. Relative to patients treated with clopidogrel (n = 1,813), those
117 patients (4.9%) suffered PDB, including 101 with BARC type treated with ticagrelor (n = 199) had a significantly higher risk for PDB
2 bleeding, while 19 patients (0.8%) experienced BARC type ≥3 (4.4 vs. 8.0%, adjusted HR: 2.05, 95% CI: 1.17–3.60, p = .01) but not

F I G U R E 2 Site of postdischarge
bleeding with bleeding academic research
consortium (BARC) ≥2
CHEN ET AL. 5

FIGURE 3 Impact of different types of postdischarge bleeding on postdischarge major cardiovascular event (MACE)

for MACE (3.4 vs. 2.0%, adjusted HR: 0.70, 95% CI: 0.25–1.93, baseline, hypertension, prior peptic ulcer, and ticagrelor along-
p = .49; Figure 4). side aspirin. Point estimates and corresponding 95% CI for each
From multivariable analysis, the factors independently associ- covariate are shown in Table 3. The strongest predictor for PDB,
ated with PDB included sex × multivessel lesion, BMI, hemoglo- quantified and ranked using the p value, was administration of
bin, triglycerides, low-density lipoprotein cholesterol (LDL-C) at ticagrelor alongside aspirin.

F I G U R E 4 Adjusted cumulative
incidences of (panel A) PDB with BARC ≥2,
(panel B) postdischarge MACE according to
subgroups receiving continuous ticagrelor or
clopidogrel therapy. BARC, bleeding
academic research consortium; MACE,
major cardiovascular event; PDB,
postdischarge bleeding. Adjusted factors
included age, sex, BMI, hypertension,
diabetes, history of peptic ulcer, and ACS
(STEMI/NSTEMI vs. UA). Aspirin +
Clopidogrel is the reference category [Color
figure can be viewed at
wileyonlinelibrary.com]
6 CHEN ET AL.

TABLE 1 Impact of postdischarge bleeding and ischemic events on 1-year all-cause mortality
Unadjusted annual
Number of Number of mortality rate (per 100 Unadjusted HR Unadjusted Adjusted HR Adjusted p
patients deaths person-year) (95%CI) p value (95%CI)a value
BARC ≥2 bleedings 117 5 4.4 1.87 (0.75–4.68) .18 1.68 (0.66–4.28) .28
BARC ≥3 bleedings 19 3 16.9 7.20 (2.25–23.04) .001 5.93 (1.63–21.52) .007
Stroke 17 2 12.4 5.17 (1.26–21.18) .02 1.71 (0.37–7.86) .49
Nonfatal MI and urgent 17 2 20.0 12.60 (3.94–40.31) .000 11.90 (2.75–51.43) .001
revascularization

Abbreviations: BARC, BARC, bleeding academic research consortium; CI, confidence interval; HR, hazard ratio; MI, myocardial infarction.
a
Adjusted for age, hypertension, diabetes, chronic renal insufficiency, peripheral vascular diseases, triple-vessel lesion, heart failure, ACS (UA vs.
STEMI/NSTEMI).

TABLE 2 Comparison of clinical data between patients with and without PDB

Postdischarge BARC ≥2 bleeding No postdischarge BARC ≥2 bleeding

(n = 117) (n = 2,264) p-Value
Demographic data
Age, median (IQR), y 63 (56, 72) 61 (53, 68) .019
Female, n (%) 40 (34.2) 521 (23.0) .006
BMI, median (IQR), kg/m2 25 (22,26) 25 (23, 27) .008
≥25 kg/m 2
37 (31.6) 937 (41.4) .037
Current drinker, n (%) 18 (15.5) 453 (20.2) .219
Medical history, n (%)
Coronary artery disease 36 (30.8) 649 (28.8) .646
Congestive heart failure 2 (1.7) 23 (1.0) .472
Hypertension 78 (66.7) 1,296 (57.2) .044
Diabetes mellitus 31 (26.5) 591 (26.2) .943
Chronic renal insufficiency 5 (4.3) 55 (2.4) .217
Cerebrovascular disease 6 (5.1) 169 (7.5) .339
Prior peptic ulcer 10 (8.5) 109 (4.8) .072
a
Prior vascular disease 2 (1.7) 25 (1.1) .551
Prior-PCI 12 (10.3) 237 (10.5) .942
Clinical presentation (%)
ACS type
STEMI 44 (37.6) 890 (39.3) .713
NSTEMI 15 (12.8) 420 (18.6) .118
UA 58 (49.6) 952 (42.0) .108
NYHA/KILLIP class ≥ II 31 (26.5) 587 (25.9) .891
Admission data and laboratory evaluation
Heart rate, median (IQR), bpm 71 (65, 80) 72 (64, 80) .767
SBP, median (IQR). mm Hg 130 (117, 138) 130 (117,141) .598
LVEF, median (IQR), % 58 (52, 63) 60 (53,65) .123
Hemoglobin, median (IQR), g/dL 135 (122, 145) 140 (129,150) .0005
Baseline hematocrit, median (IQR), % 40 (37, 43) 41 (38,44) .017
WBC, median (IQR) × 10 /L 9
7 (6, 9) 8 (6,10) .151
Platelet count, median (IQR) × 109/L 208 (176, 239) 210 (173,252) .668
Creatinine clearanceb, median (IQR) mL/min 75 (62, 101) 88 (67,109) .033
<60 mL/min 20 (20.4) 305 (16.56) .320
(Continues)
CHEN ET AL. 7

TABLE 2 (Continued)

Postdischarge BARC ≥2 bleeding No postdischarge BARC ≥2 bleeding

(n = 117) (n = 2,264) p-Value
Lesion and procedure characteristics (%)
Left main lesion 5 (4.3) 78 (3.4) .634
Triple-vessel lesion 13 (11.1) 322 (14.2) .345
Multivessel lesion 55 (47.0) 1,255 (55.4) .074
Chronic total occlusion, 41 (35.0) 851 (37.6) .579
Urgent/direct PCI 30 (25.6) 592 (26.1) .903
Vascular access site
Femoral 14 (12.0) 256 (11.3) .823
Radial 100 (85.5) 1972 (87.1) .608
Closure device used 11 (9.7) 222 (9.9) .956
Number of DESs≥2 40 (34.5) 970 (43.4) .058
Perioperative antithrombotic treatment n (%)
LMWH administered within 48 hr pre-PCI 5 (4.3) 37 (1.6) .034
GPIIb/IIIa inhibitor 30 (27.0) 479 (22.0) .212
UFH/ enoxaparin +GP IIb/IIIa inhibitor 27 (23.1) 421 (18.6) .227
Bivalirudin +GP IIb/IIIa inhibitor 0 (0.0) 9 (0.4) 1.000
Bivalirudin monotherapy 0 (0.0) 45 (2.0) .168
Antithrombotic treatment after discharge, n (%)
Continuous ticagrelor 17 (14.5) 184 (8.1) .015
Continuous clopidogrel 80 (68.4) 1,768 (78.1) .014
Warfarin, at discharge 1 (0.9) 9 (0.4) .456
c
TAT at discharge 1 (0.9) 7 (0.3) .320
Concomitant medications, n (%)
Statins 61 (52.1) 1,125 (49.7) .606
Gastric acid inhibitor 33 (28.2) 697 (30.8) .555
β-Blockers 76 (65.0) 1,416 (62.5) .599
Calcium-channel blocker 23 (19.7) 389 (17.2) .490
RAS inhibitors 64 (54.7) 1,204 (53.2) .748

Abbreviations: ACS, acute coronary syndrome; BARC, bleeding academic research consortium; BMI, body mass index; DES, drug-eluting stent; LMWH,
low-molecular-weight heparin; LVEF, left ventricular ejection fraction; NSTEMI, non-ST-segment elevation myocardial infarction; PCI, percutaneous
coronary intervention; PDB, postdischarge bleeding; RAS, renin-angiotensin system; SBP, Systolic blood pressure; STEMI, ST-segment elevation
myocardial infarction; UA, unstable angina; UFH, unfractionated heparin; WBC, white blood cell.
a
Referring to a history of cerebrovascular disease and/or peripheral artery disease.
b
Creatinine clearance was calculated with the Cockcroft-Gaut formula.
c
TAT referred to three antithrombotic therapy, including aspirin, clopidogrel, and warfarin or dabigatran.

Based on the multivariable model, we assigned points to each fac- PDB (c-statistic, 0.67 [95%CI, 0.62–0.73]). After bootstrap internal
tor and then developed a 9-item bleeding risk score—the BRIC-ACS validation, optimism-corrected c-statistics was also 0.67 (95%CI,
score (Table 4). The score was calculated using the following formula: 0.62–0.73; Table 5). The rates of PDB for BRIC-ACS score distribution
Z score = 64.49 + 3.06 × sex + 8.97 × prior peptic ulcer + 5.56 × hyp- tertiles were 1.2% (low risk: 0–20 points), 4.7% (moderate risk: 21–39
ertension − 2.62 × multivessel lesion + 8.47 × ticagrelor alongside points), and 17.3% (high risk: 40–60 points; p trend <.0001; Figure 6).
aspirin − 0.72 × BMI − 0.12 × hemoglobin − 11.97 × log10 triglycer- The performance of the BRIC-ACS bleeding score was also validated
ides − 5.13 × log10 LDL-C. The sum of the weighted integer (range in subgroups of the cohort displaying relatively good discriminatory abil-
1–60 points) estimates the risk of PDB within 1 year. The BRIC-ACS ity in the subgroups of patients with NSTEMI, STEMI, diabetes, or
score distribution in the derivation cohort and the risk of PDB in implantation of >2 DES (c-statistic, ≥0.70; Table 5). However, the risk
1 year is presented in Figure 5. The BRIC-ACS score had moderate score showed relatively poor discriminatory power for patients 75 years
ability to discriminate between patients who did and did not have a or older (c-statistic, 0.63; Table 5).
8 CHEN ET AL.

TABLE 3 Independent predictors of PDB during 1 year of T A B L E 5 Validation of the BRIC-ACS score in the overall cohort
follow-up by bootstrap resampling method and subgroups

Variables HR (95%CI) p-Value Groups AUC (95%CI)

Sex × multivessel lesion 1.236 (1.017–1.502) .033 Overall cohort 0.67 (0.62–0.73)
BMI 0.931 (0.880–0.985) .013 UA 0.62 (0.54–0.70)
Prior peptic ulcer 2.461 (1.210–5.006) .013 NSTEMI 0.80 (0.64–0.95)
Hypertension 1.742 (1.100–2.757) .018 STEMI 0.71 (0.61–0.81)
Hemoglobin 0.988 (0.978–0.997) .012 Women 0.67 (0.58–0.76)
Triglycerides 0.305 (0.120–0.772) .012 Men 0.66 (0.58–0.73)
LDL-C 0.598 (0.393–0.911) .017 Age ≥75 y 0.63 (0.45–0.82)
Ticagrelor alongside aspirin 2.318 (1.240–4.334) .009 Age <75 y 0.67 (0.61–0.74)

Abbreviations: BMI, body mass index; CI, confidence interval; HR, hazard Diabetes 0.71 (0.60–0.81)
ratio; LDL-C, low density lipoprotein cholesterol; PDB, postdischarge No diabetes 0.66 (0.59–0.73)
bleeding.
Number of DESs ≤2 0.67 (0.60–0.73)
Number of DESs >2 0.71 (0.55–0.87)
TABLE 4 The BRIC-ACS score algorithm for bedside application
Abbreviations: AUC, area under the curve; BRIC-ACS, bleeding risk in real
Variable Score world Chinese acute coronary syndrome patient; DES, drug-eluting stent;
NSTEMI, non-ST-segment elevation myocardial infarction; STEMI,
Sex 0-male, 1-female
ST-segment elevation myocardial infarction; UA, unstable angina.
Prior peptic ulcer 0-no, 1-yes
Hypertension 0-no, 1-yes
Multivessel lesion 0-no, 1-yes
4 | DISCUSSION
Ticagrelor alongside aspirin 0-no, 1-yes
BMI Actual value The BRIC-ACS study is the first nationwide, multicenter, prospective
Hemoglobin Actual value registry specifically designed to evaluate the PDB risk in Chinese ACS
Triglycerides log10triglycerides patients who underwent PCI. The main findings of the present analy-
LDL-C log10 LDL-C sis of data derived from the BRIC-ACS study are: PDB was strongly
Note: Z score = 64.49 + 3.06 × sex + 8.97 × prior peptic ulcer associated with postdischarge MACE within 1 year; The BRIC-ACS
+ 5.56 × hypertension − 2.62 × multivessel lesion + 8.47 × ticagrelor bleeding risk score, developed for the prediction of PDB within 1 year
alongside aspirin − 0.72 × BMI − 0.12 × hemoglobin − 11.97 × log10 in ACS patients who underwent PCI and with contemporary use of
triglycerides − 5.13 × log10 LDL-C.
Abbreviations: BMI, body mass index; BRIC-ACS, bleeding risk in real
two oral P2Y12, provides a useful tool particularly in patients with
world Chinese acute coronary syndrome patient; LDL-C, low density high ischemic and bleeding risk.
lipoprotein cholesterol. In the all-comers BRIC-ACS population, PDB occurred in approxi-
mately 1 of every 20 patients within 1 year of follow-up, with slightly
more than one third of PDB events occurring within 90 days. Consis-
tent with prior studies,6,22,23 gastrointestinal bleeding was the most
frequent identifiable source of PDB in the present study. Interestingly,
prior peptic ulcer was relatively more frequent in patients with PDB
(8.6 vs. 4.8%, p = .07) with gastric acid inhibitors used rather infre-
quently after discharge (28.2 vs. 30.8%, p = .55), which might underlie
the bleeding. Because proton pump inhibitors significantly reduce gas-
trointestinal bleeding in patients with selected risk factors,24 a proton
pump inhibitor is recommended to minimize bleeding while on
DAPT.2
In the present study, significant association was observed between
PDB with BARC ≥3 and all-cause mortality. We did not observed the sig-
nificant association between PDB with BARC ≥2 and all-cause mortality.
F I G U R E 5 Distribution of the bleeding risk in real world Chinese Therefore, all-cause mortality in the present study might be driven by
acute coronary syndrome patients (BRIC-ACS) risk score and
the PDB with BARC ≥3. However, due to the total number of mortality
corresponding predicted risk for postdischarge bleeding (PDB) in the
overall patient population [Color figure can be viewed at of events was small in the present study, the results should be further
wileyonlinelibrary.com] verified. However, further analysis showed that the PDB with BARC ≥2
CHEN ET AL. 9

F I G U R E 6 Kaplan–Meier estimates of
patients free from postdischarge bleeding
(PDB) in the overall derivation cohort
stratified by score tertiles [Color figure can
be viewed at wileyonlinelibrary.com]

was independently associated with higher risk for postdischarge MACE. validated the BRIC-ACS score with the bootstrap method and in sub-
The relationship between PDB and MACE is likely multifactorial. The risk groups of patients from the overall cohort. Second, the rate of PDB
factors shared between bleeding and ischemic events have explained the with BARC ≥3 within 1 year was lower than that reported in other
higher risk for recurrent ischemic events in patients with bleeding studies,6,27,31,32 which might be attributed to the inclusion of a high
25,26
events. proportion of patients with lower risk of bleeding (e.g., 42.5% of
Relative to clopidogrel alongside aspirin use, ticagrelor alongside patients with UA). Nonetheless, PDB with BARC ≥3 was indepen-
aspirin use was strongly associated with higher risk of PDB with BARC dently associated with all-cause mortality and postdischarge MACE
≥2, but not lower risk of postdischarge MACE. The latter finding is con- within 1 year.5,33 Third, although we included in the multiple regres-
sistent with that in the GRAPE study (the Greek Anti-platelet Registry).27 sion analysis as many as possible clinical and procedural risk factors
Because only a small number of patients on ticagrelor treatment potentially influencing bleeding risk, some might have been omitted.
(n = 199) were included in the present study, a larger registry study with Variables related to bleeding, such as age and creatinine clearance,
comparable numbers of ticagrelor and clopidogrel treated patients is were absent from the final BRIC-ACS score, indicating that the under-
warranted to confirm the findings in Chinese patients. lying risk factors or their relative contributions for bleeding are not
Although multiple scores have been developed to stratify the
constant.34 Fourth, because the recruitment time interval for the
bleeding risk for ACS or PCI patients, most have focused on short-term
study coincided with the beginning of ticagrelor availability in China,
events or long-term outcomes which are not directly modified by
the sample size of patients on ticagrelor treatment was small
chronic DAPT use within 1 year in a real world setting.1,7,13,14,28,29
(n = 199). Therefore, comparisons of efficacy and safety outcomes
Therefore, we developed for the first time a risk score for clinically rele-
between ticagrelor and clopidogrel treated patients should be vali-
vant PDB (BARC ≥2) which is most consistently and reproducibly
dated in further studies (such as the ongoing BRIC-ACS stage II regis-
influenced by DAPT.1,5 For the prediction of PDB with BARC ≥2, the
try). Finally, because the established BRIC-ACS bleeding risk score
present BRIC-ACS score displayed a relatively moderate discriminative
was based specifically on Chinese ACS patients after PCI, validation
power (c-statistics: 0.67) in Chinese ACS patients who underwent PCI.
is warranted in racially diverse populations and non-ACS or PCI
The performance is comparable or relatively better than that of the
patients.
previous PRECISE-DAPT and PARIS scores, both of which were vali-
dated for the prediction of PDB with BARC ≥2 in the CardioCHUVI
PCI registry study (c-statistics: 0.61 and 0.63, respectively).30 More-
over, the BRIC-ACS score performed better in patients with NSTEMI, 5 | C O N CL U S I O N S
STEMI, diabetes, and those implanted with more than two DESs (c-sta-
tistics: 0.71–0.80), it might be a useful tool to predict PDB risk in In conclusion, in a nationwide, multicenter registry study of Chinese
patients with high ischemic and bleeding risk. ACS patients who underwent PCI, PDB with BARC ≥2 was associated
Several limitations of the study should be mentioned. First, due to with higher risk for postdischarge MACE. The constructed BRIC-ACS
the relatively small sample size (n = 2,381) of the present study, the risk score had moderate performance for the discrimination of PDB,
entire cohort was used for the derivation of the BRIC-ACS score. which might be useful particularly in patients with high ischemic and
Although no independent validation cohort was established, we bleeding risk.
10 CHEN ET AL.

6 | PERSPECTIVES 5. Genereux P, Giustino G, Witzenbichler B, et al. Incidence, predictors,

and impact of post-discharge bleeding after percutaneous coronary
intervention. J Am Coll Cardiol. 2015;66:1036-1045.
6.1 | What is known? 6. Kazi DS, Leong TK, Chang TI, Solomon MD, Hlatky MA, Go AS. Asso-
ciation of spontaneous bleeding and myocardial infarction with long-
PDB with BARC ≥2 was associated with all-cause mortality in patients
term mortality after percutaneous coronary intervention. J Am Coll
underwent PCI. Less known is the impact of PDB on postdischarge MACE. Cardiol. 2015;65:1411-1420.
Moreover, methods to gauge PDB risk in real world settings dur- 7. Mathews R, Peterson ED, Chen AY, et al. In-hospital major bleeding
ing the chronic DAPT use phase within 12 months are limited. during st-elevation and non-st-elevation myocardial infarction care:
derivation and validation of a model from the action registry(r)-gwtg.
Am J Cardiol. 2011;107:1136-1143.
8. Subherwal S, Bach RG, Chen AY, et al. Baseline risk of major bleeding
6.2 | What the study adds? in non-st-segment-elevation myocardial infarction: the crusade (can
rapid risk stratification of unstable angina patients suppress adverse
PDB with BARC ≥2 is associated with higher risk for postdischarge outcomes with early implementation of the acc/aha guidelines) bleed-
MACE in Chinese ACS patients who underwent PCI. The constructed ing score. Circulation. 2009;119:1873-1882.
BRIC-ACS risk score had moderate performance for the discrimination 9. Mehran R, Pocock SJ, Nikolsky E, et al. A risk score to predict bleed-
ing in patients with acute coronary syndromes. J Am Coll Cardiol.
of PDB, which might be useful particularly in patients with high ische-
2010;55:2556-2566.
mic and bleeding risk. 10. Rao SV, McCoy LA, Spertus JA, et al. An updated bleeding model to
predict the risk of post-procedure bleeding among patients undergo-
ing percutaneous coronary intervention: a report using an expanded
6.3 | What is next? bleeding definition from the national cardiovascular data registry cat-
hpci registry. JACC Cardiovasc Interv. 2013;6:897-904.
Additional studies are needed to validate the established BRIC-ACS 11. Li S, Liu H, Liu J. Predictive performance of adding platelet reactivity
bleeding risk score, which is based on real-world Chinese ACS patients on top of crusade score for 1-year bleeding risk in patients with acute
coronary syndrome. J Thromb Thrombolysis. 2016;42:360-368.
after PCI.
12. Valle JA, Shetterly S, Maddox TM, et al. Postdischarge bleeding after
percutaneous coronary intervention and subsequent mortality and
myocardial infarction: insights from the hmo research network-stent
ACKNOWLEDGMENTS registry. Circ Cardiovasc Interv. 2016;9:e003519.
13. Costa F, van Klaveren D, James S, et al. Derivation and validation of
This study was funded by Sanofi. The funder did not participate in study the predicting bleeding complications in patients undergoing stent
design or execution, drug choice, data analysis, or reporting. The authors implantation and subsequent dual antiplatelet therapy (precise-dapt)
score: a pooled analysis of individual-patient datasets from clinical tri-
would like to thank the investigators and participants for their participa-
als. Lancet. 2017;389:1025-1034.
tion, without whom this study would not have been possible. 14. Yeh RW, Secemsky EA, Kereiakes DJ, et al. Development and valida-
tion of a prediction rule for benefit and harm of dual antiplatelet ther-
apy beyond 1 year after percutaneous coronary intervention. JAMA.
ORCID 2016;315:1735-1749.
15. Steg PG, Huber K, Andreotti F, et al. Bleeding in acute coronary syn-
Yundai Chen https://orcid.org/0000-0003-4409-9375 dromes and percutaneous coronary interventions: position paper by
the working group on thrombosis of the European society of cardiol-
Shaoping Nie https://orcid.org/0000-0001-9867-3833
ogy. Eur Heart J. 2011;32:1854-1864.
16. Hamm CW, Bassand JP, Agewall S, et al. Esc guidelines for the man-
agement of acute coronary syndromes in patients presenting without
RE FE R ENC E S persistent st-segment elevation: the task force for the management
of Acute Coronary Syndromes (acs) in patients presenting without
1. Baber U, Mehran R, Giustino G, et al. Coronary thrombosis and major persistent st-segment elevation of the European Society of Cardiol-
bleeding after pci with drug-eluting stents: risk scores from Paris. ogy (esc). Eur Heart J. 2011;32:2999-3054.
J Am Coll Cardiol. 2016;67:2224-2234. 17. Van de Werf F, Bax J, Betriu A, et al. Management of acute myocar-
2. Ibanez B, James S, Agewall S, et al. 2017 esc guidelines for the man- dial infarction in patients presenting with persistent st-segment ele-
agement of acute myocardial infarction in patients presenting with st- vation: the task force on the management of st-segment elevation
segment elevation: the task force for the management of acute myo- acute myocardial infarction of the European society of cardiology.
cardial infarction in patients presenting with st-segment elevation of Eur Heart J. 2008;29:2909-2945.
the european society of cardiology (esc). European Heart Journal. 18. Mehran R, Rao SV, Bhatt DL, et al. Standardized bleeding definitions
2018;39(2):119–177. for cardiovascular clinical trials: a consensus report from the bleeding
3. Cuisset T, Deharo P, Quilici J, et al. Benefit of switching dual anti- academic research consortium. Circulation. 2011;123:2736-2747.
platelet therapy after acute coronary syndrome: the topic (timing of 19. Thygesen K, Alpert JS, White HD, Joint ESCAAHAWHFTFftRoMI.
platelet inhibition after acute coronary syndrome) randomized study. Universal definition of myocardial infarction. Eur Heart J. 2007;28:
Eur Heart J. 2017;38:3070-3078. 2525-2538.
4. Sibbing D, Aradi D, Jacobshagen C, et al. Guided de-escalation of anti- 20. Goto S, Huang CH, Park SJ, Emanuelsson H, Kimura T. Ticagrelor
platelet treatment in patients with acute coronary syndrome undergo- vs. Clopidogrel in japanese, korean and taiwanese patients with acute
ing percutaneous coronary intervention (tropical-acs): a randomised, coronary syndrome—randomized, double-blind, phase iii philo study.
open-label, multicentre trial. Lancet. 2017;390:1747-1757. Circ J. 2015;79:2452-2460.
CHEN ET AL. 11

21. Hanley JA, McNeil BJ. The meaning and use of the area under a angina/non-st-elevation myocardial infarction (updating the 2007
receiver operating characteristic (roc) curve. Radiology. 1982;143: guideline): a report of the american college of cardiology foundation/
29-36. american heart association task force on practice guidelines developed
22. Genereux P, Cohen DJ, Mack M, et al. Incidence, predictors, and in collaboration with the american college of emergency physicians,
prognostic impact of late bleeding complications after transcatheter society for cardiovascular angiography and interventions, and society of
aortic valve replacement. J Am Coll Cardiol. 2014;64:2605-2615. thoracic surgeons. J Am Coll Cardiol. 2011;57:1920-1959.
23. Palmerini T, Benedetto U, Bacchi-Reggiani L, et al. Mortality in patients 31. Moscucci M, Fox KA, Cannon CP, et al. Predictors of major bleeding
treated with extended duration dual antiplatelet therapy after drug- in acute coronary syndromes: the global registry of acute coronary
eluting stent implantation: a pairwise and Bayesian network meta- events (grace). Eur Heart J. 2003;24:1815-1823.
analysis of randomised trials. Lancet. 2015;385:2371-2382. 32. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel
24. Bhatt DL, Cryer BL, Contant CF, et al. Clopidogrel with or without in patients with acute coronary syndromes. N Engl J Med. 2009;361:
omeprazole in coronary artery disease. N Engl J Med. 2010;363: 1045-1057.
1909-1917. 33. Brener SJ, Kirtane AJ, Stuckey TD, et al. The impact of timing of ischemic
25. Yadav M, Genereux P, Palmerini T, et al. Syntax score and the risk of and hemorrhagic events on mortality after percutaneous coronary inter-
stent thrombosis after percutaneous coronary intervention in patients vention: the adapt-des study. JACC Cardiovasc Interv. 2016;9:1450-1457.
with non-st-segment elevation acute coronary syndromes: an acuity 34. Li L, Geraghty OC, Mehta Z, Rothwell PM, Oxford Vascular S. Age-
trial substudy. Cathet Cardiovasc Interv. 2015;85:1-10. specific risks, severity, time course, and outcome of bleeding on long-
26. China Society of Cardiology of Chinese Medical Association, Editorial term antiplatelet treatment after vascular events: a population-based
Board of Chinese Journal of Cardiology. Guideline for diagnosis and cohort study. Lancet. 2017;390:490-499.
treatment of patients with ST-elevation myocardial infarction.
Zhonghua Xin Xue Guan Bing Za Zhi. 2010;38:675-690.
27. Alexopoulos D, Xanthopoulou I, Deftereos S, et al. Contemporary
antiplatelet treatment in acute coronary syndrome patients undergo- SUPPORTING INF ORMATION
ing percutaneous coronary intervention: 1-year outcomes from
Additional supporting information may be found online in the
the greek antiplatelet (grape) registry. J Thromb Haemost. 2016;14:
1146-1154. Supporting Information section at the end of this article.
28. Nikolsky E, Mehran R, Dangas G, et al. Development and validation of
a prognostic risk score for major bleeding in patients undergoing per-
cutaneous coronary intervention via the femoral approach. Eur Heart How to cite this article: Chen Y, Yin T, Xi S, et al. A risk score
J. 2007;28:1936-1945. to predict postdischarge bleeding among acute coronary
29. Montalescot G, Salette G, Steg G, et al. Development and validation
syndrome patients undergoing percutaneous coronary
of a bleeding risk model for patients undergoing elective percutane-
ous coronary intervention. Int J Cardiol. 2011;150:79-83.
intervention: BRIC-ACS study. Catheter Cardiovasc Interv.
30. Wright RS, Anderson JL, Adams CD, et al. 2011 ACCF/AHA focused 2019;1–11. https://doi.org/10.1002/ccd.28325
update of the guidelines for the management of patients with unstable