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Incidence and predictors of serious bleeding during long-term follow-up after acute coronary syndrome in a population-based cohort study

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Progress in decreasing ischemic complications in acute coronary syndrome (ACS) has come at the expense of increased bleeding risk. We estimated the long-term, post-discharge incidence of serious bleeding, characterized bleeding type, and identified predictors of bleeding and its impact on mortality in an unselected cohort of patients with ACS. In this population-based study, we included 1379 patients identified with an ACS, 2010–2014. Serious bleeding was defined as intracranial hemorrhage (ICH), bleeding requiring hospital admission, or bleeding requiring transfusion or surgery. During a median 4.6-year follow-up, 85 patients had ≥ 1 serious bleed (cumulative incidence, 8.6%; 95% confidence interval (CI) 8.3–8.9). A subgroup of 557 patients, aged ≥ 75 years had a higher incidence (13.4%) than younger patients (6.0%). The most common bleeding site was gastrointestinal (51%), followed by ICH (27%). Sixteen percent had a recurrence. Risk factors for serious bleeding were age ≥ 75 years, lower baseline hemoglobin (Hb) value, previous hypertension or heart failure. Serious bleeding was associated with increased mortality. Bleeding after ACS was fairly frequent and the most common bleeding site was gastrointestinal. Older age, lower baseline Hb value, hypertension and heart failure predicted bleeding. Bleeding did independently predict mortality.
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Incidence and predictors of serious
bleeding during long‑term
follow‑up after acute coronary
syndrome in a population‑based
cohort study
Anna Graipe*, Anders Ulvenstam, Anna‑Lotta Irevall, Lars Söderström & Thomas Mooe
Progress in decreasing ischemic complications in acute coronary syndrome (ACS) has come at the
expense of increased bleeding risk. We estimated the long‑term, post‑discharge incidence of serious
bleeding, characterized bleeding type, and identied predictors of bleeding and its impact on
mortality in an unselected cohort of patients with ACS. In this population‑based study, we included
1379 patients identied with an ACS, 2010–2014. Serious bleeding was dened as intracranial
hemorrhage (ICH), bleeding requiring hospital admission, or bleeding requiring transfusion or
surgery. During a median 4.6‑year follow‑up, 85 patients had ≥ 1 serious bleed (cumulative incidence,
8.6%; 95% condence interval (CI) 8.3–8.9). A subgroup of 557 patients, aged 75 years had a higher
incidence (13.4%) than younger patients (6.0%). The most common bleeding site was gastrointestinal
(51%), followed by ICH (27%). Sixteen percent had a recurrence. Risk factors for serious bleeding were
age ≥ 75 years, lower baseline hemoglobin (Hb) value, previous hypertension or heart failure. Serious
bleeding was associated with increased mortality. Bleeding after ACS was fairly frequent and the most
common bleeding site was gastrointestinal. Older age, lower baseline Hb value, hypertension and
heart failure predicted bleeding. Bleeding did independently predict mortality.
Bleeding complications following acute coronary syndrome (ACS) have attracted considerable attention in recent
years. e increased intensity in antithrombotic treatment during the last decades to improve outcomes in ACS
has decreased risk for ischemic events but at the expense of greater bleeding risk13. Bleeding is associated with
both morbidity and mortality46. Previous studies have found that bleeding aer ACS has an association with
mortality similar to that of myocardial infarction6, and major bleeding correlates with a more prolonged mortality
risk compared with ischemic events7. e incidence of post-discharge major bleeding within 1 year in patients
with ACS has been reported as 1.3–5.6% in previous randomized trials (RCTs) and observational studies810, and
up to one-third of patients discharged on dual antiplatelet therapy (DAPT) are reported to have had a bleeding
complication within 12months post-discharge8. Comparison of bleeding incidences among studies is dicult
because of dierences in the studied populations, follow-up times, in-hospital management, antithrombotic drugs
used, and bleeding denitions11,12. Overall, bleeding incidence has been higher in observational studies than in
RCTs because of older populations with more comorbidities and risk factors in the former13.
DAPT, consisting of aspirin plus a P2Y12 receptor antagonist, is the cornerstone of treatment in patients
with ACS. An invasive strategy with percutaneous coronary intervention (PCI) requires dual antithrombotic
therapy for up to 1year to minimize the risk of stent thrombosis and new ischemic events, although the time
may be shorter or longer depending on the type of stent and the patient’s bleeding risk14. In an observational
study, medically (non-invasively) treated patients were reported to have a higher risk for re-hospitalization
related to bleeding, as well as an increased mortality risk compared to invasively treated patients15. Previously
identied predictors of bleeding include advanced age, prior ischemic or hemorrhagic stroke, previous bleeding,
hypertension, renal failure, female sex, lower weight, diabetes, atrial brillation, and a low hemoglobin (Hb)
value1620. e most common type of major bleeding is gastrointestinal (GI), and the most fatal is intracranial21.
Most previous studies report in-hospital bleeding, and few studies have reported follow-up beyond 1year. ere
OPEN
Institution of Public Health and Clinical Medicine, Östersund, Umeå University, Umeå, Sweden. *email: anna.
graipe@regionjh.se
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is a lack of long-term follow-up observational studies of an unselected ACS population, and few studies report
recurrent bleeding events.
e aims of this study were to estimate the long-term, post-discharge incidence of bleeding, characterize
the type of bleeding, and identify predictors of bleeding and its impact on mortality in an unselected cohort of
ACS patients.
Material and methods
In this population-based study, we included all patients who were identied with an ACS during the inclusion
period of the Nurse-Based Age-Independent Intervention to Limit Evolution of Disease Aer Acute Coronary
Syndrome (NAILED-ACS) Risk Factor trial. Briey, the study cohort consisted of all patients admitted to Öster-
sund Hospital with ACS from January 1, 2010, to December 31, 2014. Östersund Hospital is the only hospital
in Jämtland-Härjedalen County, a geographically large, rural area with approximately 126,000 inhabitants. To
identify all patients who were admitted to the hospital with an ACS diagnosis, medical records were reviewed for
all patients with suspected ACS on a daily basis. ACS was dened as unstable angina (UA), consisting of chest
pain and ischemic changes on an electrocardiogram, or acute myocardial infarction (AMI) type 1, according to
the universal denition of myocardial infarction22.
Data collection and adjudication of endpoints. Patients in the NAILED-ACS cohort were followed
from the day of discharge until death, a move out of the county, or December 31, 2017. Serious bleeds were
identied through review of the discharge records for all hospitalizations at the Department of Internal Medi-
cine. To capture all bleeding complications regardless of hospital department, we identied bleeding diagnosis
(TableS1) in the local hospital inpatient register, which covers all hospital admissions, and validated the diag-
nosis by a search of the medical records. When a patient had more than one serious bleed, up to the rst three
were included. Identication and review of potential endpoint events were performed by three medical doctors,
all members of the study team. e review process followed a standardized workow routine, and events were
strictly evaluated according to study outcome denitions. Each reviewer worked with their assigned cases inde-
pendently, but consecutive meetings were held to reach consensus in complicated cases.
Serious bleeding was dened as an intracranial hemorrhage (ICH), bleeding that required hospital admission,
or bleeding that required transfusion or surgery. All bleeds were subclassied as intracranial (epidural, subdural,
intracerebral hematoma, subarachnoid bleed), GI (upper, lower, or non-classied), and other serious bleeding
(intraocular, retroperitoneal, or urinary tract bleeding). e classication was made according to International
Statistical Classication of Diseases and Related Health Problems (ICD-10) codes (TableS1).
Clinical baseline characteristics and medications at discharge were extracted from the NAILED-ACS data-
base. e variable “smoking” was dened as smoking during the past month. e variable “atrial brillation
was dened as previous atrial brillation or atrial brillation during hospitalization. e variable “estimated
glomerular ltration rate” (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collabora-
tion equation (the CKD-EPI)23, and the limit for decreased kidney function was dened as ≤ 60mL/min/1.72
m2. e limit for obesity was set to a body mass index ≥ 30kg/m2. e value of systolic blood pressure was taken
from the day before discharge and thus aer the acute stage. In Sweden, elementary school lasts 9years; to study
if education level aected bleeding outcome, we divided education level by elementary school level vs. higher.
Lipid treatment at discharge was a statin in 85% of the patients. Intervention during the hospitalization was either
PCI or coronary artery bypass gra (CABG). Heart failure during hospitalization was dened as heart failure on
X-ray, the presence of pulmonary rales, or having had intravenous treatment with diuretics.
Statistical analysis. Baseline data are presented as means for continuous variables and as counts and per-
centages for categorical variables. Data for patients with and without a bleeding event were compared with Stu-
dent’s independent samples t-tests for continuous variables, and with the Pearson Chi-square test for categorical
variables. Age is presented as medians with 25th and 75th percentiles and was compared using the Mann–Whit-
ney U test.
Kaplan − Meier analysis was used to estimate the cumulative incidence of bleeding in the whole cohort and
stratied by age (cuto, 75years). Kaplan–Meier analysis was also used to describe mortality in patients with
and without a bleeding event, and comparisons between groups were performed using the log-rank test.
A multivariable Cox proportional hazards regression model was used to identify predictors of bleeding.
Variables included in the univariable analysis had previously been described as risk factors or were of potential
importance. All variables with a p value < 0.5 were then included in the multivariable Cox model. Non-signicant
variables were excluded stepwise according to their level of signicance during subsequent runs until reach-
ing only signicant predictors. e assumption of proportional hazard was veried using scaled Schoenfeld
residuals. Because death might occur before bleeding, a competing risk analysis also was performed according
to Fine–Gray, using the same stepwise approach. In addition, a multivariable Cox regression analysis with post
discharge bleeding as a time-dependent variable was used to identify predictors of death. Results are presented
as hazard ratios (HRs) with 95% condence intervals (CIs).
Statistical analyses were performed using SPSS (version 25.0; IBM Corp, Armonk, NY, USA) and SAS soware
(version 9.4; SAS Institute Inc, Cary, NC, USA).
Ethics. e Regional Ethics Committee in Umeå approved this study on October 28, 2009 (Dnr: 09-142M),
with supplements on June 10, 2013 (Dnr: 2013-204-32M) and January 13, 2015 (Dnr: 2014-416-32M). e
study was conducted in accordance with relevant guidelines and regulations. All participants signed an informed
consent prior to randomization.
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Results
Participants. A total of 1379 patients with ACS were followed from discharge and up to 8years. A study
owchart is presented in Fig.1, and baseline characteristics are shown in Table1. e mean age of participants
was 72years, 35.5% were female, and 57.4% had only a basic level of education (i.e., elementary school or simi-
lar). Non-ST-elevation myocardial infarction (NSTEMI) was the most common index event, occurring in 63.5%
(n = 876), followed by ST-elevation myocardial infarction (STEMI) in 28.4% (n = 392) and UA in 8.0% (n = 110).
Slightly more than half (53.9%) of the population underwent invasive revascularization therapy (PCI/CABG),
and a h (19.3%) were treated with thrombolysis. In the whole cohort, 74% (n = 1021) were treated with dual
antithrombotic therapy with aspirin and a P2Y12 inhibitor (i.e., DAPT), and 1.7% (n = 24) patients had triple
antithrombotic therapy (DAPT and an oral anticoagulant (OAC)).
Bleeding incidence and subtype of bleeding. During a median follow-up of 4.6years, 85 patients had
at least one serious bleeding event, for a cumulative incidence of 8.6% (95% condence interval (CI) 8.3–8.9%)
(Fig.2). e 1-year incidence was 3.0% (95% CI 2.7–3.3%), or 42 patients. In the subgroup analysis of patients
aged 75years (n = 557), the long-term cumulative incidence of serious bleeding was signicantly higher at
13.4% (95% CI 12.9–14.0%) compared with patients aged < 75years, at 6.0% (95% CI 5.9–6.2%; p < 0.001) (Fig.3).
e most common bleeding type was GI, occurring in 51% (n = 43) of events, followed by ICH in 27% (n = 23).
Of the 23 patients with an ICH, ve had an intracerebral hematoma and nine had a subdural or a subarachnoid
hemorrhage, respectively. Fourteen patients had more than one bleeding episode post-discharge, and the second
bleeding was of GI origin in 79% (n = 11/14). ree patients had a third bleeding, all of GI origin (Table2). In
patients with more than one bleed, the median age was higher than overall, at 79 (interquartile range 68–89)
years.
Discharged patients
n=1379
In hospital death
n=85
Gastro-intestinal
hemorrhage n=43
Intracranial hemorrhage
n=23
Other serious
hemorrhage n=19
Consecutive patients
with ACSJanuary
2010-December2014
Patients with serious
bleed n=85
Figure1. Study ow chart.
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Predictors of bleeding. Patients who had a bleeding event during follow-up were older, and several comor-
bid conditions were more prevalent in this group compared with patients without a bleeding event (Table1).
Comorbidities included a history of hypertension, congestive heart failure, angina, previous CABG, lower mean
baseline Hb, and a lower mean eGFR. At discharge, treatment with warfarin was more common among those
who later experienced bleeding, whereas aspirin treatment was more common among patients without a bleed-
ing event. e use of P2Y12 did not dier between groups, and there was no signicant dierence in proportions
being treated with DAPT (67.1% with a bleed vs. 74.6% without a bleed). No patients discharged with triple
antithrombotic therapy had a bleeding event during follow-up.
Results of the univariable Cox regression analysis are shown in the supplementary material (TableS2). In
the multivariable Cox analysis (Table3), signicant predictors of bleeding were age ≥ 75years (HR 2.0; 95% CI
1.2–3.1), previous hypertension (HR 1.8; 95% CI 1.1–2.9), and previous heart failure (HR 2.2; 95% CI 1.1–4.5).
An increase in baseline Hb (HR 0.97; 95% CI 0.96–0.99) and female sex was associated with decreased risk (HR
0.6; 95% CI 0.4–0.97). Of note, bleeding risk did not dier according to level of education, subtype of index
Table 1. Baseline characteristics stratied by bleeding. n number of patients, BMI body mass index, systolic BP
blood pressure at discharge, eGFR estimated glomerular ltration rate calculated using mL/min/1.73 m2, ACS
acute coronary syndrome, STEMI ST-elevation myocardial infarction, NSTEMI non-ST-elevation myocardial
infarction, UA unstable angina, PCI percutaneous coronary intervention, CABG coronary artery bypass gra,
TIA transient ischemic attack, PAD peripheral artery disease, ACE angiotensin-converting enzyme, ARB
angiotensin receptor blocker.
Patient characteristics All patients
n = 1379 Bleed
n = 85 Non-bleed
n = 1294 p
Age, median (quartiles) 72 (63.81) 77 (69.83) 71 (63.81) < 0.001
Women, n (%) 489 (35.5) 29 (34.1) 460 (35.6) 0.785
BMI kg/m2 (mean) 27.0 27.0 27.1 0.155
Former/current smoker, n (%) 874 (60.7) 54 (63.5) 784 (61.0) 0.645
Basic education, n (%) 736 (57.4) 51 (65.4) 685 (56.8) 0.139
Systolic BP (mean) 132 132 132 0.827
Baseline Hb, mean g/L 140 134 141 < 0.001
B-glucose (mean) 6.9 7.8 6.9 0.031
eGFR (mean) 76.3 68.5 76.8 < 0.001
ACS diagnosis n (%)
STEMI 392 (28.4) 27 (31.8) 365 (28.2) 0.484
NSTEMI 876 (63.6) 50 (58.8) 826 (63.9) 0.348
UA 110 (8.0) 8 (9.4) 102 (7.9) 0.616
Revascularization, n (%)
PCI 642 (43.9) 30 (35.3) 606 (46.9) 0.038
CABG 147 (10.0) 6 (7.1) 134 (10.4) 0.329
rombolysis 266 (19.3) 16 (18.8) 250 (19.3) 0.908
Comorbidities, n (%)
Previous angina 319 (23.2) 29 (34.1) 290 (22.5) 0.01
Previous AMI 290 (21.0) 24 (28.2) 266 (20.6) 0.093
Previous PCI 120 (8.7) 12 (14.1) 107 (8.3) 0.068
Previous CABG 120 (8.7) 13 (15.3) 107 (8.3) 0.026
Previous ischemic stroke/TIA 111 (8.1) 6 (7.1) 105 (8.1) 0.299
Previous hemorrhagic stroke 7 (0.5) 1 (1.2) 6 (0.5) 0.371
Previous PAD 35 (2.5) 4 (4.7) 31 (2.4) 0.190
Hypertension 797 (57.8) 62 (72.9) 735 (56.8) 0.004
Diabetes 299 (21.7) 23 (27.1) 276 (21.3) 0.216
Atrial brillation 232 (16.8) 19 (22.4) 213 (16.5) 0.161
Congestive heart failure 70 (5.1) 10 (11.8) 60 (4.6) 0.004
COPD 75 (5.4) 8 (9.4) 67 (5.2) 0.096
Baseline medication at discharge, n (%)
Lipid-lowering treatment 1200 (87.1) 71 (83.5) 1129 (87.3) 0.313
Beta-blocker 1213 (88.0) 73 (85.9) 1140 (88.2) 0.530
ACE inhibitor/ARB 1053 (76.4) 67 (78.8) 986 (76.3) 0.589
Aspirin 1277 (92.7) 74 (87.1) 1203 (93.0) 0.040
P2Y12 receptor inhibitor 1083 (78.6) 63 (74.1) 1020 (78.9) 0.299
Anticoagulant 114 (8.3) 13 (15.3) 101 (7.8) 0.015
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event (STEMI/NSTEMI/UA), invasive revascularization, or pharmacologic treatment at discharge. Analyses of
interactions between all variables using competing risk analysis gave the same signicant results as the multi-
variable Cox analysis.
Mortality. A total of 404 patients died during follow-up, with a signicantly higher mortality among those
who had a bleeding event (48.2%) vs. those who did not (28.1%; p < 0.001). As illustrated in Fig.4, the between-
group dierence in mortality appeared aer 3–3.5years (p < 0.001). In the time-dependent multivariable Cox
DDaayyssaafftteerrddiisscchhaarrggee
300025002000150010005000
SSuurrvviivvaallwwiitthhoouuttsseerriioouussbblleeeeddiinngg
1.0
0.9
0.8
0.7
0.6
Post-ACS patients
Figure2. Cumulative incidences without serious bleedings during long-term follow-up.
Days after discharge
300025002000150010005000
Survival without serious bleeding
1.0
0.9
0.8
0.7
0.6
>=75 years
<75 years
Figure3. Cumulative incidences without serious bleedings during long-term follow-up, stratied by age.
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Table 2. Fourteen patients with more than one bleeding episode, with bleeding localization presented in order
of events. GI gastrointestinal, SAH subarachnoid hemorrhage, other includes intraocular, retroperitoneal, and
urinary tract bleeding.
Age First bleed Second bleed ird bleed
67 Other Upper GI
67 Upper GI Upper GI Upper GI
68 SAH Lower GI
75 SAH Subdural hematoma
79 Other Unspecied GI
78 SAH Unspecied GI
78 SAH Upper GI
88 Other Upper GI Lower GI
88 Upper GI Upper GI Upper GI
91 Unspecied GI Unspecied GI
68 Upper GI Upper GI
94 Other Other
83 Lower GI Upper GI
92 Upper GI Other
Table 3. Multivariable Cox regression analysis of predictors for bleeding post-discharge aer ACS. HR hazard
ratio, CI condence interval, ACS acute coronary syndrome.
Predictor HR CI p
Age ≥ 75years 2.0 1.2–3.1 0.005
Female sex 0.6 0.4–0.97 0.039
Hypertension 1.8 1.1–2.9 0.02
Previous heart failure 2.2 1.1–4.5 0.002
Baseline Hb, per g/L increase 0.97 0.96–0.99 0.0002
Days after discharge
3000250020001 50010005000
Survival
1.0
0.8
0.6
0.4
0.2
0.0
Bleeding
No bleedin
g
Figure4. Cumulative survival aer ACS, stratied by bleeding.
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analysis (Supplement TableS3) with adjustment for age and comorbid conditions, having a bleeding episode was
associated with increased risk of death (HR 1.6; 95% CI 1.1–2.4). Also, high age and several of the comorbid
conditions were signicantly associated with mortality. Higher BMI, higher education level and a history of dia-
betes were associated with decreased mortality. Treatment with statins and intervention during hospitalization
were associated with decreased risk and treatment with P2Y12 were associated with increased risk (HR1.4; 95%
CI 1.05–1.7).
Discussion
In this population-based cohort study of 1379 patients with ACS, the cumulative incidence of serious bleeding
complications post-discharge was 8.6% during a median follow-up of 4.6years and 3.0% within 1year. In patients
aged ≥ 75years, the long-term incidence (13.4%) was more than twice that among patients age < 75years (6.0%).
e most common bleeding type was GI, with predominantly upper GI hemorrhages, followed by ICH. Older age,
lower baseline Hb, hypertension, and previous heart failure predicted serious bleeding, female sex was associated
with lower bleeding risk. A post discharge bleeding did independently predict mortality.
Incidence and type of bleeding. We carried out a meticulous follow-up of bleeding events requiring
hospital care, and to our knowledge, no other study has such a long follow-up of unselected ACS patients. One
study had a similar follow-up time (4.9years), but was restricted to STEMI patients and showed an incidence of
GI bleedings of 7.8% from the time of PCI (i.e., admission)20. Of note, these authors reported a 30-day incidence
of 3.9%, which is considerably higher than in our cohort. is dierence may reect a high in-hospital bleeding
risk and adjacent to hospital discharge, associated with antithrombotic treatments and procedure-related bleed-
ing. Our more diverse population and capture only of post-discharge events may have contributed to the diver-
gence. Another study of patients treated with PCI and drug-eluting stents (62% stable angina) with a follow-up
of 7–8years showed a 5-year cumulative incidence of major bleeding (Bleeding Academic Research Consortium
3–5) of 7.4% and 8-year incidence of 10.8%. e 5-year incidence was slightly higher than ours (6.8% at 5years)
even though those authors used a denition including more severe bleedings and most of the patients were in
stable condition24. However, the continuation of DAPT beyond one year was relatively common. Voss etal., with
a follow-up time of approximately 2years, found a post-discharge incidence of 7.4% for bleeding-related re-
hospitalization. Bleeding events were identied through a diagnosis registry using ICD codes similar to ours. In
contrast, the diagnoses were not validated against the medical records for conrmation, which may have led to
an overestimation of clinically relevant events because registry-based diagnoses oen include a broader deni-
tion and secondary diagnoses21.
Most clinical trials with “long term” follow-up have a 1-year follow-up duration for bleeding risk. In the
Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial, the 1-year incidence of CURE major
bleeding was 3.7% in patients treated with clopidogrel vs. 2.7% with placebo3. In the Trial to Assess Improve-
ment in erapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–rombolysis in Myocardial
Infarction (TRITON–TIMI 38), the 15-month incidence of rombolysis in Myocardial Infarction (TIMI) major
bleeding was 2.4% in prasugrel-treated patients vs. 1.8% in clopidogrel-treated patients1. In the Platelet Inhibition
and Patient Outcomes (PLATO) trial, the one-year incidence of TIMI major bleeding was 2.8% with ticagrelor vs.
2.2% with clopidogrel2. In comparison, our one-year cumulative incidence was 3.0%. However, major bleeding
is a broad concept, and dierences in bleeding denitions make comparison dicult.
ICH is more strictly dened and therefore more easily compared across dierent studies. In our study, the
cumulative incidence of ICH within 1year was 0.7%, which is higher than in the above-mentioned clinical trials.
In the CURE trial, which reported hemorrhagic stroke, the incidence was 0.1% and equal between the clopidogrel
and placebo groups. In TRITON, the incidence of ICH was 0.3% (equal between the prasugrel and clopidogrel
groups), and in PLATO, it was 0.34% with ticagrelor vs. 0.19% with clopidogrel. Our higher incidence of ICH
may be explained by higher age and more comorbidity compared to these RCTs. Also, we included all types of
intracranial bleedings, even those of traumatic origin.
Compared with previous observational studies with similar bleeding denitions and cohorts, our results are
consistent10,15 or the values are lower25,26. Brinkert etal. found a post-discharge 1-year bleeding rate of 2.6%, and
the bleeding rate was signicantly lower in patients treated with PCI. Patients treated medically only are oen
older with more comorbidity, which can explain the dierences between the groups. Gray etal. found a 1-year
incidence of serious bleeding of 3.2% in the total cohort, but among patients older than 75years, the bleeding
rate was higher at 5.6%, in line with our ndings. ese results show the strong impact of age on bleeding risk10.
Patients with more than one bleeding episode in our study had a mean age even higher than patients with one
bleeding episode. Results from the Swedish Web-system for Enhancement and Development of Evidence-based
care in Heart disease Evaluated According to Recommended erapies (SWEDEHEART) registry, with a bleed-
ing denition and patient characteristics similar to ours, showed a 1-year (post-discharge) bleeding incidence
of 4.0–4.8% during 2010–2015. Overestimation of diagnoses obtained from the National Patient Registry may
explain the dierence (i.e., there was no review of the medical records for conrmation)25.
STEMI patients have previously been reported to have a lower incidence of major bleeding compared to
NSTEMI patients25,27, a dierence related to a lower mean age and a lower risk prole overall among STEMI
patients. In contrast to these previous reports, we found no dierence in bleeding incidence between STEMI and
NSTEMI patients. It should be noted, however, that the total number of bleeding events was relatively small in
our study, making all subgroup analyses less conclusive. Also, the dierence in age between STEMI and NSTEMI
patients was less pronounced in our cohort.
Consistent with other studies, the gut15,21,28 was the most frequent identiable source of bleeding in our study.
It was also the most common location for a second bleeding event, regardless of the location of the rst site.
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Recurrence of any type of bleeding seems fairly common, as high as 26% within the rst 12month of hospital
discharge29. A previous study found a more than doubled risk of GI bleeding aer a rst occurrence20. e use
of proton pump inhibitors has diminished the risk of GI bleeding in patients treated with antithrombotics and is
especially important in elderly patients30,31. GI bleeding is relatively common and leads to disability and discon-
tinuation of drugs, increasing the risk of ischemic events. ere is a ne balance between timing of antithrom-
botic treatment withdrawal for bleeding and the risk of a new ischemic event, and new guidelines recommend
early resumption of antithrombotics32.
Predictors. We could conrm some of the previously recognized predictors of bleeding: age, lower baseline
Hb, previous hypertension, and previous heart failure16,29,33. We could not conrm kidney failure or previous
stroke/transient ischemic attack to be associated with increased bleeding risk34,35. In previous studies, kidney
failure has predicted bleeding aer ACS (HRs 1.3–1.9)35,36, and in a study of patients with kidney failure (not
post-ACS), bleeding risk signicantly increased in correlation with decreased eGFR37. In our study, however,
kidney function was relatively good in both groups, which may explain the divergent result, and we would have
needed a larger study population to capture any impact of mild kidney failure.
A previous stroke (ischemic, and especially hemorrhagic) has been previously identied as an important
predictor of ICH36,38 but does not necessarily predict any bleeding event. We had relatively few ICH events and
few patients with a previous hemorrhagic stroke. ese factors may partly explain why we could not conrm a
previous cerebrovascular event as a predictor in our cohort.
Female sex was associated with decreased risk of post-discharge bleeding in our study cohort, in line with
the PLATO trial where female sex was associated with an overall lower risk for spontaneous (non-procedure)
major bleed9,39. Other studies have found diverging results regarding an association between female sex and
bleeding risk post-discharge29,4042. Women seem to have more minimal and nuisance bleeding complications
post-discharge compared to men16,40, small bleedings that was not included in our cohort study. e lower risk
in women could be by chance and because of unknown confounders such as less adherence to antithrombotics
among women40,43.
Mortality. We found increased mortality among patients with a bleeding event in the long term, and hav-
ing a bleeding was a signicant predictor for all-cause death, as reported in several other studies4,5,44. Mortality
was equal between patients with and without a bleeding event during the rst 3years post-discharge but then
increased in patients with a bleeding event. Surprisingly, higher BMI (≥ 30kg/m2) and diabetes were protective
and treatment with P2Y12 was associated with increased risk of death. Residual confounding may explain these
ndings but we cannot rule out a negative impact of a more aggressive platelet inhibition in the long run45. Fur-
thermore, the structured follow-up of diabetic subjects in Swedish health care may be of importance for their
long-term prognosis46.
Conclusion
With a median follow-up of 4.6years in a population-based ACS cohort, the cumulative incidence of re-hospi-
talization for serious bleeding was 8.6%. Patients aged ≥ 75years had a more than doubled incidence of serious
bleeding compared with patients < 75years. GI bleeding was most common, and recurrence of bleeding was
relatively frequent. Higher age, lower baseline Hb, prior hypertension, and previous heart failure were associ-
ated with bleeding. Female sex was associated with decreased bleeding risk. Patients with bleeding had a higher
mortality and a post discharge bleeding was a signicant predictor of increased mortality. To decrease bleeding
risk aer ACS, the future challenge is to identify the vulnerable patient, individualize treatment, and repeatedly
reevaluate bleeding risk during follow-up.
Strengths and limitations. Our cohort is relatively small, and our study is observational, with the inher-
ent related limitations. Nonetheless, the data were carefully collected with full coverage of all ACS in the catch-
ment area. We performed an accurate adjudication of bleeding endpoints requiring hospitalization, and follow-
up covered a long time period. We cannot rule out that patients experienced bleeding complications that were
not documented in patient records or that was handled in primary care, but because we included only serious
events, this seems unlikely. We used a pragmatic bleeding denition that did not require laboratory values,
which is not directly comparable to standard bleeding denitions in randomized trials. e denition we used
has been used in previous observational studies10,15,26.
We had no information about previous bleeding except for previous ICH, and we did not know if the patients
had continued or changed treatment with antithrombotic drugs post-discharge. e only OAC included was
warfarin, so the eect of the newer OACs needs further study.
Received: 27 May 2021; Accepted: 28 October 2021
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Acknowledgements
e Unit of Research, Education and Development, Region Jämtland-Härjedalen (JLL 939201), Sweden, sup-
ported this study.
Author contributions
T.M. is the main supervisor. A.G., A.U. and A.L.I. made the adjudication. A.G., with input and help from LS,
made the statistics. A.G. wrote the manuscript and all authors reviewed the manuscript.
Funding
Open access funding provided by Umea University.
Competing interests
e authors declare no competing interests.
Additional information
Supplementary Information e online version contains supplementary material available at https:// doi. org/
10. 1038/ s41598- 021- 01525-7.
Correspondence and requests for materials should be addressed to A.G.
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... Of note, even in the general population, the incidence of bleeding complications during antithrombotic treatment within the first year after ACS is high (up to 38%), with a non-negligible incidence of severe bleeds (3%−6%). [33][34][35][36] Our findings are in line with a previous retrospective study including more than 2000 haemophilia patients (A and B) recruited over more than 10 years 37 that reported 20 ACS events occurred in 19 patients. ...
Article
Introduction The increased life expectancy of patients with haemophilia A (HA) has led to a growing prevalence of cardiovascular risk factors and events. There is still scarce evidence on the safety and appropriate duration of dual antiplatelet therapy (DAPT) after acute coronary syndrome (ACS) in HA patients. Aim We describe our experience on the clinical management of Italian HA patients after ACS. Methods Nine patients with congenital HA treated with DAPT after a revascularization procedure performed for ACS have been enrolled and followed at the Angelo Bianchi Bonomi Haemophilia and Thrombosis Center in Milan between 2005 and September 2022. The safety and efficacy of DAPT with or without FVIII prophylaxis were assessed. Results Ten ACS events occurred in the nine HA patients (four mild and five severe). All events were treated with percutaneous transluminal coronary angioplasty with deployment of 1 to 3 drug‐eluting stents followed by DAPT for 1–12 months. All patients except one were treated with FVIII prophylaxis during DAPT aimed at achieving FVIII trough levels ≥20–30 IU/dL. DAPT was effective in all cases in preventing early ACS recurrence, with only a late recurrence. We observed two clinically relevant non‐major bleeds (one in a patient without FVIII prophylaxis) and three minor bleeds. No venous thrombosis occurred. Conclusion The long‐term secondary antithrombotic prevention consisting of DAPT and FVIII prophylaxis achieving a trough level of 20–30 IU/dL can be effective and safe in HA patients.
... In previous studies, the incidence of bleeding complications occurred in approximately one-third of patients discharged on dual antiplatelet therapy, and the incidence of GI bleeding was estimated to be 0.25% to 7.63% [29]. GI bleeding plays an important role in the prognosis of patients with ACS, and DM, CKD, and advanced age are important factors of bleeding complications and GI bleeding [30,31]. Bleeding events can impact duration and potency of antiplatelet therapy use. ...
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Background Diabetes mellitus (DM), chronic kidney disease (CKD), and advanced age are associated with poor outcomes in patients with acute coronary syndrome (ACS). This real-world study utilized data from the Taiwan Chang Gung Research Database (CGRD) to compare outcomes in ACS patients with DM, CKD, and the elderly. Material/Methods The study enrolled 28,613 ACS patients diagnosed based on CGRD medical records between January 2005 and December 2019. Baseline characteristics and clinical outcomes were compared among groups based on patient characteristics. Results Within the ACS cohort, 42.1% had DM, 48.2% had CKD, and 33.6% were elderly. Among them, 10.7% (3,070) were elderly patients with both DM and CKD. Elderly patients with DM and CKD had significantly higher risks of gastrointestinal bleeding (hazard ratio=11.32), cardiovascular events (HR=7.29), and all-cause mortality (HR=8.59). Patients with three or at least two of these risk factors had a 2.20–2.99-fold increased risk of recurrent ACS during the three-year follow-up period.. Conclusions Patients with the combination of DM, CKD, and advanced age (elderly) experienced an 11.32-fold increased risk of gastrointestinal bleeding, 7.29-fold increased risk of cardiovascular events, and 8.59-fold increased risk of all-cause mortality compared to those without these risk factors. Furthermore, patients with two or more of these risk factors had a 2- to 3-fold increased risk of recurrent ACS. These findings emphasize the importance of managing multiple risk factors in ACS patients to improve outcomes.
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The exposure to ticagrelor is higher in the East Asian population compared to the Caucasian population, thus, East Asians have an increased risk of bleeding. We developed a population pharmacokinetic model of ticagrelor based on a randomized 3 × 3 crossover study in healthy subjects. The area under concentration‐time curve (AUC) of Chinese patients with acute coronary syndrome was simulated based on this model. Following this, eight machine learning methods were used to construct bleeding risk models. Variables included in the final bleeding risk model were age, hypertension, body weight, AUC, drinking status, Calcium channel blockers, antidiabetic medications, β‐blockers, peripheral vascular disease, diabetes, transient ischemic attack (TIA), sex, and proton pump inhibitor (PPI). In terms of F1 scores and area under the curve of receiver operating characteristic curve (ROC‐AUC), the Random Forest model performed best among all models, with an F1 score of 0.73 and ROC‐AUC of 0.81. Moreover, the PPK model and machine learning algorithm were used to bridge the real‐world data to build a bleeding risk prediction model based on drug exposure and clinical information. Using this model, a ticagrelor regimen that is associated with a lower risk of bleeding in individuals can be obtained. This model should be further validated prospectively in clinical settings.
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GReek-AntiPlatElet Atrial Fibrillation (GRAPE-AF) registry is a multicenter, observational, non-interventional study of AF patients undergoing PCI. Primary endpoint included clinically significant bleeding rate at 12 months between different antithrombotic regimens prescribed at discharge; secondary endpoints included major adverse cardiovascular events (MACEs) as well as net adverse clinical events (NACEs). A total of 647 patients were analyzed. The majority (92.9%) were discharged on NOACs with only 7.1% receiving VKA. A little over half of patients (50.4%) received triple antithrombotic therapy (TAT) – mostly (62.9%) for ≤ 1 month – while the rest (49.6%) received dual antithrombotic therapy (DAT). Clinically significant bleeding risk was similar between TAT and DAT (HR = 1.08; 95% CI = 0.66 – 1.78), though among TAT-receiving patients, the risk was lower in those receiving TAT for ≤ 1 month (HR = 0.50; 95% CI = 0.25 – 0.99). Anticoagulant choice (NOAC vs VKA) did not significantly affect bleeding rates (P=0.258). Age, heart failure, leukemia/myelodysplasia and acute coronary syndrome were associated with increased bleeding rates. Risk of MACEs and NACEs was similar between ΤAT and DAT (HR = 1.73; 95% CI = 0.95 – 3.18, P = 0.075 and HR = 1.39; 95% CI = 0.93 – 2.08, P=0.106, respectively). In conclusion, clinically significant bleeding and ischemic rates were similar between DAT and TAT, although TAT >1 month was associated with higher bleeding risk.
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Background The incidence and predictors of bleeding after acute coronary syndrome are unclear within the real‐world setting. Our objective was to determine the incidence, types, timing, and predictors of bleeding complications following hospital discharge after acute coronary syndrome. Methods and Results We used the Clinical Practice Research Datalink, with linkage to Hospital Episode Statistics, to determine the incidence, timing, and types of bleeding events within 12 months after hospital discharge for acute coronary syndrome. We assessed independent associations between postdischarge bleeding and baseline patient characteristics using a competing risk regression model, accounting for death as a competing event. Among 27 660 patients surviving to hospital discharge, 3620 (13%) experienced bleeding complications at a median time of 123 days (interquartile range, 45–223 days) after discharge. The incidence of bleeding was 162/1000 person‐years (95% CI , 157–167/1000 person‐years) within the first 12 months after hospital discharge. Bruising (949 bleeds [26%]) was the most common type of first bleeding event, followed by gastrointestinal bleed (705 bleeds [20%]), whereas intracranial bleed was relatively rare (81 bleeds [2%]). Significant predictors of postdischarge bleeding included history of bleeding complication, oral anticoagulant prescription, history of peripheral vascular disease, chronic obstructive pulmonary disease, and advanced age (>80 years). Predictors for postdischarge bleeding varied, depending on the anatomic site of the bleeding event. Conclusions Bleeding complications after hospital discharge for acute coronary syndrome are common. Patients who experience these bleeding events have distinct baseline characteristics, which vary by anatomic site of the bleed. These characteristics can inform risk‐benefit considerations in deciding on favorable combination and duration of secondary antithrombotic therapy.
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Background Bleeding risk stratification in acute coronary syndrome is of highest clinical interest but current risk scores have limitations. We sought to develop and validate a new in‐hospital bleeding risk score for patients with acute myocardial infarction. Methods and Results From the nationwide SWEDEHEART (Swedish Web‐System for Enhancement and Development of Evidence‐Based Care in Heart Disease Evaluated According to Recommended Therapies) register, 97,597 patients with acute myocardial infarction enrolled from 2009 until 2014 were selected. A full model with 23 predictor variables and 8 interaction terms was fitted using logistic regression. The full model was approximated by a model with 5 predictors and 1 interaction term. Calibration, discrimination, and clinical utility was evaluated and compared with the ACTION (Acute Coronary Treatment and Intervention Outcomes Network) and CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines) scores. Internal and temporal validity was assessed. In‐hospital major bleeding, defined as fatal, intracranial, or requiring surgery or blood transfusion, occurred in 1356 patients (1.4%). The 5 predictors in the approximate model that constituted the SWEDEHEART score were hemoglobin, age, sex, creatinine, and C‐reactive protein. The ACTION and CRUSADE scores were poorly calibrated in the derivation cohort and therefore were recalibrated. The SWEDEHEART score showed higher discriminative ability than both recalibrated scores, overall (C‐index 0.80 versus 0.73/0.72) and in all predefined subgroups. Decision curve analysis demonstrated consistently positive and higher net benefit for the SWEDEHEART score compared with both recalibrated scores across all clinically relevant decision thresholds. The original ACTION and CRUSADE scores showed negative net benefit. Conclusions The 5‐item SWEDEHEART score discriminates in‐hospital major bleeding in patients with acute myocardial infarction and has superior model performance compared with the recalibrated ACTION and CRUSADE scores.
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Objective The primary objective was to determine the incidence of bleeding events post acute coronary syndrome (ACS) following hospital discharge. The secondary objective was to determine the prognostic impact of bleeding on mortality, major adverse cardiovascular events (MACE), myocardial re-infarction and rehospitalisation in the postdischarge setting. Design A narrative systematic review. Data source Medline, Embase, Amed and Central (Cochrane) were searched up to August 2018. Study selection For the primary objective, randomised controlled trials (RCT) and observational studies reporting on the incidence of bleeding post hospital discharge were included. For the secondary objective, RCTs and observational studies that compared patients with bleeding versus those without bleeding post hospital discharge vis-à-vis mortality, MACE, myocardial re-infarction and rehospitalisation were included. Results 53 studies (36 observational studies and 17 RCTs) with a combined cohort of 714 458 participants for the primary objectives and 187 317 for the secondary objectives were included. Follow-up ranged from 1 month to just over 4 years. The incidence of bleeding within 12 months post hospital discharge ranged from 0.20% to 37.5% in observational studies and between 0.96% and 39.4% in RCTs. The majority of bleeds occurred in the initial 3 months after hospital discharge with bruising the most commonly reported event. Major bleeding increased the risk of mortality by nearly threefold in two studies. One study showed an increased risk of MACE (HR 3.00,95% CI 2.75 to 3.27; p<0.0001) with bleeding and another study showed a non-significant association with rehospitalisation (HR 1.20,95% CI 0.95 to 1.52; p=0.13). Conclusion Bleeding complications following ACS management are common and continue to occur in the long term after hospital discharge. These bleeding complications may increase the risk of mortality and MACE, but greater evidence is needed to assess their long-term effects. PROSPERO registration number CRD42017062378.
Article
Background: The comparative efficacy and safety of ticagrelor vs. clopidogrel in older myocardial infarction (MI) patients has received limited study. Methods: We performed an observational analysis of all patients ≥80 years (n=14005) who were discharged alive with aspirin combined with either clopidogrel (60.2%) or ticagrelor (39.8%) after a MI between 2010 and 2017 registered in the national registry Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies (SWEDEHEART). Inverse probability treatment weighting was used in Cox regression models to adjust for differences in demographics, in-hospital therapies, and medications. The primary ischemic outcome (death, MI or stroke), and bleeding were obtained from national registries at 1 year. A sensitivity analysis in <80-year-old patients was performed. Results: In patients ≥80 years, the incidence of the primary ischemic outcome (HR 0.97, 95% CI 0.88-1.06) was similar for ticagrelor- and clopidogrel-treated patients. Ticagrelor was associated with a 17% and 48% higher risk of death (1.17 (1.03- 1.32)) and bleeding (1.48 (1.25- 1.76)), but a lower risk of MI (0.80 (0.70- 0.92)) and stroke (0.72 (0.56-0.93)). In <80-year-old patients the incidence of the primary ischemic outcome was 17% (0.83 (0.77-0.89)) lower with ticagrelor. Ticagrelor was associated with 15% (0.85 (0.76-0.96)) lower risk of death, 32% higher risk of bleeding (1.32 (1.18-1.47)), but lower risk of MI (0.82 (0.75-0.91)) and stroke (0.82 (0.69-0.98)). Conclusions: Ticagrelor use among elderly MI patients was associated with higher risk of bleeding and death compared with clopidogrel. A randomized study of ticagrelor vs clopidogrel in the elderly is needed.
Article
Aims: To describe the time trends of in-hospital and out-of-hospital bleeding parallel to the development of new treatments and ischaemic outcomes over the last 20 years in a nationwide myocardial infarction (MI) population. Methods and results: Patients with acute MI (n = 371 431) enrolled in the SWEDEHEART registry from 1995 until May 2018 were selected and evaluated for in-hospital bleeding and out-of-hospital bleeding events at 1 year. In-hospital bleeding increased from 0.5% to a peak at 2% 2005/2006 and thereafter slightly decreased to a new plateau around 1.3% by the end of the study period. Out-of-hospital bleeding increased in a stepwise fashion from 2.5% to 3.5 % in the middle of the study period and to 4.8% at the end of the study period. The increase in both in-hospital and out-of-hospital bleeding was parallel to increasing use of invasive strategy and adjunctive antithrombotic treatment, dual antiplatelet therapy (DAPT), and potent DAPT, while the decrease in in-hospital bleeding from 2007 to 2010 was parallel to implementation of bleeding avoidance strategies. In-hospital re-infarction decreased from 2.8% to 0.6% and out-of-hospital MI decreased from 12.6% to 7.1%. The composite out-of-hospital MI, cardiovascular death, and stroke decreased in a similar fashion from 18.4% to 9.1%. Conclusion: During the last 20 years, the introduction of invasive and more intense antithrombotic treatment has been associated with an increase in bleeding events but concomitant there has been a substantial greater reduction of ischaemic events including improved survival.
Article
Background:To date, the long-term incidence and details of major bleeding (MB) and coronary thrombotic events (CTE) in patients with everolimus-eluting stent (EES) implantation have not been made clear. Methods and Results:The study population comprised 1,193 patients treated with EES without in-hospital events between 2010 and 2011. MB was defined as the occurrence of a Bleeding Academic Research Consortium type 3 or 5 bleeding event. The mean follow-up period was 2,996±433 days. Cumulative rate of MB was 7.4% and 10.8% at 5 and 8 years, respectively. Of 46 patients with intracranial bleeding, 20 had trauma-related intracranial bleeding. Cumulative rates of definite stent thrombosis and CTE at 8 years were 0.4% and 5.9%, respectively. Multivariate analysis revealed low body mass index (<23) (hazard ratio (HR), 1.57; 95% confidence interval (CI), 1.03–2.36; P=0.03) and concomitant use of oral anticoagulants (HR, 2.17; 95% CI, 1.30–3.50; P=0.004) as independent risk factors of MB and previous PCI (HR, 2.47; 95% CI, 1.29–1.00; P=0.006) as the factor for CTE. Conclusions:MB is not uncommon and is a long-term hazard, but the occurrence of stent thrombosis is very low after EES implantation. Approximately half of the cases involving intracranial bleeding were associated with trauma.
Article
Background Dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) prevents ischemic events while increasing bleeding risk. Real‐world‐based metrics to accurately predict postdischarge bleeding (PDB) occurrence and its potential impact on postdischarge major cardiovascular event (MACE) remain undefined. This study sought to evaluate the impact of PDB on MACE occurrence, and to 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 underwent 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), respectively. 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 associated 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.
Article
Background: The rate of intracranial haemorrhage after an acute coronary syndrome has been studied in detail in the era of thrombolysis; however, in the contemporary era of percutaneous coronary intervention, most of the data have been derived from clinical trials. With this background, we aim to analyse the incidence, timing, predictors and prognostic impact of post-discharge intracranial haemorrhage in patients with acute coronary syndrome undergoing percutaneous coronary intervention. Methods: We analysed data from the BleeMACS registry (patients discharged for acute coronary syndrome and undergoing percutaneous coronary intervention from Europe, Asia and America, 2003-2014). Analyses were conducted using a competing risk framework. Uni and multivariate predictors of intracranial haemorrhage were assessed using the Fine-Gray proportional hazards regression analysis. The endpoint was 1-year post-discharge intracranial haemorrhage. Results: Of 11,136 patients, 30 presented with intracranial haemorrhage during the first year (0.27%). The median time to intracranial haemorrhage was 150 days (interquartile range 55.7-319.5). The fatality rate of intracranial haemorrhage was very high (30%). After multivariate analysis, only age (subhazard ratio 1.05, 95% confidence interval 1.01-1.07) and prior stroke/transient ischaemic attack (hazard ratio 3.29, 95% confidence interval 1.36-8.00) were independently associated with a higher risk of intracranial haemorrhage. Hypertension showed a trend to associate with higher intracranial haemorrhage rate. The combination of older age (⩾75 years), prior stroke/transient ischaemic attack, and/or hypertension allowed us to identify most of the patients with intracranial haemorrhage (86.7%). The annual rate of intracranial haemorrhage was 0.1% in patients with no risk factors, 0.2% in those with one factor, 0.6% in those with two factors and 1.3% in those with three factors. Conclusion: The incidence of intracranial haemorrhage in the first year after an acute coronary syndrome treated with percutaneous coronary intervention is low. Advanced age, previous stroke/transient ischaemic attack, and hypertension are the main predictors of increased intracranial haemorrhage risk.
Article
Introduction: Bleeding is an independent risk factor of mortality in patients with acute coronary syndromes (ACS). BleeMACS project focuses on long-term bleeding events after hospital discharge, thus we evaluated gender-related differences in post-discharge bleeding among patients with ACS. Materials and methods: We investigated 13,727 ACS patients treated with percutaneous coronary intervention and discharged on dual antiplatelet therapy (either with clopidogrel or prasugrel/ticagrelor). Endpoint was defined as intracranial bleeding or any other bleeding leading to hospitalization and/or red blood transfusion. Results: Post-discharge bleeding was reported more frequently in females as compared with males (3.7% vs. 2.7%, log-rank P = 0.001). Females (n = 3165, 23%) were older compared to men (69.0 vs. 61.5 years, P < 0.001) and with more comorbidities. Hence, in multivariate analysis female sex was not identified as an independent risk factor of bleeding (HR 1.012, CI 0.805 to 1.274, P = 0.816). Administration of newer antiplatelet agents compared to clopidogrel was associated with over twofold greater bleeding rate in females (7.3% vs. 3.5%, log-rank P = 0.004), but not in males (2.6% vs. 2.7%, log-rank P = 0.887). Differences among females remained significant after propensity score matching (7.2% vs 2.4%, log-rank P = 0.020) and multivariate analysis confirmed that newer antiplatelet agents are independent risk factor for bleeding only in women (HR 2.775, CI 1.613 to 4.774, P < 0.001). Conclusions: Bleeding events occurred more frequently in women, but female sex itself was not independent risk factor. Administration of newer antiplatelet agents was identified as independent risk factor of bleeding after hospital discharge in female gender, but not in male patients.
Article
Introduction: The aim of the current study was to assess bleeding events, including severity, localisation and prognostic impact, in a real world population of men and women with myocardial infarction (MI). Methods and results: In total 850 consecutive patients were included during 2010 and followed for one year. Bleeding complications were identified by searching of each patients' medical records and characterised according to the TIMI criteria. For this analysis, only the first event was calculated. The total incidence of bleeding events was 24.4% (81 women and 126 men, p = ns). The incidence of all in-hospital bleeding events was 13.2%, with no sex difference. Women had significantly more minor non-surgery related bleeding events than men (5% vs 2.2%, p = 0.02). During follow-up, 13.5% had a bleeding, with more non-surgery related bleeding events among women, 14.7% vs 9.7% (p = 0.03). The most common bleeding localisation was the gastrointestinal tract, more in women than men (12.1% vs 7.6%, p = 0.03). Women had also more access site bleeding complications (4% vs 1.7%, p = 0.04), while men had more surgery related bleeding complications (6.4% vs 0.9%, p ≤0.001). Increased mortality was found only in men with non-surgery related bleeding events (p = 0.008). Conclusions: Almost one in four patients experienced a bleeding complication through 12 months follow-up after a myocardial infarction. Women experienced more non-surgery related minor/minimal bleeding complications than men, predominantly GI bleeding events and access site bleeding events, with no apparent impact on outcome. In contrast men with non-surgery related bleeding complications had higher mortality. Improved bleeding prevention strategies are warranted for both men and women.